FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bhalla, K Liu, WJ Thompson, K Anders, L Devarakonda, S Dewi, R Buckley, S Hwang, BJ Polster, B Dorsey, SG Sun, YZ Sicinski, P Girnun, GD AF Bhalla, Kavita Liu, Wan-Ju Thompson, Keyata Anders, Lars Devarakonda, Srikripa Dewi, Ruby Buckley, Stephanie Hwang, Bor-Jang Polster, Brian Dorsey, Susan G. Sun, Yezhou Sicinski, Piotr Girnun, Geoffrey D. TI Cyclin D1 Represses Gluconeogenesis via Inhibition of the Transcriptional Coactivator PGC1 alpha SO DIABETES LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; GENE-EXPRESSION; OXIDATIVE-PHOSPHORYLATION; HEPATOCELLULAR-CARCINOMA; HEPATIC GLUCONEOGENESIS; MITOCHONDRIAL-FUNCTION; INSULIN-RESISTANCE; ESTROGEN-RECEPTOR; PPAR-GAMMA; IN-VIVO AB Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin 131 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC-1 alpha is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1 alpha and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis. C1 [Bhalla, Kavita; Liu, Wan-Ju; Thompson, Keyata; Dewi, Ruby; Buckley, Stephanie; Hwang, Bor-Jang; Dorsey, Susan G.; Girnun, Geoffrey D.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Anders, Lars; Devarakonda, Srikripa; Sicinski, Piotr] Dana Farber Canc Inst, Boston, MA 02115 USA. [Polster, Brian] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Dorsey, Susan G.] Univ Maryland, Sch Nursing, Dept Anesthesiol, Baltimore, MD 21201 USA. [Sun, Yezhou] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Girnun, Geoffrey D.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Girnun, Geoffrey D.] Stony Brook Sch Med, Dept Pathol, Stony Brook, NY USA. RP Girnun, GD (reprint author), Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM geoffrey.girnun@stonybrookmedicine.edu FU Maryland Cigarette Restitution Fund; [CA169919]; [DK064685] FX This work was funded in part by CA169919 and DK064685 and the Maryland Cigarette Restitution Fund to the Greenebaum Cancer Center (G.D.G.). NR 47 TC 9 Z9 9 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3266 EP 3278 DI 10.2337/db13-1283 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300015 PM 24947365 ER PT J AU Hatanaka, M Maier, B Sims, EK Templin, AT Kulkarni, RN Evans-Molina, C Mirmira, RG AF Hatanaka, Masayuki Maier, Bernhard Sims, Emily K. Templin, Andrew T. Kulkarni, Rohit N. Evans-Molina, Carmella Mirmira, Raghavendra G. TI Palmitate Induces mRNA Translation and Increases ER Protein Load in Islet beta-Cells via Activation of the Mammalian Target of Rapamycin Pathway SO DIABETES LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; PANCREATIC TRANSCRIPTION FACTOR; SATURATED FATTY-ACID; INSULIN-SECRETION; PROLIFERATION; MICE; EXPRESSION; APOPTOSIS; SURVIVAL; KINASE AB Saturated free fatty acids (FFAs) have complex effects on the islet beta-cell, acutely promoting adaptive hyperplasia but chronically impairing insulin release. The acute effects of FFAs remain incompletely defined. To elucidate these early molecular events, we incubated mouse p-cells and islets with palmitate and then studied mRNA translation by polyribosomal profiling and analyzed signaling pathways by immunoblot analysis. We found that palmitate acutely increases polyribosome occupancy of total RNA, consistent with an increase in mRNA translation. This effect on translation was attributable to activation of mammalian target of rapamycin (mTOR) pathways via L-type Ca2+ channels but was independent of insulin signaling. Longer incubations led to depletion of polyribosome-associated RNA, consistent with activation of the unfolded protein response (UPR). Pharmacologic inhibition of mTOR suppressed both the acute effects of palmitate on mRNA translation and the chronic effects on the UPR. Islets from mice fed a high-fat diet for 7 days showed increases in polyribosome-associated RNA and phosphorylation of S6K, both consistent with activation of mTOR. Our results suggest that palmitate acutely activates mRNA translation and that this increase in protein load contributes to the later UPR. C1 [Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K.; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K.; Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. [Templin, Andrew T.; Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol,Dept Med, Boston, MA 02115 USA. [Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Mirmira, RG (reprint author), Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. EM rmirmira@iu.edu FU National Institutes of Health (NIH) [R01-DK-060581, R01-DK-083583, T32-DK-065549, R01-DK-67536, R01-DK-093954]; Manpei Suzuki Diabetes Foundation; American Heart Association; VA Merit Award [I01 BX001733]; George and Frances Ball Foundation; Ball Brothers Foundation FX This work was supported by National Institutes of Health (NIH) grants R01-DK-060581 and R01-DK-083583 (to R.G.M.), a grant from the Manpei Suzuki Diabetes Foundation (to M.H.), NIH grant T32-DK-065549 (to E.K.S.), a fellowship grant from the American Heart Association (to A.T.T.), NIH grant R01-DK-67536 (to R.N.K.), NIH grant R01-DK-093954 (to C.E.-M.), VA Merit Award I01 BX001733 (to C.E.-M.), and grants from the George and Frances Ball Foundation and the Ball Brothers Foundation (both to R.G.M. and C.E.-M.). NR 51 TC 7 Z9 7 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3404 EP 3415 DI 10.2337/db14-0105 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300027 PM 24834975 ER PT J AU Orban, T Beam, CA Xu, P Moore, K Jiang, Q Deng, J Muller, S Gottlieb, P Spain, L Peakman, M AF Orban, Tihamer Beam, Craig A. Xu, Ping Moore, Keith Jiang, Qi Deng, Jun Muller, Sarah Gottlieb, Peter Spain, Lisa Peakman, Mark CA Type 1 Diabet TrialNet Abatacept S TI Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline SO DIABETES LA English DT Article ID DOUBLE-BLIND; THERAPY; MELLITUS; TRIAL AB We previously reported that continuous 24-month costimulation blockade by abatacept significantly slows the decline of beta-cell function after diagnosis of type 1 diabetes. In a mechanistic extension of that study, we evaluated peripheral blood immune cell subsets (CD4, CD8-naive, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4(+)CD25(high) regulatory T cells, and invariant NK T cells) by flow cytometry at baseline and 3, 6, 12, 24, and 30 months after treatment initiation to discover biomarkers of therapeutic effect. Using multivariable analysis and lagging of longitudinally measured variables, we made the novel observation in the placebo group that an increase in central memory (CM) CD4 T cells (CD4(+)CD45R0(+)CD62L(+)) during a preceding visit was significantly associated with C-peptide decline at the subsequent visit. These changes were significantly affected by abatacept treatment, which drove the peripheral contraction of CM CD4 T cells and the expansion of naive (CD45R0(-)CD62L(+)) CD4 T cells in association with a significantly slower rate of C-peptide decline. The findings show that the quantification of CM CD4 T cells can provide a surrogate immune marker for C-peptide decline after the diagnosis of type 1 diabetes and that costimulation blockade may exert its beneficial therapeutic effect via modulation of this subset. C1 [Orban, Tihamer] Joslin Diabet Ctr, Boston, MA 02215 USA. [Beam, Craig A.; Xu, Ping; Muller, Sarah] Univ S Florida, Dept Pediat, Div Informat & Biostat, Tampa, FL 33620 USA. [Moore, Keith; Jiang, Qi; Deng, Jun] David H Murdock Res Inst, Kannapolis, NC USA. [Gottlieb, Peter] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Spain, Lisa] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Peakman, Mark] Kings Coll London, Sch Med, Peter Gorer Dept Immunobiol, London WC2R 2LS, England. RP Orban, T (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM tihamer.orban@gmail.com RI Krammel, Vera/N-4826-2014 OI Krammel, Vera/0000-0002-8273-8396 FU Type 1 Diabetes Trial Net Study Group; National Institutes of Health through National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; The Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-DK-061010, U01-DK-061016, U01-DK-061034, U01-DK-061036, U01-DK-061040, U01-DK-061041, U01-DK-061042, U01-DK-061055, U01-DK-061058, U01-DK-084565, U01-DK-085453, U01-DK-085461, U01-DK-085463, U01-DK-085466, U01-DK-085499, U01-DK-085505, U01-DK-085509, HHSN267200800019C]; National Center for Research Resources [UL1-RR-024131, UL1-RR-024139, UL1-RR-024153, UL1-RR-024975, UL1-RR-024982, UL1-RR-025744, UL1-RR-025761, UL1-RR-025780, UL1-RR-029890, UL1-RR-031986]; General Clinical Research Center Award [M01-RR-00400]; Juvenile Diabetes Research Foundation International; American Diabetes Association FX The sponsor of the trial was the Type 1 Diabetes Trial Net Study Group. The Type 1 Diabetes Trial Net Study Group is a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development through cooperative agreements U01-DK-061010, U01-DK-061016, U01-DK-061034, U01-DK-061036, U01-DK-061040, U01-DK-061041, U01-DK-061042, U01-DK-061055, U01-DK-061058, U01-DK-084565, U01-DK-085453, U01-DK-085461, U01-DK-085463, U01-DK-085466, U01-DK-085499, U01-DK-085505, and U01-DK-085509 and contract HHSN267200800019C; the National Center for Research Resources through Clinical Translational Science Awards UL1-RR-024131, UL1-RR-024139, UL1-RR-024153, UL1-RR-024975, UL1-RR-024982, UL1-RR-025744, UL1-RR-025761, UL1-RR-025780, UL1-RR-029890, and UL1-RR-031986 and General Clinical Research Center Award M01-RR-00400; the Juvenile Diabetes Research Foundation International; and the American Diabetes Association. NR 20 TC 13 Z9 13 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3449 EP 3457 DI 10.2337/db14-0047 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300031 PM 24834977 ER PT J AU Abdo, S Shi, YX Otoukesh, A Ghosh, A Lo, CS Chenier, I Filep, JG Ingelfinger, JR Zhang, SL Chan, JSD AF Abdo, Shaaban Shi, Yixuan Otoukesh, Abouzar Ghosh, Anindya Lo, Chao-Sheng Chenier, Isabelle Filep, Janos G. Ingelfinger, Julie R. Zhang, Shao Ling Chan, John S. D. TI Catalase Overexpression Prevents Nuclear Factor Erythroid 2-Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice SO DIABETES LA English DT Article ID PROXIMAL TUBULAR CELLS; CONVERTING ENZYME-2 EXPRESSION; TRANSGENIC MICE; BARDOXOLONE METHYL; TUBULOINTERSTITIAL FIBROSIS; URINARY ANGIOTENSINOGEN; TRANSCRIPTION FACTOR; BLOOD-PRESSURE; CANCER CELLS; APOPTOSIS AB This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice. C1 [Abdo, Shaaban; Shi, Yixuan; Otoukesh, Abouzar; Ghosh, Anindya; Lo, Chao-Sheng; Chenier, Isabelle; Zhang, Shao Ling; Chan, John S. D.] Univ Montreal, Res Ctr, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Filep, Janos G.] Univ Montreal, Res Ctr, Hop Maisonneuve Rosemont, Montreal, PQ, Canada. [Ingelfinger, Julie R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA. RP Chan, JSD (reprint author), Univ Montreal, Res Ctr, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. EM john.chan@umontreal.ca FU Canadian Institutes of Health Research [MOP-97742, MOP-86450, MOP-84363, MOP 93650, MOP 16088]; National Institutes of Health [HL-48455]; Heart and Stroke Foundation of Canada FX This work was supported by grants from the Canadian Institutes of Health Research (MOP-97742 to J.G.F.; MOP-86450 to S.L.Z.; and MOP-84363, MOP 93650, and MOP 16088 to J.S.D.C.), the National Institutes of Health (HL-48455 to J.R.I.), and the Heart and Stroke Foundation of Canada (to J.S.D.C.). Editorial assistance was provided by the Centre Hospitalier de l'Universite de Montreal Research Support Office and Ovid M. Da Silva. NR 48 TC 6 Z9 6 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3483 EP 3496 DI 10.2337/db13-1830 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300034 PM 24812425 ER PT J AU Wei, D Loeken, MR AF Wei, Dan Loeken, Mary R. TI Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy SO DIABETES LA English DT Article ID ACTIVATED PROTEIN-KINASE; VITAMIN-E; CARDIOVASCULAR MALFORMATIONS; MAMMALIAN DEVELOPMENT; DEFECTS; EMBRYOS; CELLS; MOUSE; INFANTS; RISK AB Previous studies have shown that diabetic embryopathy results from impaired expression of genes that are required for formation of embryonic structures. We have focused on Pax3, a gene that is expressed in embryonic neuroepithelium and is required for neural tube closure. Pax3 expression is inhibited in embryos of diabetic mice due to hyperglycemia-induced oxidative stress. DNA methylation silences developmentally expressed genes before differentiation. We hypothesized that hypomethylation of Pax3 upon neuroepithelial differentiation may be inhibited by hyperglycemia-induced oxidative stress. We tested this using embryos of pregnant hyperglycemic mice and mouse embryonic stem cells (ESC). Methylation of a Pax3 CpG island decreased upon neurulation of embryos and formation of neuronal precursors from ESC. In ESC, this was inhibited by oxidative stress. Use of short hairpin RNA in ESC demonstrated that DNA methyltransferase 3b (Dnmt3b) was responsible for methylation and silencing of Pax3 before differentiation and by oxidative stress. Although expression of Dnmt3b was not affected by oxidative stress, DNA methyltransferase activity was increased. These results indicate that hyperglycemia-induced oxidative stress stimulates Dnmt3b activity, thereby inhibiting chromatin modifications necessary for induction of Pax3 expression during neurulation and thus providing a molecular mechanism for defects caused by Pax3 insufficiency in diabetic pregnancy. C1 [Loeken, Mary R.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Loeken, MR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. EM mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK058300]; Diabetes Endocrine Research Center [PO1DK036836] FX M.R.L. was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases under award number RO1DK058300 and was assisted by core facilities supported by a Diabetes Endocrine Research Center grant, PO1DK036836, to the Joslin Diabetes Center and by the DNA Resource Core provided by the Dana-Farber/Harvard Cancer Center. NR 50 TC 11 Z9 11 U1 2 U2 16 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3512 EP 3522 DI 10.2337/db14-0231 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300036 PM 24834974 ER PT J AU Iezzoni, LI Kurtz, SG Rao, SR AF Iezzoni, Lisa I. Kurtz, Stephen G. Rao, Sowmya R. TI Trends in U.S. adult chronic disability rates over time SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Prevalence rates; Movement difficulties; National health interview survey ID UNITED-STATES; OLDER AMERICANS; US POPULATION; HEALTH; OBESITY; DISPARITIES; LIMITATIONS; DECLINES; LIFE AB Background: Trends in the patterns and prevalence of chronic disability among U.S. residents carry important implications for public health and public policies across multiple societal sectors. Objectives: To examine trends in U.S. adult population rates of chronic disability from 1998 to 2011 using 7 different disability measures and examining the implications of trends in population age, race and ethnicity, and body mass index (BMI). Methods: We used National Health Interview Survey data on civilian, non-institutionalized U.S. residents ages >= 18 from selected years between 1998 and 2011. We used self-reported information on functional impairments, activity/participation limitations, and expected duration to create 7 chronic disability measures. We used direct standardization to account for changes in age, race/ethnicity, and BMI distributions over time. Multivariable logistic regression models identified associations of disability with sociodemographic characteristics. Results: Without adjustment, population rates of all 7 disabilities increased significantly (p < 0.0001) from 1998 to 2011. The absolute percentage change was greatest for movement difficulties: 19.3% in 1998 and 23.3% in 2011. After separate adjustments for trends in age, race/ethnicity, and BMI distributions, 6 disability types continued to show increased rates over time (p < 0.01), except for sensory disabilities. Over time, poor education, poverty, and unemployment remained significantly associated with disability. Conclusions: If these trends continue, the numbers and proportions of U.S. residents with various disabilities will continue rising in coming years. In particular, the prevalence of movement difficulties and work limitations will increase. Furthermore, disability will remain strongly associated with low levels of education, employment, and income. (C) 2014 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kurtz, Stephen G.; Rao, Sowmya R.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Rao, Sowmya R.] Bedford Veteran Affairs Med Ctr, CHOIR, Bedford, MA USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.edu FU National Cancer Institute [5R01CA160286-02] FX This work was funded by the National Cancer Institute, 5R01CA160286-02. NR 30 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 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD OCT PY 2014 VL 7 IS 4 BP 402 EP 412 DI 10.1016/j.dhjo.2014.05.007 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA AP8LW UT WOS:000342331500006 PM 25224980 ER PT J AU Miles, WO Korenjak, M Griffiths, LM Dyer, MA Provero, P Dyson, NJ AF Miles, Wayne O. Korenjak, Michael Griffiths, Lyra M. Dyer, Michael A. Provero, Paolo Dyson, Nicholas J. TI Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells SO EMBO JOURNAL LA English DT Article DE Nanos; post-transcriptional gene regulation; pRb; Pumilio; stress response ID RETINOBLASTOMA GENE; TRANSLATIONAL REGULATOR; TUMOR-SUPPRESSOR; MESSENGER-RNAS; CYCLE CONTROL; PUMILIO; DROSOPHILA; PROTEINS; CANCER; E2F AB Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE). C1 [Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Harvard Univ, Sch Med, Mol Oncol Lab, Charlestown, MA USA. [Griffiths, Lyra M.; Dyer, Michael A.] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Provero, Paolo] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Provero, Paolo] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU National Institutes of Health Public Health Service [R01 CA163698, R01 CA64402] FX We would like to acknowledge Brandon Nicoloy and Katrin Tschoep for their critical reading and helpful reading of the manuscript. We would additionally like to thank the laboratories of James Rocco, Anders Naar, Lee Zou, Jonathon Whetstine, and Mo Motamedi for their helpful suggestions and support during this work. This work was supported by National Institutes of Health Public Health Service grants R01 CA163698 and R01 CA64402 to N.J.D. N.J.D. is the James and Shirley Curvey MGH Research Scholar. NR 55 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD OCT 1 PY 2014 VL 33 IS 19 BP 2201 EP 2215 DI 10.15252/embj.201488057 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ0WL UT WOS:000342503300008 PM 25100735 ER PT J AU Liu, ES Zalutskaya, A Chae, BT Zhu, ED Gori, F Demay, MB AF Liu, Eva S. Zalutskaya, Alena Chae, Byongsoo Timothy Zhu, Eric D. Gori, Francesca Demay, Marie B. TI Phosphate Interacts With PTHrP to Regulate Endochondral Bone Formation SO ENDOCRINOLOGY LA English DT Article ID HORMONE-RELATED PEPTIDE; PROGRAMMED CELL-DEATH; PARATHYROID-HORMONE; HYPERTROPHIC CHONDROCYTES; GROWTH-PLATE; TGF-BETA; RECEPTOR; APOPTOSIS; PHOSPHORYLATION; MICE AB Phosphate and parathyroid hormone related peptide (PTHrP) are required for normal growth plate maturation. Hypophosphatemia impairs hypertrophic chondrocyte apoptosis leading to rachitic expansion of the growth plate; however, the effect of phosphate restriction on chondrocyte differentiation during endochondral bone formation has not been examined. Investigations were, therefore, undertaken to address whether phosphate restriction alters the maturation of embryonic d15.5 murine metatarsal elements. Metatarsals cultured in low phosphate media exhibited impaired chondrocyte differentiation, analogous to that seen with PTHrP-treatment of metatarsals cultured in control media. Because phosphate restriction acutely increases PTHrP expression in cultured metatarsals, studies were undertaken to determine if this increase in PTHrP plays a pathogenic role in the impaired chondrocyte differentiation observed under low phosphate conditions. In contrast to what was observed with wild-type metatarsal elements, phosphate restriction did not impair the differentiation of metatarsals isolated from PTHrP heterozygous or PTHrP knockout mice. In vivo studies in postnatal mice demonstrated that PTHrP haploinsufficiency also prevents the impaired hypertrophic chondrocyte apoptosis observed with phosphate restriction. To determine how signaling through the PTH/PTHrP receptor antagonizes the pro-apoptotic effects of phosphate, investigations were performed in primary murine hypertrophic chondrocytes. Receptor activation impaired phosphate-induced Erk1/2 phosphorylation specifically in the mitochondrial fraction and decreased levels of mitochondrial Bad, while increasing cytosolic phospho-Bad. Thus, these data demonstrate that phosphate restriction attenuates chondrocyte differentiation as well as impairing hypertrophic chondrocyte apoptosis and implicate a functional role for the PTH/PTHrP signaling pathway in the abnormalities in chondrocyte differentiation and hypertrophic chondrocyte apoptosis observed under phosphate restricted conditions. C1 [Liu, Eva S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Liu, Eva S.; Zalutskaya, Alena; Chae, Byongsoo Timothy; Zhu, Eric D.; Gori, Francesca; Demay, Marie B.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Liu, Eva S.; Zalutskaya, Alena; Gori, Francesca; Demay, Marie B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Demay, MB (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier11, Boston, MA 02114 USA. EM demay@helix.mgh.harvard.edu FU National Institutes of Health [R01 AR061376, T32 DK007529, F32 AR065386] FX This work was supported by Grants R01 AR061376, T32 DK007529, and F32 AR065386 from the National Institutes of Health. NR 30 TC 3 Z9 3 U1 0 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 3750 EP 3756 DI 10.1210/en.2014-1315 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000005 PM 25057796 ER PT J AU Castroneves, LA Jugo, RH Maynard, MA Lee, JS Wassner, AJ Dorfman, D Bronson, RT Ukomadu, C Agoston, AT Ding, L Luongo, C Guo, CC Song, HD Demchev, V Lee, NY Feldman, HA Vella, KR Peake, RW Hartigan, C Kellogg, MD Desai, A Salvatore, D Dentice, M Huang, SA AF Castroneves, Luciana A. Jugo, Rebecca H. Maynard, Michelle A. Lee, Jennifer S. Wassner, Ari J. Dorfman, David Bronson, Roderick T. Ukomadu, Chinweike Agoston, Agoston T. Ding, Lai Luongo, Cristina Guo, Cuicui Song, Huaidong Demchev, Valeriy Lee, Nicholas Y. Feldman, Henry A. Vella, Kristen R. Peake, Roy W. Hartigan, Christina Kellogg, Mark D. Desai, Anal Salvatore, Domenico Dentice, Monica Huang, Stephen A. TI Mice With Hepatocyte-Specific Deficiency of Type 3 Deiodinase Have Intact Liver Regeneration and Accelerated Recovery From Nonthyroidal Illness After Toxin-Induced Hepatonecrosis SO ENDOCRINOLOGY LA English DT Article ID THYROID-HORMONE; IODOTHYRONINE DEIODINASE; PARTIAL-HEPATECTOMY; RAT-LIVER; REQUIRES; GROWTH; CELLS; DIFFERENTIATION; PROLIFERATION; INACTIVATION AB Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome. C1 [Castroneves, Luciana A.; Jugo, Rebecca H.; Maynard, Michelle A.; Lee, Jennifer S.; Wassner, Ari J.; Guo, Cuicui; Song, Huaidong; Lee, Nicholas Y.; Huang, Stephen A.] Childrens Hosp Boston, Div Endocrinol, Thyroid Program, Boston, MA 02115 USA. [Feldman, Henry A.] Childrens Hosp Boston, Clin Res Ctr, Boston, MA 02115 USA. [Peake, Roy W.; Hartigan, Christina; Kellogg, Mark D.] Childrens Hosp Boston, Dept Lab Med, Boston, MA 02115 USA. [Huang, Stephen A.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Thyroid Sect, Boston, MA 02115 USA. [Dorfman, David; Agoston, Agoston T.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ukomadu, Chinweike; Demchev, Valeriy; Desai, Anal] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Ding, Lai] Harvard Univ, Neurodiscovery Ctr, Boston, MA 02115 USA. [Bronson, Roderick T.; Huang, Stephen A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vella, Kristen R.] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02115 USA. [Luongo, Cristina; Salvatore, Domenico; Dentice, Monica] Univ Naples Federico II, Dept Mol & Clin Endocrinol & Oncol, I-80131 Naples, Italy. RP Huang, SA (reprint author), Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM stephen.huang@childrens.harvard.edu OI SALVATORE, DOMENICO/0000-0002-4556-7620; Wassner, Ari/0000-0003-0894-9301 FU Murray Family; William F. Milton Foundation; National Institutes of Health [DK76099, HD052896] FX This work was supported by a donation from the Murray Family, the William F. Milton Foundation Award, and the National Institutes of Health Grants DK76099 and HD052896. NR 32 TC 0 Z9 0 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 4061 EP 4068 DI 10.1210/en.2013-2028 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000032 PM 25004090 ER PT J AU Guo, CC Chen, X Song, HD Maynard, MA Zhou, Y Lobanov, AV Gladyshev, VN Ganis, JJ Wiley, D Jugo, RH Lee, NY Castroneves, LA Zon, LI Scanlan, TS Feldman, HA Huang, SA AF Guo, Cuicui Chen, Xia Song, Huaidong Maynard, Michelle A. Zhou, Yi Lobanov, Alexei V. Gladyshev, Vadim N. Ganis, Jared J. Wiley, David Jugo, Rebecca H. Lee, Nicholas Y. Castroneves, Luciana A. Zon, Leonard I. Scanlan, Thomas S. Feldman, Henry A. Huang, Stephen A. TI Intrinsic Expression of a Multiexon Type 3 Deiodinase Gene Controls Zebrafish Embryo Size SO ENDOCRINOLOGY LA English DT Article ID I IODOTHYRONINE DEIODINASE; THYROID-HORMONE; RING DEIODINATION; METAMORPHOSIS; VITRO; INACTIVATION; METABOLISM; KNOCKDOWN; THYROXINE; DISEASE AB Thyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element. C1 [Guo, Cuicui; Chen, Xia; Song, Huaidong] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, State Key Lab Med Genom, Shanghai 200025, Peoples R China. [Guo, Cuicui; Chen, Xia; Song, Huaidong; Maynard, Michelle A.; Jugo, Rebecca H.; Lee, Nicholas Y.; Castroneves, Luciana A.; Huang, Stephen A.] Boston Childrens Hosp, Div Endocrinol, Thyroid Program, Boston, MA 02115 USA. [Feldman, Henry A.] Boston Childrens Hosp, Clin Res Ctr, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston Childrens Hosp,Stem Cell Program, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston Childrens Hosp,Div Hematol Oncol, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lobanov, Alexei V.; Gladyshev, Vadim N.; Huang, Stephen A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gladyshev, Vadim N.; Zon, Leonard I.; Huang, Stephen A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Scanlan, Thomas S.] Oregon Hlth & Sci Univ, Dept Physiol, Portland, OR 97239 USA. [Scanlan, Thomas S.] Oregon Hlth & Sci Univ, Dept Pharmacol, Portland, OR 97239 USA. RP Huang, SA (reprint author), Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM stephen.huang@childrens.harvard.edu FU Murray Family; National Institutes of Health [DK076099, GM061603, DK53298]; William F. Milton Foundation Award; People's Republic of China National Natural Science Foundation Program [30900503]; PhD Student Visiting Program of Shanghai Jiaotong University School of Medicine; Howard Hughes Medical Institute FX This work was supported by a donation from the Murray Family; by Grants DK076099, GM061603, and DK53298 from the National Institutes of Health; the William F. Milton Foundation Award; Grant 30900503 from the People's Republic of China National Natural Science Foundation Program; the PhD Student Visiting Program of Shanghai Jiaotong University School of Medicine; and the Howard Hughes Medical Institute (to L.I.Z.). NR 47 TC 6 Z9 6 U1 0 U2 11 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 4069 EP 4080 DI 10.1210/en.2013-2029 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000033 PM 25004091 ER PT J AU Radmanesh, F Devan, WJ Anderson, CD Rosand, J Falcone, GJ AF Radmanesh, Farid Devan, William J. Anderson, Christopher D. Rosand, Jonathan Falcone, Guido J. CA ADNI TI Accuracy of imputation to infer unobserved APOE epsilon alleles in genorne-wide genotyping data SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE apolipoprotein E; APOE; epsilon alleles; GWAS; imputation ID ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; ASSOCIATION; ONSET; RISK; GENE AB Apolipoprotein E, encoded by APOE, is the main apoprotein for catabolism of chylomicrons and very low density lipoprotein. Two common single-nucleotide polymorphisms (SNPs) in APOE, rs429358 and rs7412, determine the three epsilon-alleles that are established genetic risk factors for late-onset Alzheimer's disease (AD), cerebral amyloid angiopathy, and intracerebral hemorrhage (ICH). These two SNPs are not present in most commercially available genome-wide genotyping arrays and cannot be inferred through imputation using HapMap reference panels. Therefore, these SNPs are often separately genotyped. Introduction of reference panels compiled from the 1000 Genomes project has made imputation of these variants possible. We compared the directly genotyped and imputed SNPs that define the APOE epsilon alleles to. determine the accuracy of imputation for inference of unobserved epsilon alleles. We utilized genome-wide genotype data obtained from two cohorts of ICH and AD constituting subjects of European ancestry. Our data suggest that imputation is highly accurate, yields an acceptable proportion of missing data that is non-differentially distributed across case and control groups, and generates comparable results to genotyped data for hypothesis testing. Further, we explored the effect of imputation algorithm parameters and demonstrated that customization of these parameters yields an improved balance between accuracy and missing data for inferred genotypes. C1 [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Dept Neurol, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,185 Cambridge St,CPZN 5820, Boston, MA 02114 USA. EM cdanderson@partners.org RI Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 FU NIH-NINDS [R01NS059727]; Keane Stroke Genetics Research Fund; Edward and Maybeth Sonn Research Fund; University of Michigan General Clinical Research Center [M01 RR000042]; National Center for Research Resources; NIH-NINDS SPOTRIAS fellowship [P50NS061343]; American Brain Foundation; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Company; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; F Hoffmann-La Roche Ltd; Genentech, Inc; GE Healthcare; Irmogenetics, NV; IXECO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Synarc Inc; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; NIH [P30 AG010129, K01 AG030514] FX The Genetics of Cerebral Hemorrhage with Anticoagulation study was funded by NIH-NINDS grant R01NS059727, the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center (M01 RR000042), and by a grant from the National Center for Research Resources. GJF was supported by the NIH-NINDS SPOTRIAS fellowship grant P50NS061343. CDA was supported by a Clinical Research Training Fellowship from the American Brain Foundation. 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: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; 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; Irmogenetics, NV; IXECO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; 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, Rev October 16, 2012 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. The investigators within the ADNI contributed to the design and implementation of the ADNI and/or provided data, but did not participate in analysis or writing of this report. NR 17 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD OCT PY 2014 VL 22 IS 10 BP 1239 EP 1242 DI 10.1038/ejhg.2013.308 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ0LZ UT WOS:000342476100015 PM 24448547 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Focus article: report of the NIH task force on research standards for chronic low back pain SO EUROPEAN SPINE JOURNAL LA English DT Article DE Low back pain; Chronic low back pain; Research standards; Minimum dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony; Weiner, Debra K.] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 123 TC 13 Z9 13 U1 8 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 EI 1432-0932 J9 EUR SPINE J JI Eur. Spine J. PD OCT PY 2014 VL 23 IS 10 BP 2028 EP 2045 DI 10.1007/s00586-014-3540-3 PG 18 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AQ0EI UT WOS:000342455200002 PM 25212440 ER PT J AU Vernochet, C Damilano, F Mourier, A Bezy, O Mori, MA Smyth, G Rosenzweig, A Larsson, NG Kahn, CR AF Vernochet, Cecile Damilano, Federico Mourier, Arnaud Bezy, Olivier Mori, Marcelo A. Smyth, Graham Rosenzweig, Anthony Larsson, Nils-Goeran Kahn, C. Ronald TI Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications SO FASEB JOURNAL LA English DT Article DE TFAM; WAT; BAT; diabetes; hypertension; cardiomegaly ID TRANSCRIPTION-FACTOR; HIV-INFECTION; GENERALIZED LIPODYSTROPHY; COPY NUMBER; MICE; OBESITY; DNA; ADIPONECTIN; MAINTENANCE; INSIGHTS AB Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.-Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.-G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. C1 [Vernochet, Cecile; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Vernochet, Cecile; Damilano, Federico; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Rosenzweig, Anthony; Kahn, C. Ronald] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Damilano, Federico; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Mourier, Arnaud; Larsson, Nils-Goeran] Max Planck Inst Biol Ageing, Dept Mitochondrial Biol, Cologne, Germany. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI MOURIER, Arnaud/I-8117-2012 OI MOURIER, Arnaud/0000-0002-5413-611X FU U.S. National Institutes of Health (NIH) [R01-DK082659]; Eli Lilly Foundation; Joslin Diabetes Research Center (NIH) [P30-DK036836]; Mary K. Iacocca Professorship; NIH [R01-HL094677] FX This work was supported by U.S. National Institutes of Health (NIH) grant R01-DK082659 (C.R.K.), a grant from the Eli Lilly Foundation, Joslin Diabetes Research Center (NIH grant P30-DK036836), the Mary K. Iacocca Professorship, and NIH grant R01-HL094677 (A.R.). NR 41 TC 17 Z9 17 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD OCT PY 2014 VL 28 IS 10 BP 4408 EP 4419 DI 10.1096/fj.14-253971 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AP6XU UT WOS:000342222700019 PM 25005176 ER PT J AU Barcelo, C Etchin, J Mansour, MR Sanda, T Ginesta, MM Lobo, VJSA Real, FX Capella, G Estanyol, JM Jaumot, M Look, AT Agell, N AF Barcelo, Carles Etchin, Julia Mansour, Marc R. Sanda, Takaomi Ginesta, Mireia M. Sanchez-Arevalo Lobo, Victor J. Real, Francisco X. Capella, Gabriel Estanyol, Josep M. Jaumot, Montserrat Look, A. Thomas Agell, Neus TI Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells SO GASTROENTEROLOGY LA English DT Article DE Signal Transduction; Carcinogenesis; Oncogene; Mouse Model ID K-RAS; BINDING-PROTEIN; CANCER-CELLS; HEPATOCELLULAR-CARCINOMA; TUMOR-DEVELOPMENT; GENE-EXPRESSION; EGF RECEPTOR; LUNG-CANCER; IN-VIVO; N-RAS AB BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) involves activation of c-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) signaling, but little is known about the roles of proteins that regulate the activity of oncogenic KRAS. We investigated the activities of proteins that interact with KRAS in PDAC cells. METHODS: We used mass spectrometry to demonstrate that heterogeneous nuclear ribonucleoproteins (HNRNP) A2 and B1 (encoded by the gene HNRNPA2B1) interact with KRAS G12V. We used co-immunoprecipitation analyses to study interactions between HNRNPA2B1 and KRAS in KRAS-dependent and KRAS-independent PDAC cell lines. We knocked down HNRNPA2B1 using small hairpin RNAs and measured viability, anchorage-independent proliferation, and growth of xenograft tumors in mice. We studied KRAS phosphorylation using the Phos-tag system. RESULTS: We found that interactions between HRNPA2B1 and KRAS correlated with KRAS-dependency of some human PDAC cell lines. Knock down of HNRNPA2B1 significantly reduced viability, anchorage-independent proliferation, and formation of xenograft tumors by KRAS-dependent PDAC cells. HNRNPA2B1 knock down also increased apoptosis of KRAS-dependent PDAC cells, inactivated c-akt murine thymoma oncogene homolog 1 signaling via mammalian target of rapamycin, and reduced interaction between KRAS and phosphatidylinositide 3-kinase. Interaction between HNRNPA2B1 and KRAS required KRAS phosphorylation at serine 181. CONCLUSIONS: In KRAS-dependent PDAC cell lines, HNRNPA2B1 interacts with and regulates the activity of KRAS G12V and G12D. HNRNPA2B1 is required for KRAS activation of c-akt murine thymoma oncogene homolog 1-mammalian target of rapamycin signaling, interaction with phosphatidylinositide 3-kinase, and PDAC cell survival and tumor formation in mice. HNRNPA2B1 might be a target for treatment of pancreatic cancer. C1 [Barcelo, Carles; Jaumot, Montserrat; Agell, Neus] Univ Barcelona, Fac Med, Dept Biol Cellular Immunol & Neurociencies, IDIBAPS, Barcelona 08036, Spain. [Etchin, Julia; Mansour, Marc R.; Sanda, Takaomi; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sanda, Takaomi] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Ginesta, Mireia M.; Capella, Gabriel] ICO IDIBELL, Catalan Inst Oncol, Translat Res Lab, Hereditary Canc Program, Barcelona, Spain. [Sanchez-Arevalo Lobo, Victor J.; Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, Programa Patol Mol, Grp Carcinogenesis Epitelial, Madrid, Spain. [Estanyol, Josep M.] Univ Barcelona, CCiTUB, E-08036 Barcelona, Spain. RP Agell, N (reprint author), Univ Barcelona, Fac Med, Dept Biol Cellular Immunol & Neurociencies, C Casanova 143, Barcelona 08036, Spain. EM neusagell@ub.edu RI Real Arribas, Francisco/H-5275-2015; Agell, Neus/E-9640-2016; Estanyol, Josep M/I-1039-2015; OI Real Arribas, Francisco/0000-0001-9501-498X; Sanchez-Arevalo Lobo, Victor Javier/0000-0002-4561-1505; Agell, Neus/0000-0002-1205-6074 FU MICINN-Spain [SAF2010-20712]; RTICC (MINECO-Spain) [RD12/0036/0049, RD12/0036/0031, RD12/0036/0034]; Spanish Government FX This study was supported by MICINN-Spain (SAF2010-20712) and RTICC (MINECO-Spain; groups RD12/0036/0049, RD12/0036/0031, and RD12/0036/0034). C. Barcelo is recipient of a predoctoral fellowship "FPU" from the Spanish Government. NR 70 TC 6 Z9 8 U1 1 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2014 VL 147 IS 4 BP 882 EP U280 DI 10.1053/j.gastro.2014.06.041 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AQ0SO UT WOS:000342493200031 PM 24998203 ER PT J AU Johnson, DA Barkun, AN Cohen, LB Dominitz, JA Kaltenbach, T Martel, M Robertson, DJ Boland, CR Giardello, FM Lieberman, DA Levin, TR Rex, DK AF Johnson, David A. Barkun, Alan N. Cohen, Larry B. Dominitz, Jason A. Kaltenbach, Tonya Martel, Myriam Robertson, Douglas J. Boland, C. Richard Giardello, Frances M. Lieberman, David A. Levin, Theodore R. Rex, Douglas K. TI Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations From the US Multi-Society Task Force on Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Colonoscopy Preparation; Colonoscopy Quality; Colonoscopy; Colon Cancer Screening; Colon Polyp Detection; Bowel Preparations ID ORAL SODIUM-PHOSPHATE; RANDOMIZED CONTROLLED-TRIAL; POLYETHYLENE-GLYCOL SOLUTION; ELECTROLYTE LAVAGE SOLUTION; PLUS ASCORBIC-ACID; INVESTIGATOR-BLINDED TRIAL; HIGH-DOSE SENNA; INCREASE SCREENING COLONOSCOPY; ADENOMA DETECTION RATE; CLEAR LIQUID DIET C1 [Johnson, David A.] Eastern VA Med Sch, Norfolk, VA 23507 USA. [Barkun, Alan N.; Martel, Myriam] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Cohen, Larry B.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Vet Affairs Palo Alto, Palo Alto, CA 94304 USA. [Robertson, Douglas J.] VA Med Ctr, Portland, VA USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, White River Jct, VT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Giardello, Frances M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Johnson, DA (reprint author), Eastern VA Med Sch, Norfolk, VA 23507 USA. EM dajevms@aol.com OI Dominitz, Jason/0000-0002-8070-7086 FU Boston Scientific; Cook; Salix; Olympus America, Inc; Braintree Laboratories; Ferring Pharmaceuticals FX These authors disclose the following: David Johnson has served as a consultant and clinical investigator for Epigenomics, as a consultant for Given Imaging, and as a clinical investigator for Exact Sciences; A. Barkun has served as a consultant for Olympus, Inc, and Pendopharm, Inc, and has received clinical research support from Boston Scientific and Cook; L. B. Cohen has served as a consultant and on the speaker's bureau and received research support from Salix, and as a consultant for Braintree; T. Kaltenbach has been a research grant recipient and consultant for Olympus America, Inc, D. J. Robertson has served as a consultant for Given Imaging; D. A. Lieberman has served on the scientific advisory boards for Exact Sciences, Given Imaging, and Roche, and as a consultant for MOTUS; and D. K. Rex has received research support and served as a consultant for Braintree Laboratories and Ferring Pharmaceuticals, Given Imaging, and Olympus America Corp, has served as a consultant for Epigenomics and Exact Sciences, and has served on the speaker's bureau for Boston Scientific, Inc. The remaining authors disclose no conflicts. NR 252 TC 49 Z9 51 U1 0 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2014 VL 147 IS 4 BP 903 EP 924 DI 10.1053/j.gastro.2014.07.002 PG 22 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AQ0SO UT WOS:000342493200033 PM 25239068 ER PT J AU Cleary, JM Lima, CMSR Hurwitz, HI Montero, AJ Franklin, C Yang, JN Graham, A Busman, T Mabry, M Holen, K Shapiro, GI Uronis, H AF Cleary, James M. Lima, Caio Max S. Rocha Hurwitz, Herbert I. Montero, Alberto J. Franklin, Catherine Yang, Jianning Graham, Alison Busman, Todd Mabry, Mack Holen, Kyle Shapiro, Geoffrey I. Uronis, Hope TI A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE ABT-263; Apoptosis; Bcl-2; Bcl-xL; Gemcitabine; Navitoclax ID PANCREATIC-CANCER CELLS; RESISTANCE; CRITERIA; THERAPY; ABT-737; ABT-263; MODELS; MCL-1 AB Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors. C1 [Cleary, James M.; Shapiro, Geoffrey I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Cleary, James M.; Shapiro, Geoffrey I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Lima, Caio Max S. Rocha] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Hurwitz, Herbert I.; Uronis, Hope] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Montero, Alberto J.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. [Franklin, Catherine; Yang, Jianning; Graham, Alison; Busman, Todd; Mabry, Mack; Holen, Kyle] AbbVie Inc, N Chicago, IL USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02215 USA. RP Shapiro, GI (reprint author), Dana Farber Canc Inst, Early Drug Dev Ctr, 450 Brookline Ave,Mayer 446, Boston, MA 02215 USA. EM geoffrey_shapiro@dfci.harvard.edu FU AbbVie Inc. FX AbbVie Inc. NR 22 TC 9 Z9 11 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2014 VL 32 IS 5 BP 937 EP 945 DI 10.1007/s10637-014-0110-9 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AP9PK UT WOS:000342411500015 PM 24916770 ER PT J AU Ciombor, KK Feng, Y Benson, A Su, YJ Horton, L Short, SP Kauh, JSW Staley, C Mulcahy, M Powell, M Amiri, KI Richmond, A Berlin, J AF Ciombor, Kristen K. Feng, Yang Benson, Al Bowen, III Su, Yingjun Horton, Linda Short, Sarah P. Kauh, John Sae Wook Staley, Charles Mulcahy, Mary Powell, Mark Amiri, Katayoun I. Richmond, Ann Berlin, Jordan TI Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Hepatocellular carcinoma; Bortezomib; Doxorubicin; Proteasome inhibition ID NF-KAPPA-B; PROTEASOME INHIBITOR PS-341; ENDOTHELIAL GROWTH-FACTOR; MULTIPLE-MYELOMA CELLS; CHEMOTHERAPEUTIC-AGENTS; PROMOTER ACTIVITY; LIVER METASTASIS; TUMOR-GROWTH; ACTIVATION; EXPRESSION AB Purpose To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. Experimental Design This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. Results Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1 alpha and EMSA for NF-kappa B at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1 alpha/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. Conclusions The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious. C1 [Ciombor, Kristen K.] Ohio State Univ, Arthur G James Canc Hosp, Div Med Oncol, Dept Internal Med, Columbus, OH 43212 USA. [Ciombor, Kristen K.] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43212 USA. [Feng, Yang] Dana Farber Canc Inst, Boston, MA 02115 USA. [Benson, Al Bowen, III; Mulcahy, Mary] Northwestern Univ, Chicago, IL 60611 USA. [Su, Yingjun] Fourth Mil Med Univ, Xijing Hosp, Xian 710032, Shaanxi Provinc, Peoples R China. [Horton, Linda; Short, Sarah P.; Richmond, Ann; Berlin, Jordan] Vanderbilt Univ, Nashville, TN 37235 USA. [Horton, Linda; Richmond, Ann] Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN USA. [Kauh, John Sae Wook; Staley, Charles] Emory Univ, Atlanta, GA 30322 USA. [Amiri, Katayoun I.] Celgene Corp, Summit, NJ USA. RP Ciombor, KK (reprint author), Ohio State Univ, Arthur G James Canc Hosp, Div Med Oncol, Dept Internal Med, A445A Starling Loving Hall,320 West 10th Ave, Columbus, OH 43212 USA. EM kristen.ciombor@osumc.edu FU Public Health Service [CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625]; SRCS award from the Department of Veterans Affairs; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Public Health Service from the National Cancer Institute [5R21 CA099269-02] FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis), and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625, an SRCS award from the Department of Veterans Affairs, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Laboratory correlatives were supported by Public Health Service Grant 5R21 CA099269-02 from the National Cancer Institute. NR 49 TC 7 Z9 7 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2014 VL 32 IS 5 BP 1017 EP 1027 DI 10.1007/s10637-014-0111-8 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AP9PK UT WOS:000342411500023 PM 24890858 ER PT J AU Banerjee, T Scherzer, R Powe, NR Steffick, D Shahinian, V Saran, R Pavkov, ME Saydah, S Shlipak, MG AF Banerjee, Tanushree Scherzer, Rebecca Powe, Neil R. Steffick, Diane Shahinian, Vahakn Saran, Rajiv Pavkov, Meda E. Saydah, Sharon Shlipak, Michael G. CA Ctr Dis Control Prevention Chronic TI Race and Other Risk Factors for Incident Proteinuria in a National Cohort of HIV-Infected Veterans SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; proteinuria; race ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; ACTIVE ANTIRETROVIRAL THERAPY; ASSOCIATION; PREVALENCE; MANAGEMENT; OUTCOMES; WOMEN; INDIVIDUALS; GUIDELINES AB Background: Proteinuria in human immunodeficiency virus (HIV)-infected individuals has been associated with poorer outcomes. We examined risk factors associated with the development of proteinuria in a national registry of HIV-infected veterans. Methods: A total of 21,129 HIV-infected veterans of black and white race without preexisting kidney disease were receiving health care in the Veterans' Health Administration (VHA) medical system between 1997 and 2011. Using the VHA electronic record system, we identified kidney-related risk factors (hypertension, diabetes, and cardiovascular disease) and HIV-related risk factors (CD4 lymphocyte count, HIV RNA level, hepatitis C virus, and hepatitis B virus) for developing proteinuria. Proteinuria was defined by 2 consecutive dipstick measures of 1(+) or higher. The Fine-Gray competing risk model was used to estimate association between clinical variables and incident proteinuria, while accounting for intervening mortality events. Results: During follow-up (median = 5.3 years), 7031 patients developed proteinuria. Overall, black race compared with white race was associated with a higher risk of proteinuria {hazard ratio [95% confidence interval (CI)] = 1.51 [1.43 to 1.59]}, but the association was stronger at younger ages (P interaction <0.001). Age-stratified risk of proteinuria for blacks relative to whites was greatest among veterans,30 years [2.19 (1.66 to 2.89)] and the risk diminished with increasing age [1.14 (0.97 to 1.34) for >60 years]. We found the race difference to be stronger for the outcome of 2(+) or higher proteinuria [2.13 (1.89 to 2.39)]. Both HIV-related and traditional risk factors were also associated with incident proteinuria (P < 0.05). Conclusions: Compared with whites, risk of proteinuria was higher in black veterans with HIV infection, particularly at younger ages. In both races, HIV- and kidney-related risk factors were associated with higher proteinuria risk. C1 [Banerjee, Tanushree; Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Banerjee, Tanushree; Powe, Neil R.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Scherzer, Rebecca; Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94121 USA. [Steffick, Diane; Shahinian, Vahakn; Saran, Rajiv] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Pavkov, Meda E.; Saydah, Sharon] Ctr Dis Prevent & Control, Div Diabet Translat, Atlanta, GA USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu FU Centers for Disease Control and Prevention, Atlanta, GA [1U58DP003839] FX Supported by the Cooperative Agreement No. 1U58DP003839 from The Centers for Disease Control and Prevention, Atlanta, GA. NR 35 TC 3 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2014 VL 67 IS 2 BP 145 EP 152 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP4NT UT WOS:000342055000012 PM 25072613 ER PT J AU Zheng, L Taiwo, B Gandhi, RT Hunt, PW Collier, AC Flexner, C Bosch, RJ AF Zheng, Lu Taiwo, Babafemi Gandhi, Rajesh T. Hunt, Peter W. Collier, Ann C. Flexner, Charles Bosch, Ronald J. TI Factors Associated With CD8(+) T-Cell Activation in HIV-1-Infected Patients on Long-term Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD8(+) T-cell activation; viral suppression; age; HCV; CD4(+) T-cell count ID HEPATITIS-C VIRUS; LOW-LEVEL VIREMIA; IMMUNE ACTIVATION; HIV-INFECTION; VIRAL SUPPRESSION; RNA LEVELS; RECOVERY; REPLICATION; REGIMENS; DISEASE AB Background: Abnormal levels of CD8(+) T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious. Methods: CD8+ T-cell activation (% coexpressing CD38/HLA-DR) was analyzed on blood specimens from 833 HIV-1-infected patients on ART for >= 96 weeks with concurrent plasma HIV RNA (vRNA) <= 200 copies per milliliter. Factors associated with CD8(+) T-cell activation were assessed using generalized estimating equations to incorporate longitudinal measurements (median 4/participant). Results: Participants were 84% men, 47% white, 28% black, and 22% Hispanic, with median pre-ART age 38 years and median ART exposure 144 weeks. CD8(+) T-cell activation was higher at time-points when vRNA was 51-200 versus <= 50 copies per milliliter [mean CD8(+) T-cell activation 23.4% vs. 19.7%; adjusted difference: 1.7% (95% confidence interval: 0.1 to 3.4), P = 0.042]. Restricting to vRNA <= 50 copies per milliliter, multivariable models showed the following factors associated with higher CD8(+) T-cell activation: older age [>= 45 vs. <= 30 years: 3.6% (1.4 to 5.7), P = 0.004], hepatitis C virus antibody positivity [3.6% (0.9 to 6.2), P = 0.032], Hispanic vs. white [7.2% (5.3 to 9.0), P < 0.001], lower concurrent CD4 count [<= 200 vs. >500 cells/mm(3): 2.2% (0.7 to 3.7), P < 0.001], lower concurrent CD4/CD8 ratio [-2.6% (-3.7 to -1.5) per 0.5 unit increase, P < 0.001], and higher pre-ART CD8+ T-cell activation [2.0% (1.6 to 2.5) per 10% higher, P < 0.001]. Conclusions: In participants included in our analysis, residual low-level viremia between 51 and 200 copies per milliliter during ART was shown to be associated with greater CD8(+) T-cell activation than full suppression to <50 copies per milliliter. Older age, hepatitis C virus antibody positivity, race/ethnicity, higher pre-ART CD8(+) T-cell activation, and lower concurrent CD4/CD8 ratio and CD4(+) T-cell count also contribute to greater CD8(+) T-cell activation during suppressive ART. C1 [Zheng, Lu; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Taiwo, Babafemi] Northwestern Univ, Div Infect Dis, Chicago, IL 60611 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Gandhi, Rajesh T.] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Gandhi, Rajesh T.] Harvard, Cambridge, MA USA. [Hunt, Peter W.] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USA. [Collier, Ann C.] Univ Washington, Dept Med, Div Infect Dis, Seattle, WA USA. [Flexner, Charles] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD USA. RP Zheng, L (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, FXB Bldg,Room 613,651 Huntington Ave, Boston, MA 02115 USA. EM szheng@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [AI-68636, AI-68634, AI-38858, AI-38855, AI-69434]; Janssen; Pfizer; GlaxoSmithKline; ViiV; Abbott; Merck; Roche Molecular Systems; Schering-Plough; Boehringer-Ingelheim FX Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (AI-68636, AI-68634, AI-38858, AI-38855, and AI-69434).; B.T. has served as an advisor and/or received research support (to Northwestern University) from Janssen, Pfizer, GlaxoSmithKline, and ViiV. R. T. G. has received institutional research grant support from Abbott, ViiV, and Janssen. A. C. C. received research support (to University of Washington) from Merck, Roche Molecular Systems, and Schering-Plough, previously owned stock in Abbott, Bristol-Myers Squibb, Johnson and Johnson, and Pfizer, and was a DSMB member for a Merck-sponsored study. C. F. reports receiving research grant support from Boehringer-Ingelheim and GlaxoSmithKline for research unrelated to this study and serving as a consultant to Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Roche, Schering-Plough, Tobira Therapeutics, Tibotec, Vertex, Virostatics, and ViiV Healthcare. The remaining authors have no conflicts of interest to disclose. NR 37 TC 7 Z9 7 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2014 VL 67 IS 2 BP 153 EP 160 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP4NT UT WOS:000342055000013 PM 25072610 ER PT J AU Grannan, BL Yanamadala, V Venteicher, AS Walcott, BP Barr, JC AF Grannan, Benjamin L. Yanamadala, Vijay Venteicher, Andrew S. Walcott, Brian P. Barr, John C. TI Use of external ventriculostomy and intrathecal anti-fungal treatment in cerebral mucormycotic abscess SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Amphotericin; External ventricular drain; Intrathecal; Mucormycosis; Neurocritical care ID AMPHOTERICIN; EPIDEMIOLOGY; ZYGOMYCOSIS; MANAGEMENT; THERAPY AB Mucormycosis is an invasive fungal infection associated with a high mortality. Cerebral mucor abscesses can result secondary to rhinocerebral or hematogenous spread. Amphotericin B, posaconazole, and aggressive surgical resection are the hallmarks of treatment. While amphotericin is typically administered intravenously, less is known about the use of intrathecal amphotericin B. We describe a 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses. (C) 2014 Published by Elsevier Ltd. C1 [Walcott, Brian P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,WACC 745, Boston, MA 02115 USA. EM walcott.brian@mgh.harvard.edu NR 11 TC 0 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD OCT PY 2014 VL 21 IS 10 BP 1819 EP 1821 DI 10.1016/j.jocn.2014.01.008 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ0ML UT WOS:000342477300032 PM 24852901 ER PT J AU King, MW Resick, PA AF King, Matthew W. Resick, Patricia A. TI Data Mining in Psychological Treatment Research: A Primer on Classification and Regression Trees SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE classification and regression trees; CART; exploratory data analysis; data mining ID SELECTION; PTSD AB Data mining of treatment study results can reveal unforeseen but critical insights, such as who receives the most benefit from treatment and under what circumstances. The usefulness and legitimacy of exploratory data analysis have received relatively little recognition, however, and analytic methods well suited to the task are not widely known in psychology. With roots in computer science and statistics, statistical learning approaches offer a credible option: These methods take a more inductive approach to building a model than is done in traditional regression, allowing the data greater role in suggesting the correct relationships between variables rather than imposing them a priori. Classification and regression trees are presented as a powerful, flexible exemplar of statistical learning methods. Trees allow researchers to efficiently identify useful predictors of an outcome and discover interactions between predictors without the need to anticipate and specify these in advance, making them ideal for revealing patterns that inform hypotheses about treatment effects. Trees can also provide a predictive model for forecasting outcomes as an aid to clinical decision making. This primer describes how tree models are constructed, how the results are interpreted and evaluated, and how trees overcome some of the complexities of traditional regression. Examples are drawn from randomized clinical trial data and highlight some interpretations of particular interest to treatment researchers. The limitations of tree models are discussed, and suggestions for further reading and choices in software are offered. C1 [King, Matthew W.; Resick, Patricia A.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Resick, Patricia A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP King, MW (reprint author), VA Boston Healthcare Syst 116B 3, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave, Boston, MA 02130 USA. EM matthew.king2@va.gov NR 30 TC 9 Z9 9 U1 2 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2014 VL 82 IS 5 SI SI BP 895 EP 905 DI 10.1037/a0035886 PG 11 WC Psychology, Clinical SC Psychology GA AQ0VZ UT WOS:000342502100014 PM 24588404 ER PT J AU Pais, VM Chew, B Shaw, O Hyams, ES Matlaga, B Venkatesh, R Page, J Paterson, RF Arsovska, O Kurtz, M Eisner, BH AF Pais, Vernon M., Jr. Chew, Ben Shaw, Ojas Hyams, Elias S. Matlaga, Brian Venkatesh, Ramakrishna Page, Jay Paterson, Ryan F. Arsovska, Olga Kurtz, Michael Eisner, Brian H. TI Percutaneous Nephrolithotomy for Removal of Encrusted Ureteral Stents: A Multicenter Study SO JOURNAL OF ENDOUROLOGY LA English DT Article ID MANAGEMENT AB Purpose: Encrusted ureteral stents are a challenging endourologic problem. We performed a multi-institutional review of percutaneous nephrolithotomy (PCNL) as primary treatment for encrusted stents. Materials and Methods: We identified 36 patients who underwent PCNL for treatment of an encrusted stent. A retrospective review was performed to compile details of procedures and outcomes for these patients. Results: In 36 patients, 38 renal units underwent PCNL for encrusted ureteral stents. The mean patient age was 47.1 years (+/- 16.7), and the female:male ratio was 15:21. Mean stent indwelling time before removal was 28.2 months (+/- 27.8). The reason for long indwelling time was reported in 25 cases; these reasons included "patient unaware stent needed to be removed" (17 cases), pregnancy (2 cases), other comorbidities (3 cases), and patient incarceration (3 cases). In 3 cases, the stent had become encrusted within 3 months of placement. Mean operative time was 162 minutes (+/- 71). There were no major intraoperative complications, and no patients required blood transfusion. Litholapaxy was required for bladder coil encrustations in 22 cases (58%), and ureteroscopy with lithotripsy was required for encrustation of the ureteral portion of the stent in 13 cases (34.2%). Second look percutaneous procedures were required in 13 cases (34.2%). The stent was removed at the time of PCNL without need for concomitant or delayed ureteroscopy and/or cystolitholapaxy in 8 cases (21%). Ultimately, all stents were removed successfully. Patients were rendered stone free according to radiographs in 24 cases (63%). Conclusions: In this multicenter review, PCNL is confirmed to be a safe and effective means of addressing the retained and encrusted ureteral stent. PCNL without ureteroscopy or litholapaxy was sufficient in a minority of cases (21%). Adjunctive endourologic modalities are often required, and the surgeon should anticipate the need for concomitant antegrade ureteroscopic laser lithotripsy and/or cystolitholapaxy. Although complete stent removal can be anticipated, residual fragments are not uncommon. C1 [Pais, Vernon M., Jr.; Hyams, Elias S.] Dartmouth Hitchcock Med Ctr, Urol Sect, Lebanon, NH 03756 USA. [Chew, Ben; Paterson, Ryan F.; Arsovska, Olga] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Shaw, Ojas] NYU, Dept Urol, New York, NY USA. [Matlaga, Brian] Johns Hopkins Univ, Brady Urol Inst, Baltimore, MD USA. [Venkatesh, Ramakrishna; Page, Jay] Univ Kentucky, Dept Urol, Lexington, KY USA. [Kurtz, Michael; Eisner, Brian H.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Pais, VM (reprint author), Dartmouth Hitchcock Med Ctr, Urol Sect, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM vmp@hitchcock.org NR 13 TC 4 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 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD OCT 1 PY 2014 VL 28 IS 10 BP 1188 EP 1191 DI 10.1089/end.2014.0004 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA AQ1SP UT WOS:000342561600011 PM 24745371 ER PT J AU Lee, GC Fong, ZV Ferrone, CR Thayer, SP Warshaw, AL Lillemoe, KD Fernandez-del Castillo, C AF Lee, Grace C. Fong, Zhi Ven Ferrone, Cristina R. Thayer, Sarah P. Warshaw, Andrew L. Lillemoe, Keith D. Fernandez-del Castillo, Carlos TI High Performing Whipple Patients: Factors Associated with Short Length of Stay after Open Pancreaticoduodenectomy SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Length of stay; Pancreaticoduodenectomy; Cost; Epidural analgesia; Weekday ID INTERNATIONAL STUDY-GROUP; PANCREATIC RESECTION; OF-STAY; ROBOTIC PANCREATICODUODENECTOMY; CLINICAL PATHWAY; HOSPITAL VOLUME; UNITED-STATES; SURGERY; READMISSION; INSTITUTION AB Despite the decreasing mortality of pancreaticoduodenectomy (PD), it continues to be associated with prolonged length of postoperative hospital stay (LOS). This study aimed to determine factors that could predict short LOS after PD. Additionally, as preliminary data of minimally invasive PD emerges, we sought to determine the average LOS after open PD at a high-volume center to set a standard to which minimally invasive PD can be compared. A total of 634 consecutive patients who underwent open PD between January 2007 and December 2012 at the Massachusetts General Hospital comprised the study cohort. "High performers" were defined as patients with postoperative LOS a parts per thousand currency sign5 days. Median LOS was 7 days. A total of 61 patients (9.6 %) had LOS a parts per thousand currency sign5 days and were deemed "high performing." In multivariate logistic regression analysis, male gender (p = 0.032), neoadjuvant chemoradiation (p = 0.001), epidural success (p = 0.019), epidural duration a parts per thousand currency sign3 days (p = 0.001), lack of complications (p < 0.001), surgery on Thursday or Friday (p = 0.001), and discharge on Monday through Wednesday (p < 0.001) were independently associated with LOS a parts per thousand currency sign5 days. Readmission rate, time to readmission, and mortality were not different between the two groups. The proportion of patients with pancreatic ductal adenocarcinoma who went on to receive adjuvant therapy was no different if LOS was a parts per thousand currency sign5 or > 5 days, but high performance was predictive of beginning therapy < 8 weeks after surgery (p = 0.010). In our experience, median LOS was 7 days, and early discharge (a parts per thousand currency sign5 days) after open PD is safe and feasible in about 10 % of patients. These high performers are more likely to be male, have received neoadjuvant therapy, and had successful epidural analgesia. High performers with cancer are more likely to start chemotherapy < 8 weeks after surgery. Minimally invasive PD should be compared to this high standard for median LOS, among other quality metrics, to justify its increased cost, operative duration, and learning curve. C1 [Lee, Grace C.; Fong, Zhi Ven; Ferrone, Cristina R.; Thayer, Sarah P.; Warshaw, Andrew L.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM cfernandez@partners.org NR 46 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1760 EP 1769 DI 10.1007/s11605-014-2604-3 PG 10 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000006 PM 25091843 ER PT J AU Spiegel, BMR Kaneshiro, M Russell, MM Lin, A Patel, A Tashjian, VC Zegarski, V Singh, D Cohen, SE Reid, MW Whitman, CB Talley, J Martinez, BM Kaiser, W AF Spiegel, Brennan M. R. Kaneshiro, Marc Russell, Marcia M. Lin, Anne Patel, Anish Tashjian, Vartan C. Zegarski, Vincent Singh, Digvijay Cohen, Samuel E. Reid, Mark W. Whitman, Cynthia B. Talley, Jennifer Martinez, Bibiana M. Kaiser, William TI Validation of an Acoustic Gastrointestinal Surveillance Biosensor for Postoperative Ileus SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Postoperative Ileus; Biosensor; Health technology ID SURGERY; METAANALYSIS; RECOVERY; PATTERNS; TRIALS; SOUNDS AB Postoperative ileus (POI) can worsen outcomes, increase cost, and prolong hospitalization. An objective marker could help identify POI patients who should not be prematurely fed. We developed a disposable, non-invasive acoustic gastro-intestinal surveillance (AGIS) biosensor. We tested whether AGIS can distinguish healthy controls from patients recovering from abdominal surgery. AGIS is a disposable plastic device embedded with a microphone that adheres to the abdominal wall and connects to a computer that measures acoustic event rates. We compared intestinal rates of healthy subjects using AGIS for 60 min after a standardized meal to recordings of two postoperative groups: (1) patients tolerating standardized feeding and (2) POI patients. We compared intestinal rates among groups using ANOVA and t tests. There were 8 healthy controls, 7 patients tolerating feeding, and 25 with POI; mean intestinal rates were 0.14, 0.03, and 0.016 events per second, respectively (ANOVA p < 0.001). AGIS separated patients from controls with 100 % sensitivity and 97 % specificity. Among patients, rates were higher in fed versus POI subjects (p = 0.017). Non-invasive, abdominal acoustic monitoring distinguishes POI from non-POI subjects. Future research will test whether AGIS can identify patients at risk for development of POI and assist with postoperative feeding decisions. C1 [Russell, Marcia M.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Spiegel, Brennan M. R.; Kaneshiro, Marc; Patel, Anish; Cohen, Samuel E.; Reid, Mark W.; Talley, Jennifer] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Zegarski, Vincent; Singh, Digvijay; Kaiser, William] UCLA Wireless Hlth Inst, Henry Samueli Sch Engn & Appl Sci, Los Angeles, CA USA. [Russell, Marcia M.; Lin, Anne] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.; Kaneshiro, Marc; Tashjian, Vartan C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.; Patel, Anish; Cohen, Samuel E.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Spiegel, Brennan M. R.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Spiegel, Brennan M. R.; Reid, Mark W.; Whitman, Cynthia B.; Talley, Jennifer; Martinez, Bibiana M.] UCLA VA Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. [Spiegel, Brennan M. R.] West Los Angeles VA Med Ctr, Div Gastroenterol, Los Angeles, CA 90073 USA. [Kaiser, William] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90024 USA. RP Spiegel, BMR (reprint author), West Los Angeles VA Med Ctr, Div Gastroenterol, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu; kaiser@ee.ucla.edu NR 21 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1795 EP 1803 DI 10.1007/s11605-014-2597-y PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000010 PM 25091837 ER PT J AU Fisichella, PM Patti, MG AF Fisichella, P. Marco Patti, Marco G. TI From Heller to POEM (1914-2014): A 100-Year History of Surgery for Achalasia SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Review DE Achalasia; Heller myotomy; Laparoscopic myotomy; Thoracoscopic myotomy; Dor fundoplication; Toupet fundoplication; Surgical treatment of achalasia; POEM ID ENDOSCOPIC MYOTOMY POEM; LONG-TERM OUTCOMES; ESOPHAGEAL ACHALASIA; DOR FUNDOPLICATION; SURGICAL-TREATMENT; CARDIOSPASM; ESOPHAGOMYOTOMY; OPERATION AB The year 2014 marks the 100th anniversary of Dr. Heller's description of the surgical treatment of patients with achalasia with a cardiomyotomy. This 100-year-old operation, which is today performed laparoscopically with the addition of a partial fundoplication, is considered the treatment of choice for patients with achalasia. Our goals are to revisit the accounts from the beginning of the twentieth century in which surgeons tried to identify the pathophysiology of achalasia and proposed several operative techniques and to follow the evolution of the surgical treatment until modern days. C1 [Fisichella, P. Marco] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, Boston, MA 02132 USA. [Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Dept Surg, Ctr Esophageal Dis, Chicago, IL 60637 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM piero.fisichella@va.gov NR 44 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1870 EP 1875 DI 10.1007/s11605-014-2547-8 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000020 PM 24878993 ER PT J AU Fisichella, PM AF Fisichella, P. Marco TI The Importance of Evidence to Validate Clinical Practice and Its Significance in Making Recommendations SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Letter C1 Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, Boston, MA 02132 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM piero.fisichella@va.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1882 EP 1882 DI 10.1007/s11605-014-2595-0 PG 1 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000024 PM 25091836 ER PT J AU Horn, DM Sequist, TD AF Horn, Daniel M. Sequist, Thomas D. TI The Impact of Cost Displays on Ordering SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Letter C1 [Horn, Daniel M.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Sequist, Thomas D.] Partners Healthcare Syst, Boston, MA USA. RP Horn, DM (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1332 EP 1332 DI 10.1007/s11606-014-2945-3 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900007 PM 24990245 ER PT J AU Steinman, MA Miao, YH Boscardin, WJ Komaiko, KDR Schwartz, JB AF Steinman, Michael A. Miao, Yinghui Boscardin, W. John Komaiko, Kiya D. R. Schwartz, Janice B. TI Prescribing Quality in Older Veterans: A Multifocal Approach SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE quality assessment; pharmacoepidemiology; veterans; geriatrics ID ADVERSE DRUG-REACTIONS; POTENTIALLY INAPPROPRIATE MEDICATION; DISEASE INTERACTIONS; ELDERLY VETERANS; ADULTS; RISK; PEOPLE; FRAIL; CARE; POLYPHARMACY AB Quality prescribing for older adults involves multiple considerations. We evaluated multiple aspects of prescribing quality in older veterans to develop an integrated view of prescribing problems and to understand how the prevalence of these problems varies across clinically important subgroups of older adults. Cross-sectional observational study of veterans age 65 years and older who received medications from Department of Veterans Affairs (VA) pharmacies in 2007. Using VA pharmacy data linked with encounter, laboratory and other data, we assessed five types of prescribing problems. Among 462,405 patients age 65 and older, mean age was 75 years, 98 % were male, and patients were prescribed a median of five medications. Half of patients (50 %) had one or more prescribing problems, including 12 % taking one or more medications at an inappropriately high dose, 30 % with drug-drug interactions, 3 % with drug-disease interactions, and 26 % taking one or more Beers criteria drugs. In addition, 16 % were taking a high-risk drug (warfarin, insulin, and/or digoxin). On multivariable analysis, age was not strongly associated with four of the five types of prescribing issues assessed (relative risk < 1.3 across age groups), and comorbid burden conferred substantially increased risk only for drug-disease interactions and use of high-risk drugs. In contrast, the number of drugs used was consistently the strongest predictor of prescribing problems. Patients in the highest quartile of medication use had 6.6-fold to12.5-fold greater risk of each type of prescribing problem compared to patients in the lowest quartile (P < 0.001 for each). The number of medications used is by far the strongest risk factor for each of five types of prescribing problems. Efforts to improve prescribing should especially target patients taking multiple medications. C1 [Steinman, Michael A.; Miao, Yinghui; Boscardin, W. John; Komaiko, Kiya D. R.; Schwartz, Janice B.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94141 USA. [Steinman, Michael A.; Miao, Yinghui; Boscardin, W. John; Komaiko, Kiya D. R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94141 USA. [Schwartz, Janice B.] Jewish Home San Francisco, San Francisco, CA USA. RP Steinman, MA (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,VA Box 181G, San Francisco, CA 94141 USA. EM Mike.steinman@ucsf.edu FU NIA NIH HHS [K23 AG030999, RC1-AG036377, RC1 AG036377, P30 AG044281, 1 K23-AG030999] NR 44 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1379 EP 1386 DI 10.1007/s11606-014-2924-8 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900014 PM 25002159 ER PT J AU Jena, AB DePasse, JW Prasad, V AF Jena, Anupam B. DePasse, Jacqueline W. Prasad, Vinay TI The Declining Demand for Hospital Care as a Rationale for Duty Hour Reform SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID INTERNS; TIME AB The regulation of duty hours of physicians in training remains among the most hotly debated subjects in medical education. Although recent duty hour reforms have been chiefly motivated by concerns about resident well-being and medical errors attributable to resident fatigue, the debate surrounding duty hour reform has infrequently involved discussion of one of the most important secular changes in hospital care that has affected nearly all developed countries over the last 3 decades: the declining demand for hospital care. For example, in 1980, we show that resident physicians in US teaching hospitals provided, on average, 1,302 inpatient days of care per resident physician compared to 593 inpatient days in 2011, a decline of 54 %. This decline in the demand for hospital care by residents provides an under-recognized economic rationale for reducing residency duty hours, a rationale based solely on supply and demand considerations. Work hour reductions and growing requirements for outpatient training can be seen as an appropriate response to the shrinking demand for hospital care across the health-care sector. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] NBER, Cambridge, MA 02138 USA. [Jena, Anupam B.; DePasse, Jacqueline W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.; DePasse, Jacqueline W.; Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu OI Prasad, Vinay/0000-0002-6110-8221 FU NIH HHS [DP5 OD017897, 1DP5OD017897-01] NR 9 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1400 EP 1403 DI 10.1007/s11606-014-2901-2 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900021 PM 24866469 ER PT J AU Edwards, ST Abrams, MK Baron, RJ Berenson, RA Rich, EC Rosenthal, GE Rosenthal, MB Landon, BE AF Edwards, Samuel T. Abrams, Melinda K. Baron, Richard J. Berenson, Robert A. Rich, Eugene C. Rosenthal, Gary E. Rosenthal, Meredith B. Landon, Bruce E. TI Structuring Payment to Medical Homes After the Affordable Care Act SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID ACCOUNTABLE CARE; INNOVATION PROFILE; SYSTEM REFORM; HEALTH; SAVINGS; ORGANIZATION; MODEL; COST AB The Patient-Centered Medical Home (PCMH) is a leading model of primary care reform, a critical element of which is payment reform for primary care services. With the passage of the Affordable Care Act, the Accountable Care Organization (ACO) has emerged as a model of delivery system reform, and while there is theoretical alignment between the PCMH and ACOs, the discussion of physician payment within each model has remained distinct. Here we compare payment for medical homes with that for accountable care organizations, consider opportunities for integration, and discuss implications for policy makers and payers considering ACO models. The PCMH and ACO are complementary approaches to reformed care delivery: the PCMH ultimately requires strong integration with specialists and hospitals as seen under ACOs, and ACOs likely will require a high functioning primary care system as embodied by the PCMH. Aligning payment incentives within the ACO will be critical to achieving this integration and enhancing the care coordination role of primary care in these settings. C1 [Edwards, Samuel T.] Vet Affairs VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Edwards, Samuel T.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Edwards, Samuel T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Abrams, Melinda K.] Commonwealth Fund, New York, NY USA. [Baron, Richard J.] Amer Board Internal Med, Philadelphia, PA USA. [Berenson, Robert A.] Urban Inst, Washington, DC 20037 USA. [Rich, Eugene C.] Mathemat Policy Res, Washington, DC USA. [Rosenthal, Gary E.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Rosenthal, Gary E.] Iowa City VA Hlth Care Syst, Iowa City, IA USA. [Rosenthal, Meredith B.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Landon, Bruce E.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Landon, Bruce E.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Landon, BE (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM landon@hcp.med.harvard.edu OI Rosenthal, Meredith/0000-0003-3410-0184 NR 25 TC 16 Z9 16 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1410 EP 1413 DI 10.1007/s11606-014-2848-3 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900023 PM 24687292 ER PT J AU Pober, BR AF Pober, B. R. TI OVERVIEW OF WILLIAMS SYNDROME SO JOURNAL OF INTELLECTUAL DISABILITY RESEARCH LA English DT Meeting Abstract DE microdeletion; intellectual disability; anxiety; diabetes; vascular stenosis C1 [Pober, B. R.] Quinnipiac Univ, Netter Sch Med, Dept Med Sci, North Haven, CT USA. [Pober, B. R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Pober, B. R.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0964-2633 EI 1365-2788 J9 J INTELL DISABIL RES JI J. Intell. Disabil. Res. PD OCT PY 2014 VL 58 IS 10 BP 890 EP 891 PG 2 WC Education, Special; Genetics & Heredity; Clinical Neurology; Psychiatry; Rehabilitation SC Education & Educational Research; Genetics & Heredity; Neurosciences & Neurology; Psychiatry; Rehabilitation GA AP5YA UT WOS:000342153400032 ER PT J AU Luo, S Tsao, H AF Luo, Su Tsao, Hensin TI Epidermal, Sebaceous, and Melanocytic Nevoid Proliferations Are Spectrums of Mosaic RASopathies SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID ACTIVATING HRAS MUTATION; NEVUS SEBACEUS; PHAKOMATOSIS PIGMENTOKERATOTICA; POSTZYGOTIC HRAS; RAS MUTATIONS; SPILUS; KRAS AB Growing evidence demonstrates that various nevoid proliferations such as keratinocytic epidermal nevi and nevus sebaceous result from somatic mosaicism. Many of the mutations identified have been within the RAF/RAS/MAPK pathway, hence supporting the previously introduced term "mosaic RASopathy" for these nevi. In this issue, Kinsler et al. were among the first to characterize certain pigmented melanocytic nevi that may also fit this paradigm. To better frame these findings, we provide a summary of the analogous genotypic profiles for epidermal and melanocytic nevi from recent studies. C1 [Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St,Edwards 202A, Boston, MA 02114 USA. EM htsao@partners.org NR 17 TC 7 Z9 7 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2014 VL 134 IS 10 BP 2493 EP 2496 DI 10.1038/jid.2014.244 PG 5 WC Dermatology SC Dermatology GA AP6PT UT WOS:000342200400009 PM 25219651 ER PT J AU Hess, AT van der Kouwe, AJW Mbugua, KK Laughton, B Meintjes, EM AF Hess, Aaron T. van der Kouwe, Andre J. W. Mbugua, Kenneth K. Laughton, Barbara Meintjes, Ernesta M. TI Quality of 186 Child Brain Spectra Using Motion and B0 Shim Navigated Single Voxel Spectroscopy SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE single voxel spectroscopy; motion correction; B0 correction; navigator ID MAGNETIC-RESONANCE-SPECTROSCOPY; H-1 MR SPECTROSCOPY; SIGNAL LOSS; QUANTITATION; ARTIFACTS; FREQUENCY; INFANTS AB Purpose: To evaluate B0 shim and motion navigated single voxel spectroscopy in children. Assess the repeatability of metabolite concentrations in three regions: medial frontal grey matter, peritrigonal white matter, and basal ganglia. Determine the extent of intra-and interacquisition movement in this population. Methods: Linewidth and signal to noise ratio were calculated to assess spectral quality of 186 spectra at 3 Tesla. Repeatability was assessed on 31 repeat scans. Navigator images were used to assess localization errors, while navigator motion and shim logs were used to demonstrate the efficacy of correction needed during the scans. Results: Average linewidths +/- standard deviations of N-acetyl aspartate are 3.8 +/- 0.6 Hz, 4.4 +/- 0.5 Hz, and 4.7 6 0.8 Hz in each region, respectively. Scan-to-scan measurement variance in metabolite concentrations closely resembled the expected variance. A total of 73% and 32% of children moved before and during the acquisition, causing a voxel shift of more than 10% of the voxel volume, 1.5 mm. The predominant movement directions were sliding out of the coil and nodding (up-down rotation). First-order B0 corrections were significant (>10 mT/m) in 18 % of acquisitions. Conclusion: Prospective motion and B0 correction provides high quality repeatable spectra. The study found that most children moved between acquisitions and a substantial number moved during acquisitions. C1 [Hess, Aaron T.] Univ Oxford, Oxford Ctr Clin Magnet Resonance Res OCMR, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [van der Kouwe, Andre J. W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mbugua, Kenneth K.; Meintjes, Ernesta M.] Univ Cape Town, MRC UCT Med Imaging Res Unit, Dept Human Biol, ZA-7700 Rondebosch, South Africa. [Laughton, Barbara] Univ Stellenbosch, Childrens Infect Dis Clin Res Unit, Dept Paediat & Child Hlth, Cape Town, South Africa. [Laughton, Barbara] Tygerberg Hosp, Cape Town, South Africa. RP Hess, AT (reprint author), John Radcliffe Hosp, OCMR, Level 0,Headley Way, Oxford OX3 9DU, England. EM aaron.hess@cardiov.ox.ac.uk RI Laughton, Barbara/Q-3496-2016; OI Laughton, Barbara/0000-0001-7260-7723; Hess, Aaron/0000-0002-9289-5619 FU NIH [R21AA017410, R21MH096559, R01HD071664, U19A153217]; NRF [CPR20110614000019421] FX Contract grant sponsor: NIH; Contract grant number: R21AA017410; Contract grant number: R21MH096559; Contract grant number: R01HD071664; Contract grant number: U19A153217; Contract grant sponsor: NRF; Contract grant number: CPR20110614000019421. NR 25 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2014 VL 40 IS 4 BP 958 EP 965 DI 10.1002/jmri.24436 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8QA UT WOS:000342342500025 PM 24924772 ER PT J AU Yoshida, T Friehs, I Mummidi, S del Nido, PJ Addulnour-Nakhoul, S Delafontaine, P Valente, AJ Chandrasekar, B AF Yoshida, Tadashi Friehs, Ingeborg Mummidi, Srinivas del Nido, Pedro J. Addulnour-Nakhoul, Solange Delafontaine, Patrice Valente, Anthony J. Chandrasekar, Bysani TI Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-alpha-induced cardiomyocyte death SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Myocardial hypertrophy; Cardiac failure; Cyclical stretch; Interleukins; Inflammation ID NF-KAPPA-B; CARDIAC FIBROBLAST MIGRATION; STRETCH-INDUCED HYPERTROPHY; HEART-FAILURE; INTERLEUKIN-18 EXPRESSION; BINDING-PROTEIN; ACTIVATION; DYSFUNCTION; INDUCTION; APOPTOSIS AB Recurrent or sustained inflammation plays a causal role in the development and progression of left ventricular hypertrophy (LVH) and its transition to failure. Interleukin (IL)-18 is a potent pro-hypertrophic inflammatory cytokine. We report that induction of pressure overload in the rabbit, by constriction of the descending thoracic aorta induces compensatory hypertrophy at 4 weeks (mass/volume ratio: 1.7 +/- 0.11) and ventricular dilatation indicative of heart failure at 6 weeks (mass/volume ratio: 0.7 +/- 0.04). In concordance with this, fractional shortening was preserved at 4 weeks, but markedly attenuated at 6 weeks. We cloned rabbit IL-18, IL-18R alpha, IL-18R beta, and IL-18 binding protein (1-18BP) cDNA, and show that pressure overload, while enhancing IL-18 and IL-18R expression in hypertrophied and failing hearts, markedly attenuated the level of expression of the endogenous IL-18 antagonist IL-18BP. Cyclical mechanical stretch (10% cyclic equibiaxial stretch, 1 Hz) induced hypertrophy of primary rabbit cardiomyocytes in vitro and enhanced ANP, IL-18, and IL-18Ra expression. Further, treatment with rhIL-18 induced its own expression and that of IL-18Ra via AP-1 activation, and induced cardiomyocyte hypertrophy in part via PI3K/Akt/GATA4 signaling. In contrast, IL-18 potentiated TNF-alpha-induced cardiomyocyte death, and by itself induced cardiac endothelial cell death. These results demonstrate that pressure overload is associated with enhanced IL-18 and its receptor expression in hypertrophied and failingrabbit hearts. Since IL-18BP expression is markedly inhibited, our results indicate a positive amplification in IL-18 proinflammatory signaling during pressure overload, and suggest IL-18 as a potential therapeutic target in pathological hypertrophy and cardiac failure. Published by Elsevier Ltd. C1 [Yoshida, Tadashi; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Friehs, Ingeborg; del Nido, Pedro J.; Valente, Anthony J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Cardiac Surg, Boston, MA 02115 USA. [Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Addulnour-Nakhoul, Solange] Tulane Univ, Sch Med, Dept Med Gastroenterol, New Orleans, LA 70112 USA. [Addulnour-Nakhoul, Solange; Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA 70161 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave,SL-48, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Yoshida, Tadashi/0000-0002-4544-1497 FU U.S. Department of Veterans Affairs, Office of Research and Development Biomedical Laboratory Research and Development (ORD-BLRD) Service Award [1IO1BX000246]; NIH/National Heart, Lung, and Blood Institute Grant [HL-86787, HL-075430, HL-70241, HL-80682]; Veterans Affairs ORD-BLRD Service Award [I01BX000975]; NIH/NIGMS Tulane COBRE Pilot Project [P20GM103629] FX This work was supported by the U.S. Department of Veterans Affairs, Office of Research and Development Biomedical Laboratory Research and Development (ORD-BLRD) Service Award 1IO1BX000246 and the NIH/National Heart, Lung, and Blood Institute Grant HL-86787 (to BC), HL-075430 (IF), and HL-70241 and HL-80682 (PD). SM is supported by Veterans Affairs ORD-BLRD Service Award I01BX000975. TV is supported by a NIH/NIGMS Tulane COBRE Pilot Project (P20GM103629). The contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government. NR 41 TC 7 Z9 8 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD OCT PY 2014 VL 75 BP 141 EP 151 DI 10.1016/j.yjmcc.2014.07.007 PG 11 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AP7QL UT WOS:000342271700015 PM 25108227 ER PT J AU Vranceanu, AM Merker, VL Plotkin, SR Park, ER AF Vranceanu, Ana-Maria Merker, Vanessa L. Plotkin, Scott R. Park, Elyse R. TI The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Relaxation response; Mind-body therapies; Neurofibromatoses; Psychological resilience ID PAIN CATASTROPHIZING SCALE; EPWORTH SLEEPINESS SCALE; VALIDATION; LIFE; SUPPORT; MODEL AB NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH's Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48 % rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5 %) and only 16 completed it (50 %), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80 % completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73-1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54-0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial. C1 [Vranceanu, Ana-Maria; Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Vranceanu, Ana-Maria; Merker, Vanessa L.; Plotkin, Scott R.; Park, Elyse R.] Harvard Univ, Sch Med, Boston, MA USA. [Vranceanu, Ana-Maria; Park, Elyse R.] MGH Benson Henry Inst Mind Body Med, Boston, MA USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM avranceanu@partners.org OI Merker, Vanessa/0000-0002-4542-5227 NR 25 TC 9 Z9 9 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2014 VL 120 IS 1 BP 103 EP 109 DI 10.1007/s11060-014-1522-2 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AQ0EW UT WOS:000342456600011 PM 25022450 ER PT J AU Gandhi, CD Bulsara, KR Fifi, J Kass-Hout, T Grant, RA Almandoz, JED English, J Meyers, PM Abruzzo, T Prestigiacomo, CJ Powers, CJ Lee, SK Albani, B Do, HM Eskey, CJ Patsalides, A Hetts, S Hussain, MS Ansari, SA Hirsch, JA Kelly, M Rasmussen, P Mack, W Pride, GL Alexander, MJ Jayaraman, MV AF Gandhi, Chirag D. Bulsara, Ketan R. Fifi, Johanna Kass-Hout, Tareq Grant, Ryan A. Almandoz, Josser E. Delgado English, Joey Meyers, Philip M. Abruzzo, Todd Prestigiacomo, Charles J. Powers, Ciaran James Lee, Seon-Kyu Albani, Barbara Do, Huy M. Eskey, Clifford J. Patsalides, Athos Hetts, Steven Hussain, M. Shazam Ansari, Sameer A. Hirsch, Joshua A. Kelly, Michael Rasmussen, Peter Mack, William Pride, G. Lee Alexander, Michael J. Jayaraman, Mahesh V. CA SNIS Stand Guidelines Comm TI Platelet function inhibitors and platelet function testing in neurointerventional procedures SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID PIPELINE EMBOLIZATION DEVICE; PERCUTANEOUS CORONARY INTERVENTION; SINGLE-CENTER EXPERIENCE; UNRUPTURED INTRACRANIAL ANEURYSMS; LIGHT TRANSMISSION AGGREGOMETRY; GLYCOPROTEIN IIB/IIIA RECEPTOR; TRANSIENT ISCHEMIC ATTACK; DUAL ANTIPLATELET THERAPY; PLACEBO-CONTROLLED TRIAL; OF-CARE DEVICE C1 [Gandhi, Chirag D.; Kass-Hout, Tareq; Prestigiacomo, Charles J.] Rutgers State Univ, NJ Med Sch, Dept Neurosurg, Newark, NJ 07102 USA. [Bulsara, Ketan R.; Grant, Ryan A.] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Fifi, Johanna] Columbia Univ, St Lukes Roosevelt Hosp Ctr, Hyman Newman Inst Neurol & Neurosurg New York, New York, NY USA. [Almandoz, Josser E. Delgado] Abbott NW Hosp, Dept Intervent Neuroradiol, Minneapolis, MN 55407 USA. [English, Joey] UCSF, Dept Neurol & Radiol, San Francisco, CA USA. [Meyers, Philip M.] Columbia Presbyterian Med Ctr, Dept Neurointervent Surg, New York, NY USA. [Abruzzo, Todd] Univ Cincinnati, Dept Neurosurg, Cincinnati, OH USA. [Powers, Ciaran James] Wexner Med Ctr, Dept Neurosurg, Columbus, OH USA. [Lee, Seon-Kyu] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Albani, Barbara] Christiana Care Hlth Syst, Dept Neurointervent Surg, Newark, DE USA. [Do, Huy M.] Stanford Univ, Dept Neurosurg & Radiol, Stanford, CA 94305 USA. [Eskey, Clifford J.] Dartmouth Hitchcock Med Ctr, Dept Radiol Neurol & Neurosurg, Lebanon, NH 03766 USA. [Patsalides, Athos] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Neurol Surg, New York, NY USA. [Hetts, Steven] WUCSF, Dept Radiol, San Francisco, CA USA. [Hussain, M. Shazam] Cleveland Clin, Stroke Program, Cleveland Hts, OH USA. [Ansari, Sameer A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, NeuroEndovasc Program, Boston, MA 02114 USA. [Kelly, Michael] Univ Saskatchewan, Royal Univ Hosp, Dept Neurosurg, Saskatoon, SK, Canada. [Rasmussen, Peter] Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. [Mack, William] Univ So Calif, Dept Neurosurg, Los Angeles, CA USA. [Pride, G. Lee] UT Southwestern, Dept Neuroradiol, Dallas, TX USA. [Alexander, Michael J.] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA. [Jayaraman, Mahesh V.] Brown Univ, Warren Alpert Sch, Providence, RI 02912 USA. RP Gandhi, CD (reprint author), Rutgers State Univ, NJ Med Sch, Dept Neurosurg, Newark, NJ 07102 USA. EM gandhich@rutgers.edu RI Powers, Ciaran/E-3890-2011; OI Alexander, Michael/0000-0003-0280-809X NR 157 TC 5 Z9 5 U1 1 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD OCT PY 2014 VL 6 IS 8 BP 567 EP 577 DI 10.1136/neurintsurg-2014-011357 PG 11 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AQ1FX UT WOS:000342528400002 PM 25056369 ER PT J AU Zaidat, OO Castonguay, AC Gupta, R Sun, CHJ Martin, C Holloway, WE Mueller-Kronast, N English, JD Linfante, I Dabus, G Malisch, TW Marden, FA Bozorgchami, H Xavier, A Rai, AT Froehler, MT Badruddin, A Nguyen, TN Taqi, MA Abraham, MG Janardhan, V Shaltoni, H Novakovic, R Yoo, AJ Abou-Chebl, A Chen, PR Britz, GW Kaushal, R Nanda, A Issa, MA Nogueira, RG AF Zaidat, Osama O. Castonguay, Alicia C. Gupta, Rishi Sun, Chung-Huan J. Martin, Coleman Holloway, William E. Mueller-Kronast, Nils English, Joey D. Linfante, Italo Dabus, Guilherme Malisch, Tim W. Marden, Franklin A. Bozorgchami, Hormozd Xavier, Andrew Rai, Ansaar T. Froehler, Michael T. Badruddin, Aamir Nguyen, Thanh N. Taqi, M. Asif Abraham, Michael G. Janardhan, Vallabh Shaltoni, Hashem Novakovic, Roberta Yoo, Albert J. Abou-Chebl, Alex Chen, Peng R. Britz, Gavin W. Kaushal, Ritesh Nanda, Ashish Issa, Mohammad A. Nogueira, Raul G. TI North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID ACUTE ISCHEMIC-STROKE; ENDOVASCULAR TREATMENT; RETROSPECTIVE MULTICENTER; MECHANICAL THROMBECTOMY; ARTERY OCCLUSIONS; THERAPY; TRIAL; EXPERIENCE; DEVICE; SYSTEM AB Background Limited post-marketing data exist on the use of the Solitaire FR device in clinical practice. The North American Solitaire Stent Retriever Acute Stroke (NASA) registry aimed to assess the real world performance of the Solitaire FR device in contrast with the results from the SWIFT (Solitaire with the Intention for Thrombectomy) and TREVO 2 (Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischemic stroke) trials. Methods The investigator initiated NASA registry recruited North American sites to submit retrospective angiographic and clinical outcome data on consecutive acute ischemic stroke (AIS) patients treated with the Solitaire FR between March 2012 and February 2013. The primary outcome was a Thrombolysis in Myocardial Ischemia (TIMI) score of >= 2 or a Treatment in Cerebral Infarction (TICI) score of >= 2a. Secondary outcomes were 90 day modified Rankin Scale (mRS) score, mortality, and symptomatic intracranial hemorrhage. Results 354 patients underwent treatment for AIS using the Solitaire FR device in 24 centers. Mean time from onset to groin puncture was 363.4 +/- 239 min, mean fluoroscopy time was 32.9 +/- 25.7 min, and mean procedure time was 100.9 +/- 57.8 min. Recanalization outcome: TIMI >= 2 rate of 83.3% (315/354) and TICI >= 2a rate of 87.5% (310/354) compared with the operator reported TIMI >= 2 rate of 83% in SWIFT and TICI >= 2a rate of 85% in TREVO 2. Clinical outcome: 42% (132/315) of NASA patients demonstrated a 90 day mRS <= 2 compared with 37% (SWIFT) and 40% (TREVO 2). 90 day mortality was 30.2% (95/315) versus 17.2% (SWIFT) and 29% (TREVO 2). Conclusions The NASA registry demonstrated that the Solitaire FR device performance in clinical practice is comparable with the SWIFT and TREVO 2 trial results. C1 [Zaidat, Osama O.; Castonguay, Alicia C.; Issa, Mohammad A.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Neurol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Neurosurg, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Radiol, Milwaukee, WI 53226 USA. [Gupta, Rishi; Sun, Chung-Huan J.; Nogueira, Raul G.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Martin, Coleman; Holloway, William E.] St Lukes Kansas City, Kansas City, MO USA. [Mueller-Kronast, Nils] Delray Med Ctr, Dept Neurol, Delray Beach, FL USA. [English, Joey D.] Calif Pacific Med Ctr, San Francisco, CA USA. [Linfante, Italo; Dabus, Guilherme] Baptist Cardiac & Vasc Inst, Div Intervent Neuroradiol, Miami, FL USA. [Malisch, Tim W.; Marden, Franklin A.] Alexian Bros Med Ctr, Elk Grove Village, IL USA. [Bozorgchami, Hormozd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Xavier, Andrew] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Rai, Ansaar T.] West Virginia Univ Hosp, Dept Radiol, Morgantown, WV USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Neurosurg, Nashville, TN USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Radiol, Nashville, TN 37232 USA. [Badruddin, Aamir] Provena St Joseph Med Ctr, Joliet, IL USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Neurol, Boston, MA USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Neurosurg, Boston, MA USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Radiol, Boston, MA USA. [Taqi, M. Asif] Desert Reg Med Ctr, Palm Springs, CA USA. [Abraham, Michael G.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Janardhan, Vallabh] Texas Stroke Inst, Plano, TX USA. [Shaltoni, Hashem] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Novakovic, Roberta] UT Southwestern Med Ctr, Dept Radiol, Dallas, TX USA. [Novakovic, Roberta] UT Southwestern Med Ctr, Dept Neurol, Dallas, TX USA. [Yoo, Albert J.] Massachusetts Gen Hosp, Dept Radiol, Div Diagnost & Intervent Neuroradiol, Boston, MA 02114 USA. [Abou-Chebl, Alex] Univ Louisville, Sch Med, Dept Neurol, Louisville, KY 40292 USA. [Chen, Peng R.] Univ Texas Houston, Houston, TX USA. [Britz, Gavin W.] Methodist Neurol Inst, Dept Neurosurg, Houston, TX USA. [Kaushal, Ritesh] St Louis Univ, St Louis, MO 63103 USA. [Nanda, Ashish] Univ Missouri, Columbia, MO USA. RP Zaidat, OO (reprint author), Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Neurointervent Div, Dept Neurol, Milwaukee, WI 53226 USA. EM szaidat@mcw.edu NR 16 TC 39 Z9 39 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD OCT PY 2014 VL 6 IS 8 BP 584 EP 588 DI 10.1136/neurintsurg-2013-010895 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AQ1FX UT WOS:000342528400004 PM 24062252 ER PT J AU Smith, BA Jacobs, JV Horak, FB AF Smith, Beth A. Jacobs, Jesse V. Horak, Fay B. TI Effects of Amplitude Cueing on Postural Responses and Preparatory Cortical Activity of People With Parkinson Disease SO JOURNAL OF NEUROLOGIC PHYSICAL THERAPY LA English DT Article DE cueing; contingent negative variation; electroencephalography; event-related desynchronization; Parkinson disease; postural responses ID CEREBRAL-CORTEX; MOTOR; SET; INSTABILITY; SYNCHRONIZATION; INTEGRATION; POTENTIALS; DYNAMICS; STRATEGY; BALANCE AB Background and Purpose: Persons with Parkinson disease (PD) are unable to modify their postural responses, and show an associated increase in cortical preparatory activity for anticipated postural perturbations.(1) In this study we asked whether participants with PD could modify their postural responses and cortical preparatory activity when cued to focus on increasing movement amplitude before a series of predictable postural perturbations. Methods: Twelve participants with PD performed postural responses to 30 identical backward surface translations. We cued participants to focus on increasing movement amplitude, and examined the effects of cueing by measuring postural responses (center-of-pressure initial rate of change, automatic postural response stability, peak trunk flexion, peak ankle extension) and preparatory cortical activity (electroencephalographic measures of contingent negative variation, alpha and beta event-related desynchronization). Results: Participants with PD modified their postural responses during the amplitude trials by increasing trunk flexion, slowing center-of-pressure initial rate of change, and decreasing automatic postural response stability. However, no significant differences in contingent negative variation amplitude or alpha or beta event-related desynchronization were observed with versus without amplitude cueing. Discussion and Conclusions: Persons with PD were able to modify their feet-in-place postural responses with amplitude cueing. These changes were not associated with changes in cortical preparation during amplitude cue trials, suggesting that other regions or measures of brain function were responsible for changes in postural responses. Future studies are needed to determine the effects of long-term amplitude-cueing practice on cortical preparation and postural stability. Video Abstract available. See Video (Supplemental Digital Content 1, http://links.1ww.com/JNPT/A78) for more insights from the authors. C1 [Smith, Beth A.] Univ So Calif, Div Biokinesiol & Phys Therapy, Infant Neuromotor Control Lab, Los Angeles, CA 90089 USA. [Jacobs, Jesse V.] Univ Vermont, Dept Rehabil & Movement Sci, Human Mot Anal Lab, Burlington, VT USA. [Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Balance Disorders Lab, Portland, OR 97201 USA. [Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Smith, BA (reprint author), Univ So Calif, Div Biokinesiol & Phys Therapy, 1540 Alcazar St,CHP 155, Los Angeles, CA 90089 USA. EM beth.smith@usc.edu RI Smith, Beth A./D-2914-2014 OI Smith, Beth A./0000-0003-2531-5394 FU National Institutes of Health, National Institute of Aging [R37 A60006457]; National Institutes of Health, National Institute of Child Health and Human Development [F32 HD070796]; Medical Research Foundation of Oregon; Foundation for Physical Therapy New Investigator Fellowship Training Initiative FX Supported by National Institutes of Health, National Institute of Aging R37 A60006457 (F.B.H.); National Institutes of Health, National Institute of Child Health and Human Development F32 HD070796 (B.A.S.), Medical Research Foundation of Oregon (B.A.S.), and the Foundation for Physical Therapy New Investigator Fellowship Training Initiative (B.A.S.). Funding sources provided funding only and did not influence the work. NR 46 TC 4 Z9 4 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1557-0576 EI 1557-0584 J9 J NEUROL PHYS THER JI J. Neurol. Phys. Ther. PD OCT PY 2014 VL 38 IS 4 BP 207 EP 215 DI 10.1097/NPT.0000000000000058 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA AQ1PN UT WOS:000342553400002 PM 25198870 ER PT J AU Peacock, ZS Lee, CCY Klein, KP Kaban, LB AF Peacock, Zachary S. Lee, Cameron C. Y. Klein, Katherine P. Kaban, Leonard B. TI Orthognathic Surgery in Patients Over 40 Years of Age: Indications and Special Considerations SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID SAGITTAL SPLIT OSTEOTOMY; SYMPTOMATIC PLATE REMOVAL; OBSTRUCTIVE SLEEP-APNEA; ALVEOLAR NERVE FUNCTION; FOLLOW-UP; MAXILLOMANDIBULAR ADVANCEMENT; NEUROSENSORY DISTURBANCE; RAMUS OSTEOTOMY; COMPLICATIONS; SATISFACTION AB Purpose: To assess indications, incidence, patient experience, and outcomes of orthognathic surgery in patients over 40 years of age. Patients and Methods: This was a retrospective cohort study of all patients who underwent orthognathic surgical procedures at Massachusetts General Hospital from 1995 to 2012. Demographic variables, including age, gender, indications, date, and type of operation, were documented. Patients were divided into 2 groups by date of operation: 1) 1995 to 2002 and 2) 2003 to 2012. The predictor variable was age (> 40 vs < 40 yr). Outcome variables included indications for treatment, date of operation, length of hospital stay, and removal of hardware. Results: During the study period, 1,420 patients underwent 2,170 procedures; 911 patients (1,343 procedures) met the inclusion criteria. Group 1 consisted of 260 subjects (346 procedures, 35 patients >= 40 yr old, 13.5%) and group 2 consisted of 651 subjects (997 procedures, 89 patients >= 40 yr old, 13.8%). Subjects over 40 had longer hospital stays (P <=. 0001) than those under 40. Indications for men were more frequently functional problems, whereas women sought esthetic improvements (P =.0001). Subjects over 40 were 2.51, 2.44, and 2.72 times more likely to require hardware removal 6 months (P =.0245), 12 months (P =.0073), and 24 months (P =.0003) postoperatively than those younger than 40. Conclusion: Motivation to undergo orthognathic surgery varies by age and gender. Older patients, particularly men, tend to seek treatment for functional rather than esthetic reasons. Patients older than 40 years had longer hospital stays and an increased rate of postoperative hardware removal. (C) 2014 American Association of Oral and Maxillofacial Surgeons C1 Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Lee, Cameron C. Y.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Peacock, ZS (reprint author), Massachusetts Gen Hosp, Warren 1201,55 Fruit St, Boston, MA 02114 USA. EM zpeacock@partners.org FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; Harvard Medical School Scholars in Medicine Program FX This work was funded by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund and the Harvard Medical School Scholars in Medicine Program. NR 37 TC 6 Z9 6 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 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2014 VL 72 IS 10 BP 1995 EP 2004 DI 10.1016/j.joms.2014.03.020 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AQ0IL UT WOS:000342466500020 PM 24836418 ER PT J AU Delpire, E Staley, KJ AF Delpire, Eric Staley, Kevin J. TI Novel determinants of the neuronal Cl- concentration SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Review ID CATION-CHLORIDE COTRANSPORTERS; ROOT GANGLION NEURONS; MAMMALIAN EPITHELIAL-CELLS; POSTNATAL RAT BRAINS; INTRACELLULAR CHLORIDE; NA+-K+-2CL(-) COTRANSPORTER; NA-K-2CL COTRANSPORTER; HIPPOCAMPAL-NEURONS; SYNAPTIC INHIBITION; CORTICAL-NEURONS AB It is now a well-accepted view that cation-driven Cl(-)transporters in neurons are involved in determining the intracellular Cl- concentration. In the present review, we propose that additional factors, which are often overlooked, contribute substantially to the Cl- gradient across neuronal membranes. After briefly discussing the data supporting and opposing the role of cation-chloride cotransporters in regulating Cl-, we examine the participation of the following factors in the formation of the transmembrane Cl- gradient: (i) fixed 'Donnan' charges inside and outside the cell; (ii) the properties of water (free vs. bound); and (iii) water transport through the cotransporters. We demonstrate a steep relationship between intracellular Cl- and the concentration of fixed negative charges on macromolecules. We show that in the absence of water transport through the K+-Cl- cotransporter, a large osmotic gradient builds at concentrations below or above a set value of 'Donnan' charges, and showthat at any value of these fixed charges, the reversal potential for Cl- equates that of K+. When the movement of water across the membrane is a source of free energy, it is sufficient to modify the movement of Cl- through the cotransporter. In this scenario, the reversal potential for Cl- does not closely follow that of K+. Furthermore, our simulations demonstrate that small differences in the availability of freely diffusible water between inside and outside the cell greatly affect the Cl- reversal potential, particularly when osmolar transmembrane gradients are minimized, for example by idiogenic osmoles. We also establish that the presence of extracellular charges has little effect on the chloride reversal potential, but greatly affects the effective inhibitory conductance for Cl-. In conclusion, our theoretical analysis of the presence of fixed anionic charges and water bound on macromolecules inside and outside the cell greatly impacts both Cl- gradient and Cl- conductance across neuronal membranes. C1 [Delpire, Eric] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Staley, Kevin J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Delpire, E (reprint author), Vanderbilt Univ, Sch Med, Dept Anesthesiol, MCNT 4202,1161 21st Ave South, Nashville, TN 37212 USA. EM eric.delpire@vanderbilt.edu FU National Institutes of Health [GM074771, DK093501, NS040109, NS074772] FX Support for the authors' research comes from the National Institutes of Health grants GM074771, DK093501 to E. D. and NS040109, NS074772 to K.J.S. NR 72 TC 11 Z9 11 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD OCT 1 PY 2014 VL 592 IS 19 BP 4099 EP 4114 DI 10.1113/jphysiol.2014.275529 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AQ0ZE UT WOS:000342510400002 PM 25107928 ER PT J AU Gorrindo, T Stock, SL AF Gorrindo, Tristan Stock, Saundra L. TI Bringing Education to the Bedside: A Primer on Continuing Medical Education (CME) and Maintenance of Certification (MOC) Requirements SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID BOARD C1 [Gorrindo, Tristan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gorrindo, Tristan] Harvard Univ, Sch Med, Boston, MA USA. [Stock, Saundra L.] Univ S Florida, Tampa, FL USA. RP Gorrindo, T (reprint author), MGH Psychiat, 1 Bowdoin Sq,Ste 700, Boston, MA 02114 USA. EM Tristan.Gorrindo@mgh.harvard.edu NR 7 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2014 VL 53 IS 10 BP 1042 EP 1044 DI 10.1016/j.jaac.2014.07.009 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AP9MO UT WOS:000342404100002 PM 25245345 ER PT J AU Groen-Blokhuis, MM Middeldorp, CM Kan, KJ Abdellaoui, A van Beijsterveldt, CEM Ehli, EA Davies, GE Scheet, PA Xiao, XJ Hudziak, JJ Hottenga, JJ Neale, B Boomsma, DI AF Groen-Blokhuis, Maria M. Middeldorp, Christel M. Kan, Kees-Jan Abdellaoui, Abdel van Beijsterveldt, Catharina E. M. Ehli, Erik A. Davies, Gareth E. Scheet, Paul A. Xiao, Xiangjun Hudziak, James J. Hottenga, Jouke-Jan Neale, Ben M. Boomsma, Dorret I. CA Psychiatric Genomics Consortium TI Attention-Deficit/Hyperactivity Disorder Polygenic Risk Scores Predict Attention Problems in a Population-Based Sample of Children SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; attention problems; polygenic scores; genetics; dimensional models ID DEFICIT HYPERACTIVITY DISORDER; NETHERLANDS TWIN REGISTER; GENOME-WIDE ASSOCIATION; DEVELOPMENTAL PSYCHOPATHOLOGY; LATENT CLASS; ADHD; HERITABILITY; CHILDHOOD; STABILITY; SYMPTOMS AB Objective: Clinically, attention-deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impulsivity, and inattention and is among the most common childhood disorders. These same traits that define ADHD are variable in the general population, and the clinical diagnosis may represent the extreme end of a continuous distribution of inattentive and hyperactive behaviors. This hypothesis can be tested by assessing the predictive value of polygenic risk scores derived from a discovery sample of ADHD patients in a target sample from the general population with continuous scores of inattention and hyperactivity. In addition, the genetic overlap between ADHD and continuous ADHD scores can be tested across rater and age. Method: The Psychiatric Genomics Consortium has performed the largest genome-wide analysis (GWA) study of ADHD so far, including 5,621 clinical patients and 13,589 controls. The effects sizes of single nucleotide polymorphisms (SNPs) estimated in this meta-analysis were used to obtain individual polygenic risk scores in an independent population-based cohort of 2,437 children from the Netherlands Twin Register. The variance explained in Attention Problems (AP) scale scores by the polygenic risk scores was estimated by linear mixed modeling. Results: The ADHD polygenic risk scores significantly predicted both parent and teacher ratings of AP in preschool- and school-aged children. Conclusion: These results indicate genetic overlap between a diagnosis of ADHD and AP scale scores across raters and age groups and provides evidence for a dimensional model of ADHD. Future GWA studies on ADHD can likely benefit from the inclusion of population-based cohorts and the analysis of continuous scores. C1 [Groen-Blokhuis, Maria M.; Middeldorp, Christel M.; Kan, Kees-Jan; Abdellaoui, Abdel; van Beijsterveldt, Catharina E. M.; Hottenga, Jouke-Jan; Boomsma, Dorret I.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Groen-Blokhuis, Maria M.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Middeldorp, Christel M.] Vrije Univ Amsterdam, Med Ctr, GGZinGeest, Amsterdam, Netherlands. [Ehli, Erik A.; Davies, Gareth E.] Avera Inst Human Genet, Sioux Falls, SD USA. [Scheet, Paul A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Xiao, Xiangjun] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Hudziak, James J.] Vermont Ctr Children Youth & Families, Burlington, VT USA. [Hudziak, James J.] Univ Vermont, Coll Med, Burlington, VT USA. [Neale, Ben M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Neale, Ben M.] Harvard Univ, Sch Med, Boston, MA USA. [Neale, Ben M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Boomsma, DI (reprint author), Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM dorret@psy.vu.nl OI Middeldorp, Christel/0000-0002-6218-0428 FU ARRA [RC2 2MH08995]; European Research Council (Genetics of Mental Illness) [ERC-230374]; Spinozapremie [NWO/SPI 56-464-14192]; Neuroscience Campus Amsterdam (NCA); EMGO+ Institution; twin-family database for behavior genetics and genomics studies [NWO 480-04-004]; Genetic influences on stability and change in psychopathology from childhood to young adulthood [ZonMW 912-10-020] FX This project was supported by ARRA RC2 2MH08995; the European Research Council (Genetics of Mental Illness, ERC-230374); Spinozapremie (NWO/SPI 56-464-14192); Neuroscience Campus Amsterdam (NCA) and the EMGO+ Institution; twin-family database for behavior genetics and genomics studies (NWO 480-04-004); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMW 912-10-020). NR 46 TC 9 Z9 9 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2014 VL 53 IS 10 BP 1123 EP 1129 DI 10.1016/j.jaac.2014.06.014 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AP9MO UT WOS:000342404100013 PM 25245356 ER PT J AU Shlyankevich, J Corey, KC Garshick, MK Roh, EK Kimball, AB AF Shlyankevich, Julia Corey, Kristen C. Garshick, Marisa K. Roh, Ellen K. Kimball, Alexandra B. TI Dermatology urgent care: Enlisting help from primary care in triage decisions SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Shlyankevich, Julia; Kimball, Alexandra B.] Massachusetts Gen Hosp, Clin Unit Res Trials & Outcomes Skin, Boston, MA 02114 USA. [Shlyankevich, Julia; Roh, Ellen K.; Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Corey, Kristen C.] Univ Massachusetts, Dept Dermatol, Worcester, MA USA. [Garshick, Marisa K.] Weill Cornell Med Coll, Dept Dermatol, New York, NY USA. [Roh, Ellen K.; Kimball, Alexandra B.] Harvard Univ, Sch Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2014 VL 71 IS 4 BP 838 EP 839 DI 10.1016/j.jaad.2014.05.024 PG 2 WC Dermatology SC Dermatology GA AP6FJ UT WOS:000342172700072 PM 25219712 ER PT J AU Enamandram, M Schoch, K Miller, DD Horn, TD AF Enamandram, Monica Schoch, Kathryn Miller, Daniel D. Horn, Thomas D. TI Calcific elastosis in the setting of weight gain SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Enamandram, Monica; Horn, Thomas D.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Miller, Daniel D.] Boston Univ, Sch Med, Dermatopathol Sect, Boston, MA 02118 USA. [Schoch, Kathryn] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. RP Horn, TD (reprint author), MGPO Dermatopathol Associates, 2 Wells Ave, Newton, MA 02459 USA. EM THorn@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2014 VL 71 IS 4 BP E156 EP E158 DI 10.1016/j.jaad.2014.06.034 PG 4 WC Dermatology SC Dermatology GA AP6FJ UT WOS:000342172700029 PM 25219746 ER PT J AU Ryan, ME Palasis, S Saigal, G Singer, AD Karmazyn, B Dempsey, ME Dillman, JR Dory, CE Garber, M Hayes, LL Iyer, RS Mazzola, CA Raske, ME Rice, HE Rigsby, CK Sierzenski, PR Strouse, PJ Westra, SJ Wootton-Gorges, SL Coley, BD AF Ryan, Maura E. Palasis, Susan Saigal, Gaurav Singer, Adam D. Karmazyn, Boaz Dempsey, Molly E. Dillman, Jonathan R. Dory, Christopher E. Garber, Matthew Hayes, Laura L. Iyer, Ramesh S. Mazzola, Catherine A. Raske, Molly E. Rice, Henry E. Rigsby, Cynthia K. Sierzenski, Paul R. Strouse, Peter J. Westra, Sjirk J. Wootton-Gorges, Sandra L. Coley, Brian D. TI ACR Appropriateness Criteria Head Trauma-Child SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness criteria; head trauma; nonaccidental injury; pediatric; CT; MRI ID MAGNETIC-RESONANCE SPECTROSCOPY; PEDIATRIC BRAIN-INJURY; COMPUTED-TOMOGRAPHY; CERVICAL-SPINE; NEUROBEHAVIORAL OUTCOMES; INTRACRANIAL INJURY; RADIATION-EXPOSURE; UNIQUE FEATURES; DECISION RULE; SKULL AB Head trauma is a frequent indication for cranial imaging in children. CT is considered the first line of study for suspected intracranial injury because of its wide availability and rapid detection of acute hemorrhage. However, the majority of childhood head injuries occur without neurologic complications, and particular consideration should be given to the greater risks of ionizing radiation in young patients in the decision to use CT for those with mild head trauma. MRI can detect traumatic complications without radiation, but often requires sedation in children, owing to the examination length and motion sensitivity, which limits rapid assessment and exposes the patient to potential anesthesia risks. MRI may be helpful in patients with suspected nonaccidental trauma, with which axonal shear injury and ischemia are more common and documentation is critical, as well as in those whose clinical status is discordant with CT findings. Advanced techniques, such as diffusion tensor imaging, may identify changes occult by standard imaging, but data are currently insufficient to support routine clinical use. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Ryan, Maura E.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Palasis, Susan] Childrens Hosp Atlanta, Atlanta, GA USA. [Saigal, Gaurav] Univ Miami Hlth Syst, Miami, FL USA. [Singer, Adam D.] Univ Miami, Jackson Mem Hosp, Miami, FL 33136 USA. [Karmazyn, Boaz] Indiana Univ, James Whitcomb Riley Hosp Children, Indianapolis, IN USA. [Dempsey, Molly E.] Texas Scottish Rite Hosp Crippled Children, Dallas, TX USA. [Dillman, Jonathan R.; Strouse, Peter J.] CS Mott Childrens Hosp, Ann Arbor, MI USA. [Dory, Christopher E.] Childrens Hosp, San Diego, CA USA. [Garber, Matthew] Div Gen & Hosp Pediat, Columbia, SC USA. [Garber, Matthew] Amer Acad Pediat, Elk Grove Village, IL USA. [Hayes, Laura L.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Iyer, Ramesh S.] Seattle Childrens Hosp, Seattle, WA USA. [Mazzola, Catherine A.] New Jersey Pediat Neurosci Inst, Morristown, NJ USA. [Mazzola, Catherine A.] Amer Assoc Neurol Surg, Rolling Meadows, IL USA. [Mazzola, Catherine A.] Illinois Congress Neurol Surg, Schaumburg, IL USA. [Raske, Molly E.] St Paul Radiol PA, St Paul, MN USA. [Rice, Henry E.] Duke Univ, Med Ctr, Durham, NC USA. [Rice, Henry E.] Amer Pediat Surg Assoc, Deerfield, IL USA. [Rigsby, Cynthia K.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Sierzenski, Paul R.] Christiana Care Hlth Syst, Newark, DE USA. [Sierzenski, Paul R.] Amer Coll Emergency Phys, Irving, TX USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wootton-Gorges, Sandra L.] Univ Calif Davis, Sacramento, CA 95817 USA. [Coley, Brian D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Ryan, ME (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, 225 E Chicago Ave, Chicago, IL 60611 USA. EM mryan@luriechildrens.org OI Coley, Brian/0000-0003-0354-4727 FU Siemens Medical FX Boaz K Karmazyn, MD, receives grant funding for research into CT dose and dose reduction techniques from Siemens Medical, but does not have any ownership in or receive any direct compensation from Siemens Medical. NR 68 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2014 VL 11 IS 10 BP 939 EP 947 DI 10.1016/j.jacr.2014.07.017 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ1FY UT WOS:000342528500008 PM 25164794 ER PT J AU Stern, EJ Adam, EJ Bettman, MA Brink, JA Dreyer, KJ Frija, G Keefer, R Mildenberger, P Remedios, D Vock, P AF Stern, Eric J. Adam, E. Jane Bettman, Michael A. Brink, James A. Dreyer, Keith J. Frija, Guy Keefer, Raina Mildenberger, Peter Remedios, Denis Vock, Peter TI Proceedings from the First Global Summit on Radiological Quality and Safety SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Quality; safety; appropriateness; clinical imaging guidelines AB The ACR, the European Society of Radiology, and the International Society of Radiology held the first joint Global Summit on Radiological Quality and Safety in May 2013. The program was divided into 3 day-long themes: appropriateness of imaging, radiation protection/infrastructure, and quality and safety. Participants came from global organizations, including the International Atomic Energy Agency, the World Health Organization, and other institutions; industry and patient advocacy groups with an interest in imaging were also represented. The goal was to exchange ideas and solutions and share concerns to arrive at a better and more uniform approach to quality and safety. Participants were asked to use the information presented to develop strategies and tactics to harmonize and promote best practices worldwide. These strategies were summarized at the conclusion of the meeting. C1 [Stern, Eric J.] Univ Washington, Seattle, WA 98195 USA. [Adam, E. Jane] St George Hosp, London, England. [Bettman, Michael A.] Wake Forest Univ, Bowman Gray Sch Med, Hanover, NH USA. [Brink, James A.; Dreyer, Keith J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Frija, Guy] European Soc Radiol, Vienna, Austria. [Keefer, Raina] Amer Coll Radiol, Reston, VA USA. [Mildenberger, Peter] Univ Med Ctr, Mainz, Germany. [Remedios, Denis] Northwick Pk Hosp & Clin Res Ctr, Harrow, Middx, England. [Vock, Peter] Univ Hosp Bern, CH-3010 Bern, Switzerland. RP Stern, EJ (reprint author), Univ Washington, 1959 NE Pacific,Box 357115, Seattle, WA 98195 USA. EM estern@u.washington.edu NR 7 TC 3 Z9 3 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2014 VL 11 IS 10 BP 959 EP 967 DI 10.1016/j.jacr.2014.03.006 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ1FY UT WOS:000342528500011 PM 24836270 ER PT J AU Sabbisetti, VS Waikar, SS Antoine, DJ Smiles, A Wang, C Ravisankar, A Ito, K Sharma, S Ramadesikan, S Lee, M Briskin, R De Jager, PL Ngo, TT Radlinski, M Dear, JW Park, KB Betensky, R Krolewski, AS Bonventre, JV AF Sabbisetti, Venkata. S. Waikar, Sushrut S. Antoine, Daniel J. Smiles, Adam Wang, Chang Ravisankar, Abinaya Ito, Kazumi Sharma, Sahil Ramadesikan, Swetha Lee, Michelle Briskin, Rebeccah De Jager, Philip L. Ngo, Thanh Thu Radlinski, Mark Dear, James W. Park, Kevin B. Betensky, Rebecca Krolewski, Andrzej S. Bonventre, Joseph V. TI Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID PROXIMAL TUBULE INJURY; ACUTE-RENAL-FAILURE; URINARY BIOMARKERS; FIBROSIS; KIM-1; QUALIFICATION; CELLS; RISK AB Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury. C1 [Sabbisetti, Venkata. S.; Waikar, Sushrut S.; Wang, Chang; Ravisankar, Abinaya; Ito, Kazumi; Sharma, Sahil; Ramadesikan, Swetha; Ngo, Thanh Thu; Radlinski, Mark; Bonventre, Joseph V.] Harvard Univ, Sch Med, Dept Med, Div Renal, Boston, MA 02115 USA. [Lee, Michelle; Briskin, Rebeccah; De Jager, Philip L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Antoine, Daniel J.; Park, Kevin B.] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool L69 3BX, Merseyside, England. [Smiles, Adam; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Dear, James W.] Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Betensky, Rebecca] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Sabbisetti, VS (reprint author), Harvard Univ, Inst Med, Brigham & Womens Hosp, Room 550 576,4 Blackfan Circle, Boston, MA 02115 USA. EM vsabbisetti@partners.org; joseph_bonventre@hms.harvard.edu FU National Institutes of Health (NIH) [DK39773, DK072381, DK075941]; Gene Expression & Regulatory Networks in Human Leukocytes at the Brigham and Women's Hospital [RC2 GM093080]; Juvenile Diabetes Research Foundation [1-2008-1018]; NIH [DK041526]; CKD Biomarker Consortium [U01-DK85660]; Medical Research Council via Centre for Drug Safety Science [G0700654]; Royal Society; Wellcome Trust FX This research was supported by National Institutes of Health (NIH) grants DK39773 and DK072381 to J.V.B., DK075941 to S.S.W. Gene Expression & Regulatory Networks in Human Leukocytes at the Brigham and Women's Hospital (RC2 GM093080) to P.L.D. and Juvenile Diabetes Research Foundation research grant 1-2008-1018 and NIH grants DK041526 to A.S.K. S.S.W., & V.S. are also supported by U01-DK85660 as members of the CKD Biomarker Consortium. D.J.A. and B.K.P. would like to acknowledge the Medical Research Council (via the Centre for Drug Safety Science, grant number G0700654). D.J.A. would also like to acknowledge financial support from the Royal Society and the Wellcome Trust. NR 26 TC 56 Z9 57 U1 1 U2 16 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2014 VL 25 IS 10 BP 2177 EP 2186 DI 10.1681/ASN.2013070758 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AP9ML UT WOS:000342403800008 PM 24904085 ER PT J AU Dasgupta, D Wee, MJ Reyes, M Li, YW Simm, PJ Sharma, A Schlingmann, KP Janner, M Biggin, A Lazier, J Gessner, M Chrysis, D Tuchman, S Baluarte, HJ Levine, MA Tiosano, D Insogna, K Hanley, DA Carpenter, TO Ichikawa, S Hoppe, B Konrad, M Savendahl, L Munns, CF Lee, H Juppner, H Bergwitz, C AF Dasgupta, Debayan Wee, Mark J. Reyes, Monica Li, Yuwen Simm, Peter J. Sharma, Amita Schlingmann, Karl-Peter Janner, Marco Biggin, Andrew Lazier, Joanna Gessner, Michaela Chrysis, Dionisios Tuchman, Shamir Baluarte, H. Jorge Levine, Michael A. Tiosano, Dov Insogna, Karl Hanley, David A. Carpenter, Thomas O. Ichikawa, Shoji Hoppe, Bernd Konrad, Martin Saevendahl, Lars Munns, Craig F. Lee, Hang Jueppner, Harald Bergwitz, Clemens TI Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HEREDITARY HYPOPHOSPHATEMIC RICKETS; VITAMIN-D; IDIOPATHIC HYPERCALCIURIA; PHOSPHATE HOMEOSTASIS; INTRONIC DELETIONS; GENE; BONE; NEPHROLITHIASIS; REABSORPTION; METABOLISM AB Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na+)-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)(2) vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD. C1 [Dasgupta, Debayan; Wee, Mark J.; Reyes, Monica; Li, Yuwen; Jueppner, Harald; Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Sharma, Amita; Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Simm, Peter J.; Biggin, Andrew; Munns, Craig F.] Childrens Hosp, Inst Endocrinol & Diabet, Westmead, NSW, Australia. [Simm, Peter J.; Munns, Craig F.] Univ Sydney, Discipline Pediat & Child Hlth, Sydney, NSW 2006, Australia. [Schlingmann, Karl-Peter; Konrad, Martin] Univ Childrens Hosp, Dept Gen Pediat, Munster, Germany. [Janner, Marco] Univ Childrens Hosp, Div Pediat Endocrinol Diabetol & Metab, Bern, Germany. [Lazier, Joanna] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Gessner, Michaela; Hoppe, Bernd] Univ Hosp, Dept Pediat, Div Pediat Nephrol, Cologne, Germany. [Chrysis, Dionisios] Univ Patras, Sch Med, Dept Pediat, Div Endocrinol, GR-26110 Patras, Greece. [Tuchman, Shamir] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Div Pediat Nephrol, Washington, DC USA. [Baluarte, H. Jorge] Univ Penn, Sch Med, Div Pediat Nephrol, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Levine, Michael A.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Tiosano, Dov] Meyer Childrens Hosp, Div Pediat Endocrinol, Haifa, Israel. [Insogna, Karl] Yale Univ, Sch Med, Dept Med, Div Endocrinol, New Haven, CT 06510 USA. [Carpenter, Thomas O.] Yale Univ, Sch Med, Dept Pediat Endocrinol, New Haven, CT 06510 USA. [Hanley, David A.] Univ Calgary, Fac Med, Dept Med, Calgary, AB, Canada. [Hanley, David A.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. [Hanley, David A.] Univ Calgary, Fac Med, Dept Oncol, Calgary, AB, Canada. [Ichikawa, Shoji] Indiana Univ, Sch Med, Div Endocrinol, Indianapolis, IN USA. [Saevendahl, Lars] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier Bldg 1055, Boston, MA 02114 USA. EM cbergwitz@partners.org OI Dasgupta, Debayan/0000-0002-1064-0541; Levine, Michael/0000-0003-0036-7809 FU National Institutes of Health [R01-DK46718-20, P01-DK11794]; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [5K08-DK078361]; National Kidney Foundation; American Association for Clinical Investigation FX This work was supported by National Institutes of Health Grants R01-DK46718-20 and P01-DK11794, project IV (to H.J.), National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant 5K08-DK078361 (to C.B.), Young Investigator Awards by the National Kidney Foundation, and the American Association for Clinical Investigation (C.B.). NR 48 TC 14 Z9 16 U1 0 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2014 VL 25 IS 10 BP 2366 EP 2375 DI 10.1681/ASN.2013101085 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AP9ML UT WOS:000342403800025 PM 24700880 ER PT J AU Bromley, B Shipp, TD Lyons, J Navathe, RS Groszmann, Y Benacerraf, BR AF Bromley, Bryann Shipp, Thomas D. Lyons, Jennifer Navathe, Reshama S. Groszmann, Yvette Benacerraf, Beryl R. TI Detection of Fetal Structural Anomalies in a Basic First-Trimester Screening Program for Aneuploidy SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE early anatomic survey; fetal anomalies; first-trimester screening; nuchal translucency scan; obstetric ultrasound; sonographer ID ULTRASOUND EXAMINATION; NUCHAL TRANSLUCENCY; ABNORMALITIES; SCAN; DIAGNOSIS; ANATOMY; US AB Objectives-The purpose of this study was to determine whether first-trimester aneuploidy screening sonographyinitiallyperformed by credentialed sonographers was useful for detecting fetal anomalies between 11 and 14 weeks' gestation. Methods-We conducted a retrospective cohort study of consecutive patients referred to a private ultrasound facility between January 1, 2008, and June 30, 2012, for measurement of the nuchal translucency (NT) and crown-rump length as part of a screening protocol for aneuploidy. Patients were included if there was at least 1 live fetus with a crown-rump length between 34 and 84 mm No specific anatomic imaging protocol was followed. The presence of anomalies was based on the sonographic report and review of the medical record. The absence of anomalies was based on the report from the anatomic survey. Anomalies were categorized as lethal, major, and minor. The anomaly category and gestational age at diagnosis (<= 14 versus >14 weeks) were compared. Results-An NT scan was performed on 9692 fetuses. Anatomic surveys were done on 9077 (93.7%) of these fetuses at a mean of 18 weeks' gestation. Anomalies were detected in 180 fetuses (1.8%): SO (0.5%) at the NT scan and 130 (1.3%) at the anatomic scan. Overall, 46 of 111 fetuses (41.4%) with major or lethal anomalies were detected at the NT scan. Two suspected abnormalities at the NT scan were not present at the anatomic scan. Conclusions-First-trimester aneuploidy screening sonography initially performed by credentialed sonographers can identify a substantial proportion of major and lethal anomalies. C1 [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Benacerraf, Beryl R.] Diagnost Ultrasound Associates PC, Boston, MA USA. [Bromley, Bryann; Benacerraf, Beryl R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bromley, Bryann; Shipp, Thomas D.; Navathe, Reshama S.; Groszmann, Yvette; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann; Shipp, Thomas D.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Lyons, Jennifer] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Navathe, Reshama S.] Harvard Vanguard Med Associates, Boston, MA USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates PC, 1 Brookline Pl,Suite 506, Brookline, MA 02445 USA. EM bbsono@aol.com NR 26 TC 13 Z9 13 U1 0 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1737 EP 1745 DI 10.7863/tiltra.33.10.1737 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700003 PM 25253819 ER PT J AU Bromley, B Shipp, TD Lyons, J Groszmann, Y Navathe, RS Benacerraf, BR AF Bromley, Bryann Shipp, Thomas D. Lyons, Jennifer Groszmann, Yvette Navathe, Reshama S. Benacerraf, Beryl R. TI What Is the Importance of Second-Trimester "Soft Markers" for Trisomy 21 After an 11- to 14-Week Aneuploidy Screening Scan? SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE aneuploidy; first-trimester screening; nuchal fold; obstetric ultrasound; soft markers ID DOWN-SYNDROME; GENETIC SONOGRAPHY; TRIMESTER AB Objectives-The purpose of this study was to evaluate the importance of second-trimester "soft markers" for trisomy 21 after an 11-to 14-week aneuploidy screening scan. Methods-We conducted a retrospective cohort study of consecutive patients referred for measurement of the nuchal translucency (NT) as part of a screening protocol for aneuploidy. Patients who returned for an anatomic survey between 16 and 20 weeks' gestation were evaluated. The sonographic markers and anomalies associated with the detection of trisomy 21 in the second trimester were analyzed. Results-There were 42 fetuses (0.4%) with trisomy 21 identified in the study cohort of 9692 patients. Trisomy 21 was suspected at the NT scan in 28 fetuses (67%) and at the second-trimester anatomic survey in 14 (33%). In fetuses first suspected of having trisomy 21 in the second trimester, 9 of 14 had normal anatomic survey results, and 5 of 14 had congenital malformations. All 14 fetuses had soft markers for aneuploidy. A thickened nuchal fold was identified in 5 of 9 fetuses with trisomy 21 and normal anatomic survey results, all of whom had an NT of less than 3.0 mm at the initial screening scan. Conclusions-Second-trimester soft markers, especially a thickened nuchal fold, remain important observations in the detection of trisomy 21 by sonography among fetuses who have had first-trimester sonographic screening for aneuploidy. C1 [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Benacerraf, Beryl R.] Diagnost Ultrasound Associates PC, Boston, MA USA. [Bromley, Bryann; Benacerraf, Beryl R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Navathe, Reshama S.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann; Shipp, Thomas D.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Lyons, Jennifer] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Navathe, Reshama S.] Harvard Vanguard Med Associates, Boston, MA USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates PC, 1 Brookline Pl,Suite 506, Brookline, MA 02445 USA. EM bbsono@aol.com NR 17 TC 5 Z9 6 U1 0 U2 5 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1747 EP 1752 DI 10.7863/ultra.33.10.1747 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700004 PM 25253820 ER PT J AU Lewiss, RE Hayden, GE Murray, A Liu, YT Panebianco, N Liteplo, AS AF Lewiss, Resa E. Hayden, Geoffrey E. Murray, Alice Liu, Yiju Teresa Panebianco, Nova Liteplo, Andrew S. TI SonoGames An Innovative Approach to Emergency Ultrasound Education SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE clinical sonography; medical education; point-of-care ultrasound; SonoGames; ultrasound education ID SIMULATION; MEDICINE AB SonoGames was created by the Academy of Emergency Ultrasound for the 2012 annual meeting of the Society for Academic Emergency Medicine. The assessment of resident knowledge and of the performance of point-of-care ultrasound examinations is an integral component of ultrasound education and is required in emergency medicine residency training. With that in mind, game organizers sought to assess and improve emergency medicine residents' point-of-care ultrasound knowledge, hands-on skills, and integration of knowledge into clinical decision making. SonoGames is an annual 4-hour competition consisting of 3 rounds. In this article, we provide a description of SonoGames and provide a blueprint for an effective and successful educational event. C1 [Lewiss, Resa E.] St Lukes Roosevelt Hosp, Dept Emergency Med, New York, NY 10025 USA. [Hayden, Geoffrey E.] Med Univ S Carolina, Div Emergency Med, Charleston, SC 29425 USA. [Murray, Alice] Boston Med Ctr, Div Pediat Emergency Med, Boston, MA USA. [Liu, Yiju Teresa] George Washington Univ, Dept Emergency Med, Washington, DC USA. [Panebianco, Nova] Hosp Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Liteplo, Andrew S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Lewiss, RE (reprint author), St Lukes Roosevelt Hosp, Dept Emergency Med, 1111 Amsterdam Ave, New York, NY 10025 USA. NR 11 TC 1 Z9 1 U1 1 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1843 EP 1849 DI 10.7863/ultra.33.10.1843 PG 7 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700016 PM 25253832 ER PT J AU Kwan, SW Mortell, KE Hippe, DS Brunner, MC AF Kwan, Sharon W. Mortell, Kelly E. Hippe, Daniel S. Brunner, Michael C. TI An Economic Analysis of Sublobar Resection versus Thermal Ablation for Early-Stage Non-Small-Cell Lung Cancer SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PROSTATE-CANCER; SEER-MEDICARE; COST; SURGERY; CARE; COMORBIDITY; SURVIVAL; IMPACT AB Purpose:. To compare medical costs for a matched-pair cohort of Medicare patients with early-stage non-small,cell lung cancer (NSCLC) Who underwent treatment with sublobar resection or thermal ablation. Materials and Methods: Patients at least 65 years of age with stage IA/IB NSCLC treated with sublobar resection or thermal ablation, front 2007 to 2009 were identified from Surveillance, Epidemiology, and End Results/Medicare-linked data and matched by propensity scores. The primary outcome of interest, cost from the payees perspective, was derived from Medicare claims data A partitioned inverse probability weighted estimator was used to calculate mean and Median treatment-related costs and costs at 1, 3, 12, 18, and 24 months after treatment. Baseline characteristics, Kaplan-Meier survival curie, and calculated cost variables were compared between. the two groups. Results : The final matched cohort of 128 patients had similar baseline Characteristics and overall survival (P = .52). Patients. who underwent ablation had, significantly lower treatment-related costs than those who underwent sublobar resection (P < .001). The difference in median treatment-related cost was $16,105. At 1, month, 3 months, and 12 months after treatment, cumulative costs remained significantly different (P <= .011). Lower cost associated with ablations performed in the outpatient setting was a major contributor to the differences between the two treatment modalities, although inpatient ablations maintained a small cost advantage over sublobar resections. Conclusions : Among matched Medicare patients with stage I NSCLC, thermal ablation resulted in significantly lower treatment-related costs and cumulative medical costs 1 month, 3 months, and 12 months after treatment compared with sublobar resection. C1 [Kwan, Sharon W.; Hippe, Daniel S.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Kwan, Sharon W.] Univ Washington, Comparat Effectiveness Cost & Outcomes Res Ctr, Seattle, WA 98195 USA. [Mortell, Kelly E.] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. [Brunner, Michael C.] William S Middleton Mem Vet Adm Med Ctr, Dept Radiol, Madison, WI USA. Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Kwan, SW (reprint author), Univ Washington, Med Ctr, Dept Radiol, 1959 NE Pacific St,Suite 357115, Seattle, WA 98195 USA. EM shakwan@uw.edu FU Society of Interventional Radiology (SIR); SIR Foundation FX The authors thank William Kreuter, MPA, for his programming assistance and Robert White, MHS, for his general support. This study was partially supported by the Society of Interventional Radiology (SIR) and the SIR Foundation. This study used the linked Surveillance, Epidemiology, and End Results (SEER)/Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program of the National Cancer Institute, the Office of Research, Development, and Information, Centers for Medicare and Medicaid Services, Information Management Services, and the SEER Program tumor registries in the creation of the SEER/Medicare database. NR 21 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1558 EP 1564 DI 10.1016/j.jvir.2014.07.002 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000010 PM 25130308 ER PT J AU Deipolyi, AR Iafrate, AJ Zhu, AX Ergul, EA Ganguli, S Oklu, R AF Deipolyi, Amy R. Iafrate, A. John Zhu, Andrew X. Ergul, Emel A. Ganguli, Suvranu Oklu, Rahmi TI High Lung Shunt Fraction in Colorectal Liver Tumors Is Associated with Distant Metastasis and Decreased Survival SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; CANCER AB Purpose: To assess how intratumoral shunting relates to liver metastasis and to clinical outcome. Materials and Methods: Lung shunt fraction (LSF) was calculated from macroaggregated albumin scan after transcatheter injection of radioactive particles in 62 patients with colorectal cancer, and liver metastases evaluated for :selective internal radiation therapy (SIRT) from May 2007 to August 2012. Assessment was :performed Of how LSF, liver tumor burden, and systemic chemotherapy relate to survival and the presence of lung metastases. LSF and tumor burden were also assessed in a subset of patients who underwent genetic profiling with SNaPshot analysis. Results: Patients with higher LSF were more likely to have lung metastases and decreased survival, Whereas, tumor burden was not associated with these outcomes. Patients with genetic, mutations had significantly higher LSF than patients with no mutations. Patients who received chemotherapy before SIRT and had tow LSF had the longest Survival after SIRT. Conclusions: LSF may be a more robust marker of metastasis than tumor size. increased LSF secondary to vascular shunting within liver metastasis is an indicator of distant lesions and is associated with decreased survival after SIRT. Intratumoral shunting May provide a conduit for circulating tumor cells to access More remote organs, bypassing filtration by liver parenchyma, and may be an important factor in metastasis from colorectal Cancer. C1 [Deipolyi, Amy R.; Ergul, Emel A.; Ganguli, Suvranu; Oklu, Rahmi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. [Iafrate, A. John] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Mol Pathol, Boston, MA 02114 USA. [Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol Oncol,Ctr Liver Canc, Boston, MA 02114 USA. RP Oklu, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Intervent Radiol, 55 Fruit St,290 Gray Bigelow, Boston, MA 02114 USA. EM roklu@mgh.harvard.edu OI Deipolyi, Amy/0000-0003-3144-386X FU National Institutes of Health [RO3 CA172738]; Department of Radiology, Massachusetts General Hospital FX This study was supported by National Institutes of Health grant RO3 CA172738 (R.O.) and the Department of Radiology, Massachusetts General Hospital. NR 15 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1604 EP 1608 DI 10.1016/j.jvir.2014.06.019 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000016 PM 25086965 ER PT J AU Aparici, CM Win, AZ AF Aparici, Carina Mari Win, Aung Zaw TI Use of Positron Emission Tomography/CT to Perform Biopsy of a Mesenteric Mass SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Editorial Material C1 [Aparici, Carina Mari] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Win, Aung Zaw] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. RP Win, AZ (reprint author), San Francisco VA Med Ctr, Dept Radiol, 4150 Clement, San Francisco, CA 94121 USA. EM aungzwin@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1609 EP 1609 DI 10.1016/j.jvir.2014.05.017 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000017 PM 25255947 ER PT J AU Lezcano, C Kleffel, S Lee, NY Larson, AR Zhan, Q DoRosario, A Wang, LC Schatton, T Murphy, GF AF Lezcano, Cecilia Kleffel, Sonja Lee, Nayoung Larson, Allison R. Zhan, Qian DoRosario, Andrew Wang, Linda C. Schatton, Tobias Murphy, George F. TI Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts SO LABORATORY INVESTIGATION LA English DT Article ID HUMAN-MALIGNANT MELANOMA; STEM-LIKE CELLS; LUNG-CANCER; THERAPEUTIC IMPLICATIONS; ABERRANT EXPRESSION; TUMOR ANGIOGENESIS; COLORECTAL-CANCER; CHANNEL FORMATION; PROGNOSTIC-FACTOR; IN-VIVO AB Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents. C1 [Lezcano, Cecilia] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Kleffel, Sonja; Lee, Nayoung; Larson, Allison R.; Schatton, Tobias] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Kleffel, Sonja; Lee, Nayoung; Larson, Allison R.; Zhan, Qian; DoRosario, Andrew; Schatton, Tobias; Murphy, George F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhan, Qian; Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [DoRosario, Andrew] Dana Faber Brigham & Womens Canc Ctr, Ctr Cutaneous Oncol, Boston, MA USA. [Wang, Linda C.] Inst Canc Care, Mercy Med Ctr, Baltimore, MD USA. [Schatton, Tobias] Childrens Hosp, Transplantat Res Ctr, Boston, MA 02115 USA. RP Murphy, GF (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, 221 Longwood Ave,EBRC Suite 401, Boston, MA 02115 USA. EM gmurphy@rics.bwh.harvard.edu RI Larson, Allison/N-4263-2015 OI Larson, Allison/0000-0001-8534-7078 FU Brigham and Women's Hospital Department of Dermatology; Dermatology Foundation; [NIH-P50 CA93683]; [R01 CA58467] FX NIH-P50 CA93683 and R01 CA58467 (GFM) and Brigham and Women's Hospital Department of Dermatology Funding for Young Investigators (TS) supported the present work. IS is the recipient of a Research Career Development Award from the Dermatology Foundation. NR 52 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2014 VL 94 IS 10 BP 1092 EP 1102 DI 10.1038/labinvest.2014.99 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AQ0NW UT WOS:000342481000003 PM 25111691 ER PT J AU Min, Z Baddley, JW AF Min, Zaw Baddley, John W. TI Mollaret's meningitis SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material C1 [Min, Zaw] Allegheny Gen Hosp, Dept Med, Div Infect Dis, Allegheny Hlth Network, Pittsburgh, PA 15212 USA. [Baddley, John W.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Min, Z (reprint author), Allegheny Gen Hosp, Dept Med, Div Infect Dis, Allegheny Hlth Network, 420 East North Ave,East Wing,Suite 407, Pittsburgh, PA 15212 USA. EM zmin@wpahs.org NR 0 TC 0 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2014 VL 14 IS 10 BP 1022 EP 1022 PG 1 WC Infectious Diseases SC Infectious Diseases GA AP7HY UT WOS:000342249600043 PM 25253408 ER PT J AU Eichner, C Wald, LL Setsompop, K AF Eichner, Cornelius Wald, Lawrence L. Setsompop, Kawin TI A Low Power Radiofrequency Pulse for Simultaneous Multislice Excitation and Refocusing SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE SMS; blipped CAIPI; Multiband; PINS; RF pulse design ID SELECTIVE EXCITATION; SLICES PINS; ECHO; NUMBER AB PurposeSimultaneous multislice (SMS) acquisition enables increased temporal efficiency of MRI. Nonetheless, MultiBand (MB) radiofrequency (RF) pulses used for SMS can cause large energy deposition. Power independent of number of slices (PINS) pulses reduce RF power at cost of reduced bandwidth and increased off-resonance dependency. This work improves PINS design to further reduce energy deposition, off-resonance dependency and peak power. Theory and MethodsModifying the shape of MB RF-pulses allows for mixing with PINS excitation, creating a new pulse type with reduced energy deposition and SMS excitation characteristics. Bloch Simulations were used to evaluate excitation and off-resonance behavior of this MultiPINS pulse. In this work, MultiPINS was used for whole-brain MB=3 acquisition of high angular and spatial resolution diffusion MRI at 7 Tesla in 3 min. ResultsBy using MultiPINS, energy transmission and peak power for SMS imaging can be significantly reduced compared with PINS and MB pulses. For MB=3 acquisition in this work, MultiPINS reduces energy transmission by up to approximate to 50% compared with PINS pulses. The energy reduction was traded off to shorten the MultiPINS pulse, yielding higher signal at off-resonances for spin-echo acquisitions. ConclusionMB and PINS pulses can be combined to enable low energy and peak power SMS acquisition. Magn Reson Med 72:949-958, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Eichner, Cornelius; Wald, Lawrence L.; Setsompop, Kawin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr, Boston, MA USA. [Eichner, Cornelius] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. RP Eichner, C (reprint author), Athinoula A Martinos Ctr, 149 13th St, Charlestown, MA 02129 USA. EM ceichner@nmr.mgh.harvard.edu RI Setsompop, Kawin/P-1464-2014; Wald, Lawrence/D-4151-2009 OI Setsompop, Kawin/0000-0003-0455-7634; FU NIH Human Connectome Project [NIH U01MH093765, NIBIB R00EB012107, NIBIB R01EB006847, NCRR P41RR14075] FX Grant sponsor: NIH Human Connectome Project; Grant numbers: NIH U01MH093765, NIBIB R00EB012107, NIBIB R01EB006847, NCRR P41RR14075. NR 21 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 949 EP 958 DI 10.1002/mrm.25389 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300007 PM 25103999 ER PT J AU Muir, ER Cardenas, D Huang, SL Roby, J Li, G Duong, TQ AF Muir, Eric R. Cardenas, Damon Huang, Shiliang Roby, John Li, Guang Duong, Timothy Q. TI MRI Under Hyperbaric Air and Oxygen: Effects on Local Magnetic Field and Relaxation Times SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE oxygen therapy; BOLD; magnetic susceptibility; T1; T2; T2*; relaxation time constants ID CEREBRAL-BLOOD-FLOW; PARTIAL-PRESSURE; BRAIN; ARTIFACTS; HYPEROXIA; FMRI; SUSCEPTIBILITY; HYPERCAPNIA; HYPOXIA; TENSION AB PurposeHyperbaric oxygen therapy has shown efficacies in the treatment of a number of diseases. The goal of this study was to develop a rodent hyperbaric chamber for MRI studies and to investigate the effects of hyperbaric air and hyperbaric oxygen on local magnetic field (B-0) and MRI relaxation parameters in the rat brain. MethodsA hyperbaric chamber, constructed to fit inside an animal MRI scanner, was pressurized with air to four atmospheres, while oxygen was delivered locally via nose cone. B-0, T-2, T-2*, and T-1 maps in the rat brain were evaluated under normobaric air, hyperbaric air, and hyperbaric oxygen at 7T. ResultsUnder hyperbaric oxygen, images exhibited artifacts and temporal instability, attributable to fluctuating oxygen concentration from air and oxygen mixing near the imaging region. Physically shielding the imaging region from fluctuating oxygen concentration resolved the problems. With increasing oxygen at hyperbaric pressure, B-0 was shifted downfield with increased inhomogeneity near the ear canals and nose. Brain T-2 and T-2* were lengthened, and T-1 was shortened. ConclusionThis study establishes the means to perform MRI on rodents under hyperbaric conditions. Hyperbaric air and hyperbaric oxygen have significant effects on B-0 and tissue relaxation parameters compared with normobaric air. Magn Reson Med 72:1176-1181, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Muir, Eric R.; Cardenas, Damon; Huang, Shiliang; Roby, John; Li, Guang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Li, Guang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Cardenas, Damon] Univ Texas Hlth Sci Ctr San Antonio, Dept Biomed Engn, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Dept Vet Affairs, South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu FU National Institutes of Health [R01 NS45879, T32 HL007446] FX Grant sponsor: National Institutes of Health; Grant numbers: R01 NS45879 and T32 HL007446. NR 21 TC 5 Z9 5 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 1176 EP 1181 DI 10.1002/mrm.25027 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300030 PM 24243603 ER PT J AU Harris, CT Handler, WB Araya, Y Martinez-Santiesteban, F Alford, JK Dalrymple, B Van Sas, F Chronik, BA Scholl, TJ AF Harris, Chad T. Handler, William B. Araya, Yonathan Martinez-Santiesteban, Francisco Alford, Jamu K. Dalrymple, Brian Van Sas, Frank Chronik, Blaine A. Scholl, Timothy J. TI Development and Optimization of Hardware for Delta Relaxation Enhanced MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE coil; molecular imaging; MRI; relaxation; eddy-current ID CONTRAST AGENTS AB PurposeDelta relaxation enhanced magnetic resonance (dreMR) imaging requires an auxiliary B-0 electromagnet capable of shifting the main magnetic field within a clinical 1.5 Tesla (T) MR system. In this work, the main causes of interaction between an actively shielded, insertable resistive B-0 electromagnet and a 1.5T superconducting system are systematically identified and mitigated. MethodsThe effects of nonideal fabrication of the field-shifting magnet are taken into consideration through careful measurement during winding and improved accuracy in the design of the associated active shield. The shielding performance of the resultant electromagnet is compared against a previously built system in which the shield design was based on an ideal primary coil model. Hardware and software approaches implemented to eliminate residual image artifacts are presented in detail. ResultsThe eddy currents produced by the newly constructed dreMR system are shown to have a significantly smaller long-time-constant component, consistent with the hypothesis that less energy is deposited into the cryostat of the MR system. ConclusionWith active compensation, the dreMR imaging system is capable of 0.22T field shifts within a clinical 1.5T MRI with no significant residual eddy-current fields. Magn Reson Med 72:1182-1190, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Harris, Chad T.; Handler, William B.; Araya, Yonathan; Dalrymple, Brian; Van Sas, Frank; Chronik, Blaine A.; Scholl, Timothy J.] Univ Western Ontario, London, ON N6A 5C1, Canada. [Martinez-Santiesteban, Francisco; Chronik, Blaine A.; Scholl, Timothy J.] Robarts Res Inst, Imaging Res Labs, London, ON N6A 5C1, Canada. [Alford, Jamu K.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Alford, Jamu K.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Scholl, TJ (reprint author), Univ Western Ontario, Dept Med Biophys, London, ON N6A 5C1, Canada. EM scholl@uwo.ca RI Scholl, Timothy/I-6178-2012; Chronik, Blaine/M-2802-2013 OI Scholl, Timothy/0000-0002-0807-363X; FU Ontario Institute for Cancer Research, Smarter Imaging Program; Natural Sciences and Engineering Research Council FX Grant sponsor: The Ontario Institute for Cancer Research, Smarter Imaging Program; Grant sponsor: The Natural Sciences and Engineering Research Council. NR 14 TC 0 Z9 0 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 1182 EP 1190 DI 10.1002/mrm.25014 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300031 PM 24407990 ER PT J AU Hassett, MJ Ritzwoller, DP Taback, N Carroll, N Cronin, AM Ting, GV Schrag, D Warren, JL Hornbrook, MC Weeks, JC AF Hassett, Michael J. Ritzwoller, Debra P. Taback, Nathan Carroll, Nikki Cronin, Angel M. Ting, Gladys V. Schrag, Deb Warren, Joan L. Hornbrook, Mark C. Weeks, Jane C. TI Validating Billing/Encounter Codes as Indicators of Lung, Colorectal, Breast, and Prostate Cancer Recurrence Using 2 Large Contemporary Cohorts SO MEDICAL CARE LA English DT Article DE cancer; recurrence; administrative data; applied methods ID SEER-MEDICARE DATA; RACIAL-DIFFERENCES; FREE SURVIVAL; OLDER WOMEN; STAGE; COMORBIDITY; POPULATION; OUTCOMES; SURGERY; THERAPY AB Background: A substantial proportion of cancer-related mortality is attributable to recurrent, not de novo metastatic disease, yet we know relatively little about these patients. To fill this gap, investigators often use administrative codes for secondary malignant neoplasm or chemotherapy to identify recurrent cases in population-based datasets. However, these algorithms have not been validated in large, contemporary, routine care cohorts. Objective: To evaluate the validity of secondary malignant neoplasm and chemotherapy codes as indicators of recurrence after definitive local therapy for stage I-III lung, colorectal, breast, and prostate cancer. Research Design, Subjects, and Measures: We assessed the sensitivity, specificity, and positive predictive value (PPV) of these codes 14 and 60 months after diagnosis using 2 administrative datasets linked with gold-standard recurrence status information: CanCORS/Medicare (diagnoses 2003-2005) and HMO/Cancer Research Network (diagnoses 2000-2005). Results: We identified 929 CanCORS/Medicare patients and 5298 HMO/CRN patients. Sensitivity, specificity, and PPV ranged widely depending on which codes were included and the type of cancer. For patients with lung, colorectal, and breast cancer, the combination of secondary malignant neoplasm and chemotherapy codes was the most sensitive (75%-85%); no code-set was highly sensitive and highly specific. For prostate cancer, no code-set offered even moderate sensitivity (<= 19%). Conclusions: Secondary malignant neoplasm and chemotherapy codes could not identify recurrent cancer without some risk of misclassification. Findings based on existing algorithms should be interpreted with caution. More work is needed to develop a valid algorithm that can be used to characterize outcomes and define patient cohorts for comparative effectiveness research studies. C1 [Hassett, Michael J.; Schrag, Deb; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Hassett, Michael J.; Schrag, Deb; Weeks, Jane C.] Harvard Univ, Sch Med, Boston, MA USA. [Ritzwoller, Debra P.; Carroll, Nikki] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Taback, Nathan] Univ Toronto, Div Biostat, Toronto, ON, Canada. [Cronin, Angel M.; Ting, Gladys V.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Warren, Joan L.] NCI, Bethesda, MD 20892 USA. [Hornbrook, Mark C.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. RP Hassett, MJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, 450 Brookline Ave, Boston, MA 02215 USA. EM michael_hassett@dfci.harvard.edu FU National Cancer Institute [RC2 CA148185-01]; NCI (Cancer Research Network) [U19 CA79689]; American Society of Clinical Oncology; Susan G. Komen for the Cure; National Cancer Institute (NCI) [U01 CA093344]; Dana-Farber Cancer Institute/Cancer Research Network [U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324]; University of Iowa [U01 CA01013]; University of North Carolina [U01 CA093326]; Department of Veterans Affairs [VA HSRD CRS 02 164] FX Supported by a grant from the National Cancer Institute (RC2 CA148185-01 to J.C.W. and D. P. R.) and an NCI cooperative agreement (U19 CA79689, Cancer Research Network). The American Society of Clinical Oncology (Career Development Award) and Susan G. Komen for the Cure (Career Catalyst Award) provided salary support to M.J.H. The work of the CanCORS consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and to the Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network U01 CA093332; Harvard Medical School/Northern California Cancer Center U01 CA093324; University of Iowa U01 CA01013; University of North Carolina U01 CA093326); and by a Department of Veterans Affairs grant to the Durham VA Medical Center VA HSRD CRS 02 164. NR 23 TC 14 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2014 VL 52 IS 10 BP E65 EP E73 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AP9CK UT WOS:000342375800001 PM 23222531 ER PT J AU Rathi, Y Michailovich, O Laun, F Setsompop, K Grant, PE Westin, CF AF Rathi, Y. Michailovich, O. Laun, F. Setsompop, K. Grant, P. E. Westin, C. -F. TI Multi-shell diffusion signal recovery from sparse measurements SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Diffusion MRI; Compressed sensing; Diffusion spectrum imaging; Diffusion propagator; Kurtosis ID WATER DIFFUSION; WHITE-MATTER; HUMAN BRAIN; MRI; RECONSTRUCTION; COMPUTATION; APPROXIMATION; DISTRIBUTIONS; MINIMIZATION; ARCHITECTURE AB For accurate estimation of the ensemble average diffusion propagator (EAP), traditional multi-shell diffusion imaging (MSDI) approaches require acquisition of diffusion signals for a range of b-values. However, this makes the acquisition time too long for several types of patients, making it difficult to use in a clinical setting. In this work, we propose a new method for the reconstruction of diffusion signals in the entire q-space from highly undersampled sets of MSDI data, thus reducing the scan time significantly. In particular, to sparsely represent the diffusion signal over multiple q-shells, we propose a novel extension to the framework of spherical ridgelets by accurately modeling the monotonically decreasing radial component of the diffusion signal. Further, we enforce the reconstructed signal to have smooth spatial regularity in the brain, by minimizing the total variation (TV) norm. We combine these requirements into a novel cost function and derive an optimal solution using the Alternating Directions Method of Multipliers (ADMM) algorithm. We use a physical phantom data set with known fiber crossing angle of 45 degrees to determine the optimal number of measurements (gradient directions and b-values) needed for accurate signal recovery. We compare our technique with a state-of-the-art sparse reconstruction method (i.e., the SHORE method of Cheng et al. (2010)) in terms of angular error in estimating the crossing angle, incorrect number of peaks detected, normalized mean squared error in signal recovery as well as error in estimating the return-to-origin probability (RTOP). Finally, we also demonstrate the behavior of the proposed technique on human in vivo data sets. Based on these experiments, we conclude that using the proposed algorithm, at least 60 measurements (spread over three b-value shells) are needed for proper recovery of MSDI data in the entire q-space. (C) 2014 Elsevier B.V. All rights reserved. C1 [Rathi, Y.; Westin, C. -F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Michailovich, O.] Univ Waterloo, Dept Elect Engn, Waterloo, ON N2L 3G1, Canada. [Grant, P. E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Laun, F.] German Canc Res Ctr, Dept Med Phys Radiol, Heidelberg, Germany. [Setsompop, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Rathi, Y (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM yogesh@bwh.harvard.edu RI Setsompop, Kawin/P-1464-2014; Laun, Frederik/O-4810-2016 OI Setsompop, Kawin/0000-0003-0455-7634; Laun, Frederik/0000-0002-9269-5609 FU NIH [R01MH097979, R01MH074794, P41RR013218, P41EB015902]; Swedish research Grant [VR 2012-3682] FX This work has been supported by NIH Grants: R01MH097979 (Rathi), R01MH074794 (Westin), P41RR013218, P41EB015902 (Kikinis, Core PI: Westin), and Swedish research Grant VR 2012-3682 (Westin). NR 57 TC 8 Z9 8 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD OCT PY 2014 VL 18 IS 7 BP 1143 EP 1156 DI 10.1016/j.media.2014.06.003 PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AP7KM UT WOS:000342256200016 PM 25047866 ER PT J AU Panagiotou, G Mu, L Na, B Mukamal, KJ Mantzoros, CS AF Panagiotou, Grigorios Mu, Lin Na, Brian Mukamal, Kenneth J. Mantzoros, Christos S. TI Circulating irisin, omentin-1, and lipoprotein subparticles in adults at higher cardiovascular risk SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Fibronectin type III domain containing 5; Myokine; Atherosclerosis; Metabolic syndrome; Longitudinal biomarker ID TYPE-2 DIABETES-MELLITUS; SLEEP QUALITY INDEX; ADIPOSE-TISSUE; INSULIN-RESISTANCE; ENDOTHELIAL-CELLS; SKELETAL-MUSCLE; MESSENGER-RNA; WEIGHT-LOSS; EXERCISE; DISEASE AB Objective. Muscle and fat are now recognized as metabolism-regulating endocrine organs. However, muscle and adipocyte-derived novel cytokines such as irisin and omentin-1 remain understudied in relation to metabolic biomarkers that are associated with cardiovascular risk. Subjects and methods. Thirty-nine subjects with mean (+/- SD) BMI of 29.2 +/- 5.4 kg/m(2) and either diabetes or two other cardiovascular risk factors were enrolled in a 6-month randomized trial of low-dose ethanol. We examined cross-sectional data at baseline, 3-month, and 6-month visits to assess (1) within-person stability of novel cytokines (irisin, omentin-1, visfatin, resistin, and soluble tumor necrosis factor receptor II) and (2) their associations with metabolic parameters, particularly lipoprotein subparticle profile. Results. Repeated measures of irisin and omentin-1 were highly correlated, with intra-class correlations of 0.84 (95% CI: 0.74, 0.91; P < 0.001) and 0.81 (0.70, 0.89; P < 0.001), respectively. Irisin was negatively correlated with omentin-1 (7.4% irisin decrease per a 1-SD increment in omentin-1; 95% CI: 0.5%, 13.9%; P = 0.04). In models adjusted for age, sex, and race, irisin was negatively associated with HDL cholesterol (7.3% decrease per a 10 mg/dL increment; 1.0%, 13.3%; P = 0.02) and large HDL particles (15.5% decrease per a 1-SD or 3.5-mu mol/L increment; 5.2%, 24.7%; P = 0.005). Omentin-1 Was positively associated with mean VLDL size (3.8% increase per a 1-SD increment; 0.06%, 7.8%; P = 0.05). Adjustment for alcohol intervention, BMI, and other cytokines did not materially affect these associations. Conclusions. Irisin and omentin-1 are stable within-person, inversely associated with each other, and closely related to lipoprotein profile. These molecules may be promising markers for cardiovascular risk. (C) 2014 Elsevier Inc. All rights reserved. C1 [Panagiotou, Grigorios; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mu, Lin; Na, Brian; Mukamal, Kenneth J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM kmukamal@bidmc.harvard.edu OI Panagiotou, Grigorios/0000-0003-0690-1478 FU National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Science Research and Development Service of the VA Office of Research and Development [1I01CX000422-01A1]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources) [8UL1TR000170-05]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard University and its affiliated academic health care centers; [R21AA016110] FX The Mantzoros Laboratory is supported by the National Institute of Diabetes and Digestive and Kidney Diseases and Award 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development. This project was also supported with grant R21AA016110 (Mukamal) and Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). NR 55 TC 24 Z9 25 U1 2 U2 20 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2014 VL 63 IS 10 BP 1265 EP 1271 DI 10.1016/j.metabol.2014.06.001 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8LU UT WOS:000342331300006 PM 25060690 ER PT J AU Klein, RL Hammad, SM Baker, NL Hunt, KJ Al Gadban, MM Cleary, PA Virella, G Lopes-Virella, MF AF Klein, Richard L. Hammad, Samar M. Baker, Nathaniel L. Hunt, Kelly J. Al Gadban, Mohammed M. Cleary, Patricia A. Virella, Gabriel Lopes-Virella, Maria F. CA DCCT EDIC Res Grp TI Decreased plasma levels of select very long chain ceramide species Are associated with the development of nephropathy in type 1 diabetes SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Sphingolipids; Sphingosine; Albuminuria; Microalbuminuria; Macroalbuminuria ID ENRICHED MEMBRANE DOMAINS; INSULIN-RESISTANCE; BIOPHYSICAL PROPERTIES; SPHINGOSINE 1-PHOSPHATE; COMPLICATIONS TRIAL; SPHINGOLIPIDS; MICROALBUMINURIA; LIPOPROTEINS; METABOLISM; PREDICTOR AB Objective. Sphingolipid metabolism is altered in diabetes and we analyzed the plasma concentrations of sphingolipid species to investigate their association with the development of albuminuria in type 1 patients with diabetes. Materials and Methods. Samples were collected from 497 type 1 diabetic patients during their enrollment into the Diabetes Control and Complications Trial (DCCT). We determined plasma concentrations of multiple ceramide species and individual sphingoid bases and their phosphates using high performance liquid chromatography-tandem mass spectrometry and investigated their association with the development of albuminuria during 14-20 years of follow-up. Results. Patients exhibited normal albumin excretion rates (AER <40 mg/24 h) at the time of plasma sampling. Although the majority of patients (N = 291; 59%) exhibited normal levels of albuminuria throughout follow-up, 141 patients (28%) progressed to microalbuminuria (40 mg/24 h <= AER < 300 mg/24 h), while 65 (13%) progressed to macroalbuminuria (AER >= 300 mg/24 h). To test the association of log transformed plasma sphingolipid level with the development of albuminuria, generalized logistic regression models were used where normal, micro- and macroalbuminuria were the outcomes of interest. Models were adjusted for DCCT treatment group, baseline retinopathy, gender, baseline HbA1c %, age, AER, lipid levels, diabetes duration, and the use of ACE/ARB drugs. Increased plasma levels of very long, but not long chain ceramide species measured at DCCT baseline were associated with decreased odds to develop macroalbuminuria during the subsequent nineteen years (DCCT Baseline to EDIC year 8). Conclusion. These studies demonstrate, prospectively, that decreased plasma levels of select ceramide species are associated with the development of macroalbuminuria in type 1 diabetes. Published by Elsevier Inc. C1 [Klein, Richard L.; Lopes-Virella, Maria F.] Med Univ S Carolina, Dept Med, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Klein, Richard L.; Hunt, Kelly J.; Lopes-Virella, Maria F.] Vet Affairs Med Ctr, Ralph H Johnson Dept, Res Serv, Charleston, SC 29403 USA. [Hammad, Samar M.; Al Gadban, Mohammed M.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Baker, Nathaniel L.; Hunt, Kelly J.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Cleary, Patricia A.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Virella, Gabriel] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Klein, RL (reprint author), Med Univ S Carolina, 114 Doughty St,MSC 776, Charleston, SC 29425 USA. EM kleinrl@musc.edu; hammadsm@musc.edu FU National Institutes of Health [P01-HL55782, DK081352, DK088778, HL-079274, DK081352-S1]; Department of Veterans Affairs Merit Review Program; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK); National Institutes of Health; National Center for Research Resources through the GCRC program; Genentech, Inc. FX This work was supported by National Institutes of Health, grants P01-HL55782 & DK081352 (MLV), DK088778 (KJH), HL-079274 (SMH), DK081352-S1 (ARRA-MLV). Additional funding was obtained from the Department of Veterans Affairs Merit Review Program (MLV and RLK). The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. The DCCT/EDIC is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and the National Institutes of Health. Additional support was provided by the National Center for Research Resources through the GCRC program and by Genentech, Inc. through a cooperative research and development agreement with the NIDDK. The authors gratefully acknowledge the Lipidomics Shared Resource Facility at MUSC for their continued expert analytical contributions without which this work could not have been conducted. The technical assistance of Ms. Charlyne Chassereau and Ms. Andrea Semler also is acknowledged. The authors are also grateful to the patients in the DCCT/EDIC for their long-term participation in this important trial. NR 37 TC 8 Z9 8 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 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2014 VL 63 IS 10 BP 1287 EP 1295 DI 10.1016/j.metabol.2014.07.001 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8LU UT WOS:000342331300009 PM 25088746 ER PT J AU Kazlauskas, A AF Kazlauskas, Andrius TI Plakophilin-2 Promotes Activation of Epidermal Growth Factor Receptor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Editorial Material ID EGF RECEPTOR; PDGF RECEPTOR; MEMBRANE AB While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, K.-I. Arimoto et al. (Mol. Cell. Biol. 34: 3843-3854, 2014, doi: 10.1128/MCB.00758-14) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor receptor (EGFR) and enhances its ligand-dependent and ligand-independent activity. This discovery suggests that antagonizing PKP2 may be a new therapeutic opportunity to combat tumors in which activation of EGFR contributes to pathogenesis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02138 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02138 USA. EM andrius_kazlauskas@meei.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2014 VL 34 IS 20 BP 3778 EP 3779 DI 10.1128/MCB.00968-14 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP6UU UT WOS:000342214200001 PM 25113561 ER PT J AU Hill, SJ Clark, AP Silver, DP Livingston, DM AF Hill, Sarah J. Clark, Allison P. Silver, Daniel P. Livingston, David M. TI BRCA1 Pathway Function in Basal-Like Breast Cancer Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PLATINUM-BASED CHEMOTHERAPY; SUSCEPTIBILITY GENE BRCA1; HOMOLOGY-DIRECTED REPAIR; DOUBLE-STRAND BREAKS; INDUCED DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; TUMOR SUPPRESSION; OVARIAN-CANCER; ESTROGEN-RECEPTOR; GENOME INTEGRITY AB Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1(+/+), sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs. C1 [Hill, Sarah J.; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02138 USA. [Hill, Sarah J.; Clark, Allison P.; Silver, Daniel P.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Silver, Daniel P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02138 USA. EM david_livingston@dfci.harvard.edu FU DOD BCRP fellowship [W81XWH-08-1-0748]; NCI fellowship [1F30CA167895-01]; Susan G. Komen Foundation [SAC110022]; Breast Cancer Research Foundation; NCI SPORE grant [P50CA089393]; NCI [RO1 (R01CA136512), P01 (P01CA080111)] FX S.J.H. was initially funded by DOD BCRP fellowship W81XWH-08-1-0748 and subsequently by NCI fellowship 1F30CA167895-01. This work was supported by grants from the Susan G. Komen Foundation for the Cure (SAC110022), the Breast Cancer Research Foundation, an NCI SPORE grant (P50CA089393) in breast cancer research to the Dana-Farber/Harvard Cancer Center, and RO1 (R01CA136512) and P01 (P01CA080111) grants from NCI to D.M.L. NR 70 TC 14 Z9 15 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2014 VL 34 IS 20 BP 3828 EP 3842 DI 10.1128/MCB.01646-13 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP6UU UT WOS:000342214200006 PM 25092866 ER PT J AU Elvington, M Scheiber, M Yang, XF Lyons, K Jacqmin, D Wadsworth, C Marshall, D Vanek, K Tomlinson, S AF Elvington, Michelle Scheiber, Melissa Yang, Xiaofeng Lyons, Katherine Jacqmin, Dustin Wadsworth, Casey Marshall, David Vanek, Kenneth Tomlinson, Stephen TI Complement dependent modulation of anti-tumor immunity following radiation therapy SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Elvington, Michelle; Scheiber, Melissa; Yang, Xiaofeng; Wadsworth, Casey; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Lyons, Katherine; Jacqmin, Dustin; Marshall, David; Vanek, Kenneth] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 017 BP 222 EP 223 PG 2 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300036 ER PT J AU Ghosh, P Vaidya, A Sahoo, R Goldfine, A Herring, N Bry, L Chorev, M McElrath, T Halperin, J AF Ghosh, Pamela Vaidya, Anand Sahoo, Rupam Goldfine, Allison Herring, Neil Bry, Lynn Chorev, Michael McElrath, Thomas Halperin, Jose TI Blood levels of glycated CD59 (GCD59) as a novel biomarker for glucose handling in humans SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Ghosh, Pamela; Vaidya, Anand; Sahoo, Rupam; Chorev, Michael; Halperin, Jose] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Goldfine, Allison] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Herring, Neil; Bry, Lynn] Partners Healthcare Syst, Crimson Biospecimen Core, Boston, MA USA. [McElrath, Thomas] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Obstet & Gynecol, Boston, MA 02115 USA. RI SAHOO, RUPAM/B-3935-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 016 BP 222 EP 222 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300035 ER PT J AU Takahashi, K Ohtani, K Larvie, M Moyo, P Chigweshe, L Van Cott, E Wakamiya, N AF Takahashi, Kazue Ohtani, Katsuki Larvie, Mykol Moyo, Patience Chigweshe, Lorencia Van Cott, Elizabeth Wakamiya, Nobutaka TI The new biological aspects in CL-K1 (Collectin Kidney 1) SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Van Cott, Elizabeth] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ohtani, Katsuki; Wakamiya, Nobutaka] Asahikawa Med Univ, Dept Microbiol & Immunochem, Asahikawa, Hokkaido, Japan. NR 0 TC 0 Z9 0 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 060 BP 238 EP 238 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300079 ER PT J AU Marshall, KM He, SQ Zhong, Z Atkinson, C Tomlinson, S AF Marshall, Keely M. He, Songqing Zhong, Zhi Atkinson, Carl Tomlinson, Stephen TI Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Marshall, Keely M.; He, Songqing; Atkinson, Carl; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [He, Songqing] Guilin Med Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Guilin 541001, Guangxi, Peoples R China. [Zhong, Zhi] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 163 BP 273 EP 274 PG 2 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300182 ER PT J AU Herschhorn, A Gu, C Espy, N Richard, J Finzi, A Sodroski, JG AF Herschhorn, Alon Gu, Christopher Espy, Nicole Richard, Jonathan Finzi, Andres Sodroski, Joseph G. TI A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry SO NATURE CHEMICAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY PG9; HUMAN MONOCLONAL-ANTIBODY; CD4-BOUND CONFORMATION; RECEPTOR-BINDING; VARIABLE LOOPS; GP120; IDENTIFICATION; INFECTION; CD4 AB Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41)(3)) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A. C1 [Herschhorn, Alon; Gu, Christopher; Espy, Nicole; Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Herschhorn, Alon; Espy, Nicole; Sodroski, Joseph G.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Richard, Jonathan; Finzi, Andres] Univ Montreal, Ctr Rech, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Richard, Jonathan; Finzi, Andres] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Finzi, Andres] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Sodroski, Joseph G.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, JG (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU amfAR; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [108501-53-RKNT]; Canadian Institutes of Health Research operating grant [119334]; Fonds de la recherche en sante du Quebec Chercheur Boursier Junior fellowship [24639]; Canada Research Chair on Retroviral Entry; NIH [AI24755, GM56550] FX We thank Y. McLaughlin and E. Carpelan for manuscript preparation; the AIDS Research and the Reference Reagent Program, Division of AIDS, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH) for providing reference panels for subtype B and C HIV-1 envelope clones, CFR01_AE.269 HIV-1 envelope clone, psPAX2 plasmid, T20, maraviroc and CEM cells. We also thank B. Keele, G. M. Shaw and the Center for HIV-AIDS Vaccine Immunology Consortium for providing transmitted/founder HIV-1 envelope clones; H.-X. Liao and B.F. Haynes (Duke University Medical Center) for providing the CRF01_AE.CM244 HIV-1 envelope clone; D. Burton (The Scripps Research Institute), J. Robinson (Tulane University) and P.D. Kwong (Vaccine Research Center, NIH) for providing the anti-gp120 monoclonal antibodies; D. Flood, J. Smith and C. Shamu (Institute of Chemistry and Cell Biology, Harvard Medical School) for assistance in the high-throughput screening campaign; and E. Pery, E. Cassol, V. Misra, N. Madani, H. Haim and A.M. Princiotto from Dana-Farber Cancer Institute for helpful discussions and for providing reagents. A.H. was supported by amfAR and is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108501-53-RKNT). A.F. was supported by Canadian Institutes of Health Research operating grant number 119334 and is the recipient of a Fonds de la recherche en sante du Quebec Chercheur Boursier Junior fellowship number 24639 and a Canada Research Chair on Retroviral Entry. Support for this work was also provided by grants from the NIH to J.G.S. (grant numbers AI24755 and GM56550). NR 40 TC 20 Z9 20 U1 1 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2014 VL 10 IS 10 BP 845 EP + DI 10.1038/NCHEMBIO.1623 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ0GV UT WOS:000342462100011 PM 25174000 ER PT J AU Chaikuad, A Tacconi, EMC Zimmer, J Liang, YK Gray, NS Tarsounas, M Knapp, S AF Chaikuad, Apirat Tacconi, Eliana M. C. Zimmer, Jutta Liang, Yanke Gray, Nathanael S. Tarsounas, Madalena Knapp, Stefan TI A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics SO NATURE CHEMICAL BIOLOGY LA English DT Article ID MAP KINASE ERK2; POLY(ADP-RIBOSE) POLYMERASE; ACQUIRED-RESISTANCE; MEK INHIBITORS; RAF INHIBITION; DNA-DAMAGE; BRAF; CONFORMATION; SELECTIVITY; DISCOVERY AB Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix alpha C. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity. C1 [Chaikuad, Apirat; Knapp, Stefan] Univ Oxford, Struct Genom Consortium, Oxford, England. [Tacconi, Eliana M. C.; Zimmer, Jutta; Tarsounas, Madalena] Canc Res UK, Telomere & Genome Stabil Grp, Oxford, England. [Tacconi, Eliana M. C.; Zimmer, Jutta; Tarsounas, Madalena] Oxford Inst Radiat Oncol, MRC, Oxford, England. [Liang, Yanke; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Knapp, Stefan] George Washington Univ, Dept Biochem & Mol Med, Washington, DC USA. [Knapp, Stefan] Univ Oxford, Target Discovery Inst, Oxford, England. RP Knapp, S (reprint author), Univ Oxford, Struct Genom Consortium, Old Rd Campus,Res Bldg, Oxford, England. EM madalena.tarsounas@oncology.ox.ac.uk; stefan.knapp@ndm.ox.ac.uk OI Knapp, Stefan/0000-0001-5995-6494 FU Structural Genomics Consortium; AbbVie [1097737]; Bayer; Boehringer Ingelheim; Canada Foundation for Innovation; Canadian Institutes for Health Research; Genome Canada; GlaxoSmithKline; Janssen; Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z]; European Union FP7 Grant [278568]; Cancer Research UK; EMBO Young Investigator Program; Royal Society; Medical Research Council PhD Studentship FX S.K. is supported by the Structural Genomics Consortium, a registered charity (number 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/10/Z). A.C. is supported by the European Union FP7 Grant No. 278568 'PRIMES' (Protein interaction machines in oncogenic EGF receptor signalling). Work in M.T.'s laboratory is supported by Cancer Research UK, the EMBO Young Investigator Program and The Royal Society, and E.T. is funded by a Medical Research Council PhD Studentship. We thank the staff at Diamond Light Source for assistance during data collection at the synchrotron and H. Lee (Seoul National University) for providing the sheep anti-BRCA2 antibody. NR 58 TC 34 Z9 34 U1 3 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2014 VL 10 IS 10 BP 853 EP + DI 10.1038/NCHEMBIO.1629 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ0GV UT WOS:000342462100012 PM 25195011 ER PT J AU Al Olama, AA Kote-Jarai, Z Berndt, SI Conti, DV Schumacher, F Han, Y Benlloch, S Hazelett, DJ Wang, ZM Saunders, E Leongamornlert, D Lindstrom, S Jugurnauth-Little, S Dadaev, T Tymrakiewicz, M Stram, DO Rand, K Wan, P Stram, A Sheng, X Pooler, LC Park, K Xia, L Tyrer, J Kolonel, LN Le Marchand, L Hoover, RN Machiela, MJ Yeager, M Burdette, L Chung, CC Hutchinson, A Yu, K Goh, C Ahmed, M Govindasami, K Guy, M Tammela, TLJ Auvinen, A Wahlfors, T Schleutker, J Visakorpi, T Leinonen, KA Xu, JF Aly, M Donovan, J Travis, RC Key, TJ Siddiq, A Canzian, F Khaw, KT Takahashi, A Kubo, M Pharoah, P Pashayan, N Weischer, M Nordestgaard, BG Nielsen, SF Klarskov, P Roder, MA Iversen, P Thibodeau, SN McDonnell, SK Schaid, DJ Stanford, JL Kolb, S Holt, S Knudsen, B Coll, AH Gapstur, SM Diver, WR Stevens, VL Maier, C Luedeke, M Herkommer, K Rinckleb, AE Strom, SS Pettaway, C Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Choklcalingam, AP Cannon-Albright, L Cybulski, C Wokolorczyk, D Kluzniak, W Park, J Sellers, T Lin, HY Isaacs, WB Partin, AW Brenner, H Dieffenbach, AK Stegmaier, C Chen, C Giovannucci, EL Ma, J Stampfer, M Penney, KL Mucci, L John, EM Ingles, SA Kittles, RA Murphy, AB Pandha, H Michael, A Kierzek, AM Blot, W Signorello, LB Zheng, W Albanes, D Virtamo, J Weinstein, S Nemesure, B Carpten, J Leske, C Wu, SY Hennis, A Kibel, AS Rybicki, BA Neslund-Dudas, C Hsing, AW Chu, L Goodman, PJ Klein, EA Zheng, SL Batra, J Clements, J Spurdle, A Teixeira, MR Paulo, P Maia, S Slavov, C Kaneva, R Mitev, V Witte, JS Casey, G Gillanders, EM Seminara, D Riboli, E Hamdy, FC Coetzee, GA Li, QY Freedman, ML Hunter, DJ Muir, K Gronberg, H Nea, DE Southey, M Giles, GG Severi, G Cook, MB Nakagawa, H Wiklund, F Kraft, P Chanock, SJ Henderson, BE Easton, DF Eeles, RA Haiman, CA AF Al Olama, Ali Amin Kote-Jarai, Zsofia Berndt, Sonja I. Conti, David V. Schumacher, Fredrick Han, Ying Benlloch, Sara Hazelett, Dennis J. Wang, Zhaoming Saunders, Ed Leongamornlert, Daniel Lindstrom, Sara Jugurnauth-Little, Sara Dadaev, Tokhir Tymrakiewicz, Malgorzata Stram, Daniel O. Rand, Kristin Wan, Peggy Stram, Alex Sheng, Xin Pooler, Loreall C. Park, Karen Xia, Lucy Tyrer, Jonathan Kolonel, Laurence N. Le Marchand, Loic Hoover, Robert N. Machiela, Mitchell J. Yeager, Merideth Burdette, Laurie Chung, Charles C. Hutchinson, Amy Yu, Kai Goh, Chee Ahmed, Mahbubl Govindasami, Koveela Guy, Michelle Tammela, Teuvo L. J. Auvinen, Anssi Wahlfors, Tlina Schleutker, Johanna Visakorpi, Tapio Leinonen, Katri A. Xu, Jianfeng Aly, Markus Donovan, Jenny Travis, Ruth C. Key, Tim J. Siddiq, Afshan Canzian, Federico Khaw, Kay-Tee Takahashi, Atsushi Kubo, Michiaki Pharoah, Paul Pashayan, Nora Weischer, Maren Nordestgaard, Borge G. Nielsen, Sune F. Klarskov, Peter Roder, Martin Andreas Iversen, Peter Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Stanford, Janet L. Kolb, Suzanne Holt, Sarah Knudsen, Beatrice Coll, Antonio Hurtado Gapstur, Susan M. Diver, W. Ryan Stevens, Victoria L. Maier, Christiane Luedeke, Manuel Herkommer, Kathleen Rinckleb, Antje E. Strom, Sara S. Pettaway, Curtis Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Choklcalingam, Anand P. Cannon-Albright, Lisa Cybulski, Cezary Wokolorczyk, Dominika Kluzniak, Wojciech Park, Jong Sellers, Thomas Lin, Hui-Yi Isaacs, William B. Partin, Alan W. Brenner, Hermann Dieffenbach, Aida Karina Stegmaier, Christa Chen, Constance Giovannucci, Edward L. Ma, Jing Stampfer, Meir Penney, Kathryn L. Mucci, Lorelei John, Esther M. Ingles, Sue A. Kittles, Rick A. Murphy, Adam B. Pandha, Hardev Michael, Agnieszka Kierzek, Andrzej M. Blot, William Signorello, Lisa B. Zheng, Wei Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Nemesure, Barbara Carpten, John Leske, Cristina Wu, Suh-Yuh Hennis, Anselm Kibel, Adam S. Rybicki, Benjamin A. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Zheng, S. Lilly Batra, Jyotsna Clements, Judith Spurdle, Amanda Teixeira, Manuel R. Paulo, Paula Maia, Sofia Slavov, Chavdar Kaneva, Radka Mitev, Vanio Witte, John S. Casey, Graham Gillanders, Elizabeth M. Seminara, Daniella Riboli, Elio Hamdy, Freddie C. Coetzee, Gerhard A. Li, Qiyuan Freedman, Matthew L. Hunter, David J. Muir, Kenneth Gronberg, Henrik Nea, David E. Southey, Melissa Giles, Graham G. Severi, Gianluca Cook, Michael B. Nakagawa, Hidewaki Wiklund, Fredrik Kraft, Peter Chanock, Stephen J. Henderson, Brian E. Easton, Douglas F. Eeles, Rosalind A. Haiman, Christopher A. CA Breast Prostate Canc Cohort Consor Practical Prostate Canc Associatio COGS Consortium GAME-ON ELLIPSE Consortium TI A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; MYOSIN VI; RISK; JAPANESE; GLIOMA; 22Q13; MEN AB Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 x 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease. C1 [Al Olama, Ali Amin; Benlloch, Sara; Tyrer, Jonathan; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Kote-Jarai, Zsofia; Saunders, Ed; Leongamornlert, Daniel; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England. [Berndt, Sonja I.; Wang, Zhaoming; Hoover, Robert N.; Machiela, Mitchell J.; Yeager, Merideth; Burdette, Laurie; Chung, Charles C.; Hutchinson, Amy; Yu, Kai; Cook, Michael B.; Chanock, Stephen J.] Natl Canc Inst, US NIH, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Conti, David V.; Schumacher, Fredrick; Han, Ying; Hazelett, Dennis J.; Stram, Daniel O.; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C.; Park, Karen; Xia, Lucy; Ingles, Sue A.; Casey, Graham; Coetzee, Gerhard A.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Conti, David V.; Schumacher, Fredrick; Hazelett, Dennis J.; Stram, Daniel O.; Ingles, Sue A.; Casey, Graham; Coetzee, Gerhard A.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Wang, Zhaoming] SAIC Frederick Inc, Natl Canc Inst, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Frederick, MD USA. [Lindstrom, Sara; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Tammela, Teuvo L. J.] Univ Tampere, Tampere Univ Hosp, Dept Urol, FIN-33101 Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, Dept Epidemiol, FIN-33101 Tampere, Finland. [Wahlfors, Tlina; Schleutker, Johanna] Univ Tampere, BioMediTech, Tampere, Finland. [Wahlfors, Tlina; Schleutker, Johanna] Univ Tampere, FimLab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Turku, Inst Biomed, Dept Biochem Med, Turku, Finland. [Visakorpi, Tapio; Leinonen, Katri A.] Univ Tampere, BioMediTech, Inst Biomed Technol, Tampere, Finland. [Visakorpi, Tapio; Leinonen, Katri A.] Tampere Univ Hosp, Tampere, Finland. [Xu, Jianfeng; Zheng, S. Lilly] Wake Forest Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Aly, Markus; Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Aly, Markus] Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. [Donovan, Jenny] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Travis, Ruth C.; Key, Tim J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Takahashi, Atsushi] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Kubo, Michiaki] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Pharoah, Paul; Pashayan, Nora] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Fac Hlth & Med Sci, Herlev, Denmark. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Herlev, Denmark. [Roder, Martin Andreas; Iversen, Peter] Copenhagen Univ Hosp, Rigshosp, Copenhagen Prostate Canc Ctr, Dept Urol, Copenhagen, Denmark. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Rochester, MN USA. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Holt, Sarah] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Knudsen, Beatrice] Cedars Sinai, Translat Pathol, Los Angeles, CA USA. [Coll, Antonio Hurtado] Prostate Ctr, Vancouver, BC, Canada. [Gapstur, Susan M.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Maier, Christiane; Luedeke, Manuel] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-80290 Munich, Germany. [Rinckleb, Antje E.; Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Pettaway, Curtis] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Univ Ghana, Sch Med, Accra, Ghana. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Korle Bu Teaching Hosp, Accra, Ghana. [Truelove, Ann; Niwa, Shelley] Westat Corp, Rockville, MD USA. [Choklcalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. [Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Park, Jong; Sellers, Thomas] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Lin, Hui-Yi] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Isaacs, William B.; Partin, Alan W.] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Consortium, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Giovannucci, Edward L.; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; Signorello, Lisa B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Div Network Med, Boston, MA 02115 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Cancer Prevent Inst Calif, Fremont, CA USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M.] Univ Surrey, Fac Hlth & Med Sci, Guildford, Surrey, England. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Blot, William; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN 37235 USA. [Albanes, Demetrius; Weinstein, Stephanie] US Natl Inst Hlth, Natl Canc Inst, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Nemesure, Barbara; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm] Translat Genom Res Inst, Phoenix, AZ USA. [Kibel, Adam S.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Rybicki, Benjamin A.; Neslund-Dudas, Christine] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. [Goodman, Phyllis J.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Klein, Eric A.] Fred Hutchinson Canc Res Ctr, Ctr Stat, Southwest Oncol Grp, Seattle, WA 98104 USA. [Batra, Jyotsna; Clements, Judith] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. [Spurdle, Amanda] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Queensland, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia] Queensland Univ Technol, Sch Biomed Sci, Translat Res Inst, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.] QIMR Berghofer Med Res Inst, Mol Canc Epidemiol Lab, Brisbane, Qld, Australia. [Slavov, Chavdar] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Kaneva, Radka; Mitev, Vanio] Univ Porto, Biomed Sci Inst, Oporto, Portugal. [Witte, John S.] Med Univ Sofia, Dept Urol, Sofia, Bulgaria. [Witte, John S.] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gillanders, Elizabeth M.; Seminara, Daniella] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Li, Qiyuan; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Nea, David E.] Canc Res UK, Li Ka Shing Ctr, Cambridge Res Inst, Cambridge, England. [Nea, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Severi, Gianluca] Human Genet Fdn, Turin, Italy. [Nakagawa, Hidewaki] RIKEN, Ctr Integrat Med Sci, Lab Genome Sequencing Anal, Tokyo, Japan. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM rosalind.eeles@icr.ac.uk; haiman@usc.edu RI Albanes, Demetrius/B-9749-2015; Cook, Michael/A-5641-2009; Paulo, Paula/F-1441-2016; Teixeira, Manuel/E-4885-2011; Kubo, Michiaki/N-7947-2015; Batra, Jyotsna/B-4130-2011; Brenner, Hermann/B-4627-2017; Spurdle, Amanda/A-4978-2011 OI albright, lisa/0000-0003-2602-3668; Machiela, Mitchell/0000-0001-6538-9705; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; Leongamornlert, Daniel/0000-0002-3486-3168; Cook, Michael/0000-0002-0533-7302; Paulo, Paula/0000-0001-8387-2127; Teixeira, Manuel/0000-0002-4896-5982; Brenner, Hermann/0000-0002-6129-1572; Roder, Martin Andreas/0000-0002-0019-5333; Kierzek, Andrzej/0000-0002-2605-9057; Eeles, Rosalind/0000-0002-3698-6241; Hazelett, Dennis/0000-0003-0749-9935; Spurdle, Amanda/0000-0003-1337-7897 FU Cancer Research UK [10118, 10124, 13065, 14136]; Medical Research Council [G0401527, G0900871, G1000143]; NCI NIH HHS [R01 CA136924, P30 CA042014, P30 CA068485, P30 CA076292, P50 CA140388, R01 CA056678, R01 CA068578, R01 CA072818, R01 CA082664, R01 CA084979, R01 CA088164, R01 CA092447, R01 CA092579, R01 CA128813, R01 CA128978, R37 CA054281, RC2 CA148085, U01 CA063464, U01 CA089600, U01 CA098216, U01 CA098233, U01 CA098710, U01 CA098758, U01 CA127298, U01 CA136792, U10 CA037429, U19 CA148065, U19 CA148112, U19 CA148537, UG1 CA189974, UM1 CA182883]; NHGRI NIH HHS [U01 HG004446, U01 HG004726]; NIEHS NIH HHS [P30 ES007784, R01 ES011126]; NIGMS NIH HHS [S06 GM008016]; Prostate Cancer UK [G2011/36, G2012/48] NR 29 TC 103 Z9 103 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1103 EP 1109 DI 10.1038/ng.3094 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100013 PM 25217961 ER PT J AU Gharahkhani, P Burdon, KP Fogarty, R Sharma, S Hewitt, AW Martin, S Law, MH Cremin, K Bailey, JNC Loomis, SJ Pasquale, LR Haines, JL Hauser, MA Viswanathan, AC McGuffin, P Topouzis, F Foster, PJ Graham, SL Casson, RJ Chehade, M White, AJ Zhou, T Souzeau, E Landers, J Fitzgerald, JT Klebe, S Ruddle, JB Goldberg, I Healey, PR Mills, RA Wang, JJ Montgomery, GW Martin, NG Radford-Smith, G Whiteman, DC Brown, MA Wiggs, JL Mackey, DA Mitchell, P MacGregor, S Craig, JE AF Gharahkhani, Puya Burdon, Kathryn P. Fogarty, Rhys Sharma, Shiwani Hewitt, Alex W. Martin, Sarah Law, Matthew H. Cremin, Katie Bailey, Jessica N. Cooke Loomis, Stephanie J. Pasquale, Louis R. Haines, Jonathan L. Hauser, Michael A. Viswanathan, Ananth C. McGuffin, Peter Topouzis, Fotis Foster, Paul J. Graham, Stuart L. Casson, Robert J. Chehade, Mark White, Andrew J. Zhou, Tiger Souzeau, Emmanuelle Landers, John Fitzgerald, Jude T. Klebe, Sonja Ruddle, Jonathan B. Goldberg, Ivan Healey, Paul R. Mills, Richard A. Wang, Jie Jin Montgomery, Grant W. Martin, Nicholas G. Radford-Smith, Graham Whiteman, David C. Brown, Matthew A. Wiggs, Janey L. Mackey, David A. Mitchell, Paul MacGregor, Stuart Craig, Jamie E. CA Wellcome Trust Case Control Consor NEIGHBORHOOD Consortium TI Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INTRAOCULAR-PRESSURE; TRABECULAR MESHWORK; ACTIN-FILAMENTS; AQUEOUS-HUMOR; GENE; IDENTIFICATION; AFAP-110; ABILITY AB Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 x 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 x 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 x 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells. C1 [Gharahkhani, Puya; Law, Matthew H.; Montgomery, Grant W.; Martin, Nicholas G.; Whiteman, David C.; MacGregor, Stuart] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Burdon, Kathryn P.; Fogarty, Rhys; Sharma, Shiwani; Martin, Sarah; Zhou, Tiger; Souzeau, Emmanuelle; Landers, John; Fitzgerald, Jude T.; Mills, Richard A.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Burdon, Kathryn P.; Mackey, David A.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia. [Burdon, Kathryn P.; Hewitt, Alex W.; Ruddle, Jonathan B.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, CERA, Melbourne, Vic, Australia. [Cremin, Katie; Brown, Matthew A.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp Natl Hlth Serv NHS Fdn Trus, Biomed Res Ctr, NIHR, London, England. [Viswanathan, Ananth C.; Foster, Paul J.] UCL, Inst Ophthalmol, London, England. [McGuffin, Peter] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, MRC, London, England. [Topouzis, Fotis] Aristotle Univ Thessaloniki, Sch Med, AHEPA Hosp, Dept Ophthalmol, Thessaloniki, Greece. [Graham, Stuart L.] Macquarie Univ, Sydney, NSW 2109, Australia. [Casson, Robert J.; Chehade, Mark] Univ Adelaide, South Australian Inst Ophthalmol, Adelaide, SA, Australia. [White, Andrew J.; Healey, Paul R.; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Westmead, NSW 2145, Australia. [Klebe, Sonja] Flinders Univ S Australia, Flinders Med Ctr, Dept Anat Pathol, Adelaide, SA 5001, Australia. [Goldberg, Ivan] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Radford-Smith, Graham] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Craig, Jamie E.] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. RP Craig, JE (reprint author), Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. EM puya.gharahkhani@qimrberghofer.edu.au; jamie.craig@flinders.edu.au RI Montgomery, Grant/B-7148-2008; Hewitt, Alex/D-1936-2013; Whiteman, David/P-2728-2014; Mackey, David/H-5340-2014; Macgregor, Stuart/C-6442-2009; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014 OI Montgomery, Grant/0000-0002-4140-8139; Hewitt, Alex/0000-0002-5123-5999; Whiteman, David/0000-0003-2563-9559; Mackey, David/0000-0001-7914-4709; Gharahkhani, Puya/0000-0002-4203-5952; Martin, Nicholas/0000-0003-4069-8020; Macgregor, Stuart/0000-0001-6731-8142; Wang, Jie Jin/0000-0001-9491-4898; FU Royal Australian; New Zealand College of Ophthalmology (RANZCO) Eye Foundation; National Health and Medical Research Council (NHMRC) of Australia [535074, 1023911]; NHMRC [1031362, 1037838, 1048037, 1009844, 1031920]; Alcon Research Institute grant; Allergan Unrestricted grant; BrightFocus Foundation; Ramaciotti Establishment Grant; Queensland Cancer Fund; NHMRC of Australia [199600, 552429, 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498]; US National Cancer Institute [5 R01 CA 001833, R01 CA 136725]; NHMRC Medical Genomics Grant; US National Institutes of Health (NIH) Center for Inherited Research (CIDR), NIH/National Eye Institute (NEI) [1RO1EY018246]; Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne); NHMRC, Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases; NHMRC Senior Research Fellowships [358702, 632909]; Wellcome Trust, UK, Wellcome Trust Case Control Consortium 2 [085475B08Z, 08547508Z, 076113]; Medical Research Council (MRC) [G0401527]; Research Into Ageing [262]; NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology funds [BRC2_009]; NEI [HG005259-01]; NIH [HHSN268200782096C, EY015543, EY006827, HL73042, HL073389, EY13315, EY023646, CA87969]; NEI through American Recovery and Reinvestment Act (ARRA) [3R01EY015872-05S1, 3R01EY019126-02S1]; Harvard Glaucoma Center for Excellence; Margolis Fund; Glaucoma Research Foundation; American Health Assistance Foundation; Glaucoma Foundation; Research to Prevent Blindness; NIH GEI (Gene Environment Initiative) [U01HG04424, U01HG004728]; GENEVA Coordinating Center [U01HG004446]; Australian Research Council (ARC); NHMRC Fellowships; Australian NHMRC Fellowships; ARC; NHMRC; [EY022305]; [CA49449]; [CA55075]; [EY009149]; [HG004608]; [EY008208]; [EY015473]; [EY012118]; [EY015682]; [EY011671]; [EY09580]; [EY013178]; [RR015574]; [EY015872]; [EY010886]; [EY009847]; [EY014104]; [EY011008]; [EY144428]; [EY144448]; [EY18660]; [T32 EY007157]; [T32 EY21453-2] FX Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG): support for recruitment of ANZRAG was provided by the Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation. Genotyping was funded by the National Health and Medical Research Council (NHMRC) of Australia (#535074 and #1023911). This work was also supported by funding from NHMRC #1031362 awarded to J.E.C., NHMRC #1037838 awarded to A.W.H., NHMRC #1048037 awarded to S.L.G., NHMRC #1009844 awarded to R.J.C. and I.G., NHMRC #1031920 and an Alcon Research Institute grant awarded to D.A.M., an Allergan Unrestricted grant awarded to A.J.W., the BrightFocus Foundation and a Ramaciotti Establishment Grant. The authors acknowledge the support of B. Usher-Ridge in patient recruitment and data collection and P. Danoy and J. Hadler for genotyping.; Controls for the ANZRAG discovery cohort were drawn from the Australian Cancer Study, the Study of Digestive Health and a study of inflammatory bowel diseases. The Australian Cancer Study was supported by the Queensland Cancer Fund and the NHMRC of Australia (program number 199600, awarded to D.C.W., A.C. Green, N.K. Hayward, P.G. Parsons, D.M. Purdie and P.M. Webb, and program number 552429, awarded to D.C.W.). The Study of Digestive Health was supported by grant number 5 R01 CA 001833 from the US National Cancer Institute (awarded to D.C.W.).; The Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) sponsored the genotyping of cases with esophageal cancer and Barrett's esophagus, which were used as unscreened controls in the ANZRAG discovery cohort. BEAGESS was funded by grant R01 CA 136725 from the US National Cancer Institute.; Genotyping for part of the Australian twin control sample included in the ANZRAG replication cohort was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder of twin controls was performed by the US National Institutes of Health (NIH) Center for Inherited Research (CIDR) as part of NIH/National Eye Institute (NEI) grant 1RO1EY018246, and we are grateful to C. Day and staff We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We thank Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides and the Queensland Medical Laboratory for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. The QIMR twin and endometriosis studies were supported by grants from the NHMRC of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. and S. Hawkins. We thank M.J. Wright, M.J. Campbell, A. Caracella, S. Gordon, D.R. Nyholt, A.K. Henders, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input into project management, databases, sample processing and genotyping. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR twin collection.; Blue Mountains Eye Study (BMES): BMES was supported by the NHMRC, Canberra Australia (974159, 211069, 457349, 512423, 475604 and 529912), the Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, NHMRC Senior Research Fellowships (358702 and 632909 to J.J.W.) and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (A.C.V., P. McGuffin, P. Mitchell, F.T. and P.J.F.) for genotyping costs of the entire BMES population (085475B08Z, 08547508Z, 076113). P.J.F. is also supported by Medical Research Council (MRC) G0401527, Research Into Ageing (Ref 262) and NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology (BRC2_009) funds.; The BMES acknowledges E. Rochtchina from the Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute University of Sydney, J. Attia, R. Scott and E.G. Holliday from the University of Newcastle, J. Xie and P.N. Baird from the Centre for Eye Research Australia, University of Melbourne, M.T. Inouye, Medical Systems Biology, Department of Pathology and Department of Microbiology and Immunology, University of Melbourne and X. Sim, National University of Singapore.; NEI Glaucoma Human Genetics Collaboration (NEIGHBOR): genotyping services for the NEIGHBOR study were provided by the CIDR and were supported by the NEI through grant HG005259-01 (J.L.W.). Additionally, CIDR is funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. Collecting and processing samples for the NEIGHBOR data set was supported by the NEI through American Recovery and Reinvestment Act (ARRA) grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.). Genotype imputation and meta-analysis were supported by EY022305 (J.L.W.). Funding for the collection of cases and controls was provided by the following NIH grants: EY015543 (R.R. Allingham); EY006827 (D. Gaasterland); HL73042, HL073389, EY13315, EY023646 (M.A.H.); CA87969, CA49449, CA55075 (J.H. Kang); EY009149 (P.R. Lichter); HG004608 (C. McCarty); EY008208 (EA. Medeiros); EY015473 (L.R.P.); EY012118 (M. Pericak-Vance); EY015682 (A. Realini); EY011671, EY09580 (J.E. Richards); EY013178 (J.S. Schuman); RR015574, EY015872, EY010886, EY009847, EY014104 (J.L.W.); EY011008, EY144428, EY144448 and EY18660 (K. Zhang). J.L.W. and L.R.P. are also supported by the Harvard Glaucoma Center for Excellence and the Margolis Fund. Y. Liu is supported by the Glaucoma Research Foundation, the American Health Assistance Foundation and the Glaucoma Foundation. J.L.W., L.R.P., D.C. Musch and J.E. Richards are supported by Research to Prevent Blindness. J.N.C.B. is supported by NIH T32 EY007157 (CWRU) and T32 EY21453-2 (VUMC).; MEEI case-control sample: genotyping for the Massachusetts Eye and Ear Infirmary (MEEI) case-control sample was performed at the Broad Institute of MIT and Harvard with funding support from the NIH GEI (Gene Environment Initiative) (U01HG04424 and U01HG004728). The GENEVA Coordinating Center (U01HG004446) assisted with genotype cleaning. Imputation was supported by NIH EY022305. Collection of cases and controls was supported by NIH EY015872.; Support for molecular analysis of the associated genes was provided by the Ophthalmic Research Institute of Australia. The authors acknowledge the support of M. Philpott in collection of cadaveric human eye tissues and N. Mabarrack for initial optimization of the antibody to AFAP.; S. MacGregor is supported by Australian Research Council (ARC) and NHMRC Fellowships. G.W.M., M.A.B., K.P.B., D.C.W. and J.E.C. are supported by Australian NHMRC Fellowships. D.C.W. was funded by the ARC and G.R.-S. was funded by NHMRC during the period of this study. The authors acknowledge C. Abbot (Alcon Research Ltd.) for providing normal and glaucomatous trabecular meshwork cell lines, NTM-5 and GTM-3, respectively, as a kind gift. NR 33 TC 36 Z9 37 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1120 EP 1125 DI 10.1038/ng.3079 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100016 PM 25173105 ER PT J AU Hysi, PG Cheng, CY Springelkamp, H Macgregor, S Bailey, JNC Wojciechowski, R Vitart, V Nag, A Hewitt, AW Hohn, R Venturini, C Mirshahi, A Ramdas, WD Thorleifsson, G Vithana, E Khor, CC Stefansson, AB Liao, JM Haines, JL Amin, N Wang, YX Wild, PS Ozel, AB Li, JZ Fleck, BW Zeller, T Staffieri, SE Teo, YY Cuellar-Partida, G Luo, XY Allingham, RR Richards, JE Senft, A Karssen, LC Zheng, YF Bellenguez, C Xu, L Iglesias, AI Wilson, JF Kang, JH van Leeuwen, EM Jonsson, V Thorsteinsdottir, U Despriet, DDG Ennis, S Moroi, SE Martin, NG Jansonius, NM Yazar, S Tai, ES Amouyel, P Kirwan, J van Koolwijk, LME Hauser, MA Jonasson, F Leo, P Loomis, SJ Fogarty, R Rivadeneira, F Kearns, L Lackner, KJ de Jong, PTVM Simpson, CL Pennell, CE Oostra, BA Uitterlinden, AG Saw, SM Lotery, AJ Bailey-Wilson, JE Hofman, A Vingerling, JR Maubaret, C Pfeiffer, N Wolfs, RCW Lemij, HG Young, TL Pasquale, LR Delcourt, C Spector, TD Klaver, CCW Small, KS Burdon, KP Stefansson, K Wong, TY Viswanathan, A Mackey, DA Craig, JE Wiggs, JL van Duijn, CM Hammond, CJ Aung, T AF Hysi, Pirro G. Cheng, Ching-Yu Springelkamp, Henriet Macgregor, Stuart Bailey, Jessica N. Cooke Wojciechowski, Robert Vitart, Veronique Nag, Abhishek Hewitt, Alex W. Hohn, Rene Venturini, Cristina Mirshahi, Alireza Ramdas, Wishal D. Thorleifsson, Gudmar Vithana, Eranga Khor, Chiea-Chuen Stefansson, Arni B. Liao, Jiemin Haines, Jonathan L. Amin, Najaf Wang, Ya Xing Wild, Philipp S. Ozel, Ayse B. Li, Jun Z. Fleck, Brian W. Zeller, Tanja Staffieri, Sandra E. Teo, Yik-Ying Cuellar-Partida, Gabriel Luo, Xiaoyan Allingham, R. Rand Richards, Julia E. Senft, Andrea Karssen, Lennart C. Zheng, Yingfeng Bellenguez, Celine Xu, Liang Iglesias, Adriana I. Wilson, James F. Kang, Jae H. van Leeuwen, Elisabeth M. Jonsson, Vesteinn Thorsteinsdottir, Unnur Despriet, Dominiek D. G. Ennis, Sarah Moroi, Sayoko E. Martin, Nicholas G. Jansonius, Nomdo M. Yazar, Seyhan Tai, E-Shyong Amouyel, Philippe Kirwan, James van Koolwijk, Leonieke M. E. Hauser, Michael A. Jonasson, Fridbert Leo, Paul Loomis, Stephanie J. Fogarty, Rhys Rivadeneira, Fernando Kearns, Lisa Lackner, Karl J. de Jong, Paulus T. V. M. Simpson, Claire L. Pennell, Craig E. Oostra, Ben A. Uitterlinden, Andre G. Saw, Seang-Mei Lotery, Andrew J. Bailey-Wilson, Joan E. Hofman, Albert Vingerling, Johannes R. Maubaret, Cecilia Pfeiffer, Norbert Wolfs, Roger C. W. Lemij, Hans G. Young, Terri L. Pasquale, Louis R. Delcourt, Cecile Spector, Timothy D. Klaver, Caroline C. W. Small, Kerrin S. Burdon, Kathryn P. Stefansson, Kari Wong, Tien-Yin Viswanathan, Ananth Mackey, David A. Craig, Jamie E. Wiggs, Janey L. van Duijn, Cornelia M. Hammond, Christopher J. Aung, Tin CA BMES GWAS Grp NEIGHBORHOOD Consortium Wellcome Trust Case Control Conso TI Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma SO NATURE GENETICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; CENTRAL CORNEAL THICKNESS; COMMON VARIANTS; ASSOCIATION; METAANALYSIS; POPULATION; EXPRESSION; REDUCTION; TRIAL; RISK AB Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 x 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG. C1 [Hysi, Pirro G.; Small, Kerrin S.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Cheng, Ching-Yu; Nag, Abhishek; Vithana, Eranga; Liao, Jiemin; Zheng, Yingfeng; Saw, Seang-Mei; Wong, Tien-Yin; Aung, Tin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Khor, Chiea-Chuen; Liao, Jiemin; Wong, Tien-Yin; Aung, Tin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Khor, Chiea-Chuen; Liao, Jiemin; Teo, Yik-Ying; Zheng, Yingfeng; Tai, E-Shyong; Saw, Seang-Mei; Wong, Tien-Yin; Aung, Tin] Natl Univ Hlth Syst, Singapore, Singapore. [Cheng, Ching-Yu; Teo, Yik-Ying; Zheng, Yingfeng; Tai, E-Shyong; Saw, Seang-Mei; Wong, Tien-Yin] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Tai, E-Shyong; Saw, Seang-Mei] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Springelkamp, Henriet; Ramdas, Wishal D.; Richards, Julia E.; Despriet, Dominiek D. G.; Vingerling, Johannes R.; Wolfs, Roger C. W.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Springelkamp, Henriet; Ramdas, Wishal D.; Amin, Najaf; Karssen, Lennart C.; Iglesias, Adriana I.; van Leeuwen, Elisabeth M.; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert; Vingerling, Johannes R.; Klaver, Caroline C. W.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Macgregor, Stuart; Cuellar-Partida, Gabriel; Martin, Nicholas G.] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] Natl Human Genome Res Inst, US Natl Inst Hlth, Baltimore, MD USA. [Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Hewitt, Alex W.; Staffieri, Sandra E.; Kearns, Lisa; Mackey, David A.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Hohn, Rene; Mirshahi, Alireza; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Venturini, Cristina] UCL, Inst Ophthalmol, London, England. [Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Amgen, Reykjavik, Iceland. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Stefansson, Arni B.] Eye Clin, Reykjavik, Iceland. [Wang, Ya Xing; Xu, Liang] Capital Univ Med Sci, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Wild, Philipp S.] Univ Med Ctr Mainz, Dept Internal Med 2, Mainz, Germany. [Ozel, Ayse B.; Li, Jun Z.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Fleck, Brian W.] Natl Hlth Serv NHS Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Luo, Xiaoyan; Young, Terri L.] Duke Univ, Duke Eye Ctr, Durham, NC USA. [Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Senft, Andrea] Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany. [Bellenguez, Celine; Amouyel, Philippe] INSERM, UMR 774, F-59045 Lille, France. [Bellenguez, Celine; Amouyel, Philippe] Univ Lille 2, Lille, France. [Bellenguez, Celine; Amouyel, Philippe] Inst Pasteur, F-59019 Lille, France. [Wilson, James F.] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Kang, Jae H.; Pasquale, Louis R.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Jonsson, Vesteinn] Landspitali Natl Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Ennis, Sarah] Univ Southampton, Fac Med, Human Genet & Genom Med, Southampton SO9 5NH, Hants, England. [Moroi, Sayoko E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, Dept Ophthalmol, Groningen, Netherlands. [Yazar, Seyhan; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Amouyel, Philippe] Univ Lille, Ctr Hosp Reg, Lille, France. [Kirwan, James] Portsmouth Hosp NHS Trust, Dept Ophthalmol, Portsmouth, Hants, England. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Jonasson, Fridbert] Univ Iceland, Fac Med, Reykjavik, Iceland. [Leo, Paul] Univ Queensland, Diamantina Inst, Woollongabba, Qld, Australia. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Fogarty, Rhys; Burdon, Kathryn P.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert] Netherlands Consortium Healthy Ageing, Netherlands Genom Initiat, The Hague, Netherlands. [Lackner, Karl J.] Inst Clin Chem, Mainz, Germany. [Lackner, Karl J.] Lab Med, Mainz, Germany. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Leiden Univ, Med Ctr, Dept Ophthalmol, Leiden, Netherlands. [de Jong, Paulus T. V. M.] Acad Med Ctr, Dept Ophthalmol, Amsterdam, Netherlands. [Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Lotery, Andrew J.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Maubaret, Cecilia; Delcourt, Cecile] Univ Bordeaux, ISPED, Bordeaux, France. [Maubaret, Cecilia; Delcourt, Cecile] INSERM, Ctr INSERM Epidemiol Biostat Bordeaux U897, Bordeaux, France. [Lemij, Hans G.] Rotterdam Eye Hosp, Glaucoma Serv, Rotterdam, Netherlands. [Viswanathan, Ananth] Moorfields Eye Hosp NHS Fdn Trust, Biomed Res Ctr, NIHR, London, England. RP Aung, T (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. EM chris.hammond@kcl.ac.uk; aung_tin@yahoo.co.uk RI Delcourt, Cecile/I-2627-2013; Macgregor, Stuart/C-6442-2009; Cuellar Partida, Gabriel/P-3701-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Hewitt, Alex/D-1936-2013; wang, YA XING/K-9671-2016; Mackey, David/H-5340-2014; Cuellar Partida, Gabriel/C-6686-2017; OI Delcourt, Cecile/0000-0002-2099-0481; Macgregor, Stuart/0000-0001-6731-8142; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Hewitt, Alex/0000-0002-5123-5999; Wojciechowski, Robert/0000-0002-9593-4652; wang, YA XING/0000-0003-2749-7793; Mackey, David/0000-0001-7914-4709; Cuellar Partida, Gabriel/0000-0001-7648-4097; Yazar, Seyhan/0000-0003-0994-6196; Bailey-Wilson, Joan/0000-0002-9153-2920; Hohn, Rene /0000-0003-2870-1469; Small, Kerrin/0000-0003-4566-0005; Khor, Chiea Chuen/0000-0002-1128-4729; Hammond, Christopher/0000-0002-3227-2620; Tai, E Shyong/0000-0003-2929-8966; Karssen, Lennart C./0000-0002-1959-342X; Martin, Nicholas/0000-0003-4069-8020 FU Chief Scientist Office [CZB/4/438, CZB/4/710]; Department of Health [SRF/01/010]; Medical Research Council [MC_PC_U127561128]; NEI NIH HHS [K08 EY022943, P30 EY014104, R01 EY015473, R01 EY022124, R01 EY022305, R01 EY023512]; NHGRI NIH HHS [U01 HG004728] NR 28 TC 46 Z9 47 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1126 EP 1130 DI 10.1038/ng.3087 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100017 PM 25173106 ER PT J AU Stuckey, DW Shah, K AF Stuckey, Daniel W. Shah, Khalid TI Stem cell-based therapies for cancer treatment: separating hope from hype SO NATURE REVIEWS CANCER LA English DT Review ID MESENCHYMAL STROMAL CELLS; UROKINASE PLASMINOGEN-ACTIVATOR; NEURAL STEM/PROGENITOR CELLS; LUNG METASTASIS MODEL; INHIBIT TUMOR-GROWTH; BONE-MARROW; GENE-THERAPY; MALIGNANT GLIOMA; BRAIN-TUMORS; PROGENITOR CELLS AB Stem cell-based therapies are emerging as a promising strategy to tackle cancer. Multiple stem cell types have been shown to exhibit inherent tropism towards tumours. Moreover, when engineered to express therapeutic agents, these pathotropic delivery vehicles can effectively target sites of malignancy. This perspective considers the current status of stem cell-based treatments for cancer and provides a rationale for translating the most promising preclinical studies into the clinic. C1 [Stuckey, Daniel W.; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02114 USA. [Stuckey, Daniel W.; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Shah, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02114 USA. EM kshah@mgh.harvard.edu FU James S. McDonnell Foundation; [R01CA138922]; [R01CA173077] FX The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by grants R01CA138922, R01CA173077, and the James S. McDonnell Foundation. NR 126 TC 37 Z9 38 U1 4 U2 67 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD OCT PY 2014 VL 14 IS 10 BP 683 EP 691 DI 10.1038/nrc3798 PG 9 WC Oncology SC Oncology GA AQ1EU UT WOS:000342525500012 PM 25176333 ER PT J AU Kotton, CN AF Kotton, Camille N. TI Immunization after kidney transplantation-what is necessary and what is safe? SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID SOLID-ORGAN TRANSPLANTATION; INFLUENZA VACCINATION; ADVISORY-COMMITTEE; UNITED-STATES; PNEUMOCOCCAL VACCINE; PRACTICES ACIP; RECIPIENTS; RECOMMENDATIONS; ADULTS; LIVER AB Many transplant recipients are not protected against vaccine-preventable illnesses, primarily because vaccination is still an underutilized tool both before and after transplantation This missed opportunity for protection can result in substantial morbidity, graft loss and mortality. Immunization strategies should be formulated early in the course of renal disease to maximize the likelihood of vaccine-induced immunity, particularly as booster or secondary antibody responses are less affected by immune compromise than are primary or de novo antibody responses in naive vaccine recipients. However, live vaccines should be avoided in immunocompromised hosts. Although some concern has been raised regarding increased HLA sensitization after vaccination, no clinical data to suggest harm currently exists; overall, non-live vaccines seem to be immunogenic, protective and safe. In organ transplant recipients, some vaccines are indicated based on specific risk factors and certain vaccines, such as hepatitis B, can protect against donor-derived infection. Vaccines given to close contacts of renal transplant recipients can provide an additional layer of protection against infectious diseases. In this article, optimal vaccination of adult transplant recipients, including safety, efficacy, indication and timing, is reviewed. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Kotton, CN (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM ckotton@partners.org NR 53 TC 4 Z9 4 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD OCT PY 2014 VL 10 IS 10 BP 555 EP 562 DI 10.1038/nrneph.2014.122 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AQ0MA UT WOS:000342476200006 PM 25072119 ER PT J AU Wang, DH Liu, HS AF Wang, Danhong Liu, Hesheng TI Functional Connectivity Architecture of the Human Brain: Not All the Same SO NEUROSCIENTIST LA English DT Article DE individual differences; functional connectivity; association cortex; lateralization; evolution; fMRI ID INDIVIDUAL VARIABILITY; PREFRONTAL CORTEX; CORPUS-CALLOSUM; NETWORKS; ASYMMETRY; EVOLUTION; COGNITION; CHILDREN; FMRI; SPECIALIZATION AB Imaging studies suggest that individual differences in cognition and behavior might relate to differences in brain connectivity, particularly in the higher order association regions. Understanding the extent to which two brains can differ is crucial in clinical and basic neuroscience research. Here we highlight two major sources of variance that contribute to intersubject variability in connectivity measurements but are often mixed: the spatial distribution variability and the connection strength variability. We then offer a hypothesis about how the cortical surface expansion during human evolution may have led to remarkable intersubject variability in brain connectivity. We propose that a series of changes in connectivity architecture occurred in response to the pressure for processing efficiency in the enlarged brain. These changes not only distinguish us from our evolutionary ancestors, but also enable each individual to develop more uniquely. This hypothesis may gain support from the significant spatial correlations among evolutionary cortical expansion, the density of long-range connections, hemispheric functional specialization, and intersubject variability in connectivity. C1 [Wang, Danhong; Liu, Hesheng] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Wang, Danhong; Liu, Hesheng] Harvard Univ, Sch Med, Charlestown, MA USA. RP Liu, HS (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Suite 2301,149 13th St, Charlestown, MA 02129 USA. EM hesheng@nmr.mgh.harvard.edu RI wang, danhong/M-2699-2014 FU NIH [K25NS069805]; NARSAD FX This work was supported by NIH grant K25NS069805, and NARSAD Young Investigator Grant. NR 51 TC 6 Z9 7 U1 2 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2014 VL 20 IS 5 BP 432 EP 438 DI 10.1177/1073858414543290 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ2TB UT WOS:000342640800006 PM 25030990 ER PT J AU Sepulcre, J AF Sepulcre, Jorge TI Functional Streams and Cortical Integration in the Human Brain SO NEUROSCIENTIST LA English DT Review DE functional streams; cortical integration; multimodal integration; multisensory; visual-motor; auditory-motor ID HUMAN PARIETAL OPERCULUM; SENSORY-MOTOR INTEGRATION; PRIMATE CEREBRAL-CORTEX; CONDUCTION APHASIA; ARCUATE-FASCICULUS; CYTOARCHITECTONIC AREAS; HUMAN CONNECTOMICS; PREMOTOR CORTEX; MIRROR NEURONS; MACAQUE MONKEY AB The processing of brain information relies on the organization of neuronal networks and circuits that in the end must provide the substrate for human cognition. However, the presence of highly complex and multirelay neuronal interactions has limited our ability to disentangle the assemblies of brain systems. The present review article focuses on the latest developments to understand the architecture of functional streams of the human brain at the large-scale level. Particularly, this article presents a comprehensive framework and recent findings about how the highly modular sensory cortex, such as the visual, somatosensory, auditory, as well as motor cortex areas, connects to more parallel-organized cortical hubs in the brain's functional connectome. C1 [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Charlestown, MA USA. RP Sepulcre, J (reprint author), Harvard Univ, 52 Oxford St,Northwest Bldg,280-02, Cambridge, MA 02138 USA. EM sepulcre@nmr.mgh.harvard.edu FU Alzheimer's Association [NIRG-11-205690] FX The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Alzheimer's Association grant NIRG-11-205690 (J.S.). NR 88 TC 9 Z9 9 U1 1 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2014 VL 20 IS 5 BP 499 EP 508 DI 10.1177/1073858414531657 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ2TB UT WOS:000342640800011 PM 24737695 ER PT J AU Seyyedi, M Nadol, JB AF Seyyedi, Mohammad Nadol, Joseph B., Jr. TI Intracochlear Inflammatory Response to Cochlear Implant Electrodes in Humans SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implant; Endocochlear; Foreign body; Giant cell; Labyrinthitis; Tissue response ID FOREIGN-BODY REACTION; HUMAN TEMPORAL BONES; CHRONIC ELECTRICAL-STIMULATION; AUDITORY-NERVE; RESIDUAL HEARING; TISSUE FORMATION; HISTOPATHOLOGY; BIOMATERIALS; COMPLICATIONS; GRANULOMA AB Hypothesis: This study evaluates the types and degrees of tissue response adjacent to the electrode of multichannel cochlear implants. Background: Cochlear implant electrodes have been classified as biocompatible prostheses. Nevertheless, in some reports, electrode extrusion, chronic inflammation, and even soft failure of the implant system have been attributed to a tissue response to the electrode. Methods: All celloidin-embedded temporal bones with multichannel cochlear implants from the temporal bone collection of the Massachusetts Eye and Ear Infirmary were included in the study. A total of 28 temporal bones from 21 subjects were identified and processed for histology. The severity of cellular response including eosinophil and lymphocytic infiltration, giant cell reaction, new bone formation, and fibrosis were scored on a scale from 0 to 3 at three 1-mm segments along the electrode: first 1 mm at the cochleostomy, last 1 mm from the tip of the electrode, and midway between these proximal and distal segments. The values were compared using the Wilcoxon test. Results: A granulomatous reaction to the electrode was observed in 27 (96.4%) temporal bones. Eosinophil infiltration was observed in 7 (25%) temporal bones, suggesting an allergic reaction. The Inflammatory response to the electrode was significantly greater at the basal turn of cochlea close to the cochleostomy (p < 0.05) than distal to it. Conclusion: An inflammatory response is common after cochlear implantation, and it is more robust at the cochleostomy than distal to it, suggesting the role of trauma of insertion as a contributing factor. C1 [Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM joseph_nadol@meei.harvard.edu FU National Institute of Deafness and Other Communication Disorders [R01-DC000152] FX This study was supported by grant R01-DC000152 from the National Institute of Deafness and Other Communication Disorders. NR 44 TC 20 Z9 21 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2014 VL 35 IS 9 BP 1545 EP 1551 PG 7 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AQ0JG UT WOS:000342468700015 PM 25122600 ER PT J AU Kumarasinghe, MP Brown, I Raftopoulos, S Bourke, MJ Charlton, A de Boer, WB Eckstein, R Epari, K Gill, AJ Lam, AK Price, T Streutker, C Lauwers, GY AF Kumarasinghe, M. P. Brown, I. Raftopoulos, S. Bourke, M. J. Charlton, A. de Boer, W. B. Eckstein, R. Epari, K. Gill, A. J. Lam, A. K. Price, T. Streutker, C. Lauwers, G. Y. TI Standardised reporting protocol for endoscopic resection for Barrett oesophagus associated neoplasia: expert consensus recommendations SO PATHOLOGY LA English DT Review DE Early oesophageal neoplasia; endoscopic resections; key prognostic features; pathological assessment; standard reporting ID LYMPH-NODE METASTASIS; HIGH-GRADE DYSPLASIA; MUCOSAL RESECTION; MUSCULARIS MUCOSAE; EPITHELIAL NEOPLASMS; CRYPT DYSPLASIA; ADENOCARCINOMA; INVASION; DUPLICATION; MANAGEMENT AB Endoscopic resection (ER) is considered the therapy of choice for intraepithelial neoplasia associated with visible lesions and T1a adenocarcinoma. Pathologists are bound to encounter specimens collected via these techniques more frequently in their practice. A standardised protocol for handling, grossing, and assessing ER specimens should be adopted to ensure that all prognostic information and characteristics influencing treatment are included in reports (see Supplementary Video Abstract, http://links.lww.com/PAT/A22). The entire specimen should be appropriately oriented, processed and assessed. An ER specimen will commonly show intraepithelial neoplasia or invasive carcinoma. There are essential features that should be recorded if invasive carcinoma is found as they dictate further management and follow-up. These features are the margin status, depth of invasion, degree of differentiation and presence or absence of lymphovascular invasion. Important features such as duplication of muscularis mucosae should be recognised to avoid misinterpretation of depth of invasion. Key diagnostic and prognostic elements that are essential for optimal clinical decisions have been included in the reporting format proposed by the Structured Pathology Reporting committee of the Royal College of Pathologists of Australasia (RCPA). C1 [Kumarasinghe, M. P.; de Boer, W. B.] Queen Elizabeth II Med Ctr, PathWest, Nedlands, WA, Australia. [Kumarasinghe, M. P.; de Boer, W. B.] Univ Western Australia, Nedlands, WA 6009, Australia. [Brown, I.] Envoi Pathol, Herston, Qld, Australia. [Raftopoulos, S.] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Bourke, M. J.] Westmead Hosp, Dept Gastroenterol & Hepatol, Sydney, NSW, Australia. [Bourke, M. J.] Univ Sydney, Westmead Clin Sch, Sydney, NSW 2006, Australia. [Charlton, A.] Childrens Hosp Westmead, Dept Histopathol, Sydney, NSW, Australia. [Eckstein, R.; Gill, A. J.] Royal N Shore Hosp, Dept Anat Pathol, Sydney, NSW, Australia. [Epari, K.] St John God Hosp Murdoch, Murdoch, WA, Australia. [Epari, K.] Fremantle Hosp, Dept Surg, Fremantle, WA, Australia. [Gill, A. J.] Univ Sydney, Canc Diag & Pathol Grp, Sydney, NSW 2006, Australia. [Lam, A. K.] Griffith Univ, Griffith Med Sch, Nathan, Qld 4111, Australia. [Lam, A. K.] Griffith Univ, Griffith Hlth Inst, Nathan, Qld 4111, Australia. [Price, T.] Queen Elizabeth Hosp, Dept Med Oncol, Adelaide, SA, Australia. [Price, T.] Univ Adelaide, Adelaide, SA, Australia. [Streutker, C.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Lauwers, G. Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lauwers, G. Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Kumarasinghe, MP (reprint author), PathWest, QE11,J Block Hosp Ave, Nedlands, WA 6009, Australia. EM Priyanthi.Kumarasinghe@health.wa.gov.au RI Gill, Anthony/D-4215-2015; Brown, Ian/R-7763-2016 OI Gill, Anthony/0000-0002-9447-1967; Brown, Ian/0000-0001-6329-2547 NR 36 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD OCT PY 2014 VL 46 IS 6 BP 473 EP 480 DI 10.1097/PAT.0000000000000160 PG 8 WC Pathology SC Pathology GA AP7BB UT WOS:000342231400001 PM 25158823 ER PT J AU Vojvoda, D Stefanovics, E Rosenheck, RA AF Vojvoda, Dolores Stefanovics, Elina Rosenheck, Robert A. TI Treatment of Veterans With PTSD at a VA Medical Center: Primary Care Versus Mental Health Specialty Care SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COLLABORATIVE CARE; RANDOMIZED-TRIAL; RECENT TRENDS; IRAQ; INTERVENTION; AFGHANISTAN; DEPRESSION; PSYCHOTHERAPY; BARRIERS AB Objective: Recent military conflicts have generated significantly more demand for treatment of posttraumatic stress disorder (PTSD) as well as concerns about the adverse effects of stigma associated with specialty mental health care. This study examined the extent to which veterans diagnosed as having PTSD received treatment exclusively in primary care settings. Methods: Administrative data from the U.S. Department of Veterans Affairs (VA) Connecticut Healthcare System for fiscal year 2010 were used to compare the proportions and characteristics of veterans with PTSD (N=4,144) who were treated exclusively in a primary care setting or a mental health specialty clinic. Results: Most (87%) veterans were treated in specialty mental health clinics, and 13% were treated exclusively in primary care. In contrast, 24% of veterans with any mental health diagnosis received treatment exclusively in primary care. Comorbid psychiatric diagnoses were much more prevalent among those treated in mental health specialty clinics than in primary care (86% versus 14%), and psychotropic medications were far more likely to be filled in mental health specialty clinics than in primary care (80% versus 36%). The percentage of veterans with service-connected disabilities did not differ between the two treatment settings. Conclusions: Despite the VA's successful expansion of mental health services in primary care, the vast majority of patients with PTSD received treatment in mental health specialty clinics. Stigma does not seem to keep veterans with PTSD from receiving care in specialty mental health settings in spite of the availability of services in primary care. C1 [Vojvoda, Dolores] VA Connecticut Healthcare Syst, Dept Psychiat, US Dept Vet Affairs, West Haven, CT 06516 USA. [Vojvoda, Dolores; Stefanovics, Elina; Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Rosenheck, Robert A.] VA New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. RP Vojvoda, D (reprint author), VA Connecticut Healthcare Syst, Dept Psychiat, US Dept Vet Affairs, West Haven, CT 06516 USA. EM dolores.vojvoda@yale.edu NR 23 TC 1 Z9 1 U1 0 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD OCT PY 2014 VL 65 IS 10 BP 1238 EP 1243 DI 10.1176/appi.ps.201300204 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200010 PM 24981414 ER PT J AU Shin, HJ Greenbaum, MA Jain, S Rosen, CS AF Shin, Hana J. Greenbaum, Mark A. Jain, Shaili Rosen, Craig S. TI Associations of Psychotherapy Dose and SSRI or SNRI Refills With Mental Health Outcomes Among Veterans With PTSD SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; AFFAIRS; ADHERENCE; THERAPY; IRAQ; CARE AB Objective: This study assessed associations between psychotherapy and pharmacotherapy for posttraumatic stress disorder (PTSD) and longitudinal changes in PTSD, depression, and mental health functioning among U.S. veterans diagnosed as having PTSD. Methods: Information about self-reported symptoms experienced from.5 to over three years was collected from 482 veterans diagnosed as having PTSD. Administrative data from the U.S. Department of Veterans Affairs (VA) were used to calculate initiation of a course of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), days of medication coverage, and number of PTSD-related psychotherapy visits during the year after a baseline survey. Hierarchical linear modeling was used to analyze the effects of psychotherapy dose, initiation of an SSRI or SNRI, and medication coverage on symptoms over one year. Results: In the year after baseline, over half of the sample (55%) received no psychotherapy for PTSD, and only 8% met the VA's proposed standard of eight PTSD-related sessions within 14 weeks. Nearly half of the participants (47%) were prescribed an SSRI or SNRI and 37% completed a 90-day trial in the year after baseline. Participants' symptoms improved slightly over time. Participants who received eight or more psychotherapy sessions in 14 weeks, completed a 90-day course of SSRIs or SNRIs, or had more days of medication coverage did not improve more than participants who received less treatment. Conclusions: These dose-of-care benchmarks were not related to symptom improvement, high-lighting the importance of directly assessing the impact of particular treatments on patient outcomes rather than solely relying on process measures. C1 [Shin, Hana J.] VA Long Beach Healthcare Syst, Psychol Serv, US Dept Vet Affairs, Long Beach, CA 90822 USA. [Greenbaum, Mark A.] VA Palo Alto Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Menlo Pk, CA USA. [Jain, Shaili; Rosen, Craig S.] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA USA. [Rosen, Craig S.] Stanford Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. RP Shin, HJ (reprint author), VA Long Beach Healthcare Syst, Psychol Serv, US Dept Vet Affairs, Long Beach, CA 90822 USA. EM hana.shin@va.gov FU VA Sierra Pacific Mental Illness Research, Education and Clinical Center; VA Office of Academic Affiliations FX This work was supported by the VA Sierra Pacific Mental Illness Research, Education and Clinical Center and the VA Office of Academic Affiliations. The opinions expressed are those of the authors and do not necessarily represent the policy of the VA or the United States government. NR 21 TC 4 Z9 4 U1 1 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD OCT PY 2014 VL 65 IS 10 BP 1244 EP 1248 DI 10.1176/appi.ps.201300234 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200011 PM 24981643 ER PT J AU Bedoya, CA Traeger, L Trinh, NHT Chang, TE Brill, CD Hails, K Hagan, PN Flaherty, K Yeung, A AF Bedoya, C. Andres Traeger, Lara Trinh, Nhi-Ha T. Chang, Trina E. Brill, Charlotte D. Hails, Katherine Hagan, Patrick N. Flaherty, Katherine Yeung, Albert TI Impact of a Culturally Focused Psychiatric Consultation on Depressive Symptoms Among Latinos in Primary Care SO PSYCHIATRIC SERVICES LA English DT Article ID MENTAL-HEALTH-CARE; ETHNIC DISPARITIES; SELF-REPORT; AFRICAN-AMERICANS; MAJOR DEPRESSION; QUICK INVENTORY; UNITED-STATES; OLDER; SYMPTOMATOLOGY; OUTCOMES AB Objective: A culturally focused psychiatric (CFP) consultation service was implemented to increase engagement in mental health care and reduce depressive symptoms among adult Latino primary care patients. The aim of this study was to assess preliminary efficacy of the CFP consultation service to reduce depressive symptoms. Methods: In a randomized controlled study, primary care clinics were randomly selected to provide either the two-session CFP intervention or enhanced usual care. For CFP intervention participants, study clinicians (psychologists or psychiatrists) provided a psychiatric assessment, psychoeducation, cognitive-behavioral tools, and tailored treatment recommendations; primary care providers were provided a consultation summary. Depressive symptoms (as measured by the Quick Inventory of Depressive Symptomatology Self Rated [QIDS-SR]) were assessed at baseline and six-month follow-up. Multiple regression analysis was conducted to evaluate whether CFP intervention participants showed greater improvement in depressive symptoms at follow-up, with control for baseline depression, clinic site, and significant covariates. Results: Participants (N=118) were primarily Spanish-monolingual speakers (64%). Although depressive symptoms remained in the moderate range for both groups from baseline to six months, symptom reduction was greater among CFP intervention participants (mean +/- SD change in QIDS-SR score=3.46 +/- 5.48) than those in usual care (change=.09 +/- 4.43).The final multiple regression model indicated that participation in the CFP intervention predicted lower depressive symptoms at follow-up (unstandarclized beta=-3.09, p=.008), independent of baseline depressive symptoms, clinic site, age, gender, and employment status. Conclusions: Results suggest that Latinos experiencing depressive symptoms may benefit from a short-term CFP consultation. Findings also support the integration of psychiatric interventions for Latinos in the primary care setting. C1 [Bedoya, C. Andres; Traeger, Lara; Trinh, Nhi-Ha T.; Chang, Trina E.; Brill, Charlotte D.; Hails, Katherine; Hagan, Patrick N.; Yeung, Albert] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bedoya, C. Andres; Traeger, Lara; Trinh, Nhi-Ha T.; Chang, Trina E.; Yeung, Albert] Harvard Univ, Sch Med, Boston, MA USA. [Flaherty, Katherine] ABT Associates Inc, Cambridge, MA USA. RP Bedoya, CA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM abedoya@mgh.harvard.edu FU Robert Wood Johnson Foundation's program "Finding Answers: Disparities Research for Change" [66709]; MGH Department of Psychiatry; Bristol-Myers Squibb; Pfizer FX This research project was funded through support from the Robert Wood Johnson Foundation's program "Finding Answers: Disparities Research for Change" (grant number 66709) awarded to Dr. Trinh, principal investigator, and Dr. Bedoya), with additional support from the MGH Department of Psychiatry. The authors thank the study participants, as well as professional and support staff, at the participating sites for their commitment and participation: MGH Charlestown Healthcare Center, MGH Chelsea Healthcare Center, MGH Internal Medicine Associates, and MGH Revere Healthcare Center. The authors also thank Joseph Betancourt, M.D., M.P.H., and Alexander Green, M.D., M.P.H., for their contributions to the conception and design of the study; Jerrold Rosenbaum, M.D., and Maurizio Fava, M.D., for their support of the study; and Soo Jeong Yoon and Jenny Man for their technical assistance.; Dr. Chang has received travel funds from Bristol-Myers Squibb and Pfizer and has served as an advisor to Bristol-Myers Squibb. The other authors report no competing interests. NR 45 TC 2 Z9 2 U1 3 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD OCT PY 2014 VL 65 IS 10 BP 1256 EP 1262 DI 10.1176/appi.ps.201300088 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200013 PM 24882225 ER PT J AU Wiechers, IR Maust, DT AF Wiechers, Ilse R. Maust, Donovan T. TI Antidepressant Prescribing in Elderly Populations SO PSYCHIATRIC SERVICES LA English DT Letter ID MEDICATION C1 [Wiechers, Ilse R.] US Dept Vet Affairs, Northeast Program, Evaluat Ctr, Off Mental Hlth Operat, West Haven, CT 06516 USA. [Wiechers, Ilse R.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Maust, Donovan T.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Maust, Donovan T.] Vet Affairs Ann Arbor Healthcare Syst, Ctr Clin Management, Ann Arbor, MI USA. RP Wiechers, IR (reprint author), US Dept Vet Affairs, Northeast Program, Evaluat Ctr, Off Mental Hlth Operat, West Haven, CT 06516 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD OCT PY 2014 VL 65 IS 10 BP 1285 EP 1285 PG 1 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200020 PM 25270498 ER PT J AU De Cruz, S Littner, MR Zeidler, MR AF De Cruz, Sharon Littner, Michael R. Zeidler, Michelle R. TI Home Sleep Testing for the Diagnosis of Obstructive Sleep Apnea-Indications and Limitations SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE obstructive sleep apnea; home sleep test; auto-titrating positive airway pressure; respiratory disturbance index ID POSITIVE AIRWAY PRESSURE; CPAP TITRATION; NASAL CPAP; APNOEA/HYPOPNOEA SYNDROME; APNEA/HYPOPNEA SYNDROME; HEART HEALTH; FOLLOW-UP; POLYSOMNOGRAPHY; ASSOCIATION; RISK AB The increasing prevalence and recognition of obstructive sleep apnea (OSA) coupled with an awareness of its detrimental health consequences has resulted in the need for timely and cost efficient access to diagnostic sleep testing and treatment. As a result, increased emphasis is being placed on simplified ambulatory models for the diagnosis and treatment of OSA using home sleep testing (HST). An ambulatory sleep program requires the combination of clinical assessment for identifying patients at high risk for OSA, HST for the diagnosis of OSA, and home auto-titrating positive airway pressure units for treatment. Randomized control trials evaluating the efficacy of this ambulatory approach to diagnose and treat OSA in high-risk patients without significant medical comorbidities reveal the potential for equivalent patient outcomes when compared with the use of polysomnography and in-laboratory continuous positive airway pressure titration. C1 [De Cruz, Sharon] VA Greater Los Angeles Healthcare Syst, Div Pulm Crit Care & Sleep Med, Los Angeles, CA 90073 USA. [Littner, Michael R.; Zeidler, Michelle R.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med Clin Immunol & Allergy, Los Angeles, CA 90095 USA. [Littner, Michael R.; Zeidler, Michelle R.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Zeidler, MR (reprint author), VA Greater Los Angeles Healthcare Syst, Sleep Disorders Ctr, 11301 Wilshire Blvd 111Q, Los Angeles, CA 90073 USA. EM mzeidler@mednet.ucla.edu NR 72 TC 0 Z9 0 U1 1 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD OCT PY 2014 VL 35 IS 5 BP 552 EP 559 DI 10.1055/s-0034-1390066 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AP7QA UT WOS:000342270600004 ER PT J AU Winkelman, JW Schoerning, L Platt, S Jensen, JE AF Winkelman, John W. Schoerning, Laura Platt, Sam Jensen, J. Eric TI Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity SO SLEEP MEDICINE LA English DT Article DE Restless legs syndrome; Gamma-aminobutyric acid; Glutamate; Anterior cingulate cortex; Cerebellum; Thalamus; Periodic limb movements of sleep ID ANTERIOR CINGULATE; T2 RELAXOMETRY; PAIN; SPECTRA; CORTEX; PET AB Background: Previous research has demonstrated abnormalities in glutamate and N-acetyl aspartate (NAA) in the thalamus in individuals with restless legs syndrome (RLS) compared with healthy matched controls. However, levels of these transmitters in other RLS-related brain areas and levels of the most common inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have not been assessed. Methods: This study examined GABA, glutamate, and NAA levels in the dorsal anterior cingulate cortex (ACC), thalamus and cerebellum with the use of proton magnetic resonance spectroscopy (H-1-MRS) at 4 tesla (4 T) and Megapress difference-editing in 18 subjects with RLS and a matched control group without RLS. Actigraphy was performed on the nights before scans to assess periodic limb movements of sleep (PLMS). Results: Levels of GABA, glutamate, and NAA were no different between RLS and control subjects in any of the three voxels of interest. However, GABA levels were positively correlated with both PLM indices and RLS severity in the thalamus and negatively with both of these measures in the cerebellum in RLS subjects. In addition, NAA levels were higher in the ACC in RLS than in controls. Conclusion: Our preliminary data suggest that known cerebellar-thalamic interactions may modulate the intensity of RLS sensory and motor symptoms. In addition, anterior cingulate cortex may be associated with the affective components of the painful symptoms in this disorder. (C) 2014 Elsevier B. V. All rights reserved. C1 [Winkelman, John W.; Jensen, J. Eric] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Winkelman, John W.; Schoerning, Laura; Platt, Sam] Massachusetts Gen Hosp, Dept Psychiat, Sleep Disorders Clin Res Program, Boston, MA 02114 USA. [Winkelman, John W.; Schoerning, Laura; Platt, Sam] Massachusetts Gen Hosp, Dept Neurol, Sleep Disorders Clin Res Program, Boston, MA 02114 USA. [Jensen, J. Eric] McLean Hosp, Brain Imaging Ctr, Boston, MA USA. RP Winkelman, JW (reprint author), Massachusetts Gen Hosp, Sleep Disorders Clin Res Program, 1 Bowdoin Sq, Boston, MA 02114 USA. EM jwwinkelman@partners.org OI Platt, Samuel/0000-0003-1991-2117 FU GlaxoSmithKline FX This research was supported by an investigator-initiated research grant from GlaxoSmithKline. NR 23 TC 6 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD OCT PY 2014 VL 15 IS 10 BP 1225 EP 1230 DI 10.1016/j.sleep.2014.05.019 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AQ0VT UT WOS:000342501500007 PM 25129262 ER PT J AU Mao, SH Sendler, E Goodrich, RJ Hauser, R Krawetz, SA AF Mao, Shihong Sendler, Edward Goodrich, Robert J. Hauser, Russ Krawetz, Stephen A. TI A comparison of sperm RNA-seq methods SO SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE LA English DT Article DE Library preparation; reverse transcription and cDNA amplification; RNA purification ID SPERMATOZOAL RNAS; SPERMATOGENESIS; TRANSCRIPTOMICS; FERTILIZATION; AMPLIFICATION; SAMPLES AB A significant challenge to the effective application of RNA-seq to the complete transcript analysis of low quantity and/or degraded samples is the amplification of minimal input RNA to enable sequencing library construction. Several strategies have been commercialized in order to facilitate this goal. However, each strategy has its own specific protocols and methodology, and each may introduce unique bias and in some cases show specific preference for a collection of sequences. Our wider investigation of human spermatozoa! RNAs was able to reveal their complexity despite being generally characterized by low quantity and high fragmentation. In this study, the following four commercially available RNA-seq amplification and library protocols for the preparation of low quantity/highly fragmented samples, SMARTer (TM) Ultra Low RNA (SU) for Illumina (R) Sequencing, SeqPlex RNA Amplification (SP), Ovation (R) RNA-Seq System V2 (OR), and Ovation (R) RNA-Seq Formalin Fixed Paraffin Embedded System (FFPES) were assessed using human sperm RNAs. Further investigation analyzed the effects on the end results of two different library preparation methods, Encore NGS Multiplex System I (Enc) and Ovation Ultra low Library Systems (UL), that appeared best suited to this type of RNA, along with other potential confounding factors such as FFPE preservation. Our results indicate that for each library preparation protocol, the differences in the initial amount of input RNA and choice of RNA purification step do not generate marked differences in terms of RNA profiling. However, substantial disparity is introduced by individual amplification methods prior to library construction. These significant differences may be caused by the different priming methods or amplification strategies used in each of the four different protocols examined. The observation of intra-sample variation introduced by the choice of protocol highlights the role that external factors play in planning and subsequent reliable interpretation of results of any RNA-seq experiment. C1 [Mao, Shihong; Sendler, Edward; Goodrich, Robert J.; Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Hauser, Russ] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Mem Obstet & Gynecol Serv, Boston, MA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Krawetz, SA (reprint author), Wayne State Univ, Fac Med, Dept Obstet & Gynecol, 271 CS Mott Ctr,275 E Hancock Ave, Detroit, MI 48201 USA. EM steve@compbio.med.wayne.edu FU Harvard School of Public Health, National Institute of Environmental Health Sciences [ES017285]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [25PM6]; Charlotte B. Failing Professorship FX The authors declare no conflicts of interest. This work was supported in part by the Charlotte B. Failing Professorship to SAK., a grant to RH from Harvard School of Public Health, National Institute of Environmental Health Sciences (Grant Number ES017285) and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Contract 25PM6 in collaboration with the LIFE Study Working Group, Division of Epidemiology, Statistics, and Prevention Research who provided semen samples. NR 23 TC 8 Z9 8 U1 0 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1939-6368 EI 1939-6376 J9 SYST BIOL REPROD MED JI Syst. Biol. Reprod. Med. PD OCT PY 2014 VL 60 IS 5 BP 308 EP 315 DI 10.3109/19396368.2014.944318 PG 8 WC Andrology; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA AP7QJ UT WOS:000342271500008 PM 25077492 ER PT J AU Valerio, D Raventos, H Schmeidler, J Beeri, MS Villalobos, LM Bolanos-Palmieri, P Carrion-Baralt, JR Fornaguera, J Silverman, JM AF Valerio, Daniel Raventos, Henriette Schmeidler, James Beeri, Michal S. Mora Villalobos, Lara Bolanos-Palmieri, Patricia Carrion-Baralt, Jose R. Fornaguera, Jaime Silverman, Jeremy M. TI Association of Apolipoprotein E-e4 and Dementia Declines with Age SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Successful cognitive aging; oldest-old; dementia risk factors ID RICAN NONAGENARIANS; COSTA-RICA; RISK; DISEASE; APOE AB Objective: To study the association of dementia with apolipoprotein E-e4 (APOE-e4) and its interaction with age in a nonagenarian Costa Rican group (N-sample) and a general elderly contrast group (GE-sample). Methods: In both case-control studies, participants were cognitively intact or diagnosed with dementia. The N-sample (N = 112) was at least age 90 years; the GE-sample (N = 98) was at least age 65 years. Results: Dementia and APOE-e4 were not significantly associated in the N-sample, but were in the GE-sample. There was a significant interaction of age with APOE-e4 in the N-sample, but not in the GE-sample. Descriptively dividing the N-sample at the median (age 93 years) showed a group interaction: APOE-e4 was more associated with dementia in the younger N-sample than in the older N-sample, where six of seven APOE-e4 carriers were cognitively intact. Conclusions: The results support the reduction in association of APOE-e4 with dementia in extreme old age, consistent with a survivor effect model for successful cognitive aging. C1 [Valerio, Daniel] Hosp Nacl Geriatr & Gerontol Costa Rica, San Jose, Costa Rica. [Valerio, Daniel] Univ Costa Rica, Sch Med, San Jose, Costa Rica. [Raventos, Henriette; Mora Villalobos, Lara; Bolanos-Palmieri, Patricia] Univ Costa Rica, Ctr Invest Biol Mol & Celular, San Jose, Costa Rica. [Raventos, Henriette] Univ Costa Rica, Escuela Biol, San Jose, Costa Rica. [Schmeidler, James; Beeri, Michal S.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Beeri, Michal S.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Beeri, Michal S.] Chaim Sheba Med Ctr, Joseph Sagol Neurosci Ctr, Tel Aviv, Israel. [Carrion-Baralt, Jose R.] Univ Puerto Rico, Gerontol Program, Dept Human Dev, Grad Sch Publ Hlth, Rio Piedras, PR 00931 USA. [Fornaguera, Jaime] Univ Costa Rica, Ctr Invest Neurociencias, San Jose, Costa Rica. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Res & Dev Serv, Bronx, NY USA. RP Silverman, JM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Box 1230,One Gustave L Levy Pl, New York, NY 10029 USA. EM jeremy.silverman@mssm.edu OI Raventos, Henriette/0000-0001-9423-8308 FU NIH Fogarty International Center & National Institute on Aging grant [R21TW009258]; Universidad de Costa Rica; Alzheimer's Association FX This study was funded by a NIH Fogarty International Center & National Institute on Aging grant (R21TW009258), the Universidad de Costa Rica, and the Alzheimer's Association. NR 10 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2014 VL 22 IS 10 BP 957 EP 960 DI 10.1016/j.jagp.2014.03.008 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AP2VT UT WOS:000341934600002 PM 24731780 ER PT J AU West, RK Ravona-Springer, R Schmeidler, J Leroith, D Koifman, K Guerrero-Berroa, E Preiss, R Hoffman, H Silverman, JM Heymann, A Schnaider-Beeri, M AF West, Rebecca K. Ravona-Springer, Ramit Schmeidler, James Leroith, Derek Koifman, Keren Guerrero-Berroa, Elizabeth Preiss, Rachel Hoffman, Hadas Silverman, Jeremy M. Heymann, Anthony Schnaider-Beeri, Michal TI The Association of Duration of Type 2 Diabetes with Cognitive Performance is Modulated by Long-Term Glycemic Control SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Cognitive performance; diabetes; hemoglobin A1c ID ALZHEIMERS-DISEASE; MELLITUS; DECLINE; MEMORY; DYSFUNCTION; DEMENTIA; ADULTS; IMPACT; AGE AB Objectives: It is unclear why duration of type 2 diabetes (T2D) is associated with increased cognitive compromise. High hemoglobin A1c (HbA1c) has also been associated with dementia, and is the primary contributor to T2D complications. Here we investigated whether the association of duration of T2D with cognitive functioning is modulated by HbA1C levels. Methods: This study examined nondemented community-dwelling T2D elderly (N = 897) participating in the Israel Diabetes and Cognitive Decline study, who were assessed with a broad neuropsychological battery. Subjects were all from the Maccabi Healthcare Services, which has a Diabetes Registry with complete HbA1c measurements since 1998. Partial correlations were performed to examine the modulating effect of HbA1c on the relationship of duration of T2D with five cognitive measures, controlling for sociodemographic and cardiovascular risk factors. Results: An interaction of duration of T2D with HbA1c was associated with executive functioning (p = 0.006), semantic categorization (p = 0.019), attention/working memory (p = 0.011), and overall cognition (p = 0.006), such that the associations between duration of T2D and cognitive impairment increased as HbA1c levels increased-but not for episodic memory (p = 0.984). Conclusions: Because duration of T2D was associated with cognition in higher HbA1c levels and overall no associations were found in lower HbA1c levels, our results suggest that individuals with T2D may limit their risk of future cognitive decline by maintaining long-term good glycemic control. C1 [West, Rebecca K.; Schmeidler, James; Leroith, Derek; Guerrero-Berroa, Elizabeth; Silverman, Jeremy M.; Schnaider-Beeri, Michal] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Ravona-Springer, Ramit; Koifman, Keren; Preiss, Rachel; Hoffman, Hadas; Schnaider-Beeri, Michal] Chaim Sheba Med Ctr, Joseph Sagol Neurosci Ctr, Ramat Gan, Israel. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Heymann, Anthony; Schnaider-Beeri, Michal] Maccabi Healthcare Serv, Tel Aviv, Israel. RP West, RK (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1230,One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM rebecca.west@mssm.edu FU NIA [R01 AG034087, P50 AG05138]; Helen Bader Foundation; Irma T. Hirschl Scholar award; American Federation for Aging Research (AFAR) Young Investigator award; Alzheimer's Association grant [NIRG-11-205083] FX This study was supported by NIA grants R01 AG034087 to Dr. Beeri and P50 AG05138 to Dr. Sano, the Helen Bader Foundation, the Irma T. Hirschl Scholar award to Dr. Beeri, the American Federation for Aging Research (AFAR) Young Investigator award, and the Alzheimer's Association grant NIRG-11-205083 to Dr. Ravona-Springer. NR 20 TC 13 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2014 VL 22 IS 10 BP 1055 EP 1059 DI 10.1016/j.jagp.2014.01.010 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AP2VT UT WOS:000341934600013 PM 24534521 ER PT J AU Ebert, L Malte, C Hamlett-Berry, K Beckham, J McFall, M Saxon, A AF Ebert, Lori Malte, Carol Hamlett-Berry, Kim Beckham, Jean McFall, Miles Saxon, Andrew TI Use of a Learning Collaborative to Support Implementation of Integrated Care for Smoking Cessation for Veterans With Posttraumatic Stress Disorder SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CIGARETTE-SMOKING; PARIHS FRAMEWORK; HEALTH-SERVICES; PREVALENCE; POPULATION; DISSEMINATION; PERSPECTIVES; CHALLENGES; DEPRESSION; SCIENCE AB Objectives. We evaluated the feasibility of incorporating integrated care (IC) for smoking cessation into routine treatment for posttraumatic stress disorder (PTSD) at Department of Veterans Affairs (VA) Medical Centers and the utility of the Learning Collaborative (LC) model in facilitating implementation. Methods. We conducted 2 LCs aimed at implementing IC for smoking cessation using multidisciplinary teams comprising 70 staff members from 12 VA PTSD clinics. Using questionnaires, we evaluated providers' perceptions of the LC methodology and the effectiveness and feasibility of routine IC delivery. We assessed number of providers delivering and patients receiving IC using medical record data. Results. More than 85% of participating VA staff considered the LC to be an effective training and implementation platform. The majority thought IC effectively addressed an important need and could be delivered in routine PTSD care. All LC participants who planned to deliver IC did so (n = 52). Within 12 months of initial training, an additional 46 locally trained providers delivered IC and 395 veterans received IC. Conclusions. The LC model effectively facilitated rapid and broad implementation of IC. Facilitators and barriers to sustained use of IC are unknown and should be identified to understand how best to promote ongoing access to evidence-based treatment for smoking cessation in mental health populations. C1 [Ebert, Lori] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27701 USA. [Malte, Carol] Vet Affairs VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. [Hamlett-Berry, Kim] Dept Vet Affairs, Washington, DC USA. [Beckham, Jean] VA Midatlantic Reg Mental Illness Res Educ & Clin, Durham, NC USA. [McFall, Miles; Saxon, Andrew] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Ebert, L (reprint author), Duke Univ, Med Ctr, Evidence Based Practice Implementat Ctr, 411 West Chapel Hill St,Suite 200, Durham, NC 27701 USA. EM lori.ebert@duke.edu FU National Center for Child Traumatic Stress is the coordinating center for the National Child Traumatic Stress Network, a collaborative network of sites across the United States FX The National Center for Child Traumatic Stress is the coordinating center for the National Child Traumatic Stress Network, a collaborative network of sites across the United States, funded to enhance services and access to care for traumatized children and their families. For more information about the National Child Traumatic Stress Network visit http://www.nctsn.org. NR 38 TC 2 Z9 2 U1 1 U2 9 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2014 VL 104 IS 10 BP 1935 EP 1942 DI 10.2105/AJPH.2013.301776 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1XG UT WOS:000341865000039 PM 25208004 ER PT J AU Masia, R Peyton, S Lauwers, GY Brown, I AF Masia, Ricard Peyton, Stephen Lauwers, Gregory Y. Brown, Ian TI Gastrointestinal Biopsy Findings of Autoimmune Enteropathy A Review of 25 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Review DE autoimmune enteropathy; autoimmune enteritis; IPEX syndrome; celiac disease; graft-versus-host disease ID GOBLET-CELL ANTIBODIES; PROTRACTED DIARRHEA; GUT DISORDER; ADULT; COLITIS; DISEASE; IMMUNODEFICIENCY; HISTOPATHOLOGY; AUTOANTIBODIES; CHILDREN AB Autoimmune enteropathy (AIE) is a rare disorder characterized by severe diarrhea and small intestinal mucosal atrophy resulting from immune-mediated injury. It remains a challenging diagnosis because of its clinicopathologic variability. To better understand its histopathologic features, we describe the gastrointestinal biopsy findings of 25 patients, including children and adults. The most common finding on small intestinal biopsy (13/25 cases, 52%) was villous blunting, expansion of the lamina propria by mixed but predominantly mononuclear inflammation, and neutrophilic cryptitis with or without crypt microabscesses. In 5 cases (20%), the duodenum exhibited changes indistinguishable from celiac disease, with villous blunting and intraepithelial lymphocytosis. Increased crypt apoptosis with minimal inflammation, resembling acute graft-versus-host disease, was observed in 4 cases (16%). The remaining 3 cases (12%) exhibited a mixture of 2 or more of the above patterns. Mucosal abnormalities outside the small intestine were present in all 24 cases with available biopsies (100%), with the stomach most commonly affected (19/22 cases, 86%), followed by the colon (14/22, 64%) and esophagus (5/18, 28%). Findings in non-small intestinal sites were variable and included mixed active and chronic inflammation, chronic inflammation alone, intraepithelial lymphocytosis, and increased apoptosis resembling acute graft-versus-host disease. In summary, AIE most commonly presents as an active enteritis with villous blunting and expansion of the lamina propria by mixed inflammation. Mucosal abnormalities are frequently seen elsewhere in the gut. AIE may thus be better regarded as a pangastrointestinal autoimmune disorder, and biopsies from sites other than the small intestine may greatly facilitate its diagnosis. C1 [Masia, Ricard; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol & Lab Med, Boston, MA 02114 USA. [Peyton, Stephen; Brown, Ian] Envoi Pathol, Kelvin Grove, Qld 4059, Australia. [Brown, Ian] Pathol Queensland, Anat Pathol, Brisbane, Qld, Australia. RP Brown, I (reprint author), Envoi Pathol, 5-38 Bishop St, Kelvin Grove, Qld 4059, Australia. EM ianbrown@envoi.com.au RI Brown, Ian/R-7763-2016 OI Brown, Ian/0000-0001-6329-2547 FU National Cancer Institute of the National Institutes of Health [T32CA09216] FX R.M. is supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA09216. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 33 TC 11 Z9 12 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1319 EP 1329 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800003 PM 25188868 ER PT J AU Croce, S Young, RH Oliva, E AF Croce, Sabrina Young, Robert H. Oliva, Esther TI Uterine Leiomyomas With Bizarre Nuclei A Clinicopathologic Study of 59 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE uterus; leiomyoma; bizarre nuclei; prognosis ID SMOOTH-MUSCLE TUMORS; GIANT-CELL TUMOR; MITOTIC CHROMOSOME CONDENSATION; TERM-FOLLOW-UP; HISTONE H3; IMMUNOHISTOCHEMICAL ANALYSIS; SYMPLASTIC LEIOMYOMAS; ATYPICAL LEIOMYOMAS; UTERUS; LEIOMYOSARCOMA AB Leiomyoma with bizarre nuclei (LM-BN) is an uncommon tumor with histologic features (mononucleated or multinucleated bizarre cells that may have a diffuse distribution, prominent nucleoli, and karyorrhectic nuclei that may mimic atypical mitoses) that often causes confusion with leiomyosarcoma. Fifty-nine LM-BNs were collected from our consultation files over the years 2000 to 2011. Features recorded included patient age, therapy, tumor size, border, gross appearance, density and distribution of BN, mitotic count, karyorrhectic nuclei, prominent nucleoli, cells with conspicuous dense eosinophilic cytoplasm (rhabdoid-like), vascular changes and type of vasculature, and presence of necrosis and its nature. Follow-up information was obtained for all patients. Patients ranged in age from 25 to 75 (average 45) years (11 patients between 25 and 35 y, 20 between 36 and 45 y, 22 between 46 and 55 y, and 6 between 56 and 75 y). Forty-two underwent hysterectomy and 17 myomectomy. For 51 tumors gross findings were known. Forty (78%) had a solid white and whorled cut surface and 11 (22%) a yellow appearance. Five (10%) neoplasms showed prominent cystic degeneration, and hemorrhage and/or necrosis was seen in 9 (18%). Forty-five LM-BNs had a pushing margin with the surrounding myometrium, whereas 1 showed irregular borders. Margins could not be ascertained in the slides available in 13 cases. Twenty-eight (48%), 19 (32%), and 12 (20%) LM-BN showed low, intermediate, and high BN density. Eighteen (30%) tumors showed diffuse, 26 (44%) showed multifocal, and 15 (26%) had focal BN distribution. Mitotic counts ranged from 0 to 7/10 high-power fields (HPF) (average 1 to 2/10 HPF). Thirty-seven (63%) had <2/10 HPF, 19 (32%) had 2 to 5 mitoses/10 HPF, and in 3 tumors (5%) mitotic counts were 6, 7, and 7/10 HPF (2 with focal and 1 with diffuse BN). All but 4 LM-BNs showed karyorrhectic nuclei, striking in 12 neoplasms, mimicking atypical mitoses. Nineteen (32%) LMs had prominent eosinophilic nucleoli surrounded by a clear halo. Ischemic necrosis was detected in 21 (36%) LM-BN. Rhabdoid-like cells were noted in 24 (41%) tumors. All patients had no evidence of recurrence, ranging from 1 to 13 years (overall average 6 y; in patients with myomectomy 6.3 y with a range of 2.6 to 11 y). Our results corroborate that LM-BN is associated with a favorable outcome even in those patients only treated by myomectomy and highlights that a conservative approach can be undertaken in these patients, as many of them are of reproductive age. Because of the favorable outcome, the term LM-BN is preferable to alternative terminology including "atypical leiomyoma." C1 [Croce, Sabrina] Inst Bergonie, Dept Pathol, Bordeaux, France. [Young, Robert H.; Oliva, Esther] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM eoliva@partners.org FU "Fondation" de France; ARC grants FX Supported by "Fondation" de France (Madeleine Tillier Haudebourg and Nathalie Rumaux Rambaux) and ARC grants. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 49 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1330 EP 1339 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800004 PM 25140893 ER PT J AU Bledsoe, JR Kamionek, M Mino-Kenudson, M AF Bledsoe, Jacob R. Kamionek, Michal Mino-Kenudson, Mari TI BRAF V600E Immunohistochemistry Is Reliable in Primary and Metastatic Colorectal Carcinoma Regardless of Treatment Status and Shows High Intratumoral Homogeneity SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE BRAF; colorectal carcinoma; immunohistochemistry; VE1 ID BRAFV600E IMMUNOHISTOCHEMISTRY; MONOCLONAL-ANTIBODY; THYROID-CARCINOMA; LYNCH SYNDROME; POOR SURVIVAL; MUTATION; ADENOCARCINOMA; CANCER; SPECIMENS; COLON AB In colorectal carcinoma the evaluation of BRAF mutation status is increasingly being performed given its utility as a prognostic and predictive biomarker. However, there are conflicting reports of the sensitivity and specificity of BRAF V600E immunohistochemistry (IHC), and little is known about its reliability in tissues collected from metastatic sites or after chemotherapy, radiation therapy and/or targeted therapy. The degree of intratumoral staining heterogeneity is also not well established. We performed IHC for BRAF V600E (VE1) on 204 cases of colorectal carcinoma including 59 with the BRAF V600E mutation. These included primary (n = 147) and metastatic/recurrent (n = 57) tumors, collected before (n = 133) or after (n = 71) chemotherapy, radiation therapy and/or targeted therapy. Evaluation of a test cohort (39 cases) with knowledge of mutation status established a specific staining pattern for the mutation: diffuse cytoplasmic staining of near-uniform intensity, regardless of strength of staining. Using this pattern, pathologists at 3 levels of training independently performed blinded evaluation of the remaining cases. BRAF V600E staining was 96.3% sensitive and 98.5% specific for the mutation, including both pretreatment and posttreatment specimens. Fleiss kappa for interobserver agreement was 0.96. Staining of whole sections of the BRAF mutants showed diffuse staining in all cases and uniform or near-uniform intensity in 91%. In 20 cases with both pretreatment and posttreatment specimens, there was 100% accuracy and agreement in staining between samples. We conclude that BRAF V600E IHC is reliable for the evaluation of mutational status in colorectal carcinoma regardless of site or prior treatment history, and staining shows a high degree of intratumoral homogeneity. C1 [Bledsoe, Jacob R.; Kamionek, Michal; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 1-122,55 Fruit St, Boston, MA 02114 USA. EM mmino@partners.org FU National Cancer Institute grants [P50 CA127003, R01 CA169086] FX M.M.-K. was supported by National Cancer Institute grants P50 CA127003 and R01 CA169086. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 29 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1418 EP 1428 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800013 PM 24921639 ER PT J AU Ward, A Konya, C Mark, EJ Rosen, S AF Ward, Ashley Konya, Christine Mark, Eugene J. Rosen, Seymour TI Granulomatosis With Polyangiitis Presenting as a Renal Tumor SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE granulomatosis with polyangiitis; Wegener's granulomatosis; vasculitis; kidney tumor; antineutrophilic cytoplasmic antibody ID IMMUNE CRESCENTIC GLOMERULONEPHRITIS; WEGENERS-GRANULOMATOSIS; XANTHOGRANULOMATOUS PYELONEPHRITIS; KIDNEY; MASS; VASCULITIS; MANIFESTATION; LESION AB Inflammatory tumors of the kidney are uncommon and include primary inflammatory processes and systemic diseases such as sarcoidosis, IgG4 disease, and granulomatosis with polyangiitis (GPA). There are approximately 15 cases of the latter in the literature. Tumors in GPA are well described and have been reported in several organs including breast, orbit, mediastinum, central nervous system, and especially the lung. We report the case of a 48-year-old woman who presented with diffuse frontal headaches. Imaging showed both a cranial/sinus and renal mass. The pathology of the dura and nasal sinus biopsies were unrevealing. A nephrectomy was performed that demonstrated a discrete lesion with extensive necrosis, granulomatous inflammation, and crescentic pauci-immune glomerulonephritis, findings consistent with GPA. C1 [Ward, Ashley; Rosen, Seymour] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Konya, Christine] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Rheumatol, Boston, MA 02215 USA. [Mark, Eugene J.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ward, A (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM award3@bidmc.harvard.edu NR 34 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1444 EP 1448 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800016 PM 25025447 ER PT J AU Swerdlow, SH Jaffe, ES Brousset, P Chan, JKC de Leval, L Gaulard, P Harris, NL Pileri, S Weiss, LM AF Swerdlow, Steven H. Jaffe, Elaine S. Brousset, Pierre Chan, John K. C. de Leval, Laurence Gaulard, Philippe Harris, Nancy Lee Pileri, Stefano Weiss, Lawrence M. CA Int Lymphoma Study Grp TI Cytotoxic T-cell and NK-cell Lymphomas Current Questions and Controversies SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE cytotoxic T-cell lymphoma; gamma delta T cells; natural killer cells; enteropathy-associated T-cell lymphoma ID EPSTEIN-BARR-VIRUS; NATURAL-KILLER-CELL; NON-HODGKINS-LYMPHOMA; DISTINCT CLINICOPATHOLOGICAL ENTITY; GAMMA-DELTA; NASAL-TYPE; ALPHA-BETA; CELIAC-DISEASE; LYMPHOPROLIFERATIVE DISORDER; GASTROINTESTINAL-TRACT AB The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (alpha beta-type T cell, gamma delta T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented. C1 [Swerdlow, Steven H.] Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, Pittsburgh, PA USA. [Jaffe, Elaine S.] NCI, Bethesda, MD 20892 USA. [Harris, Nancy Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Weiss, Lawrence M.] Clarient Diagnost Serv Inc, Aliso Viejo, CA USA. [Brousset, Pierre] IUC T Oncopole, Toulouse, France. [Gaulard, Philippe] Univ Paris Est, Hop Henri Mondor, Dept Pathol, Inserm,U955, Creteil, France. [Chan, John K. C.] Queen Elizabeth Hosp, Hong Kong, Hong Kong, Peoples R China. [de Leval, Laurence] Univ Hosp Lausanne CHUV, Inst Pathol, Lausanne, Switzerland. [Pileri, Stefano] Univ Bologna, Sch Med, St Orsola Policlin, Bologna, Italy. RP Swerdlow, SH (reprint author), UPMC Hlth Syst UPMC Presbyterian, Div Hematopathol, Dept Pathol, 200 Lothrop St Room G-335, Pittsburgh, PA 15213 USA. EM swerdlowsh@upmc.edu NR 100 TC 18 Z9 18 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP E60 EP E71 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800001 PM 25025449 ER PT J AU Rogers, DJ Collins, C Carroll, R Yager, P Cummings, B Raol, N Setlur, J Maturo, S Tremblay, S Quinones, E Noviski, N Hartnick, CJ AF Rogers, Derek J. Collins, Corey Carroll, Ryan Yager, Phoebe Cummings, Brian Raol, Nikhila Setlur, Jennifer Maturo, Stephen Tremblay, Sarah Quinones, Ernesto Noviski, Natan Hartnick, Christopher J. TI Operation Airway: The First Sustainable, Multidisciplinary, Pediatric Airway Surgical Mission SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE Operation Airway; pediatric; surgical; mission ID TRACHEOSTOMY; EXPERIENCE AB Objective: This study aimed to describe the development and implementation of the first sustainable, multidisciplinary, pediatric airway surgical mission in an underserved country. Methods: This prospective, qualitative study was conducted for the first 4 Operation Airway missions in Quito, Ecuador. The major goals of the missions were to assist children with aerodigestive abnormalities, create a sustainable program where the local team could independently provide for their own patient population, develop an educational curriculum and training program for the local team, and cultivate a collaborative approach to provide successful multidisciplinary care. Results: Twenty patients ages 4 months to 21 years were included. Twenty-three bronchoscopies, 5 salivary procedures, 2 tracheostomies, 1 T-tube placement, 1 tracheocutaneous fistula closure, 2 open granuloma excisions, and 6 laryngotracheal reconstructions (LTRs) were performed. All LTR patients were decannulated. A new type of LTR (1.5 stage) was developed to meet special mission circumstances. Two videofluoroscopic swallow studies and 40 bedside swallow evaluations were performed. One local pediatric otolaryngologist, I pediatric surgeon, 3 anesthesiologists, 7 intensivists, 16 nurses, and 2 speech-language pathologists have received training. More than 25 hours of lectures were given, and a website was created collaboratively for educational and informational dissemination (http://www.masseyeandear.org/specialties/pediatrics/pediatric-ent/airway/OperationAirway/). Conclusion: We demonstrated the successful creation of the first mission stemming from a teaching institution with the goal of developing a sustainable, autonomous surgical airway program. C1 [Rogers, Derek J.; Collins, Corey; Carroll, Ryan; Yager, Phoebe; Cummings, Brian; Raol, Nikhila; Tremblay, Sarah; Noviski, Natan; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Setlur, Jennifer] Yale New Haven Med Ctr, New Haven, CT 06504 USA. [Maturo, Stephen] Brooke Army Med Ctr, San Antonio, TX USA. [Quinones, Ernesto] Metropolitan Hosp, Quito, Ecuador. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Christopher_Hartnick@meei.harvard.edu NR 10 TC 4 Z9 4 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD OCT PY 2014 VL 123 IS 10 BP 726 EP 733 DI 10.1177/0003489414534012 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA AP7MQ UT WOS:000342261800008 PM 24835243 ER PT J AU Ackman, JM Lata, PF Schuna, AA Elliott, ME AF Ackman, Jamie M. Lata, Paul F. Schuna, Arthur A. Elliott, Mary E. TI Bone Health Evaluation in a Veteran Population: A Need for the Fracture Risk Assessment Tool (FRAX) SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE osteoporosis; osteoporosis treatment; osteoporosis assessment; men ID CLINICAL-PRACTICE; MALE OSTEOPOROSIS; ZOLEDRONIC ACID; OLDER MEN; ALENDRONATE; MORTALITY; DENOSUMAB; DENSITY AB Background: Approximately 2 million men in the United States have osteoporosis, but men are seldom evaluated or treated to prevent fracture. In the expanding veteran population, the fracture risk assessment tool, FRAX, could help reduce fracture risk. However, it is unknown how many veterans would meet the FRAX treatment threshold. Objective: To determine the proportion of untreated veterans who should be considered for osteoporosis treatment according to the Fracture Risk Assessment Tool (FRAX) among a randomly selected sample of older veterans receiving care at one Veterans Hospital and to determine the proportion of veterans in the sample who had received treatment. Methods: A retrospective review of 150 randomly selected charts from male veterans at least 70 years of age and female veterans at least 65 years of age receiving primary care at the William S. Middleton Memorial Veterans Hospital, Madison, WI, between January 1, 2007, and October 1, 2010. This study focused on men, but women were included per institutional review board policy. Results: Charts from 147 men and 3 women were reviewed; 25 men had received osteoporosis treatment. Of 122 untreated men, 74 (61%) met FRAY treatment criteria, including 14 who had fractured. Although bone density testing is recommended by the National Osteoporosis Foundation for men at least 70 years old, only 21 (17%) untreated men had been tested. Conclusions: Most veterans who met FRAX criteria were not treated, including some who had had fractures. The VA should consider recommending FRAX to identify veterans at high risk for fracture. C1 [Ackman, Jamie M.] La Crosse VA Outpatient Clin, La Crosse, WI USA. [Lata, Paul F.; Schuna, Arthur A.; Elliott, Mary E.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Schuna, Arthur A.; Elliott, Mary E.] Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA. RP Elliott, ME (reprint author), Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA. EM meelliott@pharmacy.wisc.edu NR 31 TC 1 Z9 1 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD OCT PY 2014 VL 48 IS 10 BP 1288 EP 1293 DI 10.1177/1060028014542149 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP2ZX UT WOS:000341945800005 PM 24994725 ER PT J AU Lawson, EH Zingmond, DS Stey, AM Hall, BL Ko, CY AF Lawson, Elise H. Zingmond, David S. Stey, Anne M. Hall, Bruce L. Ko, Clifford Y. TI Measuring Risk-Adjusted Value Using Medicare and ACS-NSQIP Is High-Quality, Low-Cost Surgical Care Achievable Everywhere? SO ANNALS OF SURGERY LA English DT Article DE colectomy; cost; Medicare; NSQIP; quality; surgery; value ID CLAIMS DATA; SURGERY; VOLUME; ASSOCIATION; IMPROVEMENT; MORTALITY; REGISTRY AB Objective: To evaluate the relationship between risk-adjusted cost and quality for colectomy procedures and to identify characteristics of "high value" hospitals (high quality, low cost). Background: Policymakers are currently focused on rewarding high-value health care. Hospitals will increasingly be held accountable for both quality and cost. Methods: Records (2005-2008) for all patients undergoing colectomy procedures in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient claims. Cost was derived from hospital payments by Medicare. Quality was derived from the occurrence of 30-day postoperative major complications and/or death as recorded in ACS-NSQIP. Risk-adjusted cost and quality metrics were developed using hierarchical multivariable modeling, consistent with a National Quality Forum-endorsed colectomy measure. Results: The study population included 14,745 colectomy patients in 169 hospitals. Average hospitalization cost was $21,350 (SD $20,773, median $16,092, interquartile range $14,341-$ 24,598). Thirty-four percent of patients had a postoperative complication and/or death. Higher hospital quality was significantly correlated with lower cost (correlation coefficient 0.38, P < 0.001). Among hospitals classified as high quality, 52% were found to be low cost (representing highest value hospitals) whereas 14% were high cost (P = 0.001). Forty-one percent of low-quality hospitals were high cost. Highest "value" hospitals represented a mix of teaching/nonteaching affiliation, small/large bed sizes, and regional locations. Conclusions: Using national ACS-NSQIP and Medicare data, this study reports an association between higher quality and lower cost surgical care. These results suggest that high-value surgical care is being delivered in a wide spectrum of hospitals and hospital types. C1 [Lawson, Elise H.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Lawson, Elise H.; Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lawson, Elise H.; Hall, Bruce L.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Zingmond, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Stey, Anne M.] Mt Sinai Med Ctr, Icahn Sch Med, New York, NY USA. [Hall, Bruce L.] Washington Univ, St Louis Sch Med, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Barnes Jewish Hosp, St Louis, MO USA. [Hall, Bruce L.] 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. RP Lawson, EH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 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 and Medicaid Services 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 and Medicaid Services. For the remaining authors, none were declared. NR 22 TC 5 Z9 6 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD OCT PY 2014 VL 260 IS 4 BP 668 EP 679 DI 10.1097/SLA.0000000000000931 PG 12 WC Surgery SC Surgery GA AP3LL UT WOS:000341977400013 PM 25203884 ER PT J AU Hamarneh, SR Mohamed, MMR Economopoulos, KP Morrison, SA Phupitakphol, T Tantillo, TJ Gul, SS Gharedaghi, MH Tao, QS Kaliannan, K Narisawa, S Millan, JL van der Wilden, GM Fagenholz, PJ Malo, MS Hodin, RA AF Hamarneh, Sulaiman R. Mohamed, Mussa M. Rafat Economopoulos, Konstantinos P. Morrison, Sara A. Phupitakphol, Tanit Tantillo, Tyler J. Gul, Sarah S. Gharedaghi, Mohammad Hadi Tao, Qingsong Kaliannan, Kanakaraju Narisawa, Sonoko Millan, Jose L. van der Wilden, Gwendolyn M. Fagenholz, Peter J. Malo, Madhu S. Hodin, Richard A. TI A Novel Approach to Maintain Gut Mucosal Integrity Using an Oral Enzyme Supplement SO ANNALS OF SURGERY LA English DT Article DE enteral starvation; ICU patient; intestinal alkaline phosphatase; intestinal permeability; tight junctions; total parenteral nutrition ID INTESTINAL ALKALINE-PHOSPHATASE; TIGHT JUNCTION PERMEABILITY; TOTAL PARENTERAL-NUTRITION; CRITICALLY-ILL PATIENTS; EARLY ENTERAL NUTRITION; BARRIER FUNCTION; MOUSE MODEL; BACTERIAL TRANSLOCATION; UP-REGULATION; MICE AB Objective: To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis. Background: Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis. Methods: WT and IAP-KO mice were used to examine gut barrier function and tight junction protein levels during 48-hour starvation and fed states. Human ileal fluid samples were collected from 20 patients postileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 hours +/- IAP supplementation in the drinking water. Results: The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrate that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding. Conclusions: IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients. C1 [Hamarneh, Sulaiman R.; Mohamed, Mussa M. Rafat; Economopoulos, Konstantinos P.; Morrison, Sara A.; Phupitakphol, Tanit; Tantillo, Tyler J.; Gul, Sarah S.; Gharedaghi, Mohammad Hadi; Tao, Qingsong; Kaliannan, Kanakaraju; van der Wilden, Gwendolyn M.; Fagenholz, Peter J.; Malo, Madhu S.; Hodin, Richard A.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Narisawa, Sonoko; Millan, Jose L.] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. RP Hodin, RA (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM rhodin@mgh.harvard.edu RI kaliannan, kanakaraju/P-9094-2014; OI Economopoulos, Konstantinos/0000-0003-4856-0405 FU National Institute of Health [NIH/NIDDK T32 DK007754, NIH P30-DK040561] FX The authors declare no conflicting financial interests. Funding has been received from the National Institute of Health grants: NIH/NIDDK T32 DK007754 and NIH P30-DK040561 ( R.A.H.). NR 39 TC 9 Z9 9 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD OCT PY 2014 VL 260 IS 4 BP 706 EP 715 DI 10.1097/SLA.0000000000000916 PG 10 WC Surgery SC Surgery GA AP3LL UT WOS:000341977400017 PM 25203888 ER PT J AU Golshan, M Sagara, Y Wexelman, B Aydogan, F Desantis, S Min, HE Vosburgh, K Jagadeesan, J Caragacianu, D Gombos, E Jolesz, FA AF Golshan, Mehra Sagara, Yasuaki Wexelman, Barbara Aydogan, Fatih Desantis, Stephen Min, H. Elise Vosburgh, Kirby Jagadeesan, Jayender Caragacianu, Diana Gombos, Eva Jolesz, Ferenc Andras TI Pilot Study to Evaluate Feasibility of Image-Guided Breast-Conserving Therapy in the Advanced Multimodal Image-Guided Operating (AMIGO) Suite SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID CANCER AB Background. The rate of reexcision in breast-conserving surgery remains high, leading to delay in initiation of adjuvant therapy, increased cost, increased complications, and negative psychological impact to the patient. 1-3 We initiated a phase 1 clinical trial to determine the feasibility of the use of intraoperative magnetic resonance imaging (MRI) to assess margins in the advanced multimodal image-guided operating (AMIGO) suite. Methods. All patients received contrast-enhanced three-dimensional MRI while under general anesthesia in the supine position, followed by standard BCT with or without wire guidance and sentinel node biopsy. Additional margin reexcision was performed of suspicious margins and correlated to final pathology (Fig. 1). Feasibility was assessed via two components: demonstration of safety and sterility and acceptable duration of the operation and imaging; and adequacy of intraoperative MRI imaging for interpretation and its comparison to final pathology. Results. Eight patients (mean age 48.5 years), 4 with stage I breast cancer and 4 with stage II breast cancer, were recruited. All patients underwent successful BCT in the AMIGO suite with no AMIGO-specific complications or break in sterility during surgery. The mean operative time was 113 min (range 93-146 min). Conclusions. Our experience with AMIGO suggests that it is feasible to use intraoperative MRI imaging to evaluate margin assessment in real time. Further research is required to identify modalities that will lead to a reduction in reexcision in breast cancer therapy. C1 [Golshan, Mehra; Sagara, Yasuaki; Wexelman, Barbara; Aydogan, Fatih; Min, H. Elise; Caragacianu, Diana] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Golshan, Mehra; Sagara, Yasuaki; Wexelman, Barbara; Aydogan, Fatih; Min, H. Elise; Caragacianu, Diana] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aydogan, Fatih] Istanbul Univ, Cerrahpasa Med Sch, Dept Breast Surg, Istanbul, Turkey. [Desantis, Stephen] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. [Vosburgh, Kirby; Jagadeesan, Jayender; Gombos, Eva; Jolesz, Ferenc Andras] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Golshan, M (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM mgolshan@partners.org FU NIBIB NIH HHS [P41 EB015898] NR 3 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 10 BP 3356 EP 3357 DI 10.1245/s10434-014-3926-9 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AP5UN UT WOS:000342144300032 PM 25047476 ER PT J AU Hong, TS Kwak, EL AF Hong, Theodore S. Kwak, Eunice L. TI Adjuvant Therapy for Gastric Cancers: More Answers or More Questions? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID CHEMOTHERAPY; SURGERY C1 [Hong, Theodore S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02138 USA. [Kwak, Eunice L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Hong, TS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02138 USA. EM tshong1@partners.org NR 6 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 11 BP 3367 EP 3368 DI 10.1245/s10434-014-3778-3 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AP5UT UT WOS:000342144900004 PM 24841350 ER PT J AU Peterson, DJ Truong, PT Sadek, BT Alexander, CS Wiksyk, B Shenouda, M Raad, RA Taghian, AG AF Peterson, David J. Truong, Pauline T. Sadek, Betro T. Alexander, Cheryl S. Wiksyk, Bradley Shenouda, Mina Raad, Rita Abi Taghian, Alphonse G. TI Locoregional Recurrence and Survival Outcomes by Type of Local Therapy and Trastuzumab Use Among Women with Node-Negative, HER2-Positive Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; ADJUVANT CHEMOTHERAPY; CONSERVING THERAPY; PROGNOSTIC INDICATOR; RECEPTOR; RADIATION; AGE; MASTECTOMY; RADIOTHERAPY; CELLS AB While human epidermal growth factor receptor 2 (HER2) overexpression is an adverse breast cancer prognostic factor, it is unclear whether there are differences in outcomes between types of local treatment in this population. This retrospective study examined locoregional recurrence and survival in women with node-negative, HER2+ breast cancer treated with breast-conserving therapy (BCT) versus mastectomy. Subjects were 748 patients with pT1-2, N0, M0 HER2+ breast cancer, treated with BCT (n = 422) or mastectomy (n = 326). Trastuzumab was used in 54 % of subjects. The 5-year Kaplan-Meier locoregional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), and overall survival (OS) were compared between cohorts treated with BCT versus mastectomy. Subgroup analyses of LRR and survival were performed separately among patients treated with BCT or mastectomy to examine the effect of trastuzumab on outcomes in each group. Median follow-up was 4.4 years. Patients treated with mastectomy had higher proportions of grade 3 histology (69 vs 60 %, p = 0.004) and lower rates of hormone therapy (51 vs 64 %, p < 0.001) and trastuzumab therapy (50 vs 57 %, p = 0.04). The 5-year outcomes in women treated with BCT compared with mastectomy were: LRRFS 98.0 versus 98.3 % (p = 0.88), BCSS 97.2 versus 96.1 % (p = 0.70), and OS 95.5 versus 93.4 % (p = 0.19). Trastuzumab was associated with similar LRRFS and improved OS in both local treatment groups. BCT is safe in the population of women with pT1-2, N0, HER2+ breast cancer, providing high rates of locoregional control and survival equivalent to mastectomy. Trastuzumab was associated with improved survival in both groups. C1 [Peterson, David J.; Truong, Pauline T.; Wiksyk, Bradley] British Columbia Canc Agcy, Vancouver Isl Ctr, Dept Radiat Oncol, Victoria, BC, Canada. [Truong, Pauline T.] British Columbia Canc Agcy, Vancouver Isl Ctr, Breast Canc Outcomes Unit, Victoria, BC, Canada. [Truong, Pauline T.] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada. [Sadek, Betro T.; Alexander, Cheryl S.; Shenouda, Mina; Raad, Rita Abi; Taghian, Alphonse G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Peterson, DJ (reprint author), British Columbia Canc Agcy, Vancouver Isl Ctr, Dept Radiat Oncol, Victoria, BC, Canada. EM ptruong@bccancer.bc.ca RI Sadek, Betro/I-7734-2013 OI Sadek, Betro/0000-0003-0119-7207 NR 37 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 11 BP 3490 EP 3496 DI 10.1245/s10434-014-3767-6 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA AP5UT UT WOS:000342144900023 PM 24841346 ER PT J AU Goodman, JH Guarino, A Chenausky, K Klein, L Prager, J Petersen, R Forget, A Freeman, M AF Goodman, Janice H. Guarino, Anthony Chenausky, Kerry Klein, Lauri Prager, Joanna Petersen, Rebecca Forget, Avery Freeman, Marlene TI CALM Pregnancy: results of a pilot study of mindfulness-based cognitive therapy for perinatal anxiety SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Pregnancy; Anxiety; Generalized anxiety disorder; Intervention; Mindfulness; Cognitive therapy ID RANDOMIZED CONTROLLED-TRIAL; NATIONAL-COMORBIDITY-SURVEY; STATE WORRY QUESTIONNAIRE; STRESS REDUCTION PROGRAM; QUALITY-OF-LIFE; BEHAVIOR-THERAPY; MATERNAL ANXIETY; UNITED-STATES; TRANSDIAGNOSTIC TREATMENT; PSYCHIATRIC-DISORDERS AB Many women experience anxiety during pregnancy with potential negative effects on maternal, birth, and child outcomes. Because of potential risks of fetal exposure to psychotropic medications, efficacious non-pharmacologic approaches are urgently needed. However, no published studies of psychotherapeutic treatments for anxiety in pregnancy exist. Mindfulness-based cognitive therapy (MBCT) may substantially reduce anxiety and co-morbid symptoms in people with anxiety disorders. Coping with Anxiety through Living Mindfully (CALM) Pregnancy is an adaptation of MBCT designed to address anxiety in pregnant women. This study examined the feasibility, acceptability, and clinical outcomes of the CALM Pregnancy intervention in pregnant women anxiety. Twenty-four pregnant women with generalized anxiety disorder (GAD) or prominent symptoms of generalized anxiety participated in an open treatment trial of the CALM Pregnancy group intervention. Psychiatric diagnoses were determined by structured clinical interview, and self-report measures of anxiety, worry, depression, self-compassion, and mindfulness were completed at baseline and post-intervention. Qualitative feedback was elicited via questionnaire. Twenty-three participants completed the intervention with high attendance and good compliance with home practice. Completers showed statistically and clinically significant improvements in anxiety, worry, and depression, and significant increases in self-compassion and mindfulness. Of the 17 participants who met GAD criteria at baseline, only one continued to meet criteria post-intervention. Participants regarded their experience in the intervention to be overwhelmingly positive. MBCT in the form of the CALM Pregnancy intervention holds potential to provide effective, non-pharmacological treatment for pregnant women with anxiety. These promising findings warrant further testing of the intervention with a randomized controlled trial. C1 [Goodman, Janice H.; Guarino, Anthony; Chenausky, Kerry; Klein, Lauri; Prager, Joanna; Petersen, Rebecca; Forget, Avery] MGH Inst Hlth Profess, Sch Nursing, Boston, MA 02129 USA. [Freeman, Marlene] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Goodman, JH (reprint author), MGH Inst Hlth Profess, Sch Nursing, 36 1st Ave, Boston, MA 02129 USA. EM jgoodman@mghihp.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R21HD065156-01] FX This research was funded in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R21HD065156-01) to Dr. Goodman. We would also like to extend our gratitude to Fredda Zuckerman LICSW and the volunteer staff who facilitated recruitment at Massachusetts General Hospital Obstetrics and to the women who participated in the study. Special thanks to L. Klein for creating the CALM acronym. NR 103 TC 19 Z9 19 U1 6 U2 60 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD OCT PY 2014 VL 17 IS 5 BP 373 EP 387 DI 10.1007/s00737-013-0402-7 PG 15 WC Psychiatry SC Psychiatry GA AP6TG UT WOS:000342210000004 PM 24449191 ER PT J AU Tsai, AC Tomlinson, M Dewing, S le Roux, IM Harwood, JM Chopra, M Rotheram-Borus, MJ AF Tsai, Alexander C. Tomlinson, Mark Dewing, Sarah le Roux, Ingrid M. Harwood, Jessica M. Chopra, Mickey Rotheram-Borus, Mary Jane TI Antenatal depression case finding by community health workers in South Africa: feasibility of a mobile phone application SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Antenatal depression; Case finding; South Africa ID RANDOMIZED CONTROLLED-TRIAL; MOTHER-INFANT RELATIONSHIP; POSTNATAL DEPRESSION; MENTAL-HEALTH; POSTPARTUM DEPRESSION; MATERNAL DEPRESSION; LOW-INCOME; PERINATAL DEPRESSION; HOME VISITS; CAPE-TOWN AB Randomized controlled trials conducted in resource-limited settings have shown that once women with depressed mood are evaluated by specialists and referred for treatment, lay health workers can be trained to effectively administer psychological treatments. We sought to determine the extent to which community health workers could also be trained to conduct case finding using short and ultrashort screening instruments programmed into mobile phones. Pregnant, Xhosa-speaking women were recruited independently in two cross-sectional studies (N = 1,144 and N = 361) conducted in Khayelitsha, South Africa and assessed for antenatal depression. In the smaller study, community health workers with no training in human subject research were trained to administer the Edinburgh Postnatal Depression Scale (EPDS) during the routine course of their community-based outreach. We compared the operating characteristics of four short and ultrashort versions of the EPDS with the criterion standard of probable depression, defined as an EPDS-10 a parts per thousand yenaEuro parts per thousand 13. The prevalence of probable depression (475/1144 [42 %] and 165/361 [46 %]) was consistent across both samples. The 2-item subscale demonstrated poor internal consistency (Cronbach's alpha ranged from 0.55 to 0.58). All four subscales demonstrated excellent discrimination, with area under the receiver operating characteristic curve (AUC) values ranging from 0.91 to 0.99. Maximal discrimination was observed for the 7-item depressive symptoms subscale: at the conventional screening threshold of a parts per thousand yen10, it had 0.97 sensitivity and 0.76 specificity for detecting probable antenatal depression. The comparability of the findings across the two studies suggests that it is feasible to use community health workers to conduct case finding for antenatal depression. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tomlinson, Mark] Univ Stellenbosch, Dept Psychol, ZA-7600 Stellenbosch, South Africa. [Dewing, Sarah] Med Res Council South Africa, Hlth Syst Res Unit, Tygerberg, South Africa. [le Roux, Ingrid M.] Philani Child Hlth & Nutr Project, Cape Town, South Africa. [Harwood, Jessica M.; Rotheram-Borus, Mary Jane] Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Chopra, Mickey] United Nations Childrens Fund, Hlth Sect, New York, NY USA. [Rotheram-Borus, Mary Jane] Univ Calif Los Angeles, Global Ctr Child & Families, Los Angeles, CA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org RI Emchi, Karma/Q-1952-2016; OI Tsai, Alexander/0000-0001-6397-7917 FU US National Institutes of Health (NIH) [R01AA017104]; NIH [P30MH058107, P30AI028697, UL1TR000124, R25MH060482, K23MH096620]; Medical Research Council of South Africa; National Research Foundation (South Africa); Department for International Development (DfID-UK); Robert Wood Johnson Health and Society Scholars Program FX Study 1 was funded by the US National Institutes of Health (NIH) R01AA017104 and supported by NIH P30MH058107, NIH P30AI028697, and NIH UL1TR000124. Study 2 was funded by the Medical Research Council of South Africa and NIH R25MH060482. MT acknowledges the support of the National Research Foundation (South Africa) and the Department for International Development (DfID-UK). ACT also acknowledges salary support from NIH K23MH096620 and the Robert Wood Johnson Health and Society Scholars Program. We thank Mary J. O'Connor, Carol M. Worthman, Nokwanele Mbweu, Jacqueline Stewart, Mary Hartley, Dallas Swendeman, W. Scott Comulada, and Robert E. Weiss for their contributions to the design and implementation of study 1 and Novakuye Sijeku and the Philani outreach workers for data collection in study 2. NR 74 TC 12 Z9 12 U1 5 U2 21 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD OCT PY 2014 VL 17 IS 5 BP 423 EP 431 DI 10.1007/s00737-014-0426-7 PG 9 WC Psychiatry SC Psychiatry GA AP6TG UT WOS:000342210000008 PM 24682529 ER PT J AU Strangman, GE Sipes, W Beven, G AF Strangman, Gary E. Sipes, Walter Beven, Gary TI Human Cognitive Performance in Spaceflight and Analogue Environments SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Review DE long-duration spaceflight; executive function; social processing; emotional processing; hippocampus ID NORMAL-PRESSURE HYDROCEPHALUS; INTERNATIONAL BIOMEDICAL EXPEDITION; PROLONGED ANTARCTIC RESIDENCE; MANUAL TRACKING PERFORMANCE; COMPLEX DECISION-MAKING; DUAL-TASK PERFORMANCE; CEREBRAL-BLOOD-FLOW; SPACE MISSION; MENTAL PERFORMANCE; CARBON-DIOXIDE AB Maintaining intact cognitive performance is a high priority for space exploration. This review seeks to summarize the cumulative results of existing studies of cognitive performance in spaceflight and analogue environments. We focused on long-duration (>21 d) studies for which no review has previously been conducted. There were 11 published studies identified for long-duration spaceflight (N = 42 subjects) as well as 21 shorter spaceflight studies (N = 70 subjects). Overall, spaceflight cognitive studies ranged from 6-438 d in duration. Some 55 spaceflight analogue studies were also identified, ranging from 6 to 520 d. The diverse nature of experimental procedures and protocols precluded formal meta-analysis. In general, the available evidence fails to strongly support or refute the existence of specific cognitive deficits in low Earth orbit during long-duration spaceflight, which may be due in large part to small numbers of subjects. The studies consistently suggest that novel environments (spaceflight or other) induce variable alterations in cognitive performance across individuals, consistent with known astronaut experiences. This highlights the need to better quantify the magnitude and scope of this interindividual variability, and understand its underlying factors, when predicting in-flight cognitive functioning for extended periods. C1 [Strangman, Gary E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Sipes, Walter; Beven, Gary] NASA, Johnson Space Ctr, Houston, TX USA. RP Strangman, GE (reprint author), Massachusetts Gen Hosp, Neural Syst Grp, 149 13th St,Suite 2651, Charlestown, MA 02129 USA. EM strang@nmr.mgh.harvard.edu FU Wyle, Science, Technology and Engineering [T71712] FX This work was supported by Wyle, Science, Technology and Engineering, subcontract number T71712. All authors provided a professional contribution to this paper. Special thanks go to Lauren Leveton and multiple colleagues in the NASA Human Research Program's Behavioral Health and Performance element, as well as to the numerous colleagues who provided input on previous versions of this work. NR 147 TC 5 Z9 5 U1 4 U2 20 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 EI 1943-4448 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD OCT PY 2014 VL 85 IS 10 BP 1033 EP 1048 DI 10.3357/ASEM.3961.2014 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA AP7MM UT WOS:000342261400008 PM 25245904 ER PT J AU Koreth, J Kim, HT Nikiforow, S Milford, EL Armand, P Cutler, C Glotzbecker, B Ho, VT Antin, JH Soiffer, RJ Ritz, J Alyea, EP AF Koreth, John Kim, Haesook T. Nikiforow, Sarah Milford, Edgar L. Armand, Philippe Cutler, Corey Glotzbecker, Brett Ho, Vincent T. Antin, Joseph H. Soiffer, Robert J. Ritz, Jerome Alyea, Edwin P., III TI Donor Chimerism Early after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation Predicts Relapse and Survival SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Reduced-intensity; Chimerism ID COMPETING RISK; FLUDARABINE; RECOVERY; MALIGNANCIES; BUSULFAN; KINETICS; LEUKEMIA; DISEASE; IMPACT; TESTS AB The impact of early donor cell chimerism on outcomes of T cell-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), relapse, and nonrelapse mortality (NRM). We evaluated 688 patients with hematologic malignancies (48% myeloid and 52% lymphoid) and a median age of 57 years (range, 18 to 74) undergoing RIC HSCT with T cell-replete donor grafts (97% peripheral blood; 92% HLA-matched), with a median follow-up of 58.2 months (range, 12.6 to 120.7). In multivariable analysis, total donor cell and T cell chimerism at D30 and D100 each predicted RIC HSCT outcomes, with D100 total donor cell chimerism most predictive. D100 total donor cell chimerism <90% was associated with increased relapse (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.83 to 3.51; P < .0001), impaired PFS (HR, 2.01; 95% CI, 1.53 to 2.65; P < .0001), and worse OS (HR, 1.50; 95% CI, 1.11 to 2.04, P = .009), but not with NRM (HR, .76; 95% CI, .44 to 2.27; P = .33). There was no additional utility of incorporating sustained D30 to D100 total donor cell chimerism or T cell chimerism. Low donor chimerism early after RIC HSCT is an independent risk factor for relapse and impaired survival. Donor chimerism assessment early after RIC HSCT can prognosticate for long-term outcomes and help identify high-risk patient cohorts who may benefit from additional therapeutic interventions. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Koreth, John; Nikiforow, Sarah; Armand, Philippe; Cutler, Corey; Glotzbecker, Brett; Ho, Vincent T.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Alyea, Edwin P., III] Dana Farber Canc Inst, Hematol Malignancies Div, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Div Biostat & Computat Biol, Boston, MA 02215 USA. [Milford, Edgar L.] Brigham & Womens Hosp, Tissue Typing Lab, Boston, MA 02115 USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM john_koreth@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU Jock and Bunny Adams Research and Education Endowment; [P01 CA142106-06A1]; [R01 CA183559-01] FX J.K. is a Scholar in Clinical Research of the Leukemia & Lymphoma Society. This study is funded in part by the Jock and Bunny Adams Research and Education Endowment and by P01 CA142106-06A1 (J.H.A.) and R01 CA183559-01 (R.J.S.). NR 23 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2014 VL 20 IS 10 BP 1516 EP 1521 DI 10.1016/j.bbmt.2014.05.025 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AP5KC UT WOS:000342117100008 PM 24907627 ER PT J AU Saber, W Le Rademacher, J Sekeres, M Logan, B Lewis, M Mendizabal, A Leifer, E Appelbaum, FR Horowitz, MM Nakamura, R Cutler, CS AF Saber, Wael Le Rademacher, Jennifer Sekeres, Mikkael Logan, Brent Lewis, Moira Mendizabal, Adam Leifer, Eric Appelbaum, Frederick R. Horowitz, Mary M. Nakamura, Ryotaro Cutler, Corey S. TI Multicenter Biologic Assignment Trial Comparing Reduced-Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50 to 75 with Intermediate-2 and High-Risk Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design, and Methods SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Biologic assignment; MDS; Transplantation ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC SCORING SYSTEM; ACUTE MYELOGENOUS LEUKEMIA; PHASE-III; MYELOPROLIFERATIVE DISORDERS; DECISION-ANALYSIS; OLDER PATIENTS; UNITED-STATES; 1ST REMISSION; AZACITIDINE AB The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Saber, Wael; Le Rademacher, Jennifer; Logan, Brent; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Sekeres, Mikkael] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Lewis, Moira; Mendizabal, Adam] EMMES Corp, Rockville, MD USA. [Leifer, Eric] NHLBI, Bethesda, MD 20892 USA. [Appelbaum, Frederick R.] Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Seattle, WA 98195 USA. [Nakamura, Ryotaro] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Saber, W (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM wsaber@mcw.edu FU National Heart, Lung, and Blood Institute [U10 HL069294]; National Cancer Institute (NCI) of the National Institutes of Health; NCI [U24 CA076518]; NHLBI; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration of the US Department of Health and Human Services [HHSH250201200016 C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad Pharmaceuticals; Be The Match Foundation; Blue Cross and Blue Shield Association; Celgene; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck Co., Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; Well Point, Inc. FX Financial disclosure: The design and conduct of the BMT CTN 1102 is supported by Grant/Cooperative Agreement U10 HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute (NCI) of the National Institutes of Health. Data collection on alloHCT recipients will be through the CIBMTR, which is supported by Public Health Service Grant/Cooperative Agreement U24 CA076518 from the NCI, the NHLBI, and the National Institute of Allergy and Infectious Diseases; contract HHSH250201200016 C with the Health Resources and Services Administration of the US Department of Health and Human Services; grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from Allos Therapeutics, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad Pharmaceuticals; Be The Match Foundation; Blue Cross and Blue Shield Association; Celgene;Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; and Well Point, Inc.. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 49 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2014 VL 20 IS 10 BP 1566 EP 1572 DI 10.1016/j.bbmt.2014.06.010 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AP5KC UT WOS:000342117100015 PM 24972249 ER PT J AU Rajagopalan, V Vaidyanathan, M Janardhanam, VA Bradner, JE AF Rajagopalan, Vishal Vaidyanathan, Muthukumar Janardhanam, Vanisree Arambakkam Bradner, James E. TI Pre-Clinical Analysis of Changes in Intra-cellular Biochemistry of Glioblastoma Multiforme (GBM) Cells Due to c-Myc Silencing SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Glioblastoma multiforme; c-Myc; Bcl-2; Akt; Autophagy; Lipid; Glycogen ID GENE-EXPRESSION; CYCLE ENTRY; IN-VIVO; INHIBITION; TARGET; BROMODOMAIN; GROWTH; METABOLISM; APOPTOSIS; CANCER AB Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future. C1 [Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam] Univ Madras, Dept Biochem, Chennai 600025, Tamil Nadu, India. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Rajagopalan, V (reprint author), Univ Madras, Dept Biochem, Guindy Campus, Chennai 600025, Tamil Nadu, India. EM dnapolren@gmail.com FU University Grants Commission, New Delhi, India FX The study was supported by University Grants Commission, New Delhi, India. We thank the Sophisticated Analytical Instrument Facility (SAIF)-Department of Anatomy, AIIMS, New Delhi, India for providing microscopes in Electron Microscopy. We thank Dr. Aparna Rajagopalan for her critical reading and editing. We also thank University of Madras for all the infrastructure support in carrying out the experiments. NR 40 TC 5 Z9 5 U1 0 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 EI 1573-6830 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD OCT PY 2014 VL 34 IS 7 BP 1059 EP 1069 DI 10.1007/s10571-014-0083-4 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA AP5VK UT WOS:000342146600011 PM 25056450 ER PT J AU Wang, CY Kundaria, S Fernandez-Miranda, J Duvvuri, U AF Wang, Chengyuan Kundaria, Summit Fernandez-Miranda, Juan Duvvuri, Umamaheswar TI A Description of Arterial Variants in the Transoral Approach to the Parapharyngeal Space SO CLINICAL ANATOMY LA English DT Article DE robotic surgery; TORS; parapharyngeal space; arterial variants ID ROBOTIC SURGERY AB This study demonstrates variations in the vascular anatomy of the parapharyngeal space (PPS) as seen from the transoral approach compared with the transcervical approach. The PPS was dissected in injected cadaveric specimens. Anatomical measurements, including those of branches of the external and internal carotid arteries (ECA and ICA) and the styloglossus and stylopharyngeus muscles, were recorded and analyzed. In 67% (8/12) of cases, the ascending palatine artery (APA) originated from the facial artery and crossed the styloglossus muscle. The diameter of the APA at its origin was 1.4 +/- 0.3mm. In 75% (9/12) of cases, the ascending pharyngeal artery (aPA) arose from the medial surface of the ECA near its origin. In 58% (7/12) of cases, the aPA ascended vertically between the ICA and the lateral pharynx to the skull base, along the longus capitus muscle. The aPA crossed the styloglossus muscle 12.6 +/- 3.9mm from the insertion into the tongue. In 92% (11/12) of cases, the ECA and ICA were separated by the styloid diaphragm and pharyngeal venous plexus. In 8% (1/12), the ECA bulged into the parapharyngeal fat between the styloglossus and stylopharyngeus muscles adjacent to the pharyngeal constrictors. Knowledge of the precise anatomy of the PPS is important for transoral robotic surgery (TORS). Control of the vessels that supply and traverse the PPS can help the TORS surgeon avoid those critical structures and reduce surgical morbidity and potential hemorrhage. (C) 2014 Wiley Periodicals, Inc. C1 [Wang, Chengyuan] China Japan Friendship Hosp, Dept Otolaryngol Head & Neck Surg, Beijing, Peoples R China. [Wang, Chengyuan; Fernandez-Miranda, Juan] Univ Pittsburgh, Med Ctr, Dept Neurosurg, Pittsburgh, PA 15213 USA. [Kundaria, Summit; Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, UPMC Dept Otolaryngol Head & Neck Surg, Vet Affairs Pittsburgh Hlth Syst,Eye & Ear Inst, Pittsburgh, PA 15213 USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Vet Affairs Pittsburgh Hlth Syst,Eye & Ear Inst, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvuriu@upmc.edu FU Department of Veterans Affairs; University of Pittsburgh School of Medicine; PNC foundation FX Grant sponsors: Department of Veterans Affairs, University of Pittsburgh School of Medicine, and PNC foundation (U.D.). NR 9 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0897-3806 EI 1098-2353 J9 CLIN ANAT JI Clin. Anat. PD OCT PY 2014 VL 27 IS 7 BP 1016 EP 1022 DI 10.1002/ca.22273 PG 7 WC Anatomy & Morphology SC Anatomy & Morphology GA AP2NM UT WOS:000341909200013 PM 24510490 ER PT J AU Sonpavde, G Pond, GR Armstrong, AJ Clarke, SJ Vardy, JL Templeton, AJ Wang, SL Paolini, J Chen, I Chow-Maneval, E Lechuga, M Smith, MR Michaelson, MD AF Sonpavde, Guru Pond, Gregory R. Armstrong, Andrew J. Clarke, Stephen J. Vardy, Janette L. Templeton, Arnoud J. Wang, Shaw-Ling Paolini, Jolanda Chen, Isan Chow-Maneval, Edna Lechuga, Mariajose Smith, Matthew R. Michaelson, M. Dror TI Prognostic Impact of the Neutrophil-to-Lymphocyte Ratio in Men With Metastatic Castration-Resistant Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Advanced prostate cancer; Lymphocytes; Neutrophils; Prognosis; Survival ID RENAL-CELL CARCINOMA; CIRCULATING TUMOR-CELLS; PRETREATMENT NEUTROPHIL; PREOPERATIVE NEUTROPHIL; LEUKEMIA GROUP-B-9480; FOLLOW-UP; SURVIVAL; CHEMOTHERAPY; NOMOGRAM; MODEL AB This retrospective analysis of a phase III trial comparing prednisone combined with sunitinib or placebo following docetaxel for metastatic castration resistant prostate cancer demonstrated the prognostic impact of peripheral blood neutrophil-lymphocyte ratio (NLR) independent of known prognostic factors. NLR warrants external validation, given its ready and inexpensive availability, and the potential role of the host immune in modulating tumor biology. Background: We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. Methods: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. Results: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. Conclusion: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Pond, Gregory R.] McMaster Univ, Ontario Clin Oncol Grp, Hamilton, ON, Canada. [Armstrong, Andrew J.] Duke Univ, Durham, NC USA. [Clarke, Stephen J.; Vardy, Janette L.] Univ Sydney, Sydney, NSW 2006, Australia. [Templeton, Arnoud J.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Wang, Shaw-Ling; Paolini, Jolanda; Chen, Isan; Chow-Maneval, Edna; Lechuga, Mariajose] Pfizer Inc, Bridgewater, NJ USA. [Wang, Shaw-Ling] ICON Clin Res Inc, San Diego, CA USA. [Chen, Isan; Chow-Maneval, Edna] Aragon Pharmaceut, San Diego, CA USA. [Smith, Matthew R.; Michaelson, M. Dror] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Matthew R.; Michaelson, M. Dror] Harvard Univ, Sch Med, Boston, MA USA. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, 1802 6th Ave South,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu OI Michaelson, Dror/0000-0001-9249-6338; Vardy, Janette/0000-0002-5739-5790 FU Pfizer FX G. Sonpavde, M.R. Smith, and M.D. Michaelson receive research support from Pfizer. S.-L. Wang, J. Paolini, I. Chen, E. Chow-Maneval, and M. Lechuga are employed by Pfizer. A.J. Armstrong receives research support and has been a speaker for Pfizer. The authors G.R. Pond, S.J. Clarke, J.L. Vardy, and A.J. Templeton have stated that they have no conflicts of interest. NR 49 TC 9 Z9 10 U1 0 U2 10 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 317 EP 324 DI 10.1016/j.clgc.2014.03.005 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800014 PM 24806399 ER PT J AU Harshman, LC Kroeger, N Rha, SY Donskov, F Wood, L Tantravahi, SK Vaishampayan, U Rini, BI Knox, J North, S Ernst, S Yuasa, T Srinivas, S Pal, S Heng, DY Choueiri, TK AF Harshman, Lauren C. Kroeger, Nils Rha, Sun Young Donskov, Frede Wood, Lori Tantravahi, Srinivas K. Vaishampayan, Ulka Rini, Brian I. Knox, Jennifer North, Scott Ernst, Scott Yuasa, Takeshi Srinivas, Sandy Pal, Sumanta Heng, Daniel Y. Choueiri, Toni K. TI First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Everolimus; mTOR inhibitor; Targeted therapy; Temsirolimus; Treatment-naive ID PHASE-III TRIAL; INTERFERON-ALPHA; CANCER-THERAPY; SUNITINIB; EVEROLIMUS; SORAFENIB; SURVIVAL; TEMSIROLIMUS; EFFICACY; PAZOPANIB AB Using an established international renal cell carcinoma (RCC) database, we retrospectively characterized the use and efficacy of mammalian target of rapamycin (mTOR) inhibitors in treatment-naive metastatic RCC (mRCC) patients. Front-line mTOR inhibitors are used in clinical practice mostly in select patients, who have non-clear cell histology, poor prognostic features, or as part of clinical trials. Introduction/Background: Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. Patients and Methods: We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS). Results: We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients. Conclusion: Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made. (C) 2014 Elsevier Inc. All rights reserved. C1 [Harshman, Lauren C.; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Harshman, Lauren C.; Srinivas, Sandy] Stanford Canc Inst, Stanford, CA USA. [Kroeger, Nils; Heng, Daniel Y.] Tom Baker Canc Clin, Calgary, AB, Canada. [Rha, Sun Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [Donskov, Frede] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Tantravahi, Srinivas K.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Vaishampayan, Ulka] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Knox, Jennifer] Princess Margaret Canc Ctr, Toronto, ON, Canada. [North, Scott] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Ernst, Scott] London Reg Canc Program, London, ON, Canada. [Yuasa, Takeshi] JFCR, Canc Inst Hosp, Tokyo, Japan. [Pal, Sumanta] City Hope Natl Med Ctr, Duarte, CA USA. RP Harshman, LC (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Kidney Canc Ctr, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA. EM LaurenC_Harshman@dfci.harvard.edu OI Donskov, Frede/0000-0002-8449-863X FU BMS; Novartis; Pfizer; Glaxo-Smith Kline; Bristol-Myers Squibb FX Lauren C. Harshman: advisory boards for Aveo, Pfizer, and Bristol-Myers Squibb, past research funding from BMS and Novartis; Frede Donskov: research funding from Novartis; Lori Wood: consultant (uncompensated) for Pfizer and Glaxo-Smith Kline, research funding from Pfizer, Glaxo-Smith Kline, and Novartis; Ulka Vaishampayan: consultant for Novartis, honoraria from Novartis and Pfizer, research support from Pfizer; Brian I. Rini: consultant and research funding from Pfizer; Jennifer Knox: consultant for Aveo, research funding from Pfizer; Scott Ernst: consultant/advisory boards for Bristol-Myers Squib, Roche, Novartis, and Glaxo-Smith Kline; Sandy Srinivas: consultant for Pfizer, Glaxo-Smith Kline, and Genentech, research funding from Bristol-Myers Squibb, Pfizer, Glaxo-Smith Kline, and Novartis; Sumanta Pal: honoraria from Novartis; Daniel Y. Heng: consultant for Pfizer, Novartis, and Bayer; Toni K. Choueiri: advisory boards for Glaxo-Smith Kline, Pfizer, Novartis, Genentech, Bayer, and AVEO, research funding from Pfizer. The remaining authors have stated that they have no conflicts of interest. NR 29 TC 5 Z9 6 U1 0 U2 6 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 335 EP 340 DI 10.1016/j.clgc.2014.03.003 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800017 PM 24787966 ER PT J AU Khambati, HK Choueiri, TK Kollmannsberger, CK North, S Bjarnason, GA Vaishampayan, UN Wood, L Knox, JJ Tan, MH MacKenzie, MJ Donskov, F Rini, BI Heng, DYC AF Khambati, Husain K. Choueiri, Toni K. Kollmannsberger, Christian K. North, Scott Bjarnason, George A. Vaishampayan, Ulka N. Wood, Lori Knox, Jennifer J. Tan, Min-Han MacKenzie, Mary J. Donskov, Frede Rini, Brian I. Heng, Daniel Y. C. CA Int mRCC Database Consortium TI Efficacy of Targeted Therapy for Metastatic Renal Cell Carcinoma in the Elderly Patient Population SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Age; Geriatric; mRCC; Prognostic factors; Vascular endothelial growth factor ID INTERFERON-ALPHA; CANCER-PATIENTS; MANAGEMENT; SURVIVAL; IMPACT; INSUFFICIENCY; COMORBIDITY; SORAFENIB; TRIAL; OLD AB Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC), and the efficacy of this therapy in the older population is poorly understood. Data from 1381 patients with mRCC treated with first-line anti-vascular endothelial growth factor (VEGF) therapy were collected through the International mRCC Database Consortium from 12 centers. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival or shorter treatment duration. This suggests that advanced age alone should not preclude a patient from targeted therapy. Introduction/Background: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. Patients and Methods: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. Results: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those >= 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. Conclusion: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups. (C) 2014 Elsevier Inc. All rights reserved. C1 [Khambati, Husain K.; Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB T2N 4N2, Canada. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA USA. [Kollmannsberger, Christian K.] British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. [North, Scott] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Bjarnason, George A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Vaishampayan, Ulka N.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Knox, Jennifer J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Tan, Min-Han] Natl Canc Ctr, Singapore, Singapore. [MacKenzie, Mary J.] London Reg Canc Program, London, ON, Canada. [Donskov, Frede] Aarhus Univ, Aarhus, Denmark. [Rini, Brian I.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. RP Heng, DYC (reprint author), Univ Calgary, Tom Baker Canc Ctr, 1331 29th St NW, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca OI Bjarnason, Georg Arnold/0000-0001-6903-5357; Donskov, Frede/0000-0002-8449-863X FU Pfizer; Novartis; Bayer FX D.Y.C. Heng, J.J. Knox, G.A. Bjarnason, C.K. Kollmannsberger, and S. North have received consulting honoraria from Pfizer and Novartis. J.J. Knox, F. Donskov, G.A. Bjarnason, B.I. Rini, and T.K. Choueiri have received research funding from Pfizer and Novartis. J.J. Knox has received research funding from Bayer. The remaining authors have stated that they have no conflicts of interest. NR 25 TC 7 Z9 7 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 354 EP 358 DI 10.1016/j.clgc.2014.02.009 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800020 PM 24819320 ER PT J AU Mahal, BA Aizer, AA Ziehr, DR Hyatt, AS Choueiri, TK Hu, JC Hoffman, KE Sweeney, CJ Beard, CJ D'Amico, AV Martin, NE Kim, SP Trinh, QD Nguyen, PL AF Mahal, Brandon A. Aizer, Ayal A. Ziehr, David R. Hyatt, Andrew S. Choueiri, Toni K. Hu, Jim C. Hoffman, Karen E. Sweeney, Christopher J. Beard, Clair J. D'Amico, Anthony V. Martin, Neil E. Kim, Simon P. Quoc-Dien Trinh Nguyen, Paul L. TI Racial Disparities in Prostate Cancere-Specific Mortality in Men With Low-Risk Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE African-American; Health Policy; Population health; Prostatic Neoplasms; SEER ID BIOCHEMICAL DISEASE RECURRENCE; AGE-BASED DISPARITIES; AFRICAN-AMERICAN MEN; ACTIVE SURVEILLANCE; RADICAL PROSTATECTOMY; CLINICAL-TRIALS; IMPACT; RACE; MANAGEMENT; OUTCOMES AB This study examined the association of race and prostate cancere-specific mortality (PCSM) in 51,315 men with low-risk prostate cancer, using the Surveillance, Epidemiology, and End Results (SEER) database. African American men were found to have a higher risk of PCSM compared with white men, suggesting that further studies are needed to determine whether guidelines for active surveillance should take race into account. Background: Men with low-risk prostate cancer (CaP) are considered unlikely to die of CaP and have the option of active surveillance. This study evaluated whether African American (AA) men who present with low-risk disease are at higher risk for death from CaP than white men. Patients and Methods: The authors identified 56,045 men with low-risk CaP (T1-T2a, Gleason score <= 6, prostate-specific antigen <= 10 ng/mL) diagnosed between 2004 and 2009 using the Surveillance, Epidemiology, and End Results (SEER) database. Fine-Gray competing-risks regression analyses were used to analyze the effect of race on prostate cancere-specific mortality (PCSM) after adjusting for known prognostic and sociodemographic factors in 51,315 men (43,792 white; 7523 AA) with clinical follow-up information available. Results: After a median follow-up of 46 months, 258 patients (209 [0.48%] white and 49 [0.65%] AA men) died from CaP. Both AA race (adjusted hazard ratio [AHR], 1.45; 95% CI, 1.03-2.05; P = .032) and noncurative management (AHR, 1.49; 95% CI, 1.15-1.95; P = .003) were significantly associated with an increased risk of PCSM. When analyzing only patients who underwent curative treatment, AA race (AHR, 1.62; 95% CI, 1.04-2.53; P = .034) remained significantly associated with increased PCSM. Conclusion: Among men with low-risk prostate cancer, AA race compared with white race was associated with a higher risk of PCSM, raising the possibility that clinicians may need to exercise caution when recommending active surveillance for AA men with low-risk disease. Further studies are needed to ultimately determine whether guidelines for active surveillance should take race into account. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mahal, Brandon A.; Ziehr, David R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Aizer, Ayal A.] Harvard Radiat Oncol Program, Boston, MA USA. [Hyatt, Andrew S.; Beard, Clair J.; D'Amico, Anthony V.; Martin, Neil E.; Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Hyatt, Andrew S.; Choueiri, Toni K.; Sweeney, Christopher J.; Beard, Clair J.; D'Amico, Anthony V.; Martin, Neil E.; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Choueiri, Toni K.; Sweeney, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hu, Jim C.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Kim, Simon P.] Yale Univ, Canc Outcomes & Publ Policy Effectiveness Res Ctr, Dept Urol, New Haven, CT USA. [Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU David and Cynthia Chapin; Prostate Cancer Foundation; Fitz's Cancer Warriors; Hugh Simons in Honor of Frank; Anne Simons; anonymous family foundation FX This work was supported by David and Cynthia Chapin, the Prostate Cancer Foundation, Fitz's Cancer Warriors, Hugh Simons in Honor of Frank and Anne Simons, and a grant from an anonymous family foundation. Paul L. Nguyen served on an advisory board for Astellas Pharmaceuticals in June 2013. Quoc-Dien Trinh lectured on behalf of Intuitive Surgical. All other authors state that they have no conflicts of interest. NR 43 TC 12 Z9 12 U1 0 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E189 EP E195 DI 10.1016/j.clgc.2014.04.003 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800004 PM 24861952 ER PT J AU Phillips, JG Aizer, AA Chen, MH Zhang, DJ Hirsch, MS Richie, JP Tempany, CM Williams, S Hegde, JV Loffredo, MJ D'Amico, AV AF Phillips, John G. Aizer, Ayal A. Chen, Ming-Hui Zhang, Danjie Hirsch, Michelle S. Richie, Jerome P. Tempany, Clare M. Williams, Stephen Hegde, John V. Loffredo, Marian J. D'Amico, Anthony V. TI The Effect of Differing Gleason Scores at Biopsy on the Odds of Upgrading and the Risk of Death From Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE ComboGS; Pathology; Prognostic factors; Prostate cancer-specific mortality; Radical prostatectomy ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; RADIATION-THERAPY; COMPETING RISK; BRACHYTHERAPY; OUTCOMES; MODEL AB We provide evidence that differing Gleason scores (GSs) at biopsy (ComboGS) is associated with an approximately 80% decrease in the odds of upgrading and a 60% decrease in the risk of prostate cancer-specific mortality (PCSM) after definitive treatment. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. Introduction/Background: The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. Patients and Methods: Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. Results: ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). Conclusion: Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. (C) 2014 Elsevier Inc. All rights reserved. C1 [Phillips, John G.; Aizer, Ayal A.] Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Richie, Jerome P.; Williams, Stephen] Brigham & Womens Hosp, Dept Surg, Div Urol, Boston, MA 02115 USA. [Tempany, Clare M.] Brigham & Womens Hosp, Dept Radiol, Div MRI, Boston, MA 02115 USA. [Hegde, John V.] Harvard Univ, Sch Med, Boston, MA USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Phillips, JG (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, ASBI LL2,75 Francis St, Boston, MA 02115 USA. EM jphillips@lroc.harvard.edu FU NIH [EB 015898, CA 111288] FX This work was supported by NIH grants: EB 015898 and CA 111288. NR 31 TC 1 Z9 1 U1 0 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E181 EP E187 DI 10.1016/j.clgc.2014.02.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800003 PM 24721618 ER PT J AU Rose, BS Chen, MH Zhang, DJ Hirsch, MS Richie, JP Chang, SL Hegde, JV Loffredo, MJ D'Amico, AV AF Rose, Brent S. Chen, Ming-Hui Zhang, Danjie Hirsch, Michelle S. Richie, Jerome P. Chang, Stephen L. Hegde, John V. Loffredo, Marian J. D'Amico, Anthony V. TI Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Adjuvant radiation therapy; Biochemical recurrence; Over treatment; Prostate cancer; Risk stratification ID RANDOMIZED CLINICAL-TRIAL; INDEPENDENT PREDICTOR; ADJUVANT RADIOTHERAPY; POSTOPERATIVE RADIOTHERAPY; BIOCHEMICAL RECURRENCE; RADIATION-THERAPY; SALVAGE RADIATION; CANCER; FAILURE; CARCINOMA AB Multiple randomized controlled trials have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or margin-positive disease reduces the risk of biochemical recurrence after radical prostatectomy (RP); however, overtreatment might occur. We used multivariable Cox regression to study 354 men with clinical T1c to T2 prostate cancer who underwent RP without adjuvant therapy to investigate whether the maximum tumor diameter (MTD) could identify men at low risk of prostate-specific antigen (PSA) recurrence. We found that men with an MTD <= median (1.2 cm) appear to be at low risk of PSA recurrence (< 10% at 5 years with a median follow-up of 4 years) despite adverse features at RP and might not benefit from ART. Introduction/Background: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. Patients and Methods: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. Results: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23-6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA <= 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score >= 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%). Conclusion: Men with a low MTD (<= 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART. (C) 2014 Elsevier Inc. All rights reserved. C1 [Rose, Brent S.] Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Richie, Jerome P.; Chang, Stephen L.] Brigham & Womens Hosp, Div Urol, Boston, MA 02215 USA. [Hegde, John V.] Harvard Univ, Sch Med, Boston, MA USA. [Rose, Brent S.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP Rose, BS (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02215 USA. EM bsrose@partners.org NR 30 TC 1 Z9 1 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E173 EP E179 DI 10.1016/j.clgc.2014.03.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800002 PM 24787967 ER PT J AU Mollica, RF Chernoff, MC Berthold, SM Lavelle, J Lyoo, IK Renshaw, P AF Mollica, Richard F. Chernoff, Miriam C. Berthold, S. Megan Lavelle, James Lyoo, In Kyoon Renshaw, Perry TI The mental health sequelae of traumatic head injury in South Vietnamese ex-political detainees who survived torture SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; HOPKINS SYMPTOM CHECKLIST-25; CONCENTRATION-CAMP SURVIVORS; DOSE-EFFECT RELATIONSHIPS; OF-THE-LITERATURE; BRAIN-INJURY; MASS VIOLENCE; PSYCHOLOGICAL SEQUELAE; PSYCHIATRIC-DISORDERS; CAMBODIAN SURVIVORS AB Little is known about the relationship between traumatic head injury (THI) and psychiatric morbidity in torture survivors. We examine the relationship between THI and depression, PTSD, post-concussive syndrome (PCS), disability and poor health status in Vietnamese ex-political detainees who survived incarceration in Vietnamese re-education camps. A community sample of ex-political detainees (n = 337) and a non-THI, non-ex-detainee comparison group (n = 82) were surveyed. Seventy-eight percent of the ex-political detainees had experienced THI; 90.6% of the ex-political detainees and 3.6% of the comparison group had experienced 7 or more trauma events. Depression and PTSD were greater in ex-detainees than in the comparison group (40.9% vs 23.2% and 13.4% vs 0%). Dose-effect relationships for THI and trauma/torture in the ex-political detainee group were significant. Logistic regression in the pooled sample of ex-detainees and the comparison group confirmed the independent impact of THI from trauma/torture on psychiatric morbidity (OR for PTSD = 22.4; 95% CI: 3.0-165.8). These results demonstrate important effects of THI on depression and PTSD in Vietnamese ex-detainees who have survived torture. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mollica, Richard F.; Lavelle, James] Massachusetts Gen Hosp, Dept Psychiat, Harvard Program Refugee Trauma, Boston, MA 02114 USA. [Chernoff, Miriam C.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Berthold, S. Megan] Univ Connecticut, Sch Social Work, West Harford, CT USA. [Lyoo, In Kyoon] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul, South Korea. [Lyoo, In Kyoon] Ewha Womans Univ, Ewha Brain Inst, Seoul, South Korea. [Renshaw, Perry] Univ Utah, Interdept Program Neurosci, Salt Lake City, UT USA. RP Mollica, RF (reprint author), Harvard Program Refugee Trauma, 22 Putnam Ave, Cambridge, MA 02139 USA. EM rmollica@partners.org; miriam.chernoff@juno.com; megan.berthold@uconn.edu; jlavelle@partners.org; inkylyoo@ewha.ac.kr; Perry.Renshaw@hsc.utah.edu FU National Institute of Health, Bethesda, Maryland [MH R01-059559-04] FX Research for this manuscript was made possible by Grant No. MH R01-059559-04 from the National Institute of Health, Bethesda, Maryland. There are no conflicts of interest. The authors would like to acknowledge the following for their contributions to this study: (1) Vietnamese American Civic Association (VACA) and (2) Daniel H. Hovelson, BA, Harvard Program in Refugee Trauma. NR 95 TC 6 Z9 6 U1 2 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD OCT PY 2014 VL 55 IS 7 BP 1626 EP 1638 DI 10.1016/j.comppsych.2014.04.014 PG 13 WC Psychiatry SC Psychiatry GA AP5LX UT WOS:000342121800023 PM 24962448 ER PT J AU Grubbs, JA Baddley, JW AF Grubbs, James A. Baddley, John W. TI Pneumocystis jirovecii Pneumonia in Patients Receiving Tumor-Necrosis-Factor-Inhibitor Therapy: Implications for Chemoprophylaxis SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Pneumocystis jirovecii; PJP; Autoimmune disease; Biologicals; TNF inhibitor; Prophylaxis; Trimethoprim-sulfamethoxazole ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; RHEUMATOID-ARTHRITIS PATIENTS; HIV-INFECTED PATIENTS; RANDOMIZED CONTROLLED-TRIALS; SYNTHASE GENE-MUTATIONS; REAL-TIME PCR; CARINII-PNEUMONIA; SERIOUS INFECTIONS; TRIMETHOPRIM-SULFAMETHOXAZOLE; POSTMARKETING SURVEILLANCE AB Pneumocystis jirovecii pneumonia (PJP) is an important opportunistic infection that has been increasingly reported in patients with rheumatic disease. Reported incidence among patients taking TNF inhibitors (TNFi) has varied, but has usually been low. Still, disease causes significant mortality among those affected and must be considered in patients with rheumatological disease presenting with dyspnea and cough. Diagnosis can be difficult in the non-HIV population, and our understanding of the epidemiology and natural history after exposure is changing. Trimethoprim-sulfamethoxazole is believed to be the most effective agent for treatment and prophylaxis, but is associated with significant adverse effects. Given the low incidence reported in most studies of patients on TNFi, prophylaxis is probably not beneficial for this patient population as a whole. C1 [Grubbs, James A.; Baddley, John W.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Baddley, JW (reprint author), Univ Alabama Birmingham, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM jbaddley@uab.edu FU BMS FX James A. Grubbs declares that he has no conflict of interest. John W. Baddley declares that he has served as a consultant for Pfizer, Astellas, and Merck, and that he has received a research grant from BMS. NR 87 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD OCT PY 2014 VL 16 IS 10 AR 445 DI 10.1007/s11926-014-0445-4 PG 9 WC Rheumatology SC Rheumatology GA AP4UQ UT WOS:000342074700001 PM 25182673 ER PT J AU Wessels, D Lusche, DF Scherer, A Kuhl, S Myre, MA Soll, DR AF Wessels, Deborah Lusche, Daniel F. Scherer, Amanda Kuhl, Spencer Myre, Michael A. Soll, David R. TI Huntingtin regulates Ca2+ chemotaxis and K+-facilitated cAMP chemotaxis, in conjunction with the monovalent cation/H+ exchanger Nhe1, in a model developmental system: Insights into its possible role in Huntington's disease SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Huntingtin; Actin-myosin cytoskeleton; Myosin heavy chain kinase; Inositol 1,4,5-trisphosphate receptor; Cation/H+ exchanger; Calcium chemotaxis; Nhe1; Cell motility ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; HEAVY-CHAIN KINASE; SINGLE-CELL MOTILITY; CYCLIC-AMP PULSES; DICTYOSTELIUM-DISCOIDEUM; MYOSIN-II; ACTIN POLYMERIZATION; PSEUDOPOD EXTENSION; NATURAL AGGREGATION; CALCIUM AB Huntington's disease is a neurodegenerative disorder, attributable to an expanded trinucleotide repeat in the coding region of the human HIT gene, which encodes the protein huntingtin. These mutations lead to huntingtin fragment inclusions in the striatum of the brain. However, the exact function of normal huntingtin and the defect causing the disease remain obscure. Because there are indications that huntingtin plays a role in Ca2+ homeostasis, we studied the deletion mutant of the HTT ortholog in the model developmental system Dictyostelium discoideum, in which Ca2+ plays a role in receptor-regulated behavior related to the aggregation process that leads to multicellular morphogenesis. The D. discoideum tar-mutant failed to undergo both K+-facilitated chemotaxis in spatial gradients of the major chemoattractant cAMP, and chemotaxis up a spatial gradient of Ca2+, but behaved normally in Ca2+-facilitated cAMP chemotaxis and Ca2+-dependent flow-directed motility. This was the same phenotypic profile of the null mutant of Nhe1, a monovalent cation/H(+)exchanger. The htt(-)-mutant also failed to orient correctly during natural aggregation, as was the case for the Nhe1 mutant. Moreover, in a K+-based buffer the normal localization of actin was similarly defective in both htt(-) and nhe1(-) cells in a K+-based buffer, and the normal localization of Nhe1 was disrupted in the htt- mutant. These observations demonstrate that Htt and Nhe1 play roles in the same specific cation-facilitated behaviors and that Nhe1 localization is directly or indirectly regulated by Htt. Similar cation-dependent behaviors and a similar relationship between Htt and Nhe1 have not been reported for mammalian neurons and deserves investigation, especially as it may relate to Huntington's disease. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wessels, Deborah; Lusche, Daniel F.; Scherer, Amanda; Kuhl, Spencer; Soll, David R.] Univ Iowa, Dept Biol, Dev Studies Hybridoma Bank, Iowa City, IA 52242 USA. [Myre, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. RP Soll, DR (reprint author), Univ Iowa, Dept Biol, 302 BBE, Iowa City, IA 52242 USA. EM david-soll@uiowa.edu FU Developmental Studies Hybridoma Bank (DSHB) at the University of Iowa; National Resource created by the NIH; CHDI Foundation FX This research was supported by the Developmental Studies Hybridoma Bank (DSHB) at the University of Iowa, a National Resource created by the NIH, and in part by the CHDI Foundation to M.A.M. We thank Brett Hanson for assistance with the analysis of HDP. The 12E6 anti-GFP monoclonal antibody developed by Sanchez et al. (2014) was obtained from the DSHB, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA 52242. NR 71 TC 5 Z9 6 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2014 VL 394 IS 1 BP 24 EP 38 DI 10.1016/j.ydbio.2014.08.009 PG 15 WC Developmental Biology SC Developmental Biology GA AP2ME UT WOS:000341905500004 PM 25149514 ER PT J AU Cohen, E Bolus, R Khanna, D Hays, RD Chang, L Melmed, GY Khanna, P Spiegel, B AF Cohen, Erica Bolus, Roger Khanna, Dinesh Hays, Ron D. Chang, Lin Melmed, Gil Y. Khanna, Puja Spiegel, Brennan TI GERD Symptoms in the General Population: Prevalence and Severity Versus Care-Seeking Patients SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Gastroesophageal reflux disease; Patient-reported outcomes; Symptoms ID GASTROESOPHAGEAL-REFLUX DISEASE; IRRITABLE-BOWEL-SYNDROME; QUALITY-OF-LIFE; VISCERAL SENSITIVITY INDEX; REPORTED OUTCOMES; UNITED-STATES; EPIDEMIOLOGY; DISORDERS; BURDEN; VALIDATION AB Prior estimates suggest that up to 40 % of the US general population (GP) report symptoms of gastroesophageal reflux disease (GERD). However, symptoms in the GP versus patients seeking care for gastrointestinal (GI) complaints have not been compared. We estimated the prevalence and severity of GERD symptoms in the GP versus GI patients, and identified predictors of GERD severity. We hypothesized that similar to functional GI disorders, psychosocial factors would predict symptom severity in GERD as much, or perhaps more, than care-seeking behavior alone. We compared the prevalence of heartburn and regurgitation between a sample from the US GP and patients seeking GI specialty care. We compared GERD severity between groups using the NIH PROMISA (R) GERD scale. We then performed multivariable regression to identify predictors of GERD severity. There was no difference in the prevalence of heartburn between the GP and patient groups (59 vs. 59 %), but regurgitation was more common in patients versus GP (46 vs. 39 %; p = 0.004). In multivariable regression, having high visceral anxiety (p < 0.001) and being divorced or separated (p = 0.006) were associated with higher GERD severity. More than half of a GP sample reports heartburn-higher than previous series and no different from GI patients. Although regurgitation was more prevalent in patients versus the GP, there was no difference in GERD severity between groups after adjusting for other factors; care seeking in GERD appears related to factors beyond symptoms, including visceral anxiety. C1 [Cohen, Erica; Spiegel, Brennan] VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, Los Angeles, CA 90073 USA. [Cohen, Erica; Melmed, Gil Y.] Cedars Sinai Med Ctr, Dept Gastroenterol, West Hollywood, CA USA. [Bolus, Roger; Chang, Lin; Spiegel, Brennan] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Bolus, Roger; Spiegel, Brennan] UCLA VA Ctr Outcomes Res & Educ, Los Angeles, CA USA. [Khanna, Dinesh; Khanna, Puja] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. [Hays, Ron D.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Hays, Ron D.] UCLA Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA USA. [Chang, Lin] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. RP Spiegel, B (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu FU National Institutes of Health through the NIH Roadmap for Medical Research Grant [AR052177]; Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant [NIAMS 1 T32 AR053463]; ACR Research and Education Foundation Clinical Investigator Fellowship Award [2009_11]; NIAMS [K24 AR063120]; NIH/NIA [P30-AG028748, P30-AG021684]; NCMHD [2P20MD000182]; NIDDK [P50 DK64539] FX NIH/NIAMS U01 AR057936A, the National Institutes of Health through the NIH Roadmap for Medical Research Grant (AR052177). Puja Khanna was supported by Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant NIAMS 1 T32 AR053463 and ACR Research and Education Foundation Clinical Investigator Fellowship Award 2009_11. Dinesh Khanna was also supported by NIAMS K24 AR063120. Ron Hays was also supported by NIH/NIA Grants P30-AG028748 and P30-AG021684, and NCMHD Grant 2P20MD000182. Lin Chang was also supported by NIDDK P50 DK64539. NR 33 TC 7 Z9 7 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD OCT PY 2014 VL 59 IS 10 BP 2488 EP 2496 DI 10.1007/s10620-014-3181-8 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP5WH UT WOS:000342148900018 PM 24811245 ER PT J AU Walter, JM Wilson, J Ware, LB AF Walter, James M. Wilson, Jennifer Ware, Lorraine B. TI Biomarkers in acute respiratory distress syndrome: from pathobiology to improving patient care SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE acute lung injury; acute respiratory distress syndrome; biomarkers; clinical predictor; genomics; proteomics ID ACUTE LUNG INJURY; VON-WILLEBRAND-FACTOR; ENDOTHELIAL GROWTH-FACTOR; PULMONARY-EDEMA FLUID; CLARA CELL PROTEIN; GLYCATION END-PRODUCTS; AT-RISK PATIENTS; PROGNOSTIC-SIGNIFICANCE; CLINICAL-OUTCOMES; FACTOR ANTIGEN AB Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by alveolar flooding with protein-rich pulmonary edema fluid. Despite an improved understanding of ARDS pathogenesis, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help identify patients at highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. This review begins with a general description of biomarker use in clinical medicine. We then review evidence that supports the value of various ARDS biomarkers organized by the cellular injury processes central to ARDS development: endothelial injury, epithelial injury, disordered inflammation and coagulation, fibrosis, and apoptosis. Finally, we summarize the growing contributions of genomic and proteomic research and suggest ways in which the field may evolve in the coming years. C1 [Walter, James M.] Univ Calif San Francisco, Dept Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Wilson, Jennifer] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. [Ware, Lorraine B.] Vanderbilt Univ, Sch Med, Dept Med, Dept Pathol Microbiol & Immunol,Div Allergy Pulm, Nashville, TN 37212 USA. RP Walter, JM (reprint author), Univ Calif San Francisco, Dept Internal Med, San Francisco Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM James.Walter@ucsf.edu NR 111 TC 6 Z9 7 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD OCT PY 2014 VL 8 IS 5 BP 573 EP 586 DI 10.1586/17476348.2014.924073 PG 14 WC Respiratory System SC Respiratory System GA AP4QJ UT WOS:000342062700007 PM 24875533 ER PT J AU Restrepo, RD Nuccio, P Spratt, G Waugh, J AF Restrepo, Ruben D. Nuccio, Paul Spratt, Greg Waugh, Jonathan TI Current applications of capnography in non-intubated patients SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE capnography; carbon dioxide; hypoventilation; patient-controlled analgesia; procedural sedation; respiratory depression; volumetric CO2 ID MORBIDLY OBESE-PATIENTS; PROCEDURAL SEDATION; VOLUMETRIC CAPNOGRAPHY; CARBON-DIOXIDE; EMERGENCY-DEPARTMENT; PROPOFOL SEDATION; RESPIRATORY DEPRESSION; AMERICAN-SOCIETY; LUNG RECRUITMENT; CONTROLLED-TRIAL AB Current clinical guidelines recommend capnography as one of the best non-invasive methods to assess adequacy of ventilation in the non-intubated patient. Alveolar hypoventilation or respiratory depression is a serious event that occurs in a variety of clinical settings where patients receive sedatives and opioids. With the large number of procedures performed outside the operating room under the effects of sedatives and the increased use of patient-controlled analgesia, the need for capnography for monitoring has dramatically increased. Despite the succesful use of capnography to monitor ventilation in the operating room over several decades, other clinical areas have been very slow adapters of the technology and still rely heavily upon pulse oximetry to detect hypoventilation. This article reviews the most current evidence for using capnography in the non-intubated patient and summarizes the results of outcome measures reported in recent clinical trials. Capnography should be routinely used for non-intubated patients at risk for respiratory depression, in particular those receiving supplemental oxygen. C1 [Restrepo, Ruben D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Resp Care, San Antonio, TX 78229 USA. [Nuccio, Paul] Brigham & Womens Hosp, Boston, MA 02115 USA. [Nuccio, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. [Spratt, Greg] Covidien Orid Capnog, St Louis, MO 63463 USA. [Waugh, Jonathan] Univ Alabama Birmingham, Birmingham, AL 35294 USA. RP Restrepo, RD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Resp Care, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM restrepor@uthscsa.edu OI Restrepo, Ruben/0000-0003-1936-7622 NR 73 TC 0 Z9 1 U1 5 U2 14 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD OCT PY 2014 VL 8 IS 5 BP 629 EP 639 DI 10.1586/17476348.2014.940321 PG 11 WC Respiratory System SC Respiratory System GA AP4QJ UT WOS:000342062700011 PM 25020234 ER PT J AU Johnson, DA Barkun, AN Cohen, LB Dominitz, JA Kaltenbach, T Martel, M Robertson, DJ Boland, CR Giardello, FM Lieberman, DA Levin, TR Rex, DK AF Johnson, David A. Barkun, Alan N. Cohen, Larry B. Dominitz, Jason A. Kaltenbach, Tonya Martel, Myriam Robertson, Douglas J. Boland, C. Richard Giardello, Frances M. Lieberman, David A. Levin, Theodore R. Rex, Douglas K. TI Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID ORAL SODIUM-PHOSPHATE; RANDOMIZED CONTROLLED-TRIAL; POLYETHYLENE-GLYCOL SOLUTION; ELECTROLYTE LAVAGE SOLUTION; PLUS ASCORBIC-ACID; INVESTIGATOR-BLINDED TRIAL; HIGH-DOSE SENNA; INCREASE SCREENING COLONOSCOPY; ADENOMA DETECTION RATE; CLEAR LIQUID DIET AB Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States.(1) Colonoscopy can prevent CRC by the detection and removal of precancerous lesions. In addition to CRC screening and surveillance, colonoscopy is used widely for the diagnostic evaluation of symptoms and other positive CRC screening tests. Regardless of indication, the success of colonoscopy is linked closely to the adequacy of preprocedure bowel cleansing. Unfortunately, up to 20%-25% of all colonoscopies are reported to have an inadequate bowel preparation.(2,3) The reasons for this range from patient-related variables such as compliance with preparation instructions and a variety of medical conditions that make bowel cleansing more difficult to unit-specific factors (eg, extended wait times after scheduling of colonoscopy).(4) Adverse consequences of ineffective bowel preparation include lower adenoma detection rates, longer procedural time, lower cecal intubation rates, increased electrocautery risk, and shorter intervals between examinations.(3,5-7) Bowel preparation formulations intended for precolonoscopy cleansing are assessed based on their efficacy, safety, and tolerability. Lack of specific organ toxicity is considered to be a prerequisite for bowel preparations. Between cleansing efficacy and tolerability, however, the consequences of inadequate cleansing suggest that efficacy should be a higher priority than tolerability. Consequently, the choice of a bowel cleansing regimen should be based on cleansing efficacy first and patient tolerability second. However, efficacy and tolerability are closely interrelated. For example, a cleansing agent that is poorly tolerated and thus not fully ingested may not achieve an adequate cleansing. The goals of this consensus document are to provide expert, evidence-based recommendations for clinicians to optimize colonoscopy preparation quality and patient safety. Recommendations are provided using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) scoring system, which weighs the strength of the recommendation and the quality of the evidence.(8) C1 [Johnson, David A.] Eastern Vet Affairs Med Sch, Norfolk, VA 23507 USA. [Barkun, Alan N.; Martel, Myriam] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Cohen, Larry B.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dominitz, Jason A.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Vet Affairs Palo Alto, Palo Alto, CA 94304 USA. [Robertson, Douglas J.] White River Junct Vet Affairs Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, White River Jct, VT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Giardello, Frances M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Johnson, DA (reprint author), Eastern Vet Affairs Med Sch, Norfolk, VA 23507 USA. OI Dominitz, Jason/0000-0002-8070-7086 FU Veterans Health Administration FX This material is the result of work supported, in part, by resources from The Veterans Health Administration. The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs. NR 253 TC 16 Z9 16 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD OCT PY 2014 VL 80 IS 4 BP 543 EP 562 DI 10.1016/j.gie.2014.08.002 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP6CZ UT WOS:000342166400001 PM 25220509 ER PT J AU Das, KK Xiao, H Geng, X Fernandez-del-Castillo, C Morales-Oyarvide, V Daglilar, E Forcione, DG Bounds, BC Brugge, WR Pitman, MB Mino-Kenudson, M Das, KM AF Das, Koushik K. Xiao, Hong Geng, Xin Fernandez-del-Castillo, Carlos Morales-Oyarvide, Vicente Daglilar, Ebubekir Forcione, David G. Bounds, Brenna C. Brugge, William R. Pitman, Martha B. Mino-Kenudson, Mari Das, Kiron M. TI mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN) SO GUT LA English DT Article ID INTERNATIONAL CONSENSUS GUIDELINES; GASTRIC INTESTINAL METAPLASIA; MONOCLONAL-ANTIBODY; PANCREATIC CYSTS; ULCERATIVE-COLITIS; SURGICAL RESECTION; MANAGEMENT; ADENOCARCINOMA; EPITHELIUM; CANCER AB Objective Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. Design mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. Results Immunohistochemistry-Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignant IPMNs were 85% and 95%, respectively. Lesional fluid-Samples from low-and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. Conclusions mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification. C1 [Das, Koushik K.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Das, Koushik K.; Xiao, Hong; Fernandez-del-Castillo, Carlos; Morales-Oyarvide, Vicente; Daglilar, Ebubekir; Forcione, David G.; Bounds, Brenna C.; Brugge, William R.; Pitman, Martha B.; Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA USA. [Xiao, Hong; Morales-Oyarvide, Vicente; Pitman, Martha B.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Geng, Xin; Das, Kiron M.] Rutgers Robert Wood Johnson Med Sch, Div Gastroenterol, New Brunswick, NJ USA. [Fernandez-del-Castillo, Carlos; Morales-Oyarvide, Vicente] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Daglilar, Ebubekir; Forcione, David G.; Bounds, Brenna C.; Brugge, William R.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. EM koushik.das@uphs.upenn.edu; mminokenudson@partners.org FU National Institutes of Health, Bethesda, MD, USA [NIDDK, R01 DK47673, R01 DK63618]; National Cancer Institute [P50 CA127003, R01 CA169086] FX Development of mAb Das-1 was supported in part by research grants NIDDK, R01 DK47673 and R01 DK63618 to KMD from the National Institutes of Health, Bethesda, MD, USA. MMK was supported by National Cancer Institute grants P50 CA127003 and R01 CA169086. NR 44 TC 10 Z9 10 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD OCT PY 2014 VL 63 IS 10 BP 1627 EP + DI 10.1136/gutjnl-2013-306219 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP2TQ UT WOS:000341928300016 PM 24277729 ER PT J AU Shindo, ML Caruana, SM Kandil, E McCaffrey, JC Orloff, LA Porterfield, JR Shaha, A Shin, J Terris, D Randolph, G AF Shindo, Maisie L. Caruana, Salvatore M. Kandil, Emad McCaffrey, Judith C. Orloff, Lisa A. Porterfield, John R. Shaha, Ashok Shin, Jennifer Terris, David Randolph, Gregory TI Management of invasive well-differentiated thyroid cancer: An American Head and Neck Society Consensus Statement AHNS Consensus Statement SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE invasive thyroid cancer; tracheal invasion; recurrent laryngeal nerve invasion; locally aggressive thyroid cancer; vascular invasion ID RECURRENT LARYNGEAL NERVE; EXTERNAL-BEAM RADIOTHERAPY; JUGULAR-VEIN RECONSTRUCTION; SURGICAL-MANAGEMENT; AERODIGESTIVE TRACT; PAPILLARY CARCINOMA; TRACHEAL RESECTION; CLINICOPATHOLOGICAL FEATURES; LARYNGOTRACHEAL INVASION; ESOPHAGEAL INVOLVEMENT AB Background. Invasive differentiated thyroid cancer (DTC) is relatively frequent, yet there is a paucity of specific guidelines devoted to its management. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to provide clinical consensus statements based on review of the literature, synthesized with the expert opinion of the group. Methods. An expert panel, selected from membership of the AHNS, constructed the manuscript and recommendations for management of DTC with invasion of recurrent laryngeal nerve, trachea, esophagus, larynx, and major vessels based on current best evidence. A Modified Delphi survey was then constructed by another expert panelist utilizing 9 anchor points, 1=strongly disagree to 9=strongly agree. Results of the survey were utilized to determine which statements achieved consensus, near-consensus, or non-consensus. Results. After endorsement by the AHNS Endocrine Committee and Quality of Care Committee, it received final approval from the AHNS Council. (C) 2014 Wiley Periodicals, Inc. C1 [Shindo, Maisie L.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97239 USA. [Caruana, Salvatore M.] Columbia Univ, Dept Otolaryngol, New York, NY USA. [Kandil, Emad] Tulane Univ, Dept Otolaryngol, New Orleans, LA 70118 USA. [McCaffrey, Judith C.] H Lee Moffitt Canc Ctr & Res Inst, Dept Otolaryngol, Tampa, FL USA. [Orloff, Lisa A.] Stanford Univ, Stanford, CA 94305 USA. [Porterfield, John R.] Univ Alabama, Dept Otolaryngol, Tuscaloosa, AL USA. [Shaha, Ashok] Mem Sloan Kettering Canc Ctr, Dept Otolaryngol, New York, NY 10021 USA. [Shin, Jennifer] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. [Terris, David] Georgia Regents Univ, Dept Otolaryngol, Augusta, GA USA. [Randolph, Gregory] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. RP Shindo, ML (reprint author), Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, 3181 SW Sam Jackson Rd,PV 01, Portland, OR 97239 USA. EM shindom@ohsu.edu RI Shin, Jennifer/A-3169-2016 NR 84 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD OCT PY 2014 VL 36 IS 10 BP 1379 EP 1390 DI 10.1002/hed.23619 PG 12 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AP5ZK UT WOS:000342157000004 PM 24470171 ER PT J AU Colletti, G Colombo, V Mattassi, R Frigerio, A AF Colletti, Giacomo Colombo, Valeria Mattassi, Raul Frigerio, Alice TI Strangling technique to treat large cervicofacial venous malformations: A preliminary report SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE vascular anomalies; venous malformations; head and neck; facial nerve ID VASCULAR MALFORMATIONS; NECK; HEAD; MANAGEMENT; SCLEROTHERAPY; CLASSIFICATION; DIAGNOSIS; ANOMALIES; ETHANOL AB Background. Surgical removal of large cervicofacial venous malformations might be hampered by massive intraoperative bleeding. Moreover, these lesions often insinuate within normal surrounding tissue, making complete resection impossible without causing significant morbidity. Methods. Two patients affected by facial venous malformations nonresponsive to sclerotherapy underwent surgery. Bleeding and critical branching of the facial nerve within the lesion prevented the surgeons from proceeding with the removal. The unresectable malformation was decompressed by means of a number of nonresorbable stitches from the surface of the lesion to the periosteum, tailoring a permanent pressure dressing. Results. Outcomes at 12-month follow-up were stable, with good cosmetic results and satisfaction reported by both patients. No long-term side effects related to the procedure were observed. Conclusion. Decompression of large venous malformations by means of a strangling technique might represent a safe and effective procedure for those cases where a removal cannot be accomplished. (C) 2014 Wiley Periodicals, Inc. C1 [Colletti, Giacomo; Colombo, Valeria] Univ Milan, San Paolo Hosp, Dept Biomed Surg & Dent Sci, Div Maxillofacial Surg, Milan, Italy. [Mattassi, Raul] Clin Inst Humanitas Mater Domini, Ctr Vasc Malformat Stefan Belov, Dept Vasc Surg, Castellanza, Varese, Italy. [Frigerio, Alice] Harvard Univ, Massachusetts Eye & Ear Infirm, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Sch Med,Dept Otol & Laryngol,Div Facial Plast & R, Boston, MA 02114 USA. RP Frigerio, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Sch Med,Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Alice_Frigerio@meei.harvard.edu OI Frigerio, Alice/0000-0001-9202-9553; Colletti, Giacomo/0000-0001-6975-495X NR 22 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD OCT PY 2014 VL 36 IS 10 BP E94 EP E98 DI 10.1002/hed.23585 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AP5ZK UT WOS:000342157000001 PM 24375693 ER PT J AU McIntosh, N Meterko, M Burgess, JF Restuccia, JD Kartha, A Kaboli, P Charns, M AF McIntosh, Nathalie Meterko, Mark Burgess, James F., Jr. Restuccia, Joseph D. Kartha, Anand Kaboli, Peter Charns, Martin TI Organizational predictors of coordination in inpatient medicine SO HEALTH CARE MANAGEMENT REVIEW LA English DT Article DE Inpatient medicine; interprofessional coordination; intraprofessional coordination; multidisciplinary; organizational factors ID QUALITY-OF-CARE; IMPROVING-PATIENT-SAFETY; CLINICAL-OUTCOMES; SURGICAL SERVICES; JOB-SATISFACTION; TEAMWORK; PERCEPTIONS; IMPACT; COLLABORATION; PERFORMANCE AB Background: As the care of hospitalized patients becomes more complex, intraprofessional coordination among nurses and among physicians, and interprofessional coordination between these groups are likely to play an increasingly important role in the provision of hospital care. Purpose: The purpose of this study was to identify the independent effects of organizational factors on provider ratings of overall coordination in inpatient medicine (OCIM). Methodology/Approach: This was an exploratory cross-sectional, descriptive study. Primary data were collected between June 2010 and September 2011 through surveys of inpatient medicine nurse managers, physicians, and chiefs of medicine at 36 Veterans Health Administration medical centers. Secondary data from the 2011 Veterans Health Administration national survey of nurses were also used. Individual-level data were aggregated and analyzed at the facility level. Multivariate linear regression models were used to assess the relationship between 55 organizational factors and provider ratings of OCIM. C1 [McIntosh, Nathalie; Meterko, Mark; Burgess, James F., Jr.; Restuccia, Joseph D.; Charns, Martin] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [Meterko, Mark] VA Boston Healthcare Syst, Methodol & Survey Unit, Boston, MA USA. [Meterko, Mark; Burgess, James F., Jr.; Charns, Martin] Boston Univ, Dept Hlth Policy & Management, Sch Publ Hlth, Boston, MA 02215 USA. [Restuccia, Joseph D.] Boston Univ, Sch Management, Boston, MA 02215 USA. [Kartha, Anand] VA Boston Healthcare Syst Med Serv, Boston, MA USA. [Kaboli, Peter] Iowa City VA Healthcare Syst, Comprehens Access & Delivery Res & Evaluat Ctr, Iowa City, IA USA. [Kaboli, Peter] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. RP McIntosh, N (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. EM mcintnm@gmail.com NR 44 TC 4 Z9 4 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0361-6274 EI 1550-5030 J9 HEALTH CARE MANAGE R JI Health Care Manage. Rev. PD OCT-DEC PY 2014 VL 39 IS 4 BP 279 EP 292 DI 10.1097/HMR.0000000000000004 PG 14 WC Health Policy & Services SC Health Care Sciences & Services GA AP3HJ UT WOS:000341965900003 PM 24378402 ER PT J AU Leite, AF Costa, PHN Barbosa, LFP Tan, TC Gelape, CL Nunes, MCP AF Leite, Anderson Ferreira Nogueira Costa, Paulo Henrique Pederneiras Barbosa, Luisa Freire Tan, Timothy C. Gelape, Claudio Leo Pereira Nunes, Maria Carmo TI Echocardiography of a woman after valve intervention SO HEART LA English DT Editorial Material C1 [Leite, Anderson Ferreira; Nogueira Costa, Paulo Henrique; Pederneiras Barbosa, Luisa Freire; Gelape, Claudio Leo; Pereira Nunes, Maria Carmo] Univ Fed Minas Gerais, Hosp Clin, Sch Med, Belo Horizonte, MG, Brazil. [Tan, Timothy C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. RP Leite, AF (reprint author), Rua Almandina 68, BR-31010080 Belo Horizonte, MG, Brazil. EM anderson_med125@yahoo.com.br NR 4 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD OCT PY 2014 VL 100 IS 19 BP 1561 EP 1561 DI 10.1136/heartjnl-2014-305507 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP2UT UT WOS:000341931800007 PM 24700562 ER PT J AU Scragg, R Slow, S Stewart, AW Jennings, LC Chambers, ST Priest, PC Florkowski, CM Camargo, CA Murdoch, DR AF Scragg, Robert Slow, Sandy Stewart, Alistair W. Jennings, Lance C. Chambers, Stephen T. Priest, Patricia C. Florkowski, Christopher M. Camargo, Carlos A., Jr. Murdoch, David R. TI Long-Term High-Dose Vitamin D-3 Supplementation and Blood Pressure in Healthy Adults A Randomized Controlled Trial SO HYPERTENSION LA English DT Article DE blood pressure; European Continental Ancestry Group; hypertension; randomized controlled trial; therapeutic use ID CARDIOVASCULAR RISK-FACTORS; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; CHOLECALCIFEROL SUPPLEMENTATION; ENDOTHELIAL FUNCTION; PARATHYROID-HORMONE; VASCULAR HEALTH; OMRON 705IT; WEIGHT-LOSS; HYPERTENSION AB Previous randomized controlled trials of vitamin D supplementation and blood pressure (BP) mainly have given vitamin D for short periods (<6 months) or at low doses (400 IU per day). This study aims to determine whether long-term high-dose vitamin D taken for 18 months lowers BP. Adults were recruited from a healthcare organization or university into a double-blind controlled trial and randomized to receive either vitamin D 3 200 000 IU for 2 months followed by 100 000 IU monthly up to 18 months (n=161) or placebo (n=161). BP was measured at baseline, 5, and 18 months. Subjects had a mean (SD) age of 47.6 (9.7) years, 75% were women, and 94% were of European ancestry (white). Mean (SD) 25-hydroxyvitamin D 3 changed from 73 (22) nmol/L at baseline to 124 (28) nmol/L at 18 months in the vitamin D group, and from 71 (22) nmol/L to 56 (22) nmol/L in the placebo group. Mean BP was similar for the vitamin D and placebo groups at baseline (123.4/76.3 versus 122.6/75.6 mm Hg; respectively). The mean change (95% confidence interval) in BP at 18 months minus baseline in the vitamin D group compared with placebo group was -0.6 (-2.8 to 1.6) mm Hg for systolic (P=0.61) and 0.5 (-1.1, 2.2) mm Hg for diastolic (P=0.53). Long-term vitamin D supplementation, which increased mean 25-hydroxyvitamin D 3 concentration >100 nmol/L for 18 months, had no effect on systolic or diastolic BP in predominantly white, healthy adults without severe vitamin D deficiency. Beneficial effects on BP cannot be ruled out for other populations. C1 [Scragg, Robert; Stewart, Alistair W.] Univ Auckland, Sch Populat Hlth, Auckland 1, New Zealand. [Slow, Sandy; Jennings, Lance C.; Chambers, Stephen T.; Florkowski, Christopher M.; Murdoch, David R.] Univ Otago, Dept Pathol, Christchurch, New Zealand. [Priest, Patricia C.] Univ Otago, Dunedin, New Zealand. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Scragg, R (reprint author), Univ Auckland, Sch Populat Hlth, Sect Epidemiol & Biostat, Private Bag 92019,261 Morrin Rd, Auckland 1, New Zealand. EM r.scragg@auckland.ac.nz OI Scragg, Robert/0000-0003-0013-2620 FU Health Research Council of New Zealand [09-302] FX The study was funded by the Health Research Council of New Zealand (grant 09-302). NR 41 TC 18 Z9 18 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD OCT PY 2014 VL 64 IS 4 BP 725 EP 730 DI 10.1161/HYPERTENSIONAHA.114.03466 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP3PB UT WOS:000341988000009 PM 24980662 ER PT J AU Bai, Z Huang, GB Wang, DW Wang, H Westover, MB AF Bai, Zuo Huang, Guang-Bin Wang, Danwei Wang, Han Westover, M. Brandon TI Sparse Extreme Learning Machine for Classification SO IEEE TRANSACTIONS ON CYBERNETICS LA English DT Article DE Classification; extreme learning machine (ELM); quadratic programming (QP); sequential minimal optimization (SMO); sparse ELM; support vector machine (SVM); unified ELM ID SUPPORT VECTOR REGRESSION; FEEDFORWARD NETWORKS AB Extreme learning machine (ELM) was initially proposed for single-hidden-layer feedforward neural networks (SLFNs). In the hidden layer (feature mapping), nodes are randomly generated independently of training data. Furthermore, a unified ELM was proposed, providing a single framework to simplify and unify different learning methods, such as SLFNs, least square support vector machines, proximal support vector machines, and so on. However, the solution of unified ELM is dense, and thus, usually plenty of storage space and testing time are required for large-scale applications. In this paper, a sparse ELM is proposed as an alternative solution for classification, reducing storage space and testing time. In addition, unified ELM obtains the solution by matrix inversion, whose computational complexity is between quadratic and cubic with respect to the training size. It still requires plenty of training time for large-scale problems, even though it is much faster than many other traditional methods. In this paper, an efficient training algorithm is specifically developed for sparse ELM. The quadratic programming problem involved in sparse ELM is divided into a series of smallest possible sub-problems, each of which are solved analytically. Compared with SVM, sparse ELM obtains better generalization performance with much faster training speed. Compared with unified ELM, sparse ELM achieves similar generalization performance for binary classification applications, and when dealing with large-scale binary classification problems, sparse ELM realizes even faster training speed than unified ELM. C1 [Bai, Zuo; Huang, Guang-Bin; Wang, Danwei; Wang, Han] Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. [Westover, M. Brandon] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Westover, M. Brandon] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bai, Z (reprint author), Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. EM zbai1@e.ntu.edu.sg; egbhuang@ntu.edu.sg; edwwang@ntu.edu.sg; hw@ntu.edu.sg; mwestover@mgh.harvard.edu RI Huang, Guang-Bin/A-5035-2011 OI Huang, Guang-Bin/0000-0002-2480-4965 FU NINDS NIH HHS [K23 NS090900] NR 33 TC 46 Z9 48 U1 8 U2 54 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2267 EI 2168-2275 J9 IEEE T CYBERNETICS JI IEEE T. Cybern. PD OCT PY 2014 VL 44 IS 10 BP 1858 EP 1870 DI 10.1109/TCYB.2014.2298235 PG 13 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics SC Computer Science GA AP6ZV UT WOS:000342228100013 PM 25222727 ER PT J AU Matsui, A Jin, JO Johnston, CD Yamazaki, H Houri-Haddad, Y Rittling, SR AF Matsui, Aritsune Jin, Jun-O Johnston, Christopher D. Yamazaki, Hajime Houri-Haddad, Yael Rittling, Susan R. TI Pathogenic Bacterial Species Associated with Endodontic Infection Evade Innate Immune Control by Disabling Neutrophils SO INFECTION AND IMMUNITY LA English DT Article ID RESORPTION IN-VIVO; PORPHYROMONAS-GINGIVALIS; PREVOTELLA-INTERMEDIA; CELL-DEATH; FUSOBACTERIUM-NUCLEATUM; APICAL PERIODONTITIS; HEMOLYTIC-ACTIVITY; BONE DESTRUCTION; CHAMBER MODEL; MICE AB Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well-controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia. C1 [Matsui, Aritsune; Jin, Jun-O; Johnston, Christopher D.; Rittling, Susan R.] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. [Matsui, Aritsune; Johnston, Christopher D.; Yamazaki, Hajime; Rittling, Susan R.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Yamazaki, Hajime] Forsyth Inst, Dept Appl Oral Sci, Ctr Biomineralizat, Cambridge, MA USA. [Houri-Haddad, Yael] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Fac Med Dent, Dept Prosthodont, Jerusalem, Israel. RP Rittling, SR (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. EM srittling@forsyth.org FU National Institute of Dental and Craniofacial Research of NIH [R01DE22380] FX This work was supported by National Institute of Dental and Craniofacial Research of NIH under award R01DE22380. NR 59 TC 4 Z9 4 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2014 VL 82 IS 10 BP 4068 EP 4079 DI 10.1128/IAI.02256-14 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2VY UT WOS:000341935100008 PM 25024367 ER PT J AU Lin, J Bi, LJ Yu, XQ Kawai, T Taubman, MA Shen, BZ Han, XZ AF Lin, Jiang Bi, Liangjia Yu, Xiaoqian Kawai, Toshihisa Taubman, Martin A. Shen, Baozhong Han, Xiaozhe TI Porphyromonas gingivalis Exacerbates Ligature-Induced, RANKL-Dependent Alveolar Bone Resorption via Differential Regulation of Toll-Like Receptor 2 (TLR2) and TLR4 SO INFECTION AND IMMUNITY LA English DT Article ID NF-KAPPA-B; PERIODONTAL-DISEASE; IL-10 PRODUCTION; HEMAGGLUTININ B; DENDRITIC CELLS; INNATE IMMUNITY; HOST RESPONSE; PATHOGEN; LIPOPOLYSACCHARIDE; RECOGNITION AB Toll-like receptors (TLRs) play a key role in the innate immune responses to periodontal pathogens in periodontal disease. The present study was performed to determine the roles of TLR2 and TLR4 signaling in alveolar bone resorption, using a Porphyromonas gingivalis-associated ligature-induced periodontitis model in mice. Wild-type (WT), Tlr2(-/-), and Tlr4(-/-) mice (8 to 10 weeks old) in the C57/BL6 background were used. Silk ligatures were applied to the maxillary second molars in the presence or absence of live P. gingivalis infection. Ligatures were removed from the second molars on day 14, and mice were kept for another 2 weeks before sacrifice for final analysis (day 28). On day 14, there were no differences in alveolar bone resorption and gingival RANKL expression between mice treated with ligation plus P. gingivalis infection and mice treated with ligation alone. Gingival interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) expression was increased, whereas IL-10 expression was decreased in WT and Tlr2(-/-) mice but not in Tlr4(-/-) mice. On day 28, WT and Tlr4(-/-) mice treated with ligation plus P. gingivalis infection showed significantly increased bone loss and gingival RANKL expression compared to those treated with ligation alone, whereas such an increase was diminished in Tlr2(-/-) mice. Gingival TNF-alpha upregulation and IL-10 downregulation were observed only in WT and Tlr4(-/-) mice, not in Tlr2(-/-) mice. In all mice, bone resorption induced by ligation plus P. gingivalis infection was antagonized by local anti-RANKL antibody administration. This study suggests that P. gingivalis exacerbates ligature- induced, RANKL-dependent periodontal bone resorption via differential regulation of TLR2 and TLR4 signaling. C1 [Lin, Jiang; Yu, Xiaoqian; Kawai, Toshihisa; Taubman, Martin A.; Han, Xiaozhe] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Lin, Jiang; Bi, Liangjia] Harbin Med Univ, Hosp 4, Dept Stomatol, Harbin, Peoples R China. [Yu, Xiaoqian] Peking Univ, Sch & Hosp Stomatol, Dept Periodontol, Beijing 100871, Peoples R China. [Shen, Baozhong] Harbin Med Univ, Dept Radiol, Hosp 4, Harbin, Peoples R China. RP Shen, BZ (reprint author), Harbin Med Univ, Hosp 4, Dept Stomatol, Harbin, Peoples R China. EM shenbzh@vip.sina.com; xhan@forsyth.org FU NIH from the National Institute of Dental and Craniofacial Research [DE-003420, DE-021837] FX This work was supported by NIH grants DE-003420 and DE-021837 from the National Institute of Dental and Craniofacial Research. NR 45 TC 12 Z9 14 U1 2 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2014 VL 82 IS 10 BP 4127 EP 4134 DI 10.1128/IAI.02084-14 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2VY UT WOS:000341935100013 PM 25047844 ER PT J AU Jenkins, TC Knepper, BC Moore, SJ O'Leary, ST Caldwell, B Saveli, CC Pawlowski, SW Perlman, DM McCollister, BD Burman, WJ AF Jenkins, Timothy C. Knepper, Bryan C. Moore, S. Jason O'Leary, Sean T. Caldwell, Brooke Saveli, Carla C. Pawlowski, Sean W. Perlman, Daniel M. McCollister, Bruce D. Burman, William J. TI Antibiotic Prescribing Practices in a Multicenter Cohort of Patients Hospitalized for Acute Bacterial Skin and Skin Structure Infection SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID SOFT-TISSUE INFECTIONS; RESISTANT STAPHYLOCOCCUS-AUREUS; ECONOMIC OUTCOMES; CELLULITIS; CHILDREN; EMERGENCE; THERAPY; ABSCESS; VISITS; ADULTS AB OBJECTIVE. Hospitalizations for acute bacterial skin and skin structure infection (ABSSSI) are common. Optimizing antibiotic use for ABSSSIs requires an understanding of current management. The objective of this study was to evaluate antibiotic prescribing practices and factors affecting prescribing in a diverse group of hospitals. DESIGN. Multicenter, retrospective cohort study. SETTING. Seven community and academic hospitals. METHODS. Children and adults hospitalized between June 2010 and May 2012 for cellulitis, wound infection, or cutaneous abscess were eligible. The primary endpoint was a composite of 2 prescribing practices representing potentially avoidable antibiotic exposure: (1) use of antibiotics with a broad spectrum of activity against gram-negative bacteria or (2) treatment duration greater than 10 days. RESULTS. A total of 533 cases were included: 320 with nonpurulent cellulitis, 44 with wound infection or purulent cellulitis, and 169 with abscess. Of 492 cases with complete prescribing data, the primary endpoint occurred in 394 (80%) cases and varied significantly across hospitals (64%-97%; P <.001). By logistic regression, independent predictors of the primary endpoint included wound infection or purulent cellulitis (odds ratio [OR], 5.12 [95% confidence interval (CH], 1.46-17.88), head or neck involvement (OR, 2.83 [95% CI, 1.17-6.82]), adult cases (OR, 2.20 [95% CI, 1.18-4.11]), and admission to a community hospital (OR, 1.90 [95% CI, 1.05-3.44]). CONCLUSIONS. Among patients hospitalized for ABSSSI, use of antibiotics with broad gram-negative activity or treatment courses longer than 10 days were common. There may be substantial opportunity to reduce antibiotic exposure through shorter courses of therapy targeting gram-positive bacteria. C1 [Jenkins, Timothy C.; Burman, William J.] Denver Hlth, Dept Med, Denver, CO USA. [Jenkins, Timothy C.; Burman, William J.] Denver Hlth, Div Infect Dis, Denver, CO USA. [Jenkins, Timothy C.; O'Leary, Sean T.; Saveli, Carla C.; McCollister, Bruce D.; Burman, William J.] Univ Colorado, Dept Med, Sch Med, Aurora, CO USA. [Jenkins, Timothy C.; O'Leary, Sean T.; Saveli, Carla C.; McCollister, Bruce D.; Burman, William J.] Univ Colorado, Div Infect Dis, Sch Med, Aurora, CO USA. [Knepper, Bryan C.] Denver Hlth, Dept Patient Safety & Qual, Denver, CO USA. [Moore, S. Jason] Vail Valley Med Ctr, Dept Trauma & Crit Care Serv, Vail, CO USA. [O'Leary, Sean T.; Caldwell, Brooke] Childrens Hosp Colorado, Dept Med, Aurora, CO USA. [O'Leary, Sean T.] Childrens Hosp Colorado, Div Infect Dis, Aurora, CO USA. [Pawlowski, Sean W.] Colorado Infect Dis Associates, Denver, CO USA. [Perlman, Daniel M.] Porter Adventist Med Ctr, Dept Med, Denver, CO USA. [McCollister, Bruce D.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [McCollister, Bruce D.] Denver Vet Affairs Med Ctr, Div Infect Dis, Denver, CO USA. [Burman, William J.] Denver Hlth, Denver Publ Hlth, Denver, CO USA. RP Jenkins, TC (reprint author), 660 Bannock St, Denver, CO 80204 USA. EM timothy.jenkins@dhha.org FU National Institute of Allergy and Infectious Diseases, National Institute of Health [K23 AI099082] FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institute of Health (T.C.J.: K23 AI099082). NR 24 TC 13 Z9 13 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2014 VL 35 IS 10 BP 1241 EP 1250 DI 10.1086/678056 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AP2XF UT WOS:000341938600004 PM 25203177 ER PT J AU Greene, MT Fakih, MG Fowler, KE Meddings, J Ratz, D Safdar, N Olmsted, RN Saint, S AF Greene, M. Todd Fakih, Mohamad G. Fowler, Karen E. Meddings, Jennifer Ratz, David Safdar, Nasia Olmsted, Russell N. Saint, Sanjay TI Regional Variation in Urinary Catheter Use and Catheter-Associated Urinary Tract Infection: Results from a National Collaborative SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID INTENSIVE-CARE UNITS; HOSPITALIZED-PATIENTS; EXTENDED USE; STATES; PREVENTION; PHYSICIANS; FEEDBACK AB OBJECTIVE. To examine regional variation in the use and appropriateness of indwelling urinary catheters and catheter-associated urinary tract infection (CAUTI). DESIGN AND SETTING. Cross-Sectional study. PARTICIPANTS. US acute care hospitals. METHODS. Hospitals were divided into 4 regions according to the US Census Bureau. Baseline data on urinary catheter use, catheter appropriateness, and CAUTI were collected from participating units. The catheter utilization ratio was calculated by dividing the number of catheter-days by the number of patient-days. We used the National Healthcare Safety Network (NHSN) definition (number of CAUTIs per 1,000 catheter-days) and a population-based definition (number of CAUTIs per 10,000 patient-days) to calculate CAUTI rates. Logistic and Poisson regression models were used to assess regional differences. RESULTS. Data on 434,207 catheter-days over 1,400,770 patient-days were collected from 1,101 units within 726 hospitals across 34 states. Overall catheter utilization was 31%. Catheter utilization was significantly higher in non intensive care units (ICUs) in the West compared with non-ICUs in all other regions. Approximately 30%-40% of catheters in non-ICUs were placed without an appropriate indication. Catheter appropriateness was the lowest in the West. A total of 1,099 CAUTIs were observed (NHSN rate of 2.5 per 1,000 catheter-days and a population-based rate of 7.8 per 10,000 patient-days). The population-based CAUTI rate was highest in the West (8.9 CAUTIs per 10,000 patient-days) and was significantly higher compared with the Midwest, even after adjusting for hospital characteristics (P =.02). CONCLUSIONS. Regional differences in catheter use, appropriateness, and CAUTI rates were detected across US hospitals. C1 [Greene, M. Todd; Meddings, Jennifer; Saint, Sanjay] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Greene, M. Todd; Fowler, Karen E.; Meddings, Jennifer; Ratz, David; Saint, Sanjay] Vet Affairs Univ Michigan, Patient Safety Enhancement Program, Ann Arbor, MI USA. [Fakih, Mohamad G.] St John Hosp & Med Ctr, Detroit, MI USA. [Fowler, Karen E.; Ratz, David; Saint, Sanjay] Vet Affairs Ann Arbor Healthcare Syst, Hosp Outcomes Program Excellence, Ann Arbor, MI USA. [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Safdar, Nasia] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Olmsted, Russell N.] St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. RP Greene, MT (reprint author), Univ Michigan, Div Gen Med, 2800 Plymouth Rd,North Campus Res Complex Bldg 16, Ann Arbor, MI 48109 USA. EM mtgreene@med.umich.edu RI Fowler, Karen/B-5383-2015 FU Agency for Healthcare Research and Quality (AHRQ) [HHSA290201000025I, HHSA29032001T] FX This project was supported by a contract from the Agency for Healthcare Research and Quality (AHRQ; HHSA290201000025I/HHSA29032001T). NR 34 TC 11 Z9 12 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2014 VL 35 SU 3 BP S99 EP S106 DI 10.1086/677825 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AP2XP UT WOS:000341939700015 PM 25222905 ER PT J AU Zietman, AL AF Zietman, Anthony L. TI Too Much Impact? Scientific Journals and the "Impact Factor" SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM azietman@partners.org NR 14 TC 3 Z9 4 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2014 VL 90 IS 2 BP 246 EP 248 DI 10.1016/j.ijrobp.2014.07.018 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400002 PM 25304783 ER PT J AU Viswanathan, AN Erickson, B Gaffney, DK Beriwal, S Bhatia, SK Burnett, OL D'Souza, DP Patil, N Haddock, MG Jhingran, A Jones, EL Kunos, CA Lee, LJ Lin, LL Mayr, NA Petersen, I Petric, P Portelance, L Small, W Strauss, JB Townamchai, K Wolfson, AH Yashar, CM Bosch, W AF Viswanathan, Akila N. Erickson, Beth Gaffney, David K. Beriwal, Sushil Bhatia, Sudershan K. Burnett, Omer Lee, III D'Souza, David P. Patil, Nikhilesh Haddock, Michael G. Jhingran, Anuja Jones, Ellen L. Kunos, Charles A. Lee, Larissa J. Lin, Lilie L. Mayr, Nina A. Petersen, Ivy Petric, Primoz Portelance, Lorraine Small, William, Jr. Strauss, Jonathan B. Townamchai, Kanokpis Wolfson, Aaron H. Yashar, Catheryn M. Bosch, Walter TI Comparison and Consensus Guidelines for Delineation of Clinical Target Volume for CT- and MR-Based Brachytherapy in Locally Advanced Cervical Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID DOSE-RATE BRACHYTHERAPY; GUIDED ADAPTIVE BRACHYTHERAPY; PDR BRACHYTHERAPY; RADIATION-THERAPY; PROSPECTIVE TRIAL; CARCINOMA; IMPACT; RECOMMENDATIONS; OPTIMIZATION; RADIOTHERAPY AB Objective: To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3-Tesla (3-T) magnetic resonance (MR) image-based cervical-cancer brachytherapy. Methods and Materials: Twenty-three experts in gynecologic radiation oncology contoured the same 3 cervical cancer brachytherapy cases: 1 stage IIB near-complete response (CR) case with a tandem and ovoid, 1 stage IIB partial response (PR) case with tandem and ovoid with needles, and 1 stage IB2 CR case with a tandem and ring applicator. The CT contours were completed before the MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STA-PLE), with kappa statistics as a measure of agreement between participants. The conformity index was calculated for each of the 6 data sets. Dice coefficients were generated to compare the CT and MR contours of the same case. Results: For all 3 cases, the mean tumor volume was smaller on MR than on CT (P < .001). The kappa and conformity index estimates were slightly higher for CT, indicating a higher level of agreement on CT. The Dice coefficients were 89% for the stage IB2 case with a CR, 74% for the stage IIB case with a PR, and 57% for the stage IIB case with a CR. Conclusion: In a comparison of MR-contoured with CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast medium visible on the images at the time of brachytherapy. MR at the time of brachytherapy may be of greatest benefit in patients with large tumors with parametrial extension that have a partial or complete response to external beam. On the basis of these results, a 95% consensus volume was generated for CT and for MR. (C) 2014 Elsevier Inc. C1 [Viswanathan, Akila N.; Townamchai, Kanokpis] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Erickson, Beth] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gaffney, David K.] Univ Utah, Huntsman Canc Hosp, Salt Lake City, UT USA. [Yashar, Catheryn M.; Bosch, Walter] Washington Univ, St Louis, MO USA. [Beriwal, Sushil] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Bhatia, Sudershan K.] Univ Iowa, Iowa City, IA USA. [Burnett, Omer Lee, III] Univ Alabama Birmingham, Birmingham, AL USA. [D'Souza, David P.; Patil, Nikhilesh] London Hlth Sci Ctr, London, ON, Canada. [D'Souza, David P.; Patil, Nikhilesh] Univ Western Ontario, London, ON, Canada. [Haddock, Michael G.; Petersen, Ivy] Mayo Med Ctr, Rochester, MN USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Jones, Ellen L.] Univ N Carolina, Chapel Hill, NC USA. [Kunos, Charles A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lin, Lilie L.] Univ Penn, Philadelphia, PA 19104 USA. [Mayr, Nina A.] Univ Washington, Seattle, WA 98195 USA. [Petric, Primoz] Inst Oncol Ljubljana, Div Radiotherapy, Ljubljana, Slovenia. [Petric, Primoz] Natl Ctr Canc Care & Res, Dept Radiat Oncol, Doha, Qatar. [Portelance, Lorraine; Wolfson, Aaron H.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Small, William, Jr.] Loyola Univ, Strich Sch Med, Chicago, IL 60611 USA. [Strauss, Jonathan B.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Yashar, Catheryn M.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Viswanathan, AN (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, 75 Francis St,ASB 1,L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu RI Beriwal, Sushil/J-6404-2012; Patil, Nikhilesh/L-9631-2014 OI Patil, Nikhilesh/0000-0002-4391-4705 FU National Institutes of Health [R21 167800, CA81647] FX Support through National Institutes of Health R21 167800 to A. N. Viswanathan. The Advanced Technology Consortium (ATC) has received support through National Institutes of Health Grant CA81647. NR 30 TC 27 Z9 28 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2014 VL 90 IS 2 BP 320 EP 328 DI 10.1016/j.ijrobp.2014.06.005 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400014 PM 25304792 ER PT J AU Wattson, DA Hunink, MGM DiPiro, PJ Das, P Hodgson, DC Mauch, PM Ng, AK AF Wattson, Daniel A. Hunink, M. G. Myriam DiPiro, Pamela J. Das, Prajnan Hodgson, David C. Mauch, Peter M. Ng, Andrea K. TI Low-Dose Chest Computed Tomography for Lung Cancer Screening Among Hodgkin Lymphoma Survivors: A Cost-Effectiveness Analysis SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID COLLABORATIVE BRITISH COHORT; 2ND PRIMARY LUNG; INVOLVED-FIELD; ADULT SMOKERS; UNITED-STATES; DISEASE; RISK; RADIOTHERAPY; CHEMOTHERAPY; MORTALITY AB Purpose: Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. Screening with low-dose computed tomography (LDCT) may allow detection of early stage, resectable cancers. We developed a Markov decision-analytic and cost-effectiveness model to estimate the merits of annual LDCT screening among HL survivors. Methods and Materials: Population databases and HL-specific literature informed key model parameters, including lung cancer rates and stage distribution, cause-specific survival estimates, and utilities. Relative risks accounted for radiation therapy (RT) technique, smoking status (> 10 pack-years or current smokers vs not), age at HL diagnosis, time from HL treatment, and excess radiation from LDCTs. LDCT assumptions, including expected stage-shift, false-positive rates, and likely additional workup were derived from the National Lung Screening Trial and preliminary results from an internal phase 2 protocol that performed annual LDCTs in 53 HL survivors. We assumed a 3% discount rate and a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life year (QALY). Results: Annual LDCT screening was cost effective for all smokers. A male smoker treated with mantle RT at age 25 achieved maximum QALYs by initiating screening 12 years post-HL, with a life expectancy benefit of 2.1 months and an incremental cost of $34,841/QALY. Among nonsmokers, annual screening produced a QALY benefit in some cases, but the incremental cost was not below the WTP threshold for any patient subsets. As age at HL diagnosis increased, earlier initiation of screening improved outcomes. Sensitivity analyses revealed that the model was most sensitive to the lung cancer incidence and mortality rates and expected stage-shift from screening. Conclusions: HL survivors are an important high-risk population that may benefit from screening, especially those treated in the past with large radiation fields including mantle or involved-field RT. Screening may be cost effective for all smokers but possibly not for nonsmokers despite a small life expectancy benefit. (C) 2014 Elsevier Inc. C1 [Wattson, Daniel A.] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Hunink, M. G. Myriam] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Hunink, M. G. Myriam] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hunink, M. G. Myriam] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [DiPiro, Pamela J.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Das, Prajnan] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Hodgson, David C.] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Mauch, Peter M.; Ng, Andrea K.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Mauch, Peter M.; Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wattson, DA (reprint author), Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM dwattson@partners.org NR 39 TC 1 Z9 1 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2014 VL 90 IS 2 BP 344 EP 353 DI 10.1016/j.ijrobp.2014.06.013 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400017 PM 25104066 ER PT J AU Street, VA Kujawa, SG Manichaikul, A Broman, KW Kallman, JC Shilling, DJ Iwata, AJ Robinson, LC Robbins, CA Li, J Liberman, MC Tempel, BL AF Street, Valerie A. Kujawa, Sharon G. Manichaikul, Ani Broman, Karl W. Kallman, Jeremy C. Shilling, Dustin J. Iwata, Ayaka J. Robinson, Linda C. Robbins, Carol A. Li, Jin Liberman, M. Charles Tempel, Bruce L. TI Resistance to Noise-Induced Hearing Loss in 129S6 and MOLF Mice: Identification of Independent, Overlapping, and Interacting Chromosomal Regions SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE QTL; 129S6; MOLF; noise-induced hearing loss ID QUANTITATIVE TRAIT LOCI; ACOUSTIC INJURY; OXIDATIVE STRESS; MOUSE COCHLEA; PROTECTION; TRAUMA; INHERITANCE; STRAINS; CROSSES; DAMAGE AB Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 x CBACa) and (MOLF x CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17. C1 [Street, Valerie A.; Kallman, Jeremy C.; Shilling, Dustin J.; Iwata, Ayaka J.; Robinson, Linda C.; Robbins, Carol A.; Li, Jin; Tempel, Bruce L.] Univ Washington, Dept Otolaryngol HNS, VM Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. [Tempel, Bruce L.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Kujawa, Sharon G.; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Manichaikul, Ani] Univ Virginia, Div Biostat & Epidemiol, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Broman, Karl W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53706 USA. RP Tempel, BL (reprint author), Univ Washington, Dept Otolaryngol HNS, VM Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. EM bltempel@uw.edu OI Manichaikul, Ani/0000-0002-5998-795X; Broman, Karl/0000-0002-4914-6671 FU NIH [R21DC04983, R01DC06305, R01DC08577, R01DC02739, R01DC00188, P30DC04661, P30DC05209, R01GM074244]; DoD [DM102092]; NSF; Howard Hughes Medical Institute FX This work was supported by grants from the NIH including R21DC04983 (SGK), R01DC06305 (BLT), R01DC08577 (SGK), R01DC02739 (BLT), R01DC00188 (MCL), P30DC04661 (BLT), P30DC05209 (MCL), R01GM074244 (KWB), and DoD DM102092 (BLT). Additional support provided by an NSF Graduate Research Fellowship (AM) and a Howard Hughes Medical Institute Medical Research Fellow (AJI). NR 39 TC 2 Z9 2 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2014 VL 15 IS 5 BP 721 EP 738 DI 10.1007/s10162-014-0472-x PG 18 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AP6HR UT WOS:000342178800004 PM 24952082 ER PT J AU Schuth, O McLean, WJ Eatock, RA Pyott, SJ AF Schuth, Olga McLean, Will J. Eatock, Ruth Anne Pyott, Sonja J. TI Distribution of Na,K-ATPase alpha Subunits in Rat Vestibular Sensory Epithelia SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE vestibular hair cells; calyx terminals; Na,K-ATPase ID PERIPHERAL INNERVATION PATTERNS; I HAIR-CELLS; INNER-EAR; COMPARATIVE MORPHOLOGY; GLUTAMATE TRANSPORTER; CARBONIC-ANHYDRASE; NERVE CALYX; SYNAPSIN-I; K+-ATPASE; EXPRESSION AB The afferent encoding of vestibular stimuli depends on molecular mechanisms that regulate membrane potential, concentration gradients, and ion and neurotransmitter clearance at both afferent and efferent relays. In many cell types, the Na,K-ATPase (NKA) is essential for establishing hyperpolarized membrane potentials and mediating both primary and secondary active transport required for ion and neurotransmitter clearance. In vestibular sensory epithelia, a calyx nerve ending envelopes each type I hair cell, isolating it over most of its surface from support cells and posing special challenges for ion and neurotransmitter clearance. We used immunofluorescence and high-resolution confocal microscopy to examine the cellular and subcellular patterns of NKA alpha subunit expression within the sensory epithelia of semicircular canals as well as an otolith organ (the utricle). Results were similar for both kinds of vestibular organ. The neuronal NKA alpha 3 subunit was detected in all afferent endings-both the calyx afferent endings on type I hair cells and bouton afferent endings on type II hair cells-but was not detected in efferent terminals. In contrast to previous results in the cochlea, the NKA alpha 1 subunit was detected in hair cells (both type I and type II) but not in supporting cells. The expression of distinct NKA alpha subunits by vestibular hair cells and their afferent endings may be needed to support and shape the high rates of glutamatergic neurotransmission and spike initiation at the unusual type I-calyx synapse. C1 [Schuth, Olga; Pyott, Sonja J.] Univ N Carolina, Dept Biol & Marine Biol, Wilmington, NC 28403 USA. [McLean, Will J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Eatock, Ruth Anne] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. RP Pyott, SJ (reprint author), Univ N Carolina, Dept Biol & Marine Biol, 601 South Coll Rd, Wilmington, NC 28403 USA. EM pyotts@uncw.edu OI Eatock, Ruth Anne/0000-0001-7547-2051 FU UNC Wilmington; NIDCD [R01 DC0002290, DC0012347] FX We thank Dr. Dwayne Simmons for the original suggestion to compare profile and cross-sectional views of the vestibular sensory epithelia. We gratefully acknowledge funds from UNC Wilmington to O. S. and S. J. P. and from NIDCD R01 DC0002290 and DC0012347 to R. A. E. NR 42 TC 6 Z9 6 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2014 VL 15 IS 5 BP 739 EP 754 DI 10.1007/s10162-014-0479-3 PG 16 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AP6HR UT WOS:000342178800005 PM 25091536 ER PT J AU Badour, CL Ojserkis, R McKay, D Feldner, MT AF Badour, Christal L. Ojserkis, Rachel McKay, Dean Feldner, Matthew T. TI Disgust as a unique affective predictor of mental contamination following sexual trauma SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Disgust; Mental contamination; Sexual trauma; Posttraumatic stress disorder ID OBSESSIVE-COMPULSIVE DISORDER; POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-PROCESSING THERAPY; ADMINISTERED PTSD SCALE; PROLONGED EXPOSURE; SYMPTOMS; FEAR; POLLUTION; ASSAULT; OCD AB Mental contamination has been described as an internal experience of dirtiness that can arise and persist in the absence of contact with observable physical contaminants. Recent research has examined mental contamination specifically related to unwanted physical contact and sexual trauma. This study evaluated the degree to which disgust propensity and both self-focused and perpetrator-focused peritraumatic disgust were associated with mental contamination in a sample of women who experienced sexual trauma (n = 72). Results showed that peritraumatic self-focused disgust, but not peritraumatic perpetrator-focused disgust or fear, was significantly associated with mental contamination. Additionally, disgust propensity contributed significantly to the incremental validity of the model. These findings support the nascent literature showing that disgust plays a significant role in mental contamination, particularly following sexual trauma. Future research directions, and clinical/theoretical implications of these results are discussed. Published by Elsevier Ltd. C1 [Badour, Christal L.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Badour, Christal L.] Ralph H Johnson VA Med Ctr, Dept Psychiat, Charleston, SC 29401 USA. [Badour, Christal L.; Feldner, Matthew T.] Univ Arkansas, Dept Psychol Sci, Fayetteville, AR 72701 USA. [Ojserkis, Rachel; McKay, Dean] Fordham Univ, Dept Psychol, Bronx, NY 10458 USA. [Feldner, Matthew T.] Laureate Inst Brain Res, Tulsa, OK 74136 USA. RP Badour, CL (reprint author), Dept Psychiat & Behav Sci, 67 President St,MSC 861,2nd Floor IOP South Bldg, Charleston, SC 29425 USA. EM christalbadour@gmail.com FU NIMH NIH HHS [F31 MH092994, F31 MH092994-01] NR 55 TC 4 Z9 4 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD OCT PY 2014 VL 28 IS 7 BP 704 EP 711 DI 10.1016/j.janxdis.2014.07.007 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AP5LY UT WOS:000342121900010 PM 25129888 ER PT J AU Garrido, MM Boockvar, KS AF Garrido, Melissa M. Boockvar, Kenneth S. TI Perceived Symptom Targets of Antidepressants, Anxiolytics, and Sedatives: The Search for Modifiable Factors That Improve Adherence SO JOURNAL OF BEHAVIORAL HEALTH SERVICES & RESEARCH LA English DT Article ID DWELLING OLDER-ADULTS; MENTAL-HEALTH-CARE; ANXIETY DISORDERS; SELF-MANAGEMENT; DEPRESSION; ILLNESS; NONADHERENCE; MEDICATION; SERVICES; BELIEFS AB Expectations about treatment and beliefs about illness influence adherence in physical disorders, but the extent to which this occurs in mood disorders is unknown. Identifying modifiable factors, such as beliefs, may improve adherence to mood disorder medications. Data from the Collaborative Psychiatric Epidemiology Surveys were used to examine relationships among perceived symptom targets of medication (mood only, non-mood only, mood, and non-mood) and self-reported adherence to antidepressants, anxiolytics, and sedatives. The sample included 807 community-dwelling individuals with and without depression and anxiety who regularly took one of these medications in the year before the survey. Slightly over half (53.2 %) of respondents were adherent. Perceived medication purpose was only significantly related to adherence among Latino respondents. Latino respondents who viewed their symptom target as non-mood only were the most adherent. Perceived symptom targets of medications were not associated with most patients' adherence behaviors for antidepressants, anxiolytics, and sedatives. C1 [Garrido, Melissa M.; Boockvar, Kenneth S.] James J Peters VA Med Ctr, GRECC, Bronx, NY 10468 USA. [Garrido, Melissa M.; Boockvar, Kenneth S.] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Boockvar, Kenneth S.] Jewish Home Lifecare, New York, NY USA. RP Garrido, MM (reprint author), James J Peters VA Med Ctr, GRECC, 4A-17 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM melissa.garrido@mssm.edu OI Garrido, Melissa/0000-0002-8986-3536; Boockvar, Kenneth/0000-0003-1165-5558 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service [CDA 11-201/CDP 12-255, IIR 10-146]; Greenwall Foundation; National Institute of Mental Health [T32 MH16242-29]; National Palliative Care Research Center FX The authors received funding from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service CDA 11-201/CDP 12-255 and IIR 10-146; the Greenwall Foundation; the National Institute of Mental Health T32 MH16242-29; and the National Palliative Care Research Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. NR 27 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1094-3412 EI 1556-3308 J9 J BEHAV HEALTH SER R JI J. Behav. Health Serv. Res. PD OCT PY 2014 VL 41 IS 4 BP 529 EP 538 DI 10.1007/s11414-013-9342-2 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AP2TD UT WOS:000341926800012 PM 23702612 ER PT J AU Pulliam, L Calosing, C Sun, B Grunfeld, C Rempel, H AF Pulliam, Lynn Calosing, Cyrus Sun, Bing Grunfeld, Carl Rempel, Hans TI Monocyte Activation from Interferon-alpha in HIV Infection Increases Acetylated LDL Uptake and ROS Production SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID PERSISTENT LCMV INFECTION; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; FOAM CELL-FORMATION; SR-A EXPRESSION; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; CIRCULATING MONOCYTES; IMMUNE ACTIVATION; HUMAN MACROPHAGES AB Atherosclerosis is an inflammatory disease that is accelerated in human immunodeficiency virus (HIV) infection. Individuals with HIV infection have an activated type I interferon (IFN) monocyte phenotype, which may enhance uptake of modified low-density lipoprotein (LDL) thereby initiating a prefoam cell pathology and recruitment into atherosclerotic plaques. In a sampling of HIV-infected subjects, an increase in monocyte activation genes, MX1 and CXCL10, correlated with monocyte expression of the scavenger receptor A (SR-A), a major receptor for lipid uptake and foam cell formation. Monocytes from HIV-infected subjects accumulated more lipid than control uninfected subjects. We modeled increased activation in HIV infection by priming human monocytes with IFN alpha followed by exposure to acetylated LDL (acLDL). Exposure to IFN alpha increased acLDL uptake, which generated increased cellular reactive oxygen species (ROS). We posit that HIV infection augments formation of arterial plaques by triggering monocyte activation with a type I IFN profile, which induces SR-A expression, lipid uptake, and subsequent ROS production. These findings may explain in part why HIV-infected individuals with chronic immune activation have an increased risk of atherosclerosis. C1 [Pulliam, Lynn] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Lab Med, San Francisco, CA 94121 USA. [Pulliam, Lynn; Grunfeld, Carl] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Calosing, Cyrus; Sun, Bing; Rempel, Hans] Vet Affairs Med Ctr, Dept Lab Med, San Francisco, CA 94121 USA. RP Pulliam, L (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Lab Med, 4150 Clement St 113A, San Francisco, CA 94121 USA. EM lynn.pulliam@ucsf.edu NR 47 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD OCT 1 PY 2014 VL 34 IS 10 BP 822 EP 828 DI 10.1089/jir.2013.0152 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AQ1SR UT WOS:000342561800010 PM 24731171 ER PT J AU Olson, DM Cox, M Constable, M Britz, GW Lin, CB Zimmer, LO Fonarow, GC Schwamm, LH Peterson, ED AF Olson, DaiWai M. Cox, Margueritte Constable, Mark Britz, Gavin W. Lin, Cheryl B. Zimmer, Louise O. Fonarow, Gregg C. Schwamm, Lee H. Peterson, Eric D. TI Development and Initial Testing of the Stroke Rapid-Treatment Readiness Tool SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article DE acute stroke therapy; intervention; reperfusion; therapy; tPA; treatment ID ACUTE ISCHEMIC-STROKE; SHARED MENTAL MODELS; TEAM PERFORMANCE; EARLY MANAGEMENT; NEEDLE TIME; CARE; ASSOCIATION; THERAPY; COUNCIL; IMPROVEMENT AB No instruments are currently available to help health systems identify target areas for reducing door-to-needle times for the administration of intravenous tissue plasminogen activator to eligible patients with ischemic stroke. A 67-item Likert-scale survey was administered by telephone to stroke personnel at 252 U.S. hospitals participating in the "Get With The Guidelines-Stroke'' quality improvement program. Factor analysis was used to refine the instrument to a four-factor 29-item instrument that can be used by hospitals to assess their readiness to administer intravenous tissue plasminogen activator within 60 minutes of patient hospital arrival. C1 [Olson, DaiWai M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Cox, Margueritte; Constable, Mark; Lin, Cheryl B.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Constable, Mark; Lin, Cheryl B.; Peterson, Eric D.] Duke Univ, Durham, NC USA. [Britz, Gavin W.] Methodist Hosp, Houston, TX 77030 USA. [Zimmer, Louise O.] Univ N Carolina, Chapel Hill, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Schwamm, Lee H.] Harvard Univ, Boston, MA 02115 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Olson, DM (reprint author), Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. EM DaiWai.Olson@UTSouthwestern.edu FU Agency for Healthcare Research and Quality [U18HS016964] FX This project was supported by Cooperative Agreement Number U18HS016964 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. NR 35 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0888-0395 EI 1945-2810 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD OCT PY 2014 VL 46 IS 5 BP 267 EP 273 DI 10.1097/JNN.0000000000000082 PG 7 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA AP3HC UT WOS:000341965200007 PM 25099063 ER PT J AU Hage, FG AF Hage, Fadi G. TI Regadenoson for myocardial perfusion imaging: Is it safe? SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID HEART-RATE RESPONSE; ADENOSINE RECEPTOR AGONISTS; STRESS TEST; CORONARY VASODILATION; SUBMAXIMAL EXERCISE; GENE POLYMORPHISM; DOUBLE-BLIND; TRIAL; DISEASE; TOLERABILITY C1 [Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. [Hage, Fadi G.] Amer Univ Beirut, Med Ctr, Div Cardiovasc Med, Beirut, Lebanon. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 38 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2014 VL 21 IS 5 BP 871 EP 876 DI 10.1007/s12350-014-9922-4 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP6UI UT WOS:000342212900004 PM 24939324 ER PT J AU Hage, FG Iskandrian, AE AF Hage, Fadi G. Iskandrian, Ami E. TI Serious complications associated with regadenoson administration for myocardial perfusion imaging: A commentary SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID INFARCTION C1 [Hage, Fadi G.; Iskandrian, Ami E.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 11 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2014 VL 21 IS 5 BP 877 EP 879 DI 10.1007/s12350-014-9985-2 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP6UI UT WOS:000342212900005 PM 25156654 ER PT J AU Falcone, JA Salameh, TS Yi, X Cordy, BJ Mortell, WG Kabanov, AV Banks, WA AF Falcone, Joseph A. Salameh, Therese S. Yi, Xiang Cordy, Benjamin J. Mortell, William G. Kabanov, Alexander V. Banks, William A. TI Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PHOSPHATIDYLINOSITOL 4-KINASE; NEUROTRANSMITTER RELEASE; AXONAL-TRANSPORT; RAT-BRAIN; INSULIN; BLOOD; TRANSCYTOSIS; ENDOCYTOSIS; INHIBITION AB A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [I-125] ([I-125] Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [I-125] Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2-4% of the i.n. [I-125] Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [I-125] Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration. C1 [Falcone, Joseph A.; Salameh, Therese S.; Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Falcone, Joseph A.; Salameh, Therese S.; Yi, Xiang; Cordy, Benjamin J.; Mortell, William G.; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Yi, Xiang; Kabanov, Alexander V.] Univ N Carolina, Ctr Nanotechnol Drug Delivery, Chapel Hill, NC 27515 USA. [Yi, Xiang; Kabanov, Alexander V.] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27515 USA. [Kabanov, Alexander V.] Moscow MV Lomonosov State Univ, Fac Chem, Moscow 117234, Russia. RP Banks, WA (reprint author), 1660 S Columbian Way,810A Bldg 1, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU VA merit review; National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS051134]; National Institutes of Health National Institute on Aging [T32-AG000258]; Medical Student Training in Aging Research award - National Institute on Aging FX This work was supported by VA merit review; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS051134]. T.S.S. is supported by the National Institutes of Health National Institute on Aging [Grant T32-AG000258]. J.A.F. was supported by a Medical Student Training in Aging Research award that is funded by the National Institute on Aging and administered by the American Federation for Aging Research. NR 41 TC 10 Z9 10 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2014 VL 351 IS 1 BP 54 EP 60 DI 10.1124/jpet.114.216705 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP2ZC UT WOS:000341943700007 PM 25027317 ER PT J AU Delaney, RA Freehill, MT Janfaza, DR Vlassakov, KV Higgins, LD Warner, JJP AF Delaney, Ruth A. Freehill, Michael T. Janfaza, David R. Vlassakov, Kamen V. Higgins, Laurence D. Warner, Jon J. P. TI 2014 Neer Award Paper: Neuromonitoring the Latarjet procedure SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Instability; Latarjet procedure; neurologic complications; axillary nerve; musculocutaneous nerve ID SHOULDER; COMPLICATIONS; DISLOCATION; NERVE; OPERATION; PALSY AB Background: We used intraoperative neuromonitoring to define the stages of the Latarjet procedure during which the nerves are at greatest risk. Methods: Thirty-four patients with a mean age of 28.4 years were included. The Latarjet procedure was divided into 9 defined stages. Bilateral median and ulnar somatosensory evoked responses and transcranial motor evoked potentials from all arm myotomes were continuously monitored. A "nerve alert'' was defined as averaged 50% amplitude attenuation or 10% latency prolongation of ipsilateral somatosensory evoked responses and transcranial motor evoked potentials. For each nerve alert, the surgeon altered retractor placement, and if there was no response to this, the position of the operative extremity was then changed. Results: Of 34 patients, 26 (76.5%) had 45 separate nerve alert episodes. The most common stages of the procedure for a nerve alert to occur were glenoid exposure and graft insertion. The axillary nerve was involved in 35 alerts; the musculocutaneous nerve, in 22. Of the 34 patients, 7 (20.6%) had a clinically detectable nerve deficit postoperatively, all correlated with an intraoperative nerve alert. All cases involved the axillary nerve, and all resolved completely from 28 to 165 days postoperatively. Prior surgery and body mass index were not predictive of a neurologic deficit postoperatively. However, total operative time (P = .042) and duration of the stage of the procedure in which the concordant nerve alert occurred (P = .010) were statistically significant predictors of a postoperative nerve deficit. Conclusions: The nerves, in particular the axillary and musculocutaneous nerves, are at risk during the Latarjet procedure, especially during glenoid exposure and graft insertion. (C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Delaney, Ruth A.; Freehill, Michael T.; Warner, Jon J. P.] Massachusetts Gen Hosp, Boston Shoulder Inst, Boston, MA 02114 USA. [Janfaza, David R.; Vlassakov, Kamen V.] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Higgins, Laurence D.] Brigham & Womens Hosp, Boston Shoulder Inst, Boston, MA 02115 USA. RP Warner, JJP (reprint author), Yawkey Ctr Outpatient Care, Harvard Shoulder Serv, 55 Fruit St,Suite 3200,3G,Room 3-046, Boston, MA 02114 USA. EM jwarner@partners.org OI Vlassakov, Kamen/0000-0002-7704-3709 NR 17 TC 15 Z9 15 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD OCT PY 2014 VL 23 IS 10 BP 1473 EP 1480 DI 10.1016/j.jse.2014.04.003 PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AP4NO UT WOS:000342054200014 PM 24950948 ER PT J AU Russ, AL Zillich, AJ Melton, BL Russell, SA Chen, SY Spina, JR Weiner, M Johnson, EG Daggy, JK McManus, MS Hawsey, JM Puleo, AG Doebbeling, BN Saleem, JJ AF Russ, Alissa L. Zillich, Alan J. Melton, Brittany L. Russell, Scott A. Chen, Siying Spina, Jeffrey R. Weiner, Michael Johnson, Elizabette G. Daggy, Joanne K. McManus, M. Sue Hawsey, Jason M. Puleo, Anthony G. Doebbeling, Bradley N. Saleem, Jason J. TI Applying human factors principles to alert design increases efficiency and reduces prescribing errors in a scenario-based simulation SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CLINICAL DECISION-SUPPORT; PHYSICIAN ORDER ENTRY; LABORATORY MONITORING ALERTS; DRUG INTERACTION ALERTS; SUBJECTIVE WORKLOAD; SAFETY ALERTS; MEDICATION; SYSTEMS; CARE; IMPLEMENTATION AB Objective To apply human factors engineering principles to improve alert interface design. We hypothesized that incorporating human factors principles into alerts would improve usability, reduce workload for prescribers, and reduce prescribing errors. Materials and methods We performed a scenario-based simulation study using a counterbalanced, crossover design with 20 Veterans Affairs prescribers to compare original versus redesigned alerts. We redesigned drug-allergy, drug- drug interaction, and drug- disease alerts based upon human factors principles. We assessed usability (learnability of redesign, efficiency, satisfaction, and usability errors), perceived workload, and prescribing errors. Results Although prescribers received no training on the design changes, prescribers were able to resolve redesigned alerts more efficiently (median (IQR): 56 (47) s) compared to the original alerts (85 (71) s; p=0.015). In addition, prescribers rated redesigned alerts significantly higher than original alerts across several dimensions of satisfaction. Redesigned alerts led to a modest but significant reduction in workload (p=0.042) and significantly reduced the number of prescribing errors per prescriber (median (range): 2 (1- 5) compared to original alerts: 4 (1- 7); p=0.024). Discussion Aspects of the redesigned alerts that likely contributed to better prescribing include design modifications that reduced usability- related errors, providing clinical data closer to the point of decision, and displaying alert text in a tabular format. Displaying alert text in a tabular format may help prescribers extract information quickly and thereby increase responsiveness to alerts. Conclusions This simulation study provides evidence that applying human factors design principles to medication alerts can improve usability and prescribing outcomes. C1 [Russ, Alissa L.; Zillich, Alan J.; Russell, Scott A.; Chen, Siying; Weiner, Michael; Daggy, Joanne K.; Doebbeling, Bradley N.] Richard L Roudebush VA Med Ctr, Hlth Serv Res & Dev Serv CIN 13 416, Ctr Hlth Informat & Commun, Dept Vet Affairs,Vet Hlth Adm, Indianapolis, IN 46202 USA. [Russ, Alissa L.; Zillich, Alan J.; Weiner, Michael; Doebbeling, Bradley N.] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Indianapolis, IN 46204 USA. [Russ, Alissa L.; Zillich, Alan J.; Weiner, Michael; Doebbeling, Bradley N.] Regenstrief Inst Inc, Indianapolis, IN USA. [Russ, Alissa L.; Zillich, Alan J.] Purdue Univ, Coll Pharm, W Lafayette, IN 47907 USA. [Melton, Brittany L.] Univ Kansas, Sch Pharm, Lawrence, KS 66045 USA. [Spina, Jeffrey R.] VA Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Spina, Jeffrey R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Weiner, Michael] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Johnson, Elizabette G.] Purdue Univ, Dept Psychol, W Lafayette, IN 47907 USA. [Daggy, Joanne K.] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN 46202 USA. [McManus, M. Sue] Dept Vet Affairs, Dept Nephrol Serv, Temple, TX USA. [Hawsey, Jason M.] Off Informat, Dept Vet Affairs, Bay Pines, FL USA. [Puleo, Anthony G.] Off Informat, Dept Vet Affairs, Salt Lake City, UT USA. [Doebbeling, Bradley N.] Indiana Univ Purdue Univ, Sch Informat & Comp, Dept BioHlth Informat, Indianapolis, IN 46202 USA. [Saleem, Jason J.] Vet Hlth Adm, Off Informat & Analyt, Human Factors Engn, Louisville, KY USA. RP Russ, AL (reprint author), Richard L Roudebush VA Med Ctr, 1481 W 10th St,11-H, Indianapolis, IN 46202 USA. EM alissa.russ@va.gov OI Daggy, Joanne/0000-0003-0815-1746 FU VA HSRD grant [PPO 09-298]; VA HSR&D Research Career Development Awards [CDA 11-214, CDA 09-024-1, RCD 06-304-1]; VA National Center for Patient Safety, Interprofessional Fellowship Program in Patient Safety FX This work was supported by VA HSR&D grant #PPO 09-298 (PI: Alissa L Russ) and manuscript preparation was supported by the Center for Health Information and Communication, Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, CIN 13-416. (Work occurred under the Center of Excellence on Implementing Evidence-Based Practice, HFP 04-148.) Drs Russ, Saleem, and Zillich were supported by VA HSR&D Research Career Development Awards (CDA 11-214, CDA 09-024-1, and RCD 06-304-1, respectively). Drs Kobylinski and Chen were supported by the VA National Center for Patient Safety, Interprofessional Fellowship Program in Patient Safety. NR 46 TC 15 Z9 15 U1 4 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD OCT PY 2014 VL 21 IS E2 BP E287 EP E296 DI 10.1136/amiajnl-2013-002045 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AP1UV UT WOS:000341858100016 PM 24668841 ER PT J AU Forghanifard, MM Gholamin, M Moaven, O Farshchian, M Ghahraman, M Aledavood, A Abbaszadegan, MR AF Forghanifard, Mohammad Mahdi Gholamin, Mehran Moaven, Omeed Farshchian, Moein Ghahraman, Martha Aledavood, Amir Abbaszadegan, Mohammad Reza TI Neoantigen in esophageal squamous cell carcinoma for dendritic cell-based cancer vaccine development SO MEDICAL ONCOLOGY LA English DT Article DE Esophageal squamous cell carcinoma; Immuno-gene therapy; RNA vaccine; CTAs; Dendritic cell; Chimeric construct; Cytotoxicity ID CANCER/TESTIS CT ANTIGENS; IMMUNOTHERAPY; RNA; EXPRESSION; RESPONSES; STRATEGIES; INDUCTION; MELANOMA; TARGETS; GENES AB Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor which usually is diagnosed in advanced stages due to its asymptomatic course of tumorigenesis. Current therapeutic modalities are not effective enough and the 5-year survival rate of the disease is still very low which prompts the urgent need for finding novel efficient therapeutic methods. In this study, we evaluated ex vivo immune response of ESCC patients against our newly designed chimeric construct consisting of highly immunogenic cancer-testis antigens. After confirming effective expression of the in vitro transcribed chimeric mRNA in ex vivo electroporated dendritic cells (DCs) of the ESCC patients, the patients' CTLs were primed by DCs and cytotoxicity assay was performed to evaluate how the primed CTLs can recognize and target the chimeric mRNA-loaded cells. The chimeric protein was strongly expressed relative to the housekeeping gene expression in electroporated cells. The cytotoxicity of the CTLs was significantly higher in DCs loaded with chimeric mRNAs compared to mock DCs (p < 0.05) in all of the tested ESCC patients. We are introducing a novel construct that our functional study showed can stimulate and induce an effective immune response in ESCC patients. The designed chimeric mRNA-loaded DCs are capable of priming CTLs effectively and induce cytotoxicity against tumor. Therefore, loading DCs with chimeric epitopes of highly immunogenic antigens, such as cancer-testis antigens, are potentially interesting and effective therapeutic modalities for immunotherapy of ESCC. C1 [Forghanifard, Mohammad Mahdi] Islamic Azad Univ, Damghan Branch, Dept Biol, Damghan, Iran. [Gholamin, Mehran; Abbaszadegan, Mohammad Reza] Mashhad Univ Med Sci, Avicenna Res Inst, Div Human Genet, Immunol Res Ctr, Mashhad 9196773117, Iran. [Moaven, Omeed] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Farshchian, Moein] Ferdowsi Univ Mashhad, Dept Biol, Fac Sci, Mashhad, Iran. [Ghahraman, Martha; Abbaszadegan, Mohammad Reza] Mashhad Univ Med Sci, Sch Med, Med Genet Res Ctr, Mashhad 9196773117, Iran. [Aledavood, Amir] Mashhad Univ Med Sci, Dept Radiotherapy & Oncol, Mashhad 9196773117, Iran. RP Abbaszadegan, MR (reprint author), Mashhad Univ Med Sci, Avicenna Res Inst, Div Human Genet, Immunol Res Ctr, Bu Ali Sq, Mashhad 9196773117, Iran. EM abbaszadeganmr@mums.ac.ir OI Moaven, Omeed/0000-0002-0560-0457 FU MUMS [88098] FX The authors gratefully acknowledge the colleagues at the Departments of Surgery and Pathology in Omid, Qaem and Imam Reza hospitals of MUMS, Mashhad, for samples preparation. We are grateful to Dr. Mojtaba Sankian, Dr. Mohsen Tehrani and Ms. Maliheh Moghadam at Immunobiochemistry Lab, Immunology Research Center, Avicenna Research Institute, Mashhad, as well as our colleagues at Division of Human Genetics, for their kind help and support in technical aspects. This study was supported by the grant number 88098 from the Vice Chancellor for Research at MUMS. NR 30 TC 4 Z9 4 U1 0 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD OCT PY 2014 VL 31 IS 10 AR 191 DI 10.1007/s12032-014-0191-5 PG 7 WC Oncology SC Oncology GA AP4WG UT WOS:000342079600010 PM 25178937 ER PT J AU Shalaurova, I Connelly, MA Garvey, WT Otvos, JD AF Shalaurova, Irina Connelly, Margery A. Garvey, W. Timothy Otvos, James D. TI Lipoprotein Insulin Resistance Index: A Lipoprotein Particle-Derived Measure of Insulin Resistance SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; NICOTINIC-ACID; GLUCOSE-TOLERANCE; SUPPRESSION TEST; LIFE-STYLE; SENSITIVITY; PREVENTION; ATHEROSCLEROSIS; SECRETION; OBESITY AB Background: Lipoprotein particle sizes and concentrations are characteristically altered in patients with insulin resistance (IR) or type 2 diabetes mellitus (T2DM). This study assessed the ability of an IR score, based on nuclear magnetic resonance (NMR)-derived lipoprotein information, to detect IR in otherwise healthy individuals. Methods: Lipoprotein subclass and size information were evaluated for strength of association with IR, as measured by homeostasis model assessment of insulin resistance (HOMA-IR) in the Multi-Ethnic Study of Atherosclerosis (MESA). To increase the likelihood of identifying subjects with IR, six lipoprotein measures were combined into a single algorithm. The resulting assay [Lipoprotein Insulin Resistance Index (LP-IR)] was developed using HOMA-IR in 4972 nondiabetic subjects from MESA and verified independently using glucose disposal rates (GDRs) measured during hyperinsulinemic-euglycemic clamps in 56 insulin-sensitive, 46 insulin-resistant, and 46 untreated subjects with T2DM. Results: LP-IR exhibited stronger associations with HOMA-IR (r = 0.51) and GDR (r = -0.53) than each of the individual lipoprotein parameters as well as the triglycerides/high-density lipoprotein cholesterol (TGs/HDL-C) ratio (r = 0.41 and -0.44, respectively). In MESA, associations between the LP-IR score and HOMA-IR were strong in men (r = 0.51), women (r = 0.52), European Americans (r = 0.58), African Americans (r = 0.48), Chinese Americans (r = 0.49), and Hispanic Americans (r = 0.45). When LP-IR was categorized by HOMA-IR and either body mass index (BMI) or fasting plasma glucose (FPG), subgroups were revealed whose LP-IR scores were high (>= 50), despite having normal BMIs (<24 kg/m(2)) or FPG (<100 mg/dL). Conclusions: LP-IR scores had strong associations with multiple measures, HOMA-IR, and GDR, the former being more reflective of hepatic and the latter of peripheral insulin sensitivity, and may represent a simple means to identify individuals with IR. C1 [Shalaurova, Irina; Connelly, Margery A.; Otvos, James D.] LipoScience Inc, Raleigh, NC 27616 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. RP Otvos, JD (reprint author), LipoScience Inc, 2500 Sumner Blvd, Raleigh, NC 27616 USA. EM jotvos@liposcience.com FU Merit Review program of the Department of Veterans Affairs; National Institutes of Health [DK-038765, DK-083562]; UAB Diabetes Research Center [P60-DK079626] FX The authors gratefully acknowledge Drs. Deborah Winegar and Ray Pourfarzib for careful review of the manuscript and scientific comments. This work was supported in part by the Merit Review program of the Department of Veterans Affairs, the National Institutes of Health (DK-038765 and DK-083562), and the UAB Diabetes Research Center (P60-DK079626). NR 37 TC 17 Z9 17 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD OCT PY 2014 VL 12 IS 8 BP 422 EP 429 DI 10.1089/met.2014.0050 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AP5XR UT WOS:000342152500003 PM 24959989 ER PT J AU Yoo, B Ifediba, MA Ghosh, S Medarova, Z Moore, A AF Yoo, Byunghee Ifediba, Marytheresa A. Ghosh, Subrata Medarova, Zdravka Moore, Anna TI Combination Treatment with Theranostic Nanoparticles for Glioblastoma Sensitization to TMZ SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Theranostic; Nanoparticle; Glioblastoma multiforme; siRNA; MRI; Chlorotoxin; Targeting; Temozolomide ID IRON-OXIDE NANOPARTICLES; MGMT PROMOTER METHYLATION; MALIGNANT GLIOMA; BRAIN-TUMORS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PREDICTS RESPONSE; CELL INVASION; BONE-MARROW; TEMOZOLOMIDE; CHLOROTOXIN AB Tumor resistance to chemotherapeutic drugs is one of the major obstacles in the treatment of glioblastoma multiforme (GBM). In this study, we attempted to modulate tumor response to chemotherapy by combination treatment that included experimental (small interference RNA (siRNA), chlorotoxin) and conventional (temozolomide, TMZ) therapeutics. siRNA therapy was used to silence O-6-methylguanine methyltransferase (MGMT), a key factor in brain tumor resistance to TMZ. For targeting of tumor cells, we used chlorotoxin (CTX), a peptide with antitumoral properties. siRNA and CTX were conjugated to iron oxide nanoparticles (NP) that served as the drug carrier and allowed the means to monitor the changes in tumor volume by magnetic resonance imaging (MRI). Theranostic nanoparticles (termed CTX-NP-siMGMT) were internalized by T98G glioblastoma cells in vitro leading to enhancement of TMZ toxicity. Combination treatment of mice bearing orthotopic tumors with CTX-NP-siMGMT and TMZ led to significant retardation of tumor growth, which was monitored by MRI. While our results demonstrate that siRNA delivery by targeted nanoparticles resulted in modulating tumor response to chemotherapy in GBM, they also point to a significant contribution of CTX to tumor cell death. C1 [Yoo, Byunghee; Ifediba, Marytheresa A.; Ghosh, Subrata; Medarova, Zdravka; Moore, Anna] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Mol Imaging Lab,MGH HST Athinoula A Martinos Ctr, Charlestown, MA 02129 USA. [Ifediba, Marytheresa A.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Moore, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Mol Imaging Lab,MGH HST Athinoula A Martinos Ctr, Bldg 75,13th St, Charlestown, MA 02129 USA. EM amoore@helix.mgh.harvard.edu FU [T32CA009502] FX This work was supported in part by T32CA009502 (PI Anna Moore). NR 49 TC 10 Z9 10 U1 4 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD OCT PY 2014 VL 16 IS 5 BP 680 EP 689 DI 10.1007/s11307-014-0734-3 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP5RG UT WOS:000342135800012 PM 24696184 ER PT J AU Hernandez-Duran, S Ogilvy, CS AF Hernandez-Duran, Silvia Ogilvy, Christopher S. TI Clinical outcomes of patients with vertebral artery dissection treated endovascularly: a meta-analysis SO NEUROSURGICAL REVIEW LA English DT Review DE Vertebral artery dissection; Cervical artery dissection; Endovascular treatment; Meta-analysis ID CONNECTIVE-TISSUE ABNORMALITIES; INFERIOR CEREBELLAR ARTERY; OF-THE-LITERATURE; SUBARACHNOID HEMORRHAGE; VERTEBROBASILAR DISSECTION; STENT PLACEMENT; INTRACRANIAL DISSECTIONS; COIL EMBOLIZATION; NATURAL-HISTORY; ACUTE STAGE AB The purpose of this study was to present a meta-analysis on the safety and efficacy of different endovascular modalities when treating vertebral artery dissections, since ideal treatment remains controversial. We performed a meta-analysis of 39 retrospective studies involving different treatment modalities for vertebral artery dissections in adults and obtained weighted pooled proportional outcome and mortality ratios with a random effects model. Overall, 75.11 % (confidence interval (CI) 68.89-80.84, I (2) 66.89 %) had excellent outcomes, 10.10 % (CI 6.83-15.56, I (2) 65.64 %) had good outcomes, and 13.70 % (CI 9.64-18.35, I (2) 60.33 %) had poor outcomes. Postoperative complications occurred in 10.52 % (CI 6.87-14.84, I (2) 62.48 %), with 2.73 % (CI 1.64-4.10, I (2) 0.0 %) exhibiting vasospasm, 3.03 % (CI 1.88-4.46, I (2) 0.0 %) experiencing postoperative rebleeding, and 6.31 % (CI 3.57-9.76, I (2) 60.92 %) showing ischemia. Overall mortality was 8.69 % (CI 6.13-11.64, I (2) 33.76 %). When compared to these overall ratios, different treatment modality subgroups did not differ significantly, except for the proximal occlusion group, with poor outcome ratio = 26.96 % (difference 13.26, CI 0.02-30.04, p = 0.0403) and mortality ratio = 21.36 % (difference 12.67, CI 0.94-28.86, p = 0.0189). Different endovascular treatment modalities are comparatively safe and effective in the management of vertebral artery dissection. Their reduced operative time, minimal invasiveness, and overall safety render them a suitable option for intervention-amenable dissections. C1 [Hernandez-Duran, Silvia; Ogilvy, Christopher S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA USA. [Hernandez-Duran, Silvia] Univ Costa Rica, Sch Med, San Jose, Costa Rica. RP Hernandez-Duran, S (reprint author), Apdo 1232-1007, San Jose, Costa Rica. EM drahernandezduran@gmail.com; cogilvy@bidmc.harvard.edu NR 65 TC 5 Z9 5 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5607 EI 1437-2320 J9 NEUROSURG REV JI Neurosurg. Rev. PD OCT PY 2014 VL 37 IS 4 BP 569 EP 577 DI 10.1007/s10143-014-0541-y PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AP6MS UT WOS:000342192500007 PM 24715276 ER PT J AU Ray, LA Courtney, KE Ghahremani, DG Miotto, K Brody, A London, ED AF Ray, Lara A. Courtney, Kelly E. Ghahremani, Dara G. Miotto, Karen Brody, Arthur London, Edythe D. TI Varenicline, low dose naltrexone, and their combination for heavy-drinking smokers: human laboratory findings SO PSYCHOPHARMACOLOGY LA English DT Article DE Naltrexone; Varenicline; Heavy drinker; Smoker; Human lab; Craving ID RANDOMIZED CONTROLLED-TRIAL; RECEPTOR PARTIAL AGONIST; PLACEBO-CONTROLLED TRIAL; NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION TREATMENT; COGNITIVE-BEHAVIORAL THERAPY; SUSTAINED-RELEASE BUPROPION; ALCOHOL-DEPENDENT SUBJECTS; DOUBLE-BLIND; WEIGHT-GAIN AB Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available. The present study used a double-blind, randomized, 2 x 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n = 130) of heavy-drinking daily smokers (a parts per thousand yen10 cigarettes/day). All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration = 0.06 g/dl) and after smoking the first cigarette of the day. The combination of VAR + L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol "high," and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period. These preliminary findings indicate that clinical studies of the combination of VAR + L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers. C1 [Ray, Lara A.; Courtney, Kelly E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Ray, Lara A.; Ghahremani, Dara G.; Miotto, Karen; Brody, Arthur; London, Edythe D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Brody, Arthur] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA 90095 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. RP Ray, LA (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM lararay@psych.ucla.edu RI Courtney, Kelly/L-6041-2016 OI Courtney, Kelly/0000-0002-9280-2435 FU California Tobacco Related Disease Research Program [TRDRP 18KT-0020]; National Institute on Drug Abuse [DA030898]; UCLA Clinical and Translational Science Institute (CTSI) [UL1RR033176, UL1TR000124]; UCLA Training Program in Translational Neuroscience of Drug Abuse [T32 DA024635]; GSK FX This research was supported grants from the California Tobacco Related Disease Research Program (TRDRP 18KT-0020) and from the National Institute on Drug Abuse (DA030898) to LAR. Support for this study was also provided by a grant from the UCLA Clinical and Translational Science Institute (CTSI), grants UL1RR033176 and UL1TR000124. KEC was supported by the UCLA Training Program in Translational Neuroscience of Drug Abuse (T32 DA024635). LAR is a paid consultant for GSK. None of the authors have any other conflicts of interest to disclose. NR 80 TC 10 Z9 10 U1 4 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2014 VL 231 IS 19 BP 3843 EP 3853 DI 10.1007/s00213-014-3519-0 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AP2SU UT WOS:000341925800003 PM 24733235 ER PT J AU Sanz, F Restrepo, MI Fernandez-Fabrellas, E Cervera, A Briones, ML Novella, L Aguar, MC Chiner, E Fernandez, JF Blanquer, J AF Sanz, Francisco Restrepo, Marcos I. Fernandez-Fabrellas, Estrella Cervera, Angela Luisa Briones, Maria Novella, Laura Carmen Aguar, Maria Chiner, Eusebi Fernandez, Juan F. Blanquer, Jose TI Does prolonged onset of symptoms have a prognostic significance in community-acquired pneumonia? SO RESPIROLOGY LA English DT Article DE antibiotic; community-acquired pneumonia; complication; outcome; risk factor ID PRIMARY-CARE; MANAGEMENT; MORTALITY; SEVERITY; RISK; PREDICTION; GUIDELINES; INFECTION; DATABASE; OUTCOMES AB Background and objectiveSeverity assessment is made at the time of the initial clinical presentation in patients with community-acquired pneumonia (CAP). It is unclear how the gap between time of presentation and duration of symptoms onset may impact clinical outcomes. Here we evaluate the association of prolonged onset of symptoms (POS) and the impact on clinical outcomes among hospitalized patients with CAP. MethodsThis was a prospective, multicentre study of CAP in Spain. The primary outcomes were the clinical factors associated with POS defined as days from symptoms onset to pneumonia diagnosis >7 days. The secondary outcomes were intensive care unit (ICU) admission, the presence of suppurative complications, septic shock and 30-day mortality. ResultsWe enrolled 1038 patients diagnosed of CAP: 152 (14.6%) patients had a POS. In multivariate analysis, the presence of prior corticosteroid therapy, alcohol abuse, prior antibiotic therapy, and confusion, urea, respiratory rate, blood pressure and age 65 years or older score 0-1 was independently associated with POS. Patients with POS had a higher incidence of suppurative complications, but not of 30-day mortality when compared with a shorter onset of symptoms. ConclusionsApproximately 15% of patients diagnosed with CAP had POS. Risk factors associated with POS were previous corticosteroids and antibiotic therapy, alcoholism and less severe pneumonia. POS was associated with a higher rate of suppurative complications and less need for ICU admission. Onset of symptoms for more than 7 days is found in nearly 15% of patients with CAP. Prior corticosteroid therapy, antibiotic therapy, alcohol abuse and CURB-65 score 0-1 were independently associated with prolonged symptoms onset. Those patients had a higher incidence of suppurative complications, but not of 30-day mortality. C1 [Sanz, Francisco; Fernandez-Fabrellas, Estrella; Cervera, Angela; Novella, Laura] Consorci Hosp Gen Univ Valencia, Dept Pulmonol, Valencia 46014, Spain. [Luisa Briones, Maria] Hosp Clin Univ Valencia, Dept Pulmonol, Valencia, Spain. [Carmen Aguar, Maria] Hosp Arnau Vilanova, Dept Pulmonol, Valencia, Spain. [Chiner, Eusebi; Blanquer, Jose] Hosp St Joan, Dept Pulmonol, Alacant, Spain. [Restrepo, Marcos I.; Fernandez, Juan F.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Crit Care Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.] Vet Evidence Based Res Disseminat & Implementat C, San Antonio, TX USA. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Sanz, F (reprint author), Consorci Hosp Gen Univ Valencia, Dept Pulmonol, Av Trescruces 2, Valencia 46014, Spain. EM sanz_fraher@gva.es NR 28 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD OCT PY 2014 VL 19 IS 7 BP 1073 EP 1079 DI 10.1111/resp.12346 PG 7 WC Respiratory System SC Respiratory System GA AP5OZ UT WOS:000342129800021 PM 24995803 ER PT J AU Sarr, MG Warshaw, AL AF Sarr, Michael G. Warshaw, Andrew L. TI Disclosure of Funding Sources and Conflicts of Interest in Phase III Surgical Trials: Survey of 10 General Surgery Journals SO WORLD JOURNAL OF SURGERY LA English DT Editorial Material C1 [Sarr, Michael G.] Mayo Clin, Dept Surg, Rochester, MN 55905 USA. [Warshaw, Andrew L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sarr, MG (reprint author), Mayo Clin, Dept Surg, 200 First St SW, Rochester, MN 55905 USA. EM sarr.michael@mayo.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD OCT PY 2014 VL 38 IS 10 BP 2494 EP 2494 DI 10.1007/s00268-014-2648-2 PG 1 WC Surgery SC Surgery GA AP6SY UT WOS:000342209200002 ER PT J AU Kuhlthau, K Payakachat, N Delahaye, J Hurson, J Pyne, JM Kovacs, E Tilford, JM AF Kuhlthau, Karen Payakachat, Nalin Delahaye, Jennifer Hurson, Jill Pyne, Jeffrey M. Kovacs, Erica Tilford, J. Mick TI Quality of life for parents of children with autism spectrum disorders SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Health-related quality of life; Parent; Parent well-being; Depression ID HEALTH-CARE NEEDS; PSYCHIATRIC-DISORDERS; ASPERGER-SYNDROME; NATIONAL-SURVEY; MEDICAL HOME; MOTHERS; EQ-5D; STRESS; FAMILY; STATES AB This project describes health-related quality of life (HRQoL) of parents of children with autism spectrum disorders (ASDs) using mixed methods. Parents of children with ASDs (N = 224) reported on their HRQoL, depression, and caregiving burden using quantitative tools. HRQoL scores were slightly worse than from those in normative populations especially related to stress and mental health. For example, parents reported average HRQoL scores from SF-6D of 0.74, which was clinically significant lower than an average normative U.S. population. 40% of parents reported having clinical depression symptoms. Married parents reported lower depression symptoms than parents who were not. In addition, families with three or more children with special health care needs (CSHCN) reported lower HRQL and higher caregiving burden than families with less CSHCN. In the qualitative study, we conducted five focus groups to gain insight as to the reasons a child's ASD might influence a parent's HRQoL. Qualitative data further supports the notion that parental HRQoL was negatively influenced by their child's ASDs. Studies that seek to quantify the influence of ASDs and to assess the effect of interventions for children with ASDs may consider measuring the effects on family members as well. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kuhlthau, Karen; Delahaye, Jennifer; Hurson, Jill] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Kuhlthau, Karen] Harvard Univ, Dept Pediat, Sch Med, Cambridge, MA 02138 USA. [Payakachat, Nalin] Univ Arkansas Med Sci, Div Pharmaceut Evaluat & Policy, Coll Pharm, Little Rock, AR 72205 USA. [Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, Ctr Mental Hlth Outcomes Res, North Little Rock, AR 72114 USA. [Kovacs, Erica] Div Child & Adolescent Psychiat, Columbia Dev Neuropsychiat Program, New York, NY 10019 USA. [Tilford, J. Mick] Univ Arkansas Med Sci, Coll Publ Hlth 2226, Little Rock, AR 72205 USA. RP Kuhlthau, K (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM kkuhlthau@mgh.harvard.edu NR 64 TC 6 Z9 6 U1 5 U2 46 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD OCT PY 2014 VL 8 IS 10 BP 1339 EP 1350 DI 10.1016/j.rasd.2014.07.002 PG 12 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA AO7SE UT WOS:000341552100009 ER PT J AU Kanal, KM Chung, JH Wang, J Bhargava, P Gunn, ML Shuman, WP Stewart, BK AF Kanal, Kalpana M. Chung, Jonathan H. Wang, Jin Bhargava, Puneet Gunn, Martin L. Shuman, William P. Stewart, Brent K. TI Impact of Incremental Increase in CT Image Noise on Detection of Low-contrast Hypodense Liver Lesions SO ACADEMIC RADIOLOGY LA English DT Article DE CT; image noise; radiation dose; liver lesion detection ID TUBE CURRENT MODULATION; Z-AXIS MODULATION; DOSE REDUCTION; CHEST CT; ROW CT; PHANTOM; OPTIMIZATION; QUALITY; ABDOMEN; PELVIS AB Rationale and Objectives: To determine the impact of incremental increases in computed tomography (CT) image noise on detection of low-contrast hypodense liver lesions. Material and Methods: We studied 50 CT examinations acquired at image noise index (NI) of 15 and hypodense liver lesions and 50 examinations with no lesions. Validation of a noise addition tool to be used in the evaluation of the CT examinations was performed with a liver phantom. Using this tool, three 100-image sets were assembled: an NI of 17.4 (simulating 75% of the original patient radiation dose), 21.2 (simulating 50% dose), and 29.7 (simulating 25%). Three readers scored certainty of lesion presence using a five-point Likert scale. Results: For original images (NI 15) plus images with NI of 17.4 and 21.2, sensitivity was > 90% threshold (range, 95%-98%). For images with NI of 29.7, sensitivity was-just below the threshold (89%). Reader A(z) values for receiver operating characteristic curves were good for original, NI 17.4, and NI 21.2 images (0.976, 0.973, and 0.96, respectively). For NI of 29.7, the A(z) decreased to 0.913. Detection sensitivity was < 90% for both lesion size < 10 mm (85%) and lesion-to-liver contrast < 60 Hounsfield units (85%) only at NI 29.7. Conclusions: For low-contrast lesion detection in liver CT, image noise can be increased up to NI 21.2 (a 50% patient radiation dose reduction) without substantial reduction in sensitivity. C1 [Kanal, Kalpana M.; Bhargava, Puneet; Gunn, Martin L.; Shuman, William P.; Stewart, Brent K.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Chung, Jonathan H.] Natl Jewish Hlth, Dept Radiol, Denver, CO USA. [Wang, Jin] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Bhargava, Puneet] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA USA. RP Kanal, KM (reprint author), Univ Washington, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA. EM kkanal@uw.edu OI Bhargava, Puneet/0000-0002-3849-9666 NR 19 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD OCT PY 2014 VL 21 IS 10 BP 1233 EP 1239 DI 10.1016/j.acra.2014.05.011 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP1AS UT WOS:000341799400003 PM 25086952 ER PT J AU Taylor, MJ Charman, T Robinson, EB Hayiou-Thomas, ME Happe, F Dale, PS Ronald, A AF Taylor, Mark J. Charman, Tony Robinson, Elise B. Hayiou-Thomas, Marianna E. Happe, Francesca Dale, Philip S. Ronald, Angelica TI Language and Traits of Autism Spectrum Conditions: Evidence of Limited Phenotypic and Etiological Overlap SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE autism; receptive language; twin study ID CAST CHILDHOOD ASPERGER; SUSCEPTIBILITY GENE; TWIN DATA; IMPAIRMENT; DISORDERS; POPULATION; CHILDREN; ASSOCIATION; MATHEMATICS; COMORBIDITY AB Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by approximate to 3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation=-0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation=0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier. (c) 2014 Wiley Periodicals, Inc. C1 [Taylor, Mark J.; Ronald, Angelica] Univ London, Genes Environm Lifespan Lab, Ctr Brain & Cognit Dev, Dept Psychol Sci, London WC1E 7JL, England. [Charman, Tony] Kings Coll London, Dept Psychol, Inst Psychiat, London WC2R 2LS, England. [Robinson, Elise B.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Hayiou-Thomas, Marianna E.] Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. [Happe, Francesca] Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Dale, Philip S.] Univ New Mexico, Dept Speech & Hearing Sci, Albuquerque, NM 87131 USA. RP Taylor, MJ (reprint author), Univ London, Sch Psychol Sci, Ctr Brain, Genes Environm Lifespan Lab, 32 Torrington Sq, London WC1E 7JL, England. EM mj.taylor@bbk.ac.uk RI Dale, Philip/A-2254-2009; Charman, Tony/A-2085-2014; Ronald, Angelica/C-7812-2009; Taylor, Mark/D-4853-2017; OI Dale, Philip/0000-0002-7697-8510; Charman, Tony/0000-0003-1993-6549; Ronald, Angelica/0000-0002-9576-2176; Taylor, Mark/0000-0001-5161-4182; Robinson, Elise/0000-0003-2314-2792; Happe, Francesca/0000-0001-9226-4000 FU UK Medical Research Council [G0901245 G0500079]; Medical Research Council; Economic and Social Research Council FX Grant sponsor: UK Medical Research Council; Grant number: G0901245 G0500079; Grant sponsor: Medical Research Council and Economic and Social Research Council. NR 54 TC 4 Z9 4 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT PY 2014 VL 165 IS 7 BP 587 EP 595 DI 10.1002/ajmg.b.32262 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA AP3MB UT WOS:000341979000006 PM 25088445 ER PT J AU Attaman, JA Stanic, AK Kim, M Lynch, MP Rueda, BR Styer, AK AF Attaman, Jill A. Stanic, Aleksandar K. Kim, Minji Lynch, Maureen P. Rueda, Bo R. Styer, Aaron K. TI The Anti-Inflammatory Impact of Omega-3 Polyunsaturated Fatty Acids During the Establishment of Endometriosis-Like Lesions SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Cyclooxygenase-2; endometriosis; immune; interleukin-6; omega-3 fatty acids; polyunsaturated fatty acids ID TRANSGENIC MICE; ELEVATED OMEGA-3-FATTY-ACIDS; STROMAL CELLS; FAT-1 MICE; CYCLOOXYGENASE-2; TUMORIGENESIS; SUPPLEMENTATION; EXPRESSION; WOMEN; FLUID AB Problem The anti-inflammatory impact of three polyunsaturated fatty acids (3-PUFA) in endometriosis is incompletely understood. The effect of 3-PUFA on endometriosis-like lesions is evaluated as a potential anti-inflammatory treatment target. Method of StudyWild Type (WT) and transgenic Fat-1 mice (high levels of endogenous 3-PUFA) were utilized in a uterine tissue transplant endometriosis model. Experimental donorxhost pairs included: WTxWT (WW), WTxFat-1 (WF), and Fat-1xFat-1 (FF). Cytokine content (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, IFN-, TNF-, MCP-1 and RANTES) and immunocellular composition in lesions was determined. ResultsIntralesion IL-6 in WF hosts was 99-fold lower than WW hosts (P=0.03). Compared to WW host lesions, Cox-2 levels were decreased in WF [1.5-fold (P=0.02)] and FF [1.2-fold (P=0.01)] host lesions, respectively, and intralesion VEGF expression was increased [1.8-fold; P=0.02 (WF) and 1.5-fold; P=0.01 (FF)]. Lesions in FF hosts demonstrated reduced phosphohistone 3 expression (70%; P=0.03) compared to WW control hosts. ConclusionsSystemic host 3-PUFA levels influence immune, angiogenic, and proliferative factors implicated in the early establishment of endometriosis. C1 [Attaman, Jill A.] Harvard Vanguard Med Associates, Dept Obstet & Gynecol, Boston, MA USA. [Attaman, Jill A.; Stanic, Aleksandar K.; Kim, Minji; Lynch, Maureen P.; Rueda, Bo R.; Styer, Aaron K.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Stanic, Aleksandar K.; Lynch, Maureen P.; Rueda, Bo R.; Styer, Aaron K.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Styer, AK (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Thier 9, Boston, MA 02114 USA. EM astyer@partners.org OI Stanic-Kostic, Aleksandar/0000-0003-1946-6436 FU Physician Scientist Career Development Award; Executive Committee on Research and Multicultural Affairs Office; Massachusetts General Hospital; Harvard Medical School; Vincent Memorial Hospital Research Funds FX We gratefully acknowledge James H. Ware, Ph.D., Department of Biostatistics, Harvard School of Public Health. The author(s) received the following financial support for funding of this research: Physician Scientist Career Development Award, Executive Committee on Research and Multicultural Affairs Office, Massachusetts General Hospital, Harvard Medical School (to AK Styer), Vincent Memorial Hospital Research Funds (to BR Rueda and AK Styer). NR 32 TC 4 Z9 5 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD OCT PY 2014 VL 72 IS 4 BP 392 EP 402 DI 10.1111/aji.12276 PG 11 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA AP2DT UT WOS:000341883400005 PM 24898804 ER PT J AU Duffy, SA Ronis, DL Karvonen-Gutierrez, CA Ewing, LA Dalack, GW Smith, PM Carmody, TP Hicks, T Hermann, C Reeves, P Flanagan, P AF Duffy, Sonia A. Ronis, David L. Karvonen-Gutierrez, Carrie A. Ewing, Lee A. Dalack, Gregory W. Smith, Patricia M. Carmody, Timothy P. Hicks, Thomas Hermann, Christopher Reeves, Pamela Flanagan, Petra TI Effectiveness of the Tobacco Tactics Program in the Department of Veterans Affairs SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Cessation; Health services research; Tobacco control; Treatment and intervention; Veterans ID SMOKING-CESSATION INTERVENTIONS; ACUTE MYOCARDIAL-INFARCTION; NICOTINE REPLACEMENT; AFRICAN-AMERICANS; HEALTH-CARE; HOSPITALIZED SMOKERS; ETHNIC DISPARITIES; RANDOMIZED-TRIAL; GUIDELINES; QUIT AB The purpose was to determine the effectiveness of the Tobacco Tactics program in three Veterans Affairs hospitals. In this effectiveness trial, inpatient nurses were educated to provide the Tobacco Tactics intervention in Ann Arbor and Detroit, while Indianapolis was the control site (N = 1,070). Smokers were surveyed and given cotinine tests. The components of the intervention included nurse counseling, brochure, DVD, manual, pharmaceuticals, 1-800-QUIT-NOW card, and post-discharge telephone calls. There were significant improvements in 6-month quit rates in the pre- to post-intervention time periods in Ann Arbor (p = 0.004) and Detroit (p < 0.001) compared to Indianapolis. Pre- versus post-intervention quit rates were 4 % compared to 13 % in Detroit, were similar (6 %) pre- and post-intervention in Ann Arbor, and dropped from 26 % to 12 % in Indianapolis. The Tobacco Tactics program, which meets the Joint Commission standards that apply to all inpatient smokers, has the potential to significantly decrease smoking among Veterans. C1 [Duffy, Sonia A.; Karvonen-Gutierrez, Carrie A.; Ewing, Lee A.] Ann Arbor VA Ctr Clin Management Res Hlth Serv Re, Ann Arbor, MI 48105 USA. [Duffy, Sonia A.] Univ Michigan, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Duffy, Sonia A.; Dalack, Gregory W.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Smith, Patricia M.] Northern Ontario Sch Med, Greater Sudbury, ON, Canada. [Carmody, Timothy P.] San Francisco VA Med Ctr, San Francisco, CA USA. [Hicks, Thomas] Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Hermann, Christopher; Reeves, Pamela] John D Dingell VA Med Ctr, Detroit, MI USA. [Flanagan, Petra] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Duffy, Sonia A.; Ronis, David L.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. RP Duffy, SA (reprint author), Ann Arbor VA Ctr Clin Management Res Hlth Serv Re, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM bump@umich.edu NR 48 TC 4 Z9 4 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD OCT PY 2014 VL 48 IS 2 BP 265 EP 274 DI 10.1007/s12160-014-9605-z PG 10 WC Psychology, Multidisciplinary SC Psychology GA AP1EF UT WOS:000341808600016 PM 24823842 ER PT J AU Paris, JJ Cummings, BM Moore, MP AF Paris, John J. Cummings, Brian M. Moore, M. Patrick, Jr. TI "Brain Death," "Dead," and Parental Denial The Case of Jahi McMath SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article C1 [Paris, John J.] Boston Coll, Chestnut Hill, MA 02167 USA. [Cummings, Brian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moore, M. Patrick, Jr.] Boston Coll, Sch Law, Newton, MA USA. RP Paris, JJ (reprint author), Boston Coll, Chestnut Hill, MA 02167 USA. NR 35 TC 7 Z9 7 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD OCT PY 2014 VL 23 IS 4 BP 371 EP 382 DI 10.1017/S0963180114000048 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA AO8VW UT WOS:000341634200001 PM 25033028 ER PT J AU Dolman, AJ Loggia, ML Edwards, RR Gollub, RL Kong, J Napadow, V Wasan, AD AF Dolman, Andrew J. Loggia, Marco L. Edwards, Robert R. Gollub, Randy L. Kong, Jian Napadow, Vitaly Wasan, Ajay D. TI Phenotype Matters The Absence of a Positive Association Between Cortical Thinning and Chronic Low Back Pain When Controlling for Salient Clinical Variables SO CLINICAL JOURNAL OF PAIN LA English DT Article DE chronic low back pain; cortical thickness; brain morphometry; clinical research methods ID LOW-BACK-PAIN; GRAY-MATTER; DEPRESSION SCALE; HOSPITAL ANXIETY; OLDER-ADULTS; BRAIN; CLASSIFICATION; QUESTIONNAIRE; INTENSITY; VALIDITY AB Aims/Objectives/Background: Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations. Methods: We conducted cortical thickness and voxel-based morphometry (VBM) analyses in 14 cLBP patients with a discogenic component to their pain, not taking opioids or benzodiazepines, and not depressed or anxious. They were age and gender matched to 14 pain-free controls (PFCs). An ROI-driven analysis (regions of interest) was conducted, using 18 clusters from a previous arterial spin labeling study demonstrating greater regional cerebral blood flow (rCBF) in these cLBP subjects than the PFCs. Cortical thickness and VBM-based gray matter volume measurements were obtained from a structural MRI scan and group contrasts were calculated. Results: Multivariate analysis of variance showed a trend toward cortical thickening in the right paracentral lobule in cLBP subjects (F-1,F-17 = 3.667, P < 0.067), and significant thickening in the right rostral middle frontal gyrus (F-1,F-17 = 6.880, P < 0.014). These clusters were non-significant after including age as a covariate (P < 0.891; P < 0.279). A whole-brain cortical thickness and VBM analysis also did not identify significant clusters of thinning or thickening. Exploratory analyses identified group differences for correlations between age and cortical thickness of the right rostral middle frontal gyrus (cLBP: R = = -0.03, P = 0.9; PFCs: R = -0.81, P < 0.001), that is, PFCs demonstrated age-related thinning while cLBP patients did not. Conclusions: Our pilot results suggest that controlling for affect, age, and concurrent medications may reduce or eliminate some of the previously reported structural brain alterations in cLBP. C1 [Dolman, Andrew J.; Edwards, Robert R.; Napadow, Vitaly] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Loggia, Marco L.; Napadow, Vitaly] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Loggia, Marco L.; Gollub, Randy L.; Kong, Jian] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. RP Wasan, AD (reprint author), UPMC Pain Med, 5750 Ctr Ave,Suite 400, Pittsburgh, PA 15206 USA. EM adw63@pitt.edu OI Gollub, Randy L./0000-0002-9434-4044 FU NIH/NIDA [1K23DA020681-01A1] FX Supported by NIH/NIDA 1K23DA020681-01A1. The authors declare no conflict of interest. NR 41 TC 3 Z9 3 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 EI 1536-5409 J9 CLIN J PAIN JI Clin. J. Pain PD OCT PY 2014 VL 30 IS 10 BP 839 EP 845 DI 10.1097/AJP.0000000000000043 PG 7 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AP1MP UT WOS:000341834800002 PM 24135900 ER PT J AU Zisook, S Iglewicz, A Avanzino, J Maglione, J Glorioso, D Zetumer, S Seay, K Vahia, I Young, I Lebowitz, B Pies, R Reynolds, C Simon, N Shear, MK AF Zisook, Sidney Iglewicz, Alana Avanzino, Julie Maglione, Jeanne Glorioso, Danielle Zetumer, Samuel Seay, Kathryn Vahia, Ipsit Young, Ilanit Lebowitz, Barry Pies, Ronald Reynolds, Charles Simon, Naomi Shear, M. Katherine TI Bereavement: Course, Consequences, and Care SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Bereavement; Grief; Mourning; Complicated grief; Persistent complex bereavement disorder; Major depressive disorder; Major depressive episode; Post-traumatic stress disorder ID COMPLICATED GRIEF; ANXIETY DISORDERS; MAJOR DEPRESSION; RISK-FACTORS; CONJUGAL BEREAVEMENT; COMMUNITY SAMPLE; DIURNAL CORTISOL; NATIONAL SAMPLE; PHYSICAL HEALTH; YOUNG-ADULTS AB This paper discusses each of several potential consequences of bereavement. First, we describe ordinary grief, followed by a discussion of grief gone awry, or complicated grief (CG). Then, we cover other potential adverse outcomes of bereavement, each of which may contribute to, but are not identical with, CG: general medical comorbidity, mood disorders, post-traumatic stress disorder, anxiety, and substance use. C1 [Zisook, Sidney; Iglewicz, Alana; Maglione, Jeanne; Seay, Kathryn; Young, Ilanit; Lebowitz, Barry] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92161 USA. [Zisook, Sidney; Iglewicz, Alana; Avanzino, Julie; Maglione, Jeanne; Zetumer, Samuel; Young, Ilanit] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Zisook, Sidney; Iglewicz, Alana; Avanzino, Julie; Maglione, Jeanne; Zetumer, Samuel; Young, Ilanit] Vet Med & Res Fdn, La Jolla, CA USA. [Glorioso, Danielle; Vahia, Ipsit] Univ Calif San Diego, Ctr Hlth Aging, La Jolla, CA 92161 USA. [Seay, Kathryn] Univ Calif & San Diego State Joint Doctoral Progr, La Jolla, CA USA. [Seay, Kathryn] Vet Med Educ & Res Fdn, La Jolla, CA USA. [Lebowitz, Barry] Columbia Univ, Dept Biostat & Psychiat, New York, NY USA. [Pies, Ronald] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Pies, Ronald] Tufts Univ, Sch Med, Dept Psychiat, Boston, MA 02111 USA. [Reynolds, Charles] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Reynolds, Charles] Univ Pittsburgh, Western Psychiat Inst & Clin, Grad Sch Publ Hlth, Dept Community & Behav Hlth Sci, Pittsburgh, PA 15213 USA. [Simon, Naomi] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi] Massachusetts Gen Hosp, Complicated Grief Program, Boston, MA 02114 USA. [Shear, M. Katherine] Columbia Univ, Sch Social Work, Complicated Grief Treatment Res Program, New York, NY USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Zisook, S (reprint author), Univ Calif San Diego, Dept Psychiat, 3350 La Jolla Village Dr, La Jolla, CA 92161 USA. EM szisook@ucsd.edu FU Majda Foundation; John A. Hartford Foundation; Bristol-Myers Squibb; Forest; Pfizer; Lilly; National Institute of Mental Health; National Institute on Aging; National Center for Minority Health Disparities; National Heart Lung and Blood Institute; Center for Medicare and Medicaid Services (CMS); Patient Centered Outcomes Research Institute (PCORI); Commonwealth of Pennsylvania; National Palliative Care Research Center (NPCRC); Clinical and Translational Science Institute (CTSI); American Foundation for Suicide Prevention; National Institutes of Health [P60 MD000207, P30 MH090333, UL1RR024153, UL1TR000005]; UPMC Endowment in Geriatric Psychiatry; Highland Street Foundation; NIMH; American Foundation for Suicide Prevention (AFSP); DOD; MGH Psychiatry Academy; NIMH [MH60783, MH70741]; NIH; [NIMH-5R01MH085297]; [AFSP-LSRG-S-172-12] FX Sidney Zisook has received the following grants: NIMH-5R01MH085297, AFSP-LSRG-S-172-12, and a grant from The Majda Foundation.; Alana Iglewicz received an unrestricted travel grant from John A. Hartford Foundation.; Charles Reynolds reports receiving pharmaceutical support for NIH-sponsored research studies from Bristol-Myers Squibb, Forest, Pfizer, and Lilly; receiving grants from the National Institute of Mental Health, National Institute on Aging, National Center for Minority Health Disparities, National Heart Lung and Blood Institute, Center for Medicare and Medicaid Services (CMS), Patient Centered Outcomes Research Institute (PCORI), the Commonwealth of Pennsylvania, the John A Hartford Foundation, National Palliative Care Research Center (NPCRC), Clinical and Translational Science Institute (CTSI), and the American Foundation for Suicide Prevention; and serving on the American Association for Geriatric Psychiatry editorial review board. He has received an honorarium as a speaker from MedScape/WEB MD. He is the co-inventor (Licensed Intellectual Property) of Psychometric analysis of the Pittsburgh Sleep Quality Index (PSQI) PRO10050447 (PI: Buysse). Supported by the National Institutes of Health through Grant Numbers P60 MD000207; P30 MH090333; UL1RR024153, UL1TR000005; and the UPMC Endowment in Geriatric Psychiatry; Naomi Simon has received grants from the Highland Street Foundation, NIMH, American Foundation for Suicide Prevention (AFSP) and DOD. She has received honoraria/consultation fees from the MGH Psychiatry Academy.; M. Katherine Shear has received the following grants: NIMH (MH60783 and MH70741) and AFSP. NR 109 TC 7 Z9 7 U1 9 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2014 VL 16 IS 10 AR 482 DI 10.1007/s11920-014-0482-8 PG 10 WC Psychiatry SC Psychiatry GA AP1KG UT WOS:000341827500010 PM 25135781 ER PT J AU Kelley, MJ Shi, JX Ballew, B Hyland, PL Li, WQ Rotunno, M Alcorta, DA Liebsch, NJ Mitchell, J Bass, S Roberson, D Boland, J Cullen, M He, J Burdette, L Yeager, M Chanock, SJ Parry, DM Goldstein, AM Yang, XHR AF Kelley, Michael J. Shi, Jianxin Ballew, Bari Hyland, Paula L. Li, Wen-Qing Rotunno, Melissa Alcorta, David A. Liebsch, Norbert J. Mitchell, Jason Bass, Sara Roberson, David Boland, Joseph Cullen, Michael He, Ji Burdette, Laurie Yeager, Meredith Chanock, Stephen J. Parry, Dilys M. Goldstein, Alisa M. Yang, Xiaohong R. TI Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma SO HUMAN GENETICS LA English DT Article ID TRANSCRIPTION FACTOR; BRACHYURY; PROTEIN; POPULATION; SURVIVAL; COMPLEX AB Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95 % CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95 % CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T. C1 [Kelley, Michael J.; Alcorta, David A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27705 USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Durham, NC 27705 USA. [Shi, Jianxin; Ballew, Bari; Hyland, Paula L.; Li, Wen-Qing; Rotunno, Melissa; Mitchell, Jason; Bass, Sara; Roberson, David; Boland, Joseph; Cullen, Michael; He, Ji; Burdette, Laurie; Yeager, Meredith; Chanock, Stephen J.; Parry, Dilys M.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Liebsch, Norbert J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Mitchell, Jason; Bass, Sara; Roberson, David; Boland, Joseph; Cullen, Michael; He, Ji; Burdette, Laurie; Yeager, Meredith] SAIC Frederick Inc, Canc Genom Res Lab, Bethesda, MD 20892 USA. RP Yang, XHR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM royang@mail.nih.gov RI Li, Wenqing/N-2293-2014 OI Li, Wenqing/0000-0002-1283-4091 FU National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program; Chordoma Foundation FX We thank Deborah Zametkin for her outstanding skills as a research nurse; Drs. Gladys M. Glenn and Mary L. McMaster for their careful clinical evaluations of patients and family members; Dr. Nicholas J. Patronas for reviewing the MR images; Cancer Genomics Research Laboratory for sequencing and bioinformatic analyses; and, especially, the patients and their families for their participation. This work was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program, and a grant from the Chordoma Foundation (M.J.K.). NR 21 TC 10 Z9 10 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD OCT PY 2014 VL 133 IS 10 BP 1289 EP 1297 DI 10.1007/s00439-014-1463-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AP1KP UT WOS:000341828900006 PM 24990759 ER PT J AU Bailey, JNC Yaspan, BL Pasquale, LR Hauser, MA Kang, JH Loomis, SJ Brilliant, M Budenz, DL Christen, WG Fingert, J Gaasterland, D Gaasterland, T Kraft, P Lee, RK Lichter, PR Liu, YT McCarty, CA Moroi, SE Richards, JE Realini, T Schuman, JS Scott, WK Singh, K Sit, AJ Vollrath, D Wollstein, G Zack, DJ Zhang, K Pericak-Vance, MA Allingham, RR Weinreb, RN Haines, JL Wiggs, JL AF Bailey, Jessica N. Cooke Yaspan, Brian L. Pasquale, Louis R. Hauser, Michael A. Kang, Jae H. Loomis, Stephanie J. Brilliant, Murray Budenz, Donald L. Christen, William G. Fingert, John Gaasterland, Douglas Gaasterland, Terry Kraft, Peter Lee, Richard K. Lichter, Paul R. Liu, Yutao McCarty, Catherine A. Moroi, Sayoko E. Richards, Julia E. Realini, Tony Schuman, Joel S. Scott, William K. Singh, Kuldev Sit, Arthur J. Vollrath, Douglas Wollstein, Gadi Zack, Donald J. Zhang, Kang Pericak-Vance, Margaret A. Allingham, R. Rand Weinreb, Robert N. Haines, Jonathan L. Wiggs, Janey L. TI Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; OXIDATIVE STRESS; COMMON VARIANTS; VIGABATRIN; THERAPY; GENES; SUSCEPTIBILITY; MUTATIONS; RATIONALE; PATTERNS AB Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets. C1 [Bailey, Jessica N. Cooke; Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Pasquale, Louis R.; Loomis, Stephanie J.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02138 USA. [Pasquale, Louis R.; Kang, Jae H.; Loomis, Stephanie J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Hauser, Michael A.; Liu, Yutao; Allingham, R. Rand] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.; Liu, Yutao] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Brilliant, Murray] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Budenz, Donald L.] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. [Christen, William G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Ophthalmol, Iowa City, IA 52242 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Anat Cell Biol, Iowa City, IA USA. [Gaasterland, Douglas] Eye Doctors Washington, Chevy Chase, MD USA. [Gaasterland, Terry] Univ Calif San Diego, Scripps Genome Ctr, San Diego, CA 92103 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lee, Richard K.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Lichter, Paul R.; Moroi, Sayoko E.; Richards, Julia E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Realini, Tony] WVU Eye Inst, Dept Ophthalmol, Morgantown, WV USA. [Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Dept Ophthalmol, UPMC Eye Ctr, Pittsburgh, PA 15260 USA. [Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Inst Human Genom, Miami, FL 33136 USA. [Singh, Kuldev] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Sit, Arthur J.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Vollrath, Douglas] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Zack, Donald J.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Zhang, Kang; Weinreb, Robert N.] Univ Calif San Diego, Hamilton Eye Ctr, Dept Ophthalmol, San Diego, CA 92103 USA. RP Wiggs, JL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02138 USA. EM janey_wiggs@meei.harvard.edu OI Zack, Don/0000-0002-7966-1973 FU Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA); Research to Prevent Blindness, Inc. (New York, NY); Arthur Ashley Foundation; Glaucoma Research Foundation (San Francisco, CA); American Health Assistance Foundation (Clarksburg, MD); Glaucoma Foundation (New York, NY); National Human Genome Research Institute (Bethesda, MD) [GLAUGEN: HG004728, HG004424, HG004446]; National Eye Institute [HG005259-01]; National Institutes of Health [HHSN268200782096C]; National Eye Institute (Bethesda, MD) through ARA [EY015872, EY019126]; National Institutes of Health (Bethesda, MD) [EY015872, EY015543, EY006827, HL073389, EY13315, EY09611, EY009149, HG004608, EY008208, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, EY010886, EY009847, EY011008, EY144428, EY144448, EY18660]; NIH [T32EY021453] FX The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA) support LRP and JLW. LRP, JER and JLW are also supported by Research to Prevent Blindness, Inc. (New York, NY). The Arthur Ashley Foundation also supports Dr. Pasquale. The Glaucoma Research Foundation (San Francisco, CA), American Health Assistance Foundation (Clarksburg, MD), and the Glaucoma Foundation (New York, NY) support YL. The following National Institutes of Health Grants support the maintenance of the Nurses Health Study and Health Professionals Follow-up, allowing these health professionals to contribute to this analysis: CA87969, CA49449, UM1 CA167552, and HL35464. The following Grants from the National Human Genome Research Institute (Bethesda, MD) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), HG004446 (C. Laurie, U. Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through Grant HG005259-01 (JLW). In addition, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The National Eye Institute (Bethesda, MD) through ARA Grants EY015872 (JLW) and EY019126 (MAH) supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, MD) Grants: EY015543 (RRA), EY006827 (DG), HL073389 (Hauser, E), EY13315 (MAH), EY09611 (Hankinson, S), EY015473 (LRP), EY009149 (PRL), HG004608 (CAM), EY008208 (Medeiros, P.), EY015473 (LRP), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY013178 (JSS), EY015872 (JLW), EY010886 (JLW), EY009847 (JLW), EY011008 (Zangwill, L), EY144428 (KZ), EY144448 (KZ), EY18660 (KZ). None of the authors have any commercial interests in the subject of the manuscript or in entities discussed in the manuscript. BL Yaspan and JN Cooke Bailey were supported in part by NIH Grant T32EY021453. NR 47 TC 6 Z9 6 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD OCT PY 2014 VL 133 IS 10 BP 1319 EP 1330 DI 10.1007/s00439-014-1468-7 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AP1KP UT WOS:000341828900009 PM 25037249 ER PT J AU Morasco, BJ Lovejoy, TI Turk, DC Crain, A Hauser, P Dobscha, SK AF Morasco, Benjamin J. Lovejoy, Travis I. Turk, Dennis C. Crain, Aysha Hauser, Peter Dobscha, Steven K. TI Biopsychosocial factors associated with pain in veterans with the hepatitis C virus SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Chronic pain; Biopsychosocial model; Hepatitis C ID UNITED-STATES; PSYCHOSOCIAL FACTORS; RISK-FACTORS; PREVALENCE; INFECTION; VALIDATION; FIBROMYALGIA; POPULATION; FIBROSIS; INTERFERENCE AB Little research has examined etiological factors associated with pain in patients with the hepatitis C virus (HCV). The purpose of this study was to evaluate the relationship between biopsychosocial factors and pain among patients with HCV. Patients with HCV and pain (n = 119) completed self-report measures of pain, mental health functioning, pain-specific psychosocial variables (pain catastrophizing, self-efficacy for managing pain, social support), prescription opioid use, and demographic characteristics. In multivariate models, biopsychosocial factors accounted for 37 % of the variance in pain severity and 56 % of the variance in pain interference. In adjusted models, factors associated with pain severity include pain catastrophizing and social support, whereas variables associated with pain interference were age, pain intensity, prescription opioid use, and chronic pain self-efficacy (all p values < 0.05). The results provide empirical support for incorporating the biopsychosocial model in evaluating and treating chronic pain in patients with HCV. C1 [Morasco, Benjamin J.; Lovejoy, Travis I.; Crain, Aysha; Dobscha, Steven K.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, R&D99, Portland, OR 97239 USA. [Morasco, Benjamin J.; Lovejoy, Travis I.; Dobscha, Steven K.] Portland VA Med Ctr, Ctr Study Chron Comorbid Med & Psychiat Disorders, Portland, OR 97239 USA. [Morasco, Benjamin J.; Lovejoy, Travis I.; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Turk, Dennis C.] Univ Washington, Ctr Pain Res Impact Measurement & Effectiveness, Seattle, WA 98195 USA. [Hauser, Peter] VISN 22 Network Off, Long Beach, CA USA. [Hauser, Peter] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, R&D99, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU NIDA NIH HHS [K23DA023467, R01 DA034083, K23 DA023467] NR 57 TC 3 Z9 3 U1 1 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD OCT PY 2014 VL 37 IS 5 BP 902 EP 911 DI 10.1007/s10865-013-9549-y PG 10 WC Psychology, Clinical SC Psychology GA AP1LB UT WOS:000341830300009 PM 24338521 ER PT J AU Zhao, YL Cudkowicz, ME Shefner, JM Krivickas, L David, WS Vriesendorp, F Pestronk, A Caress, JB Katz, J Simpson, E Rosenfeld, J Pascuzzi, R Glass, J Rezania, K Harmatz, JS Schoenfeld, D Greenblatt, DJ AF Zhao, Yanli Cudkowicz, Merit E. Shefner, Jeremy M. Krivickas, Lisa David, William S. Vriesendorp, Francine Pestronk, Alan Caress, James B. Katz, Jonathan Simpson, Ericka Rosenfeld, Jeffrey Pascuzzi, Robert Glass, Jonathan Rezania, Kourosh Harmatz, Jerold S. Schoenfeld, David Greenblatt, David J. TI Systemic Pharmacokinetics and Cerebrospinal Fluid Uptake of Intravenous Ceftriaxone in Patients With Amyotrophic Lateral Sclerosis SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE amyotrophic lateral sclerosis; ceftriaxone; plasma pharmacokinetics; cerebrospinal fluid uptake; HPLC micromethod ID BETA-LACTAM ANTIBIOTICS; PLASMA-PROTEIN BINDING; CEPHALOSPORINS; DIFFUSION; KINETICS; CHILDREN; ALS; PHARMACODYNAMICS; MENINGITIS; STROKE AB The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25minutes) every 12hours of either: placebo and placebo; 2g ceftriaxone and placebo; or 2g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14L (0.17L/kg); elimination half-life, 8-9h; total clearance, 17-21mL/min (0.22-0.25mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 mu M (0.55 mu g/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS. C1 [Zhao, Yanli; Harmatz, Jerold S.; Greenblatt, David J.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Cudkowicz, Merit E.; Krivickas, Lisa; David, William S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol Clin Res Inst, Boston, MA USA. [Shefner, Jeremy M.; Vriesendorp, Francine] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Pestronk, Alan] Washington Univ, Dept Neurol, St Louis, MO USA. [Caress, James B.] Wake Forest Univ, Dept Neurol, Winston Salem, NC 27109 USA. [Katz, Jonathan] Calif Pacific Med Ctr, Dept Neurol, San Francisco, CA USA. [Simpson, Ericka] Methodist Neurol Inst, Dept Neurol, Houston, TX USA. [Rosenfeld, Jeffrey] Univ Calif San Francisco Fresno, Dept Neurol, Neurosci Inst, Fresno, CA USA. [Pascuzzi, Robert] Indiana Univ, Dept Neurol, Indianapolis, IN 46204 USA. [Glass, Jonathan] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Rezania, Kourosh] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Greenblatt, DJ (reprint author), Tufts Univ, Sch Med, 136 Harrison Ave, Boston, MA 02111 USA. EM dj.greenblatt@tufts.edu OI Caress, James/0000-0002-5814-6083 FU National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health [U01 NS049640-05]; Institute of Clinical and Translational Sciences [UL1 TR000448] FX This research was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (U01 NS049640-05), and from the Institute of Clinical and Translational Sciences (UL1 TR000448). NR 33 TC 2 Z9 2 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2014 VL 54 IS 10 BP 1180 EP 1187 DI 10.1002/jcph.317 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP1EG UT WOS:000341808800012 PM 24771634 ER PT J AU Freeman, MP Cohen, LS McInerney, K AF Freeman, Marlene P. Cohen, Lee S. McInerney, Kathryn TI Omega-3 Fatty Acids and Gestational Length in a High-Risk Psychiatric Population Due to Psychiatric Morbidity and Medication Exposure During Pregnancy SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE pregnancy; depression; omega-3; antidepressant; antipsychotic; gestational length ID POLYUNSATURATED FATTY-ACIDS; RANDOMIZED-CONTROLLED-TRIAL; FISH-OIL SUPPLEMENTATION; SEROTONIN REUPTAKE INHIBITORS; PRETERM BIRTH; PROSPECTIVE COHORT; ERYTHROCYTE OMEGA-3; GROWTH MEASURES; FETAL-GROWTH; WOMEN AB Objective: Premature birth is associated with infant morbidity and mortality. Women with psychiatric disorders represent an at-risk population for premature delivery and other obstetrical complications. The primary aim of this study was to assess the association between omega-3 fatty acid use and length of gestation. Methods: Data from the National Pregnancy Registry for Atypical Antipsychotics were used. This prospective study included pregnant women exposed and unexposed to atypical antipsychotics during pregnancy. The outcomes of gestational length, birth weight, and preeclampsia were examined in relation to omega-3 use during pregnancy. Omega-3 use was operationalized from a first-trimester interview as a dichotomous variable. Results: Of 361 women who were examined for eligibility, 233 women had a singleton birth as well as a valid response on the omega-3 item and information on at least one of the outcome measures. Ninety-seven (41.6%) women used omega-3 during pregnancy. Omega-3 users were older, more educated, and more likely to be married than nonusers. The users were less likely to have smoked during their first trimester and were marginally less likely to use antidepressant medications anytime during pregnancy. There were no significant differences in primary diagnoses or atypical antipsychotic, alcohol, or prenatal vitamin use. In an un-adjusted model, there was a significant increase of between 4 and 5 days (0.65 weeks; 0.00-1.25) in gestational length among the omega-3 users. This result was no longer significant after adjusting for confounding variables, with an increase of approximately 4 days (0.53 weeks; -0.11 to 1.16). Omega-3 use was not significantly associated with a difference in birth weight or preeclampsia. Conclusions: We found a trend for a modestly increased length of gestation among the omega-3 fatty acid users, although these were not significant after controlling for the exposures of smoking and antidepressant use. We did not find a decreased risk for preeclampsia among the users of omega-3 fatty acids or increased birth weight. In consideration of the risk factors for obstetrical and neonatal complications as well as implications for infant and child development, it would be clinically important to understand the variables that may additively decrease obstetrical risks in this population. C1 [Freeman, Marlene P.; Cohen, Lee S.] Harvard Univ, Sch Med, Boston, MA USA. [McInerney, Kathryn] Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Freeman, MP (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM mfreeman@partners.org FU Lilly; GlaxoSmithKline; Bayer; Bristol-Myers Squibb; Cephalon; Forest; National Institute on Aging; National Institute of Mental Health; Ortho-McNeil-Janssen Pharmaceuticals; Pfizer; Sunovion; National Institutes of Health FX Marlene P. Freeman JDS therapeutics (consulting); received support from Lilly and GlaxoSmithKline (grant); Lundbeck, Takeda, Otsuka, Genentech, as well as Johnson & Johnson (advisory boards); and DSM Nutritionals (medical editing).; Lee S. Cohen received support from GlaxoSmithKline (research); Lilly, Noven, and PamLab (consultant); and Bayer, Bristol-Myers Squibb, Cephalon, Forest, National Institute on Aging, National Institute of Mental Health, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, Sunovion, as well as National Institutes of Health (grants). NR 58 TC 0 Z9 0 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2014 VL 34 IS 5 BP 627 EP 632 DI 10.1097/JCP.0000000000000168 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA AP1EO UT WOS:000341809700017 PM 25006815 ER PT J AU Chou, SH Mantzoros, C AF Chou, Sharon H. Mantzoros, Christos TI Role of leptin in human reproductive disorders SO JOURNAL OF ENDOCRINOLOGY LA English DT Review DE leptin; metabolism; reproduction; neuroendocrinology ID POLYCYSTIC-OVARY-SYNDROME; FUNCTIONAL HYPOTHALAMIC AMENORRHEA; INDUCED LUTEINIZING-HORMONE; BODY-MASS INDEX; ENDOCRINE-METABOLIC ABERRATIONS; ACTIVE ANTIRETROVIRAL THERAPY; PRIMED OVARIECTOMIZED RATS; LEAN HYPOLEPTINEMIC WOMEN; RECOMBINANT HUMAN LEPTIN; NEUROPEPTIDE-Y AB Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin. C1 [Chou, Sharon H.] Univ Chicago, Sect Adult & Pediat Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Mantzoros, Christos] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. RP Mantzoros, C (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, 330 Brookline Ave,FD-876, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu NR 152 TC 19 Z9 19 U1 1 U2 19 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD OCT PY 2014 VL 223 IS 1 BP T49 EP T62 DI 10.1530/JOE-14-0245 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP2CY UT WOS:000341881300006 PM 25056118 ER PT J AU Goodman, M Carpenter, D Tang, CY Goldstein, KE Avedon, J Fernandez, N Mascitelli, KA Blair, NJ New, AS Triebwasser, J Siever, LJ Hazlett, EA AF Goodman, Marianne Carpenter, David Tang, Cheuk Y. Goldstein, Kim E. Avedon, Jennifer Fernandez, Nicolas Mascitelli, Kathryn A. Blair, Nicholas J. New, Antonia S. Triebwasser, Joseph Siever, Larry J. Hazlett, Erin A. TI Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI ID POSTTRAUMATIC-STRESS-DISORDER; AFFECTIVE INSTABILITY; FEMALE-PATIENTS; FUNCTIONAL MRI; FMRI; DEPRESSION; WOMEN; DYSREGULATION; METAANALYSIS; VALIDATION AB Objective: Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (Al) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of Al in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets Al by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. Methods: Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measufed with the Difficulty in Emotion Regulation (DERS) scale. Results: fMRI results showed the predicted Group x Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale). Conclusion: These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation. Published by Elsevier Ltd. C1 [Goodman, Marianne; Goldstein, Kim E.; New, Antonia S.; Triebwasser, Joseph; Siever, Larry J.; Hazlett, Erin A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Goodman, Marianne; Avedon, Jennifer; Fernandez, Nicolas; Mascitelli, Kathryn A.; Blair, Nicholas J.; New, Antonia S.; Siever, Larry J.; Hazlett, Erin A.] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr MIRECC 3, Bronx, NY USA. [Carpenter, David; Tang, Cheuk Y.] Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA. [Goodman, Marianne; Triebwasser, Joseph; Siever, Larry J.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Goodman, M (reprint author), James J Peters VA Med Ctr, MIRECC, Room 6A-44, Bronx, NY 10468 USA. EM marianne.goodman@va.gov FU Veterans' Administration Advanced Career Development Award [3277-06-109]; NIMH [R01-MH073911]; National Center for Advancing Translational Sciences, a component of the National Institutes of Health [UL1TR000067] FX This research was supported by a Veterans' Administration Advanced Career Development Award (3277-06-109) to MG, NIMH Grant R01-MH073911 to EAH, Grant UL1TR000067 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health, and additional resources from the Mount Sinai GCRC, VISN 3 Mental Illness Research, Education and Clinical Center (MIRECC), James J. Peters Research Foundation. NR 71 TC 25 Z9 26 U1 6 U2 45 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2014 VL 57 BP 108 EP 116 DI 10.1016/j.jpsychires.2014.06.020 PG 9 WC Psychiatry SC Psychiatry GA AO7RK UT WOS:000341550100014 PM 25038629 ER PT J AU Greenberg, JL Reuman, L Hartmann, AS Kasarskis, I Wilhelm, S AF Greenberg, Jennifer L. Reuman, Lillian Hartmann, Andrea S. Kasarskis, Irina Wilhelm, Sabine TI Visual hot spots: An eye tracking study of attention bias in body dysmorphic disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Body dysmorphic disorder; BDD; Eye tracking; Attention bias; Obsessive-compulsive spectrum ID OBSESSIVE-COMPULSIVE DISORDER; POPULATION-BASED SURVEY; PREVALENCE; SCALE; PHENOMENOLOGY; RELIABILITY; VALIDITY; THERAPY; AGE AB Attentional biases have been implicated in the development and maintenance of BDD. In particular, a visual attention bias toward one's unattractive features and others' attractive features (negative bias), might underlie BDD symptoms. Healthy individuals typically pay more attention to others' unattractive and their own attractive features (positive bias). This study used eye tracking to examine visual attention in individuals with BDD relative to healthy controls (HC). We also explored the role of avoidance in attention bias. Participants with BDD and primary face/head concerns (n = 19) and HC (n = 20) completed computerized tasks and questionnaires. Eye movement data (i.e., fixations, dwell time) were recorded while participants viewed images of their own and a control face (selected for average attractiveness and neutral expression). Participants rated distress and perceived most and least attractive features of their own and another face. BDD participants demonstrated a negative mean total bias score compared to HC (fixation: p = 0.24; dwell: p = 0.08). Age (fixation: p = 0.006; dwell: p = 0.03) and gender (fixation: p = 0.03; dwell: p = 0.03) moderated the relationship. Avoidance was associated with a positive bias in BDD. Results suggest individuals with BOO overfocus on negative attributes, a potential factor in the disorder's etiology and maintenance. Conversely, HC had a more balanced focus on their traits. Elucidating the role of attention bias could help to identify risk and maintenance factors in BDD. (C) 2014 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Greenberg, JL (reprint author), Massachusetts Gen Hosp, Simches Res Bldg,185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM jlgreenberg@mgh.harvard.edu FU International Obsessive Compulsive Disorder Foundation FX This research was supported in part by a grant from the International Obsessive Compulsive Disorder Foundation awarded to Dr. Greenberg. NR 36 TC 6 Z9 6 U1 2 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2014 VL 57 BP 125 EP 132 DI 10.1016/j.jpsychires.2014.06.015 PG 8 WC Psychiatry SC Psychiatry GA AO7RK UT WOS:000341550100016 PM 25005739 ER PT J AU Heidenreich, PA Zhao, X Hernandez, AF Yancy, CW Schwamm, LH Albert, NM Fonarow, GC AF Heidenreich, Paul A. Zhao, Xin Hernandez, Adrian F. Yancy, Clyde W. Schwamm, Lee H. Albert, Nancy M. Fonarow, Gregg C. TI Impact of an Expanded Hospital Recognition Program for Heart Failure Quality of Care SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE awards; healthcare quality assessment; healthcare quality indicators; heart failure ID ACUTE MYOCARDIAL-INFARCTION; NEW-YORK-STATE; GUIDELINES PROGRAM; CARDIAC-SURGERY; MORTALITY; HAD AB Background-In 2009, the Get With The Guidelines-Heart Failure program enhanced the standard recognition of hospitals by offering additional recognition if hospitals performed well on certain quality measures. We sought to determine whether initiation of this enhanced recognition opportunity led to acceleration in quality of care for all hospitals participating in the program. Methods and Results-We examined hospital-level performance on 9 quality-of-care (process) measures that were added to an existing recognition program (based on existing published performance measures). The rate of increase in use over time 6 months to 2 years after the start of the program was compared with the rate of increase in use for the measures during the 18-month period prior to the start of the program. Use increased for all 9 new quality measures from 2008 to 2011. Among 4 measures with baseline use near or lower than 50%, a statistically significant greater increase in use during the program was seen for implantable cardioverter defibrillator use (program versus preprogram use: odds ratio 1.14, 95% CI 1.06 to 1.23). Among the 5 measures for which baseline use was 50% or higher, the increase in influenza vaccination rates actually slowed. There was no evidence of adverse impact on the 4 established quality measures, a composite of which actually increased faster during the expanded program (adjusted odds ratio 1.08, 95% CI 1.01 to 1.15). Conclusions-A program providing expanded hospital recognition for heart failure had mixed results in accelerating the use of 9 quality measures. C1 [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Zhao, Xin; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Yancy, Clyde W.] Northwestern Univ, NW Mem Hosp, Bluhm Cardiovasc Inst, Chicago, IL 60611 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Albert, Nancy M.] Cleveland Clin, Cleveland, OH 44106 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Heidenreich, PA (reprint author), 111C Cardiol,3801 Miranda Ave, Palo Alto, CA 94306 USA. EM paul.heidenreich@va.gov FU Medtronic; GlaxoSmithKline; Ortho-McNeil; American Heart Association Pharmaceutical Roundtable; Veteran Administration's Quality Enhancement and Research Initiative [04-326] FX The Get With The Guidelines-Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. Dr Heidenreich is supported by a grant from the Veteran Administration's Quality Enhancement and Research Initiative 04-326. NR 12 TC 2 Z9 2 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 OCT PY 2014 VL 3 IS 5 AR e000950 DI 10.1161/JAHA.114.000950 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200005 PM 25208954 ER PT J AU Ho, JE Arora, P Walford, GA Ghorbani, A Guanaga, DP Dhakal, BP Nathan, DI Buys, ES Florez, JC Newton-Cheh, C Lewis, GD Wang, TJ AF Ho, Jennifer E. Arora, Pankaj Walford, Geoffrey A. Ghorbani, Anahita Guanaga, Derek P. Dhakal, Bishnu P. Nathan, Daniel I. Buys, Emmanuel S. Florez, Jose C. Newton-Cheh, Christopher Lewis, Gregory D. Wang, Thomas J. TI Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cGMP; insulin resistance; obesity; phosphodiesterase type 5 inhibition ID BETA-CELL FUNCTION; NITRIC-OXIDE SYNTHASE; SKELETAL-MUSCLE; AMBULATORY INDIVIDUALS; NATRIURETIC PEPTIDES; PLASMA-GLUCOSE; SENSITIVITY; RISK; HYPERTENSION; ASSOCIATION AB Background-Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase-5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results-We conducted a randomized, double-blinded, placebo-controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (>= 10 mu U/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m(2)) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI >= 36.2 kg/m(2)), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P = 0.02, respectively). Furthermore, one measure of beta-cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P = 0.009) and in the subgroup with severe obesity (P = 0.01). Conclusion-Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on beta-cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. C1 [Ho, Jennifer E.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Arora, Pankaj] Univ Alabama Birmingham, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Dhakal, Bishnu P.; Newton-Cheh, Christopher; Lewis, Gregory D.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Nathan, Daniel I.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ghorbani, Anahita] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Guanaga, Derek P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Cambridge, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. RP Ho, JE (reprint author), Boston Univ, Med Ctr, 88 East Newton St,C-818, Boston, MA 02118 USA. EM Jennifer.Ho@bmc.org OI Ho, Jennifer/0000-0002-7987-4768; Arora, Pankaj/0000-0003-2420-3550 FU National Institutes of Health [K23-HL116780, R01-HL098283, R01-HL113933, R01-HL086875]; American Heart Association [10SDG2610313]; Boston University School of Medicine Department of Medicine Career Investment Award; Massachusetts General Hospital Research Scholars Award FX This study was supported, in part, by the National Institutes of Health (K23-HL116780 to Dr Ho; R01-HL098283 and R01-HL113933 to Dr Newton-Cheh; and R01-HL086875 to Dr Wang), the American Heart Association (10SDG2610313 to Dr Buys), a Boston University School of Medicine Department of Medicine Career Investment Award to Dr Ho, and a Massachusetts General Hospital Research Scholars Award to Dr Florez. NR 28 TC 4 Z9 4 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 OCT PY 2014 VL 3 IS 5 AR e001001 DI 10.1161/JAHA.114.001001 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200008 PM 25213566 ER PT J AU Sayadi, O Puppala, D Ishaque, N Doddamani, R Merchant, FM Barrett, C Singh, JP Heist, EK Mela, T Martinez, JP Laguna, P Armoundas, AA AF Sayadi, Omid Puppala, Dheeraj Ishaque, Nosheen Doddamani, Rajiv Merchant, Faisal M. Barrett, Conor Singh, Jagmeet P. Heist, E. Kevin Mela, Theofanie Pablo Martinez, Juan Laguna, Pablo Armoundas, Antonis A. TI A Novel Method to Capture the Onset of Dynamic Electrocardiographic Ischemic Changes and its Implications to Arrhythmia Susceptibility SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE ECG delineation; intracardiac signals; ischemic index; myocardial infarction; wavelet transform ID ACUTE MYOCARDIAL-ISCHEMIA; CORONARY-ARTERY OCCLUSION; FREQUENCY QRS COMPONENTS; SUB-ENDOCARDIAL ISCHEMIA; ST-SEGMENT DEVIATION; QT INTERVAL; INFARCTION; STANDARD; ECG; LEAD AB Background-This study investigates the hypothesis that morphologic analysis of intracardiac electrograms provides a sensitive approach to detect acute myocardial infarction or myocardial infarction-induced arrhythmia susceptibility. Large proportions of irreversible myocardial injury and fatal ventricular tachyarrhythmias occur in the first hour after coronary occlusion; therefore, early detection of acute myocardial infarction may improve clinical outcomes. Methods and Results-We developed a method that uses the wavelet transform to delineate electrocardiographic signals, and we have devised an index to quantify the ischemia-induced changes in these signals. We recorded body-surface and intracardiac electrograms at baseline and following myocardial infarction in 24 swine. Statistically significant ischemia-induced changes after the initiation of occlusion compared with baseline were detectable within 30 seconds in intracardiac left ventricle (P<0.0016) and right ventricle-coronary sinus (P<0.0011) leads, 60 seconds in coronary sinus leads (P<0.0002), 90 seconds in right ventricle leads (P<0.0020), and 360 seconds in body-surface electrocardiographic signals (P<0.0022). Intracardiac leads exhibited a higher probability of detecting ischemia-induced changes than body-surface leads (P<0.0381), and the right ventricle-coronary sinus configuration provided the highest sensitivity (96%). The 24-hour ECG recordings showed that the ischemic index is statistically significantly increased compared with baseline in lead I, aVR, and all precordial leads (P<0.0388). Finally, we showed that the ischemic index in intracardiac electrograms is significantly increased preceding ventricular tachyarrhythmic events (P<0.0360). Conclusions-We present a novel method that is capable of detecting ischemia-induced changes in intracardiac electrograms as early as 30 seconds following myocardial infarction or as early as 12 minutes preceding tachyarrhythmic events. C1 [Sayadi, Omid; Puppala, Dheeraj; Ishaque, Nosheen; Doddamani, Rajiv; Armoundas, Antonis A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Barrett, Conor; Singh, Jagmeet P.; Heist, E. Kevin; Mela, Theofanie] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Div Cardiol, Boston, MA 02114 USA. [Pablo Martinez, Juan; Laguna, Pablo] Univ Zaragoza, Biomed Signal Interpretat & Computat Simulat BSIC, Aragon Inst Engn Res, IIS Aragon, Zaragoza, Aragon, Spain. [Pablo Martinez, Juan; Laguna, Pablo] Ctr Invest Biomed Red Bioingn Biomat & Nanomed CI, Zaragoza, Aragon, Spain. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org RI Martinez, Juan Pablo/A-2759-2009; OI Martinez, Juan Pablo/0000-0002-7503-3339; laguna, Pablo/0000-0003-3434-9254 FU Scientist Development Grant [0635127N]; Founders Affiliate Postdoctoral Fellowship from the American Heart Association [12POST9310001]; Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology from the Heart Rhythm Society [13-FA-32-HRS]; NIH [1R21AG035128]; Center for Integration of Medicine and Innovative Technology (CIMIT); Spanish government (MINECO); European Union (FEDER) [TEC2010-21703-C03-02, TEC2013-42140-R]; European Social Fund; Aragon government under Grupo Consolidado BSICoS; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard University; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources) FX This work was supported by a Scientist Development Grant (0635127N), a Founders Affiliate Postdoctoral Fellowship (12POST9310001) from the American Heart Association, the Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology (13-FA-32-HRS) from the Heart Rhythm Society, and by NIH grant 1R21AG035128. This work was also supported by a Fellowship and a Science Award from the Center for Integration of Medicine and Innovative Technology (CIMIT), by the Spanish government (MINECO) and European Union (FEDER) under projects TEC2010-21703-C03-02 and TEC2013-42140-R and by the European Social Fund and the Aragon government under Grupo Consolidado BSICoS. This work 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 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). NR 33 TC 3 Z9 3 U1 1 U2 2 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 OCT PY 2014 VL 3 IS 5 AR e001055 DI 10.1161/JAHA.114.001055 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200013 PM 25187521 ER PT J AU Malkoski, SP Cleaver, TG Thompson, JJ Sutton, WP Haeger, SM Rodriguez, KJ Lu, SL Merrick, D Wang, XJ AF Malkoski, Stephen P. Cleaver, Timothy G. Thompson, Joshua J. Sutton, Whitney P. Haeger, Sarah M. Rodriguez, Karen J. Lu, Shi-Long Merrick, Daniel Wang, Xiao-Jing TI Role of PTEN in Basal Cell Derived Lung Carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE non-small cell lung cancer; adenocarcinoma; squamous cell carcinoma; Kras ID BRONCHIOALVEOLAR STEM-CELLS; TUMOR-SUPPRESSOR GENE; MOUSE MODEL; II RECEPTOR; CANCER; ADENOCARCINOMA; INACTIVATION; CARCINOMA; ORIGIN; MUTANT AB Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor receptor type II (TGFRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types. (c) 2013 Wiley Periodicals, Inc. C1 [Malkoski, Stephen P.; Cleaver, Timothy G.; Thompson, Joshua J.; Sutton, Whitney P.; Haeger, Sarah M.; Rodriguez, Karen J.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Malkoski, Stephen P.; Wang, Xiao-Jing] Univ Colorado Denver, Dept Pathol, Aurora, CO USA. [Lu, Shi-Long; Wang, Xiao-Jing] Univ Colorado Denver, Dept Otolaryngol, Aurora, CO USA. [Merrick, Daniel] Denver VA Med Ctr, Dept Pathol, Denver, CO USA. RP Malkoski, SP (reprint author), Div Pulm Sci & Crit Care Med, 12700 E 19th Ave,RC2,Room 9112,Mail Stop C272, Aurora, CO 80045 USA. FU American Cancer Society Institutional Research Grant Pilot Project [57-001-50]; National Lung Cancer Partnership; NIH [K08 CA131483 DE015953 P30CA046934] FX Grant sponsor: American Cancer Society Institutional Research Grant Pilot Project; Grant number: IRG #57-001-50; Grant sponsor: National Lung Cancer Partnership and the NIH; Grant number: K08 CA131483 DE015953 P30CA046934 NR 37 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2014 VL 53 IS 10 BP 841 EP 846 DI 10.1002/mc.22030 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AP4QI UT WOS:000342062600008 PM 23625632 ER PT J AU Ren, X Ott, HC AF Ren, X. Ott, H. C. TI On the road to bioartificial organs SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE Bioartificial organs; Decellularization; Bioprinting; Organoid; Tissue engineering; Organ engineering ID PLURIPOTENT STEM-CELLS; HUMAN LUNG; IN-VIVO; REGENERATIVE MEDICINE; ENDOTHELIAL-CELLS; SMALL-MOLECULE; BLOOD-VESSELS; ORTHOTOPIC TRANSPLANTATION; DIRECTED DIFFERENTIATION; PHENOTYPIC HETEROGENEITY AB Biological organs are highly orchestrated systems with well-coordinated positioning, grouping, and interaction of different cell types within their specialized extracellular environment. Bioartificial organs are intended to be functional replacements of native organs generated through bioengineering techniques and hold the potential to alleviate donor organ shortage for transplantation. The development, production, and evaluation of such bioartificial organs require synergistic efforts of biology, material science, engineering, and medicine. In this review, we highlight the emerging platforms enabling structured assembly of multiple cell types into functional grafts and discuss recent advances and challenges in the development of bioartificial organs, including cell sources, in vitro organ culture, in vivo evaluation, and clinical considerations. C1 [Ren, X.; Ott, H. C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Ren, X.; Ott, H. C.] Harvard Univ, Sch Med, Boston, MA USA. [Ott, H. C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Ott, H. C.] Harvard Stem Cell Inst, Boston, MA USA. RP Ott, HC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, 185 Cambridge St,CPZN 4800, Boston, MA 02114 USA. EM hott@mgh.harvard.edu NR 95 TC 3 Z9 3 U1 5 U2 68 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2014 VL 466 IS 10 BP 1847 EP 1857 DI 10.1007/s00424-014-1504-4 PG 11 WC Physiology SC Physiology GA AP2SH UT WOS:000341924500001 PM 24691559 ER PT J AU Zimmet, SE Min, RJ Comerota, AJ Meissner, MH Carman, TL Rathbun, SW Jaff, MR Wakefield, TW Feied, CF AF Zimmet, Steven E. Min, Robert J. Comerota, Anthony J. Meissner, Mark H. Carman, Teresa L. Rathbun, Suman W. Jaff, Michael R. Wakefield, Thomas W. Feied, Craig F. TI Core content for training in venous and lymphatic medicine SO PHLEBOLOGY LA English DT Article DE Curriculum; professional education; medical education; venous medicine; phlebology; lymphatic medicine; venous and lymphatic medicine training; fellowship training/standards; core content in venous and lymphatic medicine; specialization; clinical competence; certification AB The major venous societies in the United States share a common mission to improve the standards of medical practitioners, the educational goals for teaching and training programs in venous disease, and the quality of patient care related to the treatment of venous disorders. With these important goals in mind, a task force made up of experts from the specialties of dermatology, interventional radiology, phlebology, vascular medicine, and vascular surgery was formed to develop a consensus document describing the Core Content for venous and lymphatic medicine and to develop a core educational content outline for training. This outline describes the areas of knowledge considered essential for practice in the field, which encompasses the study, diagnosis, and treatment of patients with acute and chronic venous and lymphatic disorders. The American Venous Forum and the American College of Phlebology have endorsed the Core Content. C1 [Zimmet, Steven E.] Zimmet Vein & Dermatol, Austin, TX USA. [Min, Robert J.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Comerota, Anthony J.] Jobst Vasc Inst, Toledo, OH USA. [Meissner, Mark H.] Univ Washington, Sch Med, Dept Surg, Seattle, WA 98195 USA. [Carman, Teresa L.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Rathbun, Suman W.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. [Wakefield, Thomas W.] Univ Michigan Hlth Syst, Vasc Surg Sect, Dept Surg, Ann Arbor, MI USA. [Feied, Craig F.] Georgetown Univ, Sch Med, Dept Emergency Med, Washington, DC USA. RP Zimmet, SE (reprint author), 1500 W 34 th St, Austin, TX 78703 USA. EM zimmet@drzimmet.com NR 0 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0268-3555 EI 1758-1125 J9 PHLEBOLOGY JI Phlebology PD OCT PY 2014 VL 29 IS 9 BP 587 EP 593 DI 10.1177/0268355514545120 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AP1HI UT WOS:000341818500003 PM 25059735 ER PT J AU Benson, G de Felipe, J Xiaodong Sano, M AF Benson, Gloria de Felipe, Jesus Xiaodong Sano, Mary TI Performance of Spanish-speaking community-dwelling elders in the United States on the Uniform Data Set SO ALZHEIMERS & DEMENTIA LA English DT Article DE Spanish speakers; Neuropsychological test; Normative performance; Elderly; Alzheimer's ID ALZHEIMERS-DISEASE CENTERS; NEUROPSYCHOLOGICAL ASSESSMENT; POPULATIONS; BATTERY; UDS AB Background: Spanish is the second-most common language spoken in the United States, and Spanish speakers represent one third of the aging population. The National Alzheimer's Coordinating Center's Uniform Data Set implemented a Spanish neuropsychological battery. Previous work described the neuropsychological performance for English speakers. Here we describe performance on the Spanish version. Methods: Data from 276 Spanish speakers with normal cognition were summarized, with descriptive tables of performance on individual cognitive tests. Regression techniques were used to evaluate the effect of demographics on cognitive performance. Results: Spanish speakers were younger (70.0 vs 74.0 years) and less educated (10.7 vs 15.7 years) with more females (76% vs 63% female) than the previously described English speakers. Higher education and lower age were associated with better performance. Conclusion: This national cohort of well-characterized Spanish-speaking elders provides descriptive data on cognitive performance, an important tool for clinical and research efforts. (C) 2014 The Alzheimer's Association. All rights reserved. C1 [Benson, Gloria; Xiaodong; Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [de Felipe, Jesus] Fdn Jimenez Diaz Hosp, Dept Psychiat, Madrid, Spain. [de Felipe, Jesus] Univ Camilo Jose Cela, Villanueva De La Canada, Spain. [Xiaodong; Sano, Mary] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Sano, M (reprint author), Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. EM mary.sano@mssm.edu FU National Institute on Aging; Fundacion de Conchita Rabago de Jimenez Diaz; [U01 AG016976]; [AG005138] FX This study is supported by the National Institute on Aging. The NACC database is funded by grant U01 AG016976 to The Mount Sinai School of Medicine Alzheimer's Disease Research Center, which is supported by grant AG005138. Jesus de Felipe was supported by the Fundacion de Conchita Rabago de Jimenez Diaz. NR 24 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD OCT PY 2014 VL 10 IS 5 SU 1 BP S338 EP S343 DI 10.1016/j.jalz.2013.09.002 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA CZ0WW UT WOS:000366828100011 PM 24418057 ER PT J AU Fargo, KN Aisen, P Albert, M Au, R Corrada, MM DeKosky, S Drachman, D Fillit, H Gitlin, L Haas, M Herrup, K Kawas, C Khachaturian, AS Khachaturian, ZS Klunk, W Knopman, D Kukull, WA Lamb, B Logsdon, RG Maruff, P Mesulam, M Mobley, W Mohs, R Morgan, D Nixon, RA Paul, S Petersen, R Plassman, B Potter, W Reiman, E Reisberg, B Sano, M Schindler, R Schneider, LS Snyder, PJ Sperling, RA Yaffe, K Bain, LJ Thies, WH Carrillo, MC AF Fargo, Keith N. Aisen, Paul Albert, Marilyn Au, Rhoda Corrada, Maria M. DeKosky, Steven Drachman, David Fillit, Howard Gitlin, Laura Haas, Magali Herrup, Karl Kawas, Claudia Khachaturian, Ara S. Khachaturian, Zaven S. Klunk, William Knopman, David Kukull, Walter A. Lamb, Bruce Logsdon, Rebecca G. Maruff, Paul Mesulam, Marsel Mobley, William Mohs, Richard Morgan, David Nixon, Ralph A. Paul, Steven Petersen, Ronald Plassman, Brenda Potter, William Reiman, Eric Reisberg, Barry Sano, Mary Schindler, Rachel Schneider, Lon S. Snyder, Peter J. Sperling, Reisa A. Yaffe, Kristine Bain, Lisa J. Thies, William H. Carrillo, Maria C. CA Alzheimer's Assoc Natl Plan TI 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease SO ALZHEIMERS & DEMENTIA LA English DT Editorial Material DE Policy; National Plan to Address Alzheimer's Disease; Milestones ID AFRICAN-AMERICANS; HYPOTHETICAL MODEL; DYNAMIC BIOMARKERS; DRUG-DEVELOPMENT; CLINICAL-TRIALS; DEMENTIA; RECRUITMENT; PREVALENCE; CHALLENGES; DIAGNOSIS AB With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations. (C) 2014 The Alzheimer's Association. C1 [Fargo, Keith N.; Thies, William H.; Carrillo, Maria C.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. [Aisen, Paul; Mobley, William] Univ Calif San Diego, Sch Med, Dept Neurosci, San Diego, CA 92103 USA. [Albert, Marilyn] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Au, Rhoda] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Au, Rhoda] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Corrada, Maria M.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Corrada, Maria M.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [DeKosky, Steven] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [DeKosky, Steven] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [DeKosky, Steven] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Drachman, David] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Fillit, Howard] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, Alzheimers Drug Discovery Fdn, New York, NY 10029 USA. [Fillit, Howard] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. Johns Hopkins Univ, Dept Community Publ Hlth, Baltimore, MD USA. [Gitlin, Laura] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Haas, Magali] Orion Bionetworks, Cambridge, MA USA. [Herrup, Karl] Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China. [Herrup, Karl] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Kowloon, Hong Kong, Peoples R China. [Kawas, Claudia] Univ Calif Irvine, Dept Neurobiol & Behav, Dept Neurol, Irvine, CA USA. [Kawas, Claudia] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA. [Khachaturian, Ara S.] Natl Biomed Res Eth Council, Rockville, MD USA. [Khachaturian, Zaven S.] PAD2020, Rockville, MD USA. [Klunk, William] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Knopman, David; Petersen, Ronald] Mayo Clin, Coll Med, Alzheimers Dis Res Ctr, Dept Neurol, Rochester, MN USA. [Kukull, Walter A.] Univ Washington, NACC, Seattle, WA 98195 USA. [Kukull, Walter A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lamb, Bruce] Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44106 USA. [Logsdon, Rebecca G.] Univ Washington, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Maruff, Paul] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia. [Maruff, Paul] CogState Ltd, Melbourne, Vic, Australia. [Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Mohs, Richard] Eli Lilly & Co, Neurosci Early Clin Dev, Indianapolis, IN 46285 USA. [Morgan, David] Univ S Florida, Byrd Alzheimers Inst, Tampa, FL USA. [Nixon, Ralph A.] NYU, Dept Psychiat, Langone Med Ctr, New York, NY 10016 USA. [Nixon, Ralph A.] NYU, Dept Cell Biol, Langone Med Ctr, New York, NY 10016 USA. [Nixon, Ralph A.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Paul, Steven] Fdn Natl Inst Hlth, Bethesda, MD USA. [Plassman, Brenda] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Potter, William] Fdn Natl Inst Hlth, Neuroscience Steering Comm Biomarkers Consortium, Phoenix, AZ USA. [Reiman, Eric] Univ Arizona, Coll Med, Banner Alzheimers Inst, Phoenix, AZ USA. [Reiman, Eric] Univ Arizona, Coll Med, Dept Psychiat, Phoenix, AZ USA. [Reisberg, Barry] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Reisberg, Barry] NYU, Sch Med, Alzheimers Dis Res Ctr, New York, NY USA. [Schindler, Rachel] Pfizer Inc, New York, NY USA. [Schneider, Lon S.] Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA USA. [Snyder, Peter J.] Brown Univ, Alpert Med Sch, Dept Neurol, Providence, RI 02912 USA. [Snyder, Peter J.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. EM mcarrillo@alz.org OI Reisberg, Barry/0000-0002-9104-7423; Kukull, Walter/0000-0001-8761-9014; corrada, maria/0000-0002-8168-8593; Maruff, Paul/0000-0002-6947-9537 NR 48 TC 14 Z9 14 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD OCT PY 2014 VL 10 IS 5 SU 1 BP S430 EP S452 DI 10.1016/j.jalz.2014.08.103 PG 23 WC Clinical Neurology SC Neurosciences & Neurology GA CZ0WW UT WOS:000366828100023 ER PT J AU Si, Y Cui, XQ Kim, S Wians, R Sorge, R Oh, SJ Kwan, T AlSharabati, M Lu, L Claussen, G Anderson, T Yu, SH Morgan, D Kazamel, M King, PH AF Si, Ying Cui, Xianqin Kim, Soojin Wians, Robert Sorge, Robert Oh, Shin J. Kwan, Thaddeus AlSharabati, Mohammad Lu, Liang Claussen, Gwen Anderson, Tina Yu, Shaohua Morgan, Dylan Kazamel, Mohamed King, Peter H. TI Smads as muscle biomarkers in amyotrophic lateral sclerosis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: To identify molecular signatures in muscle from patients with amyotrophic lateral sclerosis (ALS) that could provide insight into the disease process and serve as biomarkers. Methods: RNA sequencing was performed on ALS and control muscle samples to identify Smad family members as potential markers of disease. Validation studies were performed in a cohort of 27 ALS patients and 33 controls. The markers were assessed in the G93A superoxide dismutase (SOD) 1 mouse at different stages of disease and in a model of sciatic nerve injury. Results: Smad8, and to a lesser extent Smad1 and 5, mRNAs were significantly elevated in human ALS muscle samples. The markers displayed a remarkably similar pattern in the G93A SOD1 mouse model of ALS with increases detected at preclinical stages. Expression at the RNA and protein levels as well as protein activation (phosphorylation) significantly increased with disease progression in the mouse. The markers were also elevated to a lesser degree in gastrocnemius muscle following sciatic nerve injury, but then reverted to baseline during the muscle reinnervation phase. Interpretation: These data indicate that Smad1, 5, 8 mRNA and protein levels, as well as Smad phosphorylation, are elevated in ALS muscle and could potentially serve as markers of disease progression or regression. C1 [Si, Ying; Kim, Soojin; Wians, Robert; Oh, Shin J.; Kwan, Thaddeus; AlSharabati, Mohammad; Lu, Liang; Claussen, Gwen; Anderson, Tina; Morgan, Dylan; Kazamel, Mohamed; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Cui, Xianqin; Yu, Shaohua] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Sorge, Robert] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Oh, Shin J.; Lu, Liang; Kazamel, Mohamed] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. [King, Peter H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. RP King, PH (reprint author), Suite 260 Sparks Ctr,1720 2nd Ave S, Birmingham, AL 35294 USA. EM pking@uab.edu FU BLRD VA [I01 BX003035, I01 BX001148]; NINDS NIH HHS [K08 NS057664, R01 NS064133, P30 NS047466, R21 NS081743, R21 NS085497] NR 44 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD OCT PY 2014 VL 1 IS 10 BP 778 EP 787 DI 10.1002/acn3.117 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KN UT WOS:000209815600004 PM 25493269 ER PT J AU Horky, LL Gerbaudo, VH Zaitsev, A Plesniak, W Hainer, J Govindarajulu, U Kikinis, R Dietrich, J AF Horky, Laura L. Gerbaudo, Victor H. Zaitsev, Alexander Plesniak, Wen Hainer, Jon Govindarajulu, Usha Kikinis, Ron Dietrich, Jorg TI Systemic chemotherapy decreases brain glucose metabolism SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum-based chemotherapy on glucose metabolism in the brain of cancer patients. Methods: Using sequential FDG-PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non-small-cell lung cancer. Results: Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts. Interpretation: Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients. C1 [Horky, Laura L.; Gerbaudo, Victor H.; Zaitsev, Alexander; Plesniak, Wen; Hainer, Jon; Govindarajulu, Usha; Kikinis, Ron] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Div Nucl Med, 75 Francis St, Boston, MA 02115 USA. [Dietrich, Jorg] Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Div Neurooncol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. [Dietrich, Jorg] Harvard Med Sch, Ctr Regenerat Med, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. RP Dietrich, J (reprint author), Harvard Med Sch, Dept Neurol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM Dietrich.Jorg@mgh.harvard.edu FU NCI NIH HHS [K12 CA090354]; NCRR NIH HHS [P41 RR013218]; NIBIB NIH HHS [P41 EB015898, U54 EB005149, P41 EB015902] NR 45 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD OCT PY 2014 VL 1 IS 10 BP 788 EP 798 DI 10.1002/acn3.121 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KN UT WOS:000209815600005 PM 25493270 ER PT J AU Zingone, A Wang, WX Corrigan-Cummins, M Wu, SP Plyler, R Korde, N Kwok, M Manasanch, EE Tageja, N Bhutani, M Mulquin, M Zuchlinski, D Yancey, MA Roschewski, M Zhang, Y Roccaro, AM Ghobrial, IM Calvo, KR Landgren, O AF Zingone, Adriana Wang, Weixin Corrigan-Cummins, Meghan Wu, S. Peter Plyler, Ryan Korde, Neha Kwok, Mary Manasanch, Elisabet E. Tageja, Nishant Bhutani, Manisha Mulquin, Marcia Zuchlinski, Diamond Yancey, Mary Ann Roschewski, Mark Zhang, Yong Roccaro, Aldo M. Ghobrial, Irene M. Calvo, Katherine R. Landgren, Ola TI Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease SO CYTOKINE LA English DT Article DE Multiple myeloma; Chemokines; CXCL8 ID UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; PROGRESSION; CELLS; TRANSACTIVATION; MIGRATION; RECEPTOR; CANCER; RISK AB Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls -> SMM -> MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment. Published by Elsevier Ltd. C1 [Zingone, Adriana; Wu, S. Peter; Korde, Neha; Kwok, Mary; Manasanch, Elisabet E.; Tageja, Nishant; Bhutani, Manisha; Mulquin, Marcia; Zuchlinski, Diamond; Yancey, Mary Ann; Roschewski, Mark; Landgren, Ola] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Wang, Weixin; Corrigan-Cummins, Meghan; Plyler, Ryan; Calvo, Katherine R.] NIH, Hematol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Zhang, Yong; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, New York, NY 10065 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org OI Roccaro, Aldo/0000-0002-1872-5128 FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD OCT PY 2014 VL 69 IS 2 BP 294 EP 297 DI 10.1016/j.cyto.2014.05.017 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AO6RB UT WOS:000341478100019 PM 25043675 ER PT J AU Ju, YS Futreal, CA Gerstung, M Martincorena, I Nik-Zainal, S Ramakrishna, M Davies, HR Papaemmanuil, E Gundem, G Shlien, A Bolli, N Behjati, S Tarpey, PS Nangalia, J Massie, CE Butler, AP Teague, JW Vassiliou, GS Green, AR Du, MQ Unnikrishnan, A Pimanda, JE Teh, BT Munshi, N Greaves, M Vyas, P El-Naggar, AK Santarius, T Collins, VP Grundy, R Taylor, JA Hayes, DN Malkin, D Foster, CS Warren, AY Whitaker, HC Brewer, D Eeles, R Cooper, C Neal, D Visakorpi, T Isaacs, WB Bova, GS Flanagan, AM Futreal, PA Lynch, AG Chinnery, PF McDermott, U Stratton, MR Campbell, PJ AF Ju, Young Seok Alexandrov, Ludmil B. Gerstung, Moritz Martincorena, Inigo Nik-Zainal, Serena Ramakrishna, Manasa Davies, Helen R. Papaemmanuil, Elli Gundem, Gunes Shlien, Adam Bolli, Niccolo Behjati, Sam Tarpey, Patrick S. Nangalia, Jyoti Massie, Charles E. Butler, Adam P. Teague, Jon W. Vassiliou, George S. Green, Anthony R. Du, Ming-Qing Unnikrishnan, Ashwin Pimanda, John E. Teh, Bin Tean Munshi, Nikhil Greaves, Mel Vyas, Paresh El-Naggar, Adel K. Santarius, Tom Collins, V. Peter Grundy, Richard Taylor, Jack A. Hayes, D. Neil Malkin, David Foster, Christopher S. Warren, Anne Y. Whitaker, Hayley C. Brewer, Daniel Eeles, Rosalind Cooper, Colin Neal, David Visakorpi, Tapio Isaacs, William B. Bova, G. Steven Flanagan, Adrienne M. Futreal, P. Andrew Lynch, Andy G. Chinnery, Patrick F. McDermott, Ultan Stratton, Michael R. Campbell, Peter J. CA ICGC Breast Canc Grp ICGC Chronic Myeloid Disorders Grp ICGC Prostate Canc Grp TI Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer SO ELIFE LA English DT Article ID 21 BREAST CANCERS; POPULATION-GENETICS; POLYMERASE-GAMMA; LAGGING-STRAND; HUMAN-DISEASE; STEM-CELLS; GENOME; HETEROPLASMY; REPLICATION; EVOLUTION AB Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mitochondrial DNA (mtDNA) are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors across 31 histologies. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication. C1 [Ju, Young Seok; Alexandrov, Ludmil B.; Gerstung, Moritz; Martincorena, Inigo; Nik-Zainal, Serena; Ramakrishna, Manasa; Davies, Helen R.; Papaemmanuil, Elli; Gundem, Gunes; Shlien, Adam; Bolli, Niccolo; Behjati, Sam; Tarpey, Patrick S.; Nangalia, Jyoti; Massie, Charles E.; Butler, Adam P.; Teague, Jon W.; Vassiliou, George S.; Futreal, P. Andrew; Stratton, Michael R.; ICGC Breast Canc Grp; ICGC Chronic Myeloid Disorders Grp] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. [Nangalia, Jyoti; Massie, Charles E.; Vassiliou, George S.; Green, Anthony R.; Du, Ming-Qing; Santarius, Tom; Collins, V. Peter; Warren, Anne Y.; McDermott, Ultan; Campbell, Peter J.] Cambridge Univ Hosp NHS Trust, Cambridge, England. [Nangalia, Jyoti; Massie, Charles E.; Vassiliou, George S.; Green, Anthony R.; Campbell, Peter J.] Univ Cambridge, Dept Hematol, Cambridge, England. [Unnikrishnan, Ashwin; Pimanda, John E.] Univ New S Wales, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Teh, Bin Tean] Natl Canc Ctr, Lab Canc Epigenome, Singapore, Singapore. [Teh, Bin Tean] Duke Nus Grad Med Sch, Singapore, Singapore. [Munshi, Nikhil] Dana Farber Canc Inst, Boston, MA 02115 USA. [Greaves, Mel; Brewer, Daniel; Eeles, Rosalind; Cooper, Colin] Inst Canc Res, Sutton, Surrey, England. [Vyas, Paresh] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [El-Naggar, Adel K.; Futreal, P. Andrew] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Grundy, Richard] Univ Nottingham, Childrens Brain Tumor Res Ctr, Nottingham NG7 2RD, England. [Taylor, Jack A.] NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Hayes, D. Neil] Univ N Carolina, Chapel Hill, NC 27515 USA. [Malkin, David] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Whitaker, Hayley C.; Neal, David; ICGC Prostate Canc Grp] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. [Foster, Christopher S.] Univ Liverpool, London, England. [Foster, Christopher S.] HCA Pathol Labs, London, England. [Brewer, Daniel; Cooper, Colin] Univ E Anglia, Norwich NR4 7TJ, Norfolk, England. [Visakorpi, Tapio; Bova, G. Steven] Univ Tampere, Inst Biomed Technol, FIN-33101 Tampere, Finland. [Visakorpi, Tapio; Bova, G. Steven] Univ Tampere, BioMediTech, FIN-33101 Tampere, Finland. [Isaacs, William B.] Johns Hopkins Univ, Baltimore, MD USA. [Flanagan, Adrienne M.] Royal Natl Orthopaed Hosp, Stanmore, Middx, England. [Flanagan, Adrienne M.] UCL, UCL Canc Inst, London, England. [Chinnery, Patrick F.] Univ Newcastle, Inst Med Genet, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England. RP Campbell, PJ (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. EM pc8@sanger.ac.uk RI Ju, Young Seok/E-1324-2012; Bolli, Niccolo/D-4057-2011; OI taylor, jack/0000-0001-5303-6398; Ju, Young Seok/0000-0002-5514-4189; Bolli, Niccolo/0000-0002-1018-5139; Massie, Charlie/0000-0003-2314-4843; Ehinger, Anna/0000-0001-9225-7396; Gerstung, Moritz/0000-0001-6709-963X; Eeles, Rosalind/0000-0002-3698-6241; Vassiliou, George/0000-0003-4337-8022; Vyas, Paresh/0000-0003-3931-0914; McDermott, Ultan/0000-0001-9032-4700; Martin, Sancha/0000-0001-6213-5259; Unnikrishnan, Ashwin/0000-0001-5168-8755 FU Wellcome Trust; British Lung Foundation; Health Innovation Challenge Fund; Kay Kendall Leukaemia Fund; Chordoma Foundation; Adenoid Cystic Carcinoma Research Foundation; EMBO long-term fellowship [ALTF 1203-2012, ALTF 1287-2012]; National Institute for Health Research (NIHR) UCLH Biomedical Research Centre; Leukaemia Lymphoma Research; Cancer Research UK; Leukemia Lymphoma Society; European Union (BASIS); National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative [G0500966/75466]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX Data used in this manuscript are described in the supplementary materials (Supplementary file 1). We thank Thomas Bleazard at Faculty of Medical and Human Sciences, University of Manchester for discussion and assistance with manuscript preparation. We would like to thank The Cancer Genome Atlas (TCGA) Project Team and their specimen donors for providing sequencing data. This work was supported by the Wellcome Trust, the British Lung Foundation, the Health Innovation Challenge Fund, the Kay Kendall Leukaemia Fund, the Chordoma Foundation and the Adenoid Cystic Carcinoma Research Foundation. Y.S.J and I.M. are supported by EMBO long-term fellowship (ALTF 1203-2012 and ALTF 1287-2012, respectively). P.J.C. is a Wellcome Trust Senior Clinical Fellow. Support was provided to A.M.F. by the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre. A.R.G. receives support from Leukaemia Lymphoma Research, Cancer Research UK and the Leukemia Lymphoma Society. Samples from Addenbrooke's Hospital were collected with support from the NIHR Cambridge Biomedical Resource Centre. The ICGC Breast Cancer Consortium was supported by a grant from the European Union (BASIS) and the Wellcome Trust. The ICGC Prostate Cancer Consortium was funded by Cancer Research UK. We would also like to acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466) which has funded tissue and urine collections in Cambridge. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (J.A.T.). We obtained informed consent and consent to publish from participants enrolled. NR 59 TC 45 Z9 45 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 1 PY 2014 VL 3 AR e02935 DI 10.7554/eLife.02935 PG 53 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AR2JI UT WOS:000343409900003 ER PT J AU Khawaja, RDA Singh, S Madan, R Sharma, A Padole, A Pourjabbar, S Digumarthy, S Shepard, JA Kalra, MK AF Khawaja, Ranish Deedar Ali Singh, Sarabjeet Madan, Rachna Sharma, Amita Padole, Atul Pourjabbar, Sarvenaz Digumarthy, Subba Shepard, Jo-Anne Kalra, Mannudeep K. TI Ultra low-dose chest CT using filtered back projection: Comparison of 80-, 100- and 120 kVp protocols in a prospective randomized study SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Radiation dose reduction; Chest CT; Filtered back projection ID STATISTICAL ITERATIVE RECONSTRUCTION; COMPUTED-TOMOGRAPHY; IMAGE QUALITY; PULMONARY NODULES; REDUCTION; EXPERIENCE AB Purpose: To assess lesion detection and diagnostic image quality of filtered back projection (FBP) reconstruction technique in ultra low-dose chest CT examinations. Methods and materials: In this IRB-approved ongoing prospective clinical study, 116 CT-image-series at four different radiation-doses were performed for 29 patients (age, 57-87 years; F:M - 15:12; BMI 16-32 kg/m(2)). All patients provided written-informed-consent for the acquisitions of additional ultra low-dose (ULD) series on a 256-slice MDCT (iCT, Philips Healthcare). In-addition to their clinical standard-dose chest CT (SD, 120 kV mean CTDIvol, 6 +/- 1 mGy), ULD-CT was subsequently performed at three-dose-levels (0.9 mGy [120 kV]; 0.5 mGy [100 kV] and 0.2 mGy [80 kV[). Images were reconstructed with FBP (2.5 mm*1.25 mm) resulting into four-stacks: SD-FBP (reference-standard), FBP0.9, FBP0.5, and FBP0.2. Four thoracic-radiologists from two-teaching-hospitals independently-evaluated data for lesion-detection and visibility-of-small-structures. Friedman's-non-parametric-test with post hoc Dunn's-test was used for data-analysis. Results: Interobserver-agreement was substantial between radiologists (k = 0.6-0.8). With pooled analysis, 146-pulmonary (27-groundglass-opacities, 64-solid-lung-nodules, 7-consolidations, 27-emphysema) and 347-mediastinal/soft tissue lesions (87-mediastinal, 46-hilar, 62-axillary-lymphnodes, and 11-mediastinal-masses) were evaluated. Compared to the SD-FBP, 100% pulmonary-lesions were seen with FBP0.9, up to 81% with FBP0.5 (missed: 4), and up to 30% with FBP0.2 images (missed: 16). Compared to SD-FBP, all enlarged mediastinal-lymph-nodes were seen with FBP0.9 images. All mediastinal-masses (>2 cm, 11/11) were seen equivalent to SD-FBP images at 0.9 mGy. Across all sizes of patients, FBP0.9 images had optimal visualization for lung findings. They were optimal for mediastinal soft tissues for only non-obese patients. Conclusion: Filtered-back-projection technique allows optimal lesion detection and acceptable image quality for chest-CT examinations at CDTIvol of 0.9 mGy for lung and mediastinal findings in selected sizes of patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Khawaja, Ranish Deedar Ali; Singh, Sarabjeet; Sharma, Amita; Padole, Atul; Pourjabbar, Sarvenaz; Digumarthy, Subba; Shepard, Jo-Anne; Kalra, Mannudeep K.] Massachusetts Gen Hosp, Div Thorac Radiol, MGH Imaging, Boston, MA 02114 USA. [Khawaja, Ranish Deedar Ali; Singh, Sarabjeet; Madan, Rachna; Sharma, Amita; Padole, Atul; Pourjabbar, Sarvenaz; Digumarthy, Subba; Shepard, Jo-Anne; Kalra, Mannudeep K.] Harvard Univ, Sch Med, Boston, MA USA. [Madan, Rachna] Brigham & Womens Hosp, Div Thorac Radiol, Boston, MA 02115 USA. RP Khawaja, RDA (reprint author), 25 New Chardon St,4th Floor, Boston, MA 02114 USA. EM rkhawaja@mgh.harvard.edu OI Padole, Atul/0000-0002-3917-4871 FU Radiological Society of North America (RSNA); GE Healthcare; Philips Healthcare; Society of Thoracic Radiology; RSNA Educational Scholar Grant FX S.S. received research funding from the Radiological Society of North America (RSNA), GE Healthcare, Philips Healthcare, and the Society of Thoracic Radiology. M.K.K. has received RSNA Educational Scholar Grant. The remaining authors have no financial disclosures and had full control of study data during the study. NR 24 TC 8 Z9 8 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD OCT PY 2014 VL 83 IS 10 BP 1934 EP 1944 DI 10.1016/j.ejrad.2014.06.024 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO5WL UT WOS:000341417000034 PM 25063211 ER PT J AU Fava, M Gommoll, C Chen, C Greenberg, WM Ruth, A D'Souza, I Terner-Rosenthal, J AF Fava, M. Gommoll, C. Chen, C. Greenberg, W. M. Ruth, A. D'Souza, I. Terner-Rosenthal, J. TI The efficacy of levomilnacipran extended-release (ER) in the treatment of patients with depression-associated fatigue symptoms SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Fava, M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gommoll, C.; Chen, C.; Greenberg, W. M.; D'Souza, I.; Terner-Rosenthal, J.] Forest Res Inst, Jersey City, NJ USA. [Ruth, A.] Prescott Med Commun Grp, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.f.009 BP S456 EP S457 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700219 ER PT J AU Jeon, H Heo, JY Kim, JH Lim, BN Park, SJ Fava, M Mischoulon, D Kang, EH Roh, S Lee, D AF Jeon, H. Heo, J. Y. Kim, J. H. Lim, B. N. Park, S. J. Fava, M. Mischoulon, D. Kang, E. H. Roh, S. Lee, D. TI Sleep quality, posttraumatic stress, depression, and human errors in train drivers: a population-based nationwide study in South Korea SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Jeon, H.; Heo, J. Y.; Kim, J. H.; Lee, D.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Psychiat, Seoul, South Korea. [Lim, B. N.; Park, S. J.] Seoul Natl Univ, Seoul, South Korea. [Fava, M.; Mischoulon, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Kang, E. H.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Roh, S.] Seoul Natl Hosp, Mental Hlth Res, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.1.k.023 BP S354 EP S354 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700053 ER PT J AU Papakostas, G Dragheim, M Nielsen, RZ AF Papakostas, G. Dragheim, M. Nielsen, R. Z. TI Efficacy and tolerability of vortioxetine is independent of previous treatment in MDD patients switched after an inadequate response SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol ID MAJOR DEPRESSIVE DISORDER; DOUBLE-BLIND; AGOMELATINE C1 [Papakostas, G.] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Dragheim, M.] H Lundbeck & Co AS, Brintellix Sci Team, Copenhagen, Denmark. [Nielsen, R. Z.] H Lundbeck & Co AS, Brintellix Clin Sci, Copenhagen, Denmark. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.f.024 BP S466 EP S466 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700234 ER PT J AU Singh, J Fedgchin, M Daly, E De Boer, P Cooper, K Lim, P Pinter, C Murrough, J Sanacora, G Shelton, R Kurian, B Winokur, A Fava, M Manji, H Drevets, W Van Nueten, L AF Singh, J. Fedgchin, M. Daly, E. De Boer, P. Cooper, K. Lim, P. Pinter, C. Murrough, J. Sanacora, G. Shelton, R. Kurian, B. Winokur, A. Fava, M. Manji, H. Drevets, W. Van Nueten, L. TI Onset of efficacy of ketamine in treatment-resistant depression: a double-blind, randomised, placebo-controlled, dose frequency study SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Singh, J.; Fedgchin, M.; Daly, E.; Manji, H.; Drevets, W.] Janssen Res & Dev LLC, Neurosci, Titusville, NJ USA. [De Boer, P.; Van Nueten, L.] Janssen Res & Dev, Neurosci, Beerse, Belgium. [Cooper, K.] Janssen Res & Dev LLC, Clin Biostat, Spring House, PA USA. [Lim, P.] Janssen Res & Dev LLC, Clin Biostat, Titusville, NJ USA. [Pinter, C.] Janssen Res & Dev LLC, GTM, Titusville, NJ USA. [Murrough, J.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Sanacora, G.] Yale Univ, Sch Med, New Haven, CT USA. [Shelton, R.] Univ Alabama, Sch Med, Birmingham, W Midlands, England. [Kurian, B.] UT Southwestern Med Ctr, Dept Psychiat, Dallas, TX USA. [Winokur, A.] Inst Living, Psychiat, Hartford, CT USA. [Fava, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fava, M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RI Murrough, James/J-7129-2013 OI Murrough, James/0000-0001-6286-1242 NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.b.017 BP S387 EP S388 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700107 ER PT J AU Felker, GM Ahmad, T Anstrom, KJ Adams, KF Cooper, LS Ezekowitz, JA Fiuzat, M Houston-Miller, N Januzzi, JL Leifer, ES Mark, DB Desvigne-Nickens, P Paynter, G Pina, IL Whellan, DJ O'Connor, CM AF Felker, G. Michael Ahmad, Tariq Anstrom, Kevin J. Adams, Kirkwood F. Cooper, Lawton S. Ezekowitz, Justin A. Fiuzat, Mona Houston-Miller, Nancy Januzzi, James L. Leifer, Eric S. Mark, Daniel B. Desvigne-Nickens, Patrice Paynter, Gayle Pina, Ileana L. Whellan, David J. O'Connor, Christopher M. TI Rationale and Design of the GUIDE-IT Study Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure SO JACC-HEART FAILURE LA English DT Article DE biomarkers; clinical trial; heart failure ID BRAIN-NATRIURETIC PEPTIDE; RANDOMIZED CLINICAL-TRIALS; VAL-HEFT; SYSTOLIC DYSFUNCTION; DISEASE MANAGEMENT; PRIMARY-CARE; IMPROVE HF; BNP; CARDIOLOGY; MORTALITY AB OBJECTIVES The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of < 1,000 pg/ml compared with usual care in high-risk patients with systolic heart failure (HF). BACKGROUND Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction <= 40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of < 1,000 pg/ml. Patients in either arm of the study are followed up at regular intervals and after treatment adjustments for a minimum of 12 months. The primary endpoint of the study is time to cardiovascular death or first hospitalization for HF. Secondary endpoints include time to cardiovascular death and all-cause mortality, cumulative mortality, health-related quality of life, resource use, cost-effectiveness, and safety. CONCLUSIONS The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (C) 2014 by the American College of Cardiology Foundation. C1 [Felker, G. Michael; Ahmad, Tariq; Fiuzat, Mona; Mark, Daniel B.; O'Connor, Christopher M.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Felker, G. Michael; Ahmad, Tariq; Anstrom, Kevin J.; Fiuzat, Mona; Mark, Daniel B.; Paynter, Gayle; O'Connor, Christopher M.] Duke Univ, Med Ctr, Div Cardiol, Duke Clin Res Inst, Durham, NC 27710 USA. [Adams, Kirkwood F.] Univ N Carolina, Div Cardiol, Chapel Hill, NC USA. [Cooper, Lawton S.; Leifer, Eric S.; Desvigne-Nickens, Patrice] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Ezekowitz, Justin A.] Univ Alberta, Div Cardiol, Edmonton, AB T6G 2M7, Canada. [Houston-Miller, Nancy] Stanford Univ, Div Cardiol, Palo Alto, CA 94304 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, Div Cardiol, Bronx, NY USA. [Whellan, David J.] Thomas Jefferson Univ, Div Cardiol, Philadelphia, PA 19107 USA. RP Felker, GM (reprint author), Duke Clin Res Inst, DUMC Box 3850, Durham, NC 27710 USA. EM michael.felker@duke.edu OI Mark, Daniel/0000-0001-6340-8087 FU National Heart Lung and Blood Institute [1R01HL105448-01A1, 1R01HL105451-01A1, 1R01HL105457-01A1]; Roche Diagnostics; BG Medicine; Critical Diagnostics; Daland Fellowship; National Institutes of Health; Alere Inc.; Siemens; Singulex; Thermo Fisher Scientific; Sphingotec; Amgen; Zensun; AstraZeneca; Gilead; Eli Lilly; Bristol-Myers Squibb; AGA Medical FX The GUIDE-IT study is funded by grants 1R01HL105448-01A1, 1R01HL105451-01A1, and 1R01HL105457-01A1 from the National Heart Lung and Blood Institute. Substudies for echocardiography as well as the GUIDE-IT biobank were funded by a grant from Roche Diagnostics. Dr. Felker has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics and has served as a consultant for Roche Diagnostics, Singulex, and HDL. Dr. Ahmad has received support from the Daland Fellowship in Clinical Investigation. Dr. Anstrom has served as a consultant for Abbott Vascular, AstraZeneca, Bristol-Myers Squibb, Gilead, Pfizer Inc., GlaxoSmithKline, Promedior, and Ikria; has served a member of data and safety monitoring boards for the National Institutes of Health, University of North Carolina, University of Miami, Forest Laboratories, Pfizer Inc., GlaxoSmithKline, and Vertex Pharmaceuticals; and is part owner of Biscardia, Inc. Dr. Adams has received research funding from Roche Diagnostics and Critical Diagnostics and has served as a consultant for Roche Diagnostics. Dr. Ezekowitz has received research funding from the National Institutes of Health and Alere Inc. Dr. Fiuzat has served as a consultant for Roche Diagnostics and has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics. Dr. Januzzi has served as a consultant for Critical Diagnostics and Novartis and has received research funding from Critical Diagnostics, Roche Diagnostics, Siemens, Singulex, Thermo Fisher Scientific, Sphingotec, Amgen, and Zensun. Dr. Mark has received grant funding from AstraZeneca, Gilead, Eli Lilly, Bristol-Myers Squibb, and AGA Medical; and has served as a consultant for Janssen, Medtronic, and Somahlution. Dr. O'Connor has served as a consultant for Roche Diagnostics and has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper. NR 44 TC 26 Z9 26 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 457 EP 465 DI 10.1016/j.jchf.2014.05.007 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500006 PM 25194287 ER PT J AU Ahmad, T Fiuzat, M Pencina, MJ Geller, NL Zannad, F Cleland, JGF Snider, JV Blankenberg, S Adams, KF Redberg, RF Kim, JB Mascette, A Mentz, RJ O'Connor, CM Felker, GM Januzzi, JL AF Ahmad, Tariq Fiuzat, Mona Pencina, Michael J. Geller, Nancy L. Zannad, Faiez Cleland, John G. F. Snider, James V. Blankenberg, Stephan Adams, Kirkwood F. Redberg, Rita F. Kim, Jae B. Mascette, Alice Mentz, Robert J. O'Connor, Christopher M. Felker, G. Michael Januzzi, James L. TI Charting a Roadmap for Heart Failure Biomarker Studies SO JACC-HEART FAILURE LA English DT Article DE biomarkers; heart failure; studies ID NATRIURETIC-PEPTIDE-MEASUREMENTS; BNP MEASUREMENTS USEFUL; DIAGNOSTIC-ACCURACY; PREDICTION MODELS; RANDOMIZED-TRIAL; RISK PREDICTION; THERAPY; RECLASSIFICATION; ROSUVASTATIN; MANAGEMENT AB Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers. (C) 2014 by the American College of Cardiology Foundation. C1 [Ahmad, Tariq; Fiuzat, Mona; Pencina, Michael J.; Mentz, Robert J.; O'Connor, Christopher M.; Felker, G. Michael; Januzzi, James L.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Ahmad, Tariq; Fiuzat, Mona; O'Connor, Christopher M.; Felker, G. Michael] Duke Clin Res Inst, Durham, NC USA. [Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Zannad, Faiez; Mascette, Alice] Nancy Univ, Nancy, France. [Cleland, John G. F.] Univ Hull, Kingston Upon Hull, Yorks, England. [Snider, James V.] Crit Diagnost, San Diego, CA USA. [Blankenberg, Stephan] Johannes Gutenberg Univ Mainz, D-55122 Mainz, Germany. [Adams, Kirkwood F.] Univ N Carolina, Div Cardiol, Chapel Hill, NC USA. [Redberg, Rita F.] UCSF, Div Cardiol, San Francisco, CA USA. [Kim, Jae B.] Amgen Inc, Thousand Oaks, CA USA. [Mascette, Alice] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org OI Cleland, John/0000-0002-1471-7016 FU BG Medicine; Critical Diagnostics; Roche Diagnostics; Thermo Fisher; Singulex; Siemens AG FX Drs. Fiuzat and O'Connor have received research funding from BG Medicine, Critical Diagnostics, and Roche Diagnostics. Dr. Pencina served as a data safety and monitoring board member for DC Devices and the Cardiovascular Clinical Science Foundation; and served as a consultant for BioVentrix. Dr. Zannad has received research funding from BG Medicine and Roche Diagnostics; and served as a consultant for BG Medicine. Dr. Cleland has received research funding from Roche Diagnostics. Dr. Snider is an employee of Critical Diagnostics. Dr. Kim is an employee of Amgen. Dr. Mentz has received honoraria from Bristol-Myers Squibb and Novartis. Dr. Felker has received research funding from BG Medicine, Critical Diagnostics, and Roche Diagnostics; and has served as a consultant for BG Medicine and Roche Diagnostics. Dr. Januzzi has served as an advisor or consultant for Critical Diagnostics; and has received research funding from Critical Diagnostics, Roche Diagnostics, BG Medicine, Thermo Fisher, Singulex, and Siemens AG. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this article. NR 50 TC 29 Z9 29 U1 3 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 477 EP 488 DI 10.1016/j.jchf.2014.02.005 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500009 PM 24929535 ER PT J AU Zile, MR Gaasch, WH Patel, K Aban, IB Ahmed, A AF Zile, Michael R. Gaasch, William H. Patel, Kanan Aban, Inmaculada B. Ahmed, Ali TI Adverse Left Ventricular Remodeling in Community-Dwelling Older Adults Predicts Incident Heart Failure and Mortality SO JACC-HEART FAILURE LA English DT Article DE heart failure; left ventricle; structural remodeling ID ESSENTIAL-HYPERTENSION; MYOCARDIAL-INFARCTION; EJECTION FRACTION; PRESSURE-OVERLOAD; AORTIC-STENOSIS; WALL STRESS; HYPERTROPHY; GEOMETRY; MASS; PATTERNS AB OBJECTIVES This study sought to determine whether specific patterns of adverse left ventricular (LV) structural remodeling are associated with differential rates of cardiovascular (CV) outcomes. BACKGROUND It is not known whether a stepwise combinatorial assessment of LV volume, mass, and geometry done to define specific remodeling patterns provides incremental prognostic information. METHODS A total of 3,181 Cardiovascular Health Study participants (mean age, 73 years of age; 60% women, 5% African American) were categorized by LV remodeling patterns and related to a multivariate-adjusted (age, sex, race, ejection fraction, hypertension, myocardial infarction, diabetes mellitus, chronic kidney disease) analysis of CV outcomes (incident heart failure [HF], all-cause mortality, and a combined endpoint of HF and mortality) over a 13-year follow-up period. RESULTS Examined independently, either left ventricular enlargement (LVE) or left ventricular hypertrophy (LVH) was associated with a higher risk of HF (32%, 34%, respectively) than with normal geometry (17%; p < 0.001). When LV volume and mass were used in combination, important incremental prognostic information was achieved. In the absence of LVE, HF was more common in those with LVH than in those with normal mass (32% vs. 16%, respectively; p < 0.001). In the presence of LVE, HF was more common in those with LVH than in those with normal mass (37% vs. 29%, respectively; p = 0.021). The subgroup with normal volume and mass but relative wall thickness (RWT) >0.42 carried a higher risk of HF (21%) than those with normal geometry (15%; p = 0.011). Once LVH or LVE was present, the addition of RWT to this analysis did not affect HF rate. Similar results were obtained for the other CV outcomes. CONCLUSIONS Stepwise combinatorial assessment of LV volume, mass, and geometry provides incremental prognostic information regarding CV outcomes. (C) 2014 by the American College of Cardiology Foundation. C1 [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Zile, Michael R.] Vet Affairs Med Ctr, Ralph H Johnson Dept, Charleston, SC 29403 USA. [Gaasch, William H.] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Patel, Kanan; Aban, Inmaculada B.; Ahmed, Ali] Univ Alabama Birmingham, Birmingham, AL USA. [Ahmed, Ali] Dept Vet Affairs Med Ctr, Birmingham, AL USA. RP Zile, MR (reprint author), Med Univ S Carolina, Dept Med, Div Cardiol, Ashley River Towers,Room 7067,25 Courtenay Dr, Charleston, SC 29425 USA. EM zilem@musc.edu FU Research Service of the Department of Veterans Affairs [5101CX000415-02, 5101BX000487-04]; National Institutes of Health from the National Heart, Lung, and Blood Institute [R01-HL097047] FX Dr. Zile is supported by the Research Service of the Department of Veterans Affairs (5101CX000415-02 and 5101BX000487-04). Dr. Ahmed is supported by National Institutes of Health R01-HL097047 from the National Heart, Lung, and Blood Institute and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 28 TC 21 Z9 22 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 512 EP 522 DI 10.1016/j.jchf.2014.03.016 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500013 PM 25194295 ER PT J AU Jha, MK Minhajuddin, A Thase, ME Jarrett, RB AF Jha, Manish Kumar Minhajuddin, Abu Thase, Michael E. Jarrett, Robin B. TI Improvement in self-reported quality of life with cognitive therapy for recurrent major depressive disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Quality of life; Major depressive disorder; Cognitive therapy ID NATIONAL-EPIDEMIOLOGIC-SURVEY; LONG-TERM COURSE; REPORT QIDS-SR; PSYCHOMETRIC PROPERTIES; DOUBLE-BLIND; SATISFACTION QUESTIONNAIRE; PSYCHOSOCIAL DISABILITY; CLINICAL-SIGNIFICANCE; RANDOMIZED-TRIAL; QUICK INVENTORY AB Background: Major depressive disorder (MDD) is common, often recurrent and/or chronic. Theoretically, assessing quality of life (QoL) in addition to the current practice of assessing depressive symptoms has the potential to offer a more comprehensive evaluation of the effects of treatment interventions and course of illness. Methods: Before and after acute-phase cognitive therapy (CT), 492 patients from Continuation Phase Cognitive Therapy Relapse Prevention trial (Jarrett et al., 2013; Jarrett and Thase, 2010) completed the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Inventory of Depressive Symptomatology Self-report (IDS-SR) and Beck Depression Inventory (BDI); clinicians completed Hamilton Rating Scale for Depression-17-items. Repeated measures analysis of variance evaluated the improvement in QoL before/after CT and measured the effect sizes. Change analyses to assess clinical significance (Hageman and Arrindell, 1999) were conducted. Results: At the end of acute-phase Cr, a repeated measure analysis of variance produced a statistically significant increase in Q-LES-Q scores with effect sizes of 0.48-13%; 76.9-91.4% patients reported clinically significant improvement. Yet, only 11-38.2% QoL scores normalized. An analysis of covariance showed that change in depression severity (covariates=IDS-SR, BDI) completely accounted for the improvement in Q-LES-Q scores. Limitations: There were only two time points of observation; clinically significant change analyses lacked matched normal controls; and generalizability is constrained by sampling characteristics. Conclusions: Quality of life improves significantly in patients with recurrent MDD after CT; however, this improvement is completely accounted for by change in depression severity. Normalization of QoL in all patients may require targeted, additional, and/or longer treatment. (C) 2014 Elsevier B.V. All rights reserved. C1 [Jha, Manish Kumar; Jarrett, Robin B.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Minhajuddin, Abu] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. RP Jha, MK (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM manishjha2201@yahoo.com; Robin.Jarrett@UTSouthwestern.edu FU National Institute of Mental Health [K24MH001571, R01MH058397, R01MH069619, R01MH058356, R01MH069618] FX This report was supported by Grants Nos. K24MH001571, R01MH058397, and R01MH069619 (to Robin B. Jarrett, Ph.D.) and R01MH058356 and R01MH069618 (to Michael E. Thase, M.D.) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health (NIMH) or the National Institutes of Health (NIH). NR 61 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT 1 PY 2014 VL 167 BP 37 EP 43 DI 10.1016/j.jad.2014.05.038 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700007 PM 25082112 ER PT J AU Tondo, L Visioli, C Preti, A Baldessarini, RJ AF Tondo, Leonardo Visioli, Caterina Preti, Antonio Baldessarini, Ross J. TI Bipolar disorders following initial depression: Modeling predictive clinical factors SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Depressive onset; Diagnosis; Major depression; Prediction ID UNIPOLAR DEPRESSION; DIAGNOSIS; ILLNESS; EPISODE; ADOLESCENTS; COMORBIDITY; TRANSITION; ALCOHOL; DEFICIT; BRIDGE AB Objective: Most first lifetime episodes among persons eventually diagnosed with bipolar disorder are depressive, often with years of delay to a final differentiation from unipolar major depression. To support early differentiation, we tested several predictive factors for association with later diagnoses of bipolar disorder. Method: With data from mood-disorder patients with first-lifetime episodes of major depression, we used multivariate, logistic modeling and Bayesian methods including Receiver Operating Characteristic curves to evaluate ability of one or more selected factors to differentiate patients who later met DSM-IV-TR diagnostic criteria for bipolar disorder and not unipolar major depressive disorder. Results: We analyzed data from 2146 patients (642 bipolar, 1504 unipolar) at risk for 13 years following initial depressive episodes. In multivariate modeling for 812 subjects with information on all clinical factors considered, seven significantly and independently differentiated bipolar from unipolar disorders, ranking (by significance): (a) >= 4 previous depressive episodes, (b) suicidal acts, (c) cyclothymic temperament, (d) family history of bipolar disorder, (e) substance-abuse, (f) younger-at-onset, or onset-age <25, and (g) male sex; four of these (c, d, f, g) can be identified at illness-onset. Bayesian analysis indicated optimal sensitivity and specificity at 2-4 factors/person and correct classification of 64-67% of cases, and ROC analysis of factors/person yielded a significant area-under-the-curve of 0.72 [CI: 0.68-0.75]. Conclusions: In multivariate modeling, 7 factors were significantly and independently associated with bipolar disorder diagnosed up to 13 years after initial depression. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tondo, Leonardo; Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Bipolar Disorder Res, Mailman Res Ctr, McLean Div, Boston, MA 02114 USA. [Tondo, Leonardo; Visioli, Caterina; Preti, Antonio] Ctr Lucia Bini Mood Disorders Ctr, Cagliari, Italy. [Tondo, Leonardo; Visioli, Caterina; Preti, Antonio] Ctr Lucia Bini Mood Disorders Ctr, Rome, Italy. [Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Tondo, L (reprint author), McLean Hosp, Mailman Res Ctr 212, 115 Mill St, Belmont, MA 02478 USA. EM ltondo@mclean.harvard.edu FU Aretaeus Research Fund; Stanley Medical Research Institute; Sardinia Regional Master-and-Back Fellowship; Bruce J. Anderson Foundation; McLean Private Donors Psychopharmacology Research Fund FX Supported in part by the Aretaeus Research Fund and Stanley Medical Research Institute (to LT), by a Sardinia Regional Master-and-Back Fellowship (to CV), a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RJB). The funding sources had no role in the analysis of data or preparation of this report. NR 40 TC 13 Z9 14 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT 1 PY 2014 VL 167 BP 44 EP 49 DI 10.1016/j.jad.2014.05.043 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700008 PM 25082113 ER PT J AU Bobo, WV Reilly-Harrington, NA Ketter, TA Brody, BD Kinrys, G Kemp, DE Shelton, RC McElroy, SL Sylvia, LG Kocsis, JH McInnis, MG Friedman, ES Singh, V Tohen, M Bowden, CL Deckersbach, T Calabrese, JR Thase, ME Nierenberg, AA Rabideau, DJ Schoenfeld, DA Faraone, SV Kamali, M AF Bobo, William V. Reilly-Harrington, Noreen A. Ketter, Terence A. Brody, Benjamin D. Kinrys, Gustavo Kemp, David E. Shelton, Richard C. McElroy, Susan L. Sylvia, Louisa G. Kocsis, James H. McInnis, Melvin G. Friedman, Edward S. Singh, Vivek Tohen, Mauricio Bowden, Charles L. Deckersbach, Thilo Calabrese, Joseph R. Thase, Michael E. Nierenberg, Andrew A. Rabideau, Dustin J. Schoenfeld, David A. Faraone, Stephen V. Kamali, Masoud TI Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the bipolar CHOICE trial (vol 161, pg 30, 2014) SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Correction C1 [Bobo, William V.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. [Reilly-Harrington, Noreen A.; Kinrys, Gustavo; Sylvia, Louisa G.; Deckersbach, Thilo; Nierenberg, Andrew A.; Rabideau, Dustin J.; Schoenfeld, David A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ketter, Terence A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Brody, Benjamin D.; Kocsis, James H.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Kemp, David E.; Calabrese, Joseph R.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Shelton, Richard C.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Lindner Ctr HOPE, Cincinnati, OH USA. [McInnis, Melvin G.; Kamali, Masoud] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Singh, Vivek; Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Tohen, Mauricio] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Bobo, WV (reprint author), Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. EM Bobo.William@mayo.edu NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT 1 PY 2014 VL 167 BP 259 EP 260 DI 10.1016/j.jad.2014.06.025 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700040 ER PT J AU Lu, Y Goti, V Chaturvedula, A Haberer, JE Fossler, MJ Sale, ME Bangsberg, D Baeten, J Celum, C Hendrix, CW AF Lu, Y. Goti, V. Chaturvedula, A. Haberer, J. E. Fossler, M. J. Sale, M. E. Bangsberg, D. Baeten, J. Celum, C. Hendrix, C. W. TI Population Pharmacokinetics of Tenofovir in HIV-1 Uninfected Members of Sero-discordant Couples and Effect of Dose Reporting Methods: An Analysis from the Partners PrEP Study SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lu, Y.; Hendrix, C. W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Goti, V.; Chaturvedula, A.] Mercer Univ, Macon, GA 31207 USA. [Haberer, J. E.; Bangsberg, D.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Fossler, M. J.] GlaxoSmithKline, King Of Prussia, PA USA. [Sale, M. E.] Next Level Solut Inc, Fresno, CA USA. [Baeten, J.; Celum, C.] Univ Washington, Seattle, WA 98195 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2014 VL 41 SU 1 MA W-003 BP S72 EP S72 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000150 ER PT J AU Madrasi, K Chaturvedula, A Haberer, J Sale, M Fossler, M Bangsberg, D Baeten, J Celum, C Hendrix, C AF Madrasi, Kumpal Chaturvedula, Ayyappa Haberer, Jessica Sale, Mark Fossler, Michael Bangsberg, David Baeten, Jared Celum, Connie Hendrix, Craig TI Markov Mixed Effects Modeling of Adherence using MEMS (R) Dosing Records from Partner's PrEP Ancillary Adherence Substudy SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Madrasi, Kumpal; Chaturvedula, Ayyappa] Mercer Univ, Macon, GA 31207 USA. [Haberer, Jessica; Bangsberg, David] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Hendrix, Craig] Johns Hopkins Univ, Baltimore, MD USA. [Sale, Mark] Next Level Solut LLC, Seattle, WA USA. [Fossler, Michael] GlaxoSmithKline, Seattle, WA USA. [Baeten, Jared; Celum, Connie] Univ Washington, Seattle, WA 98195 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2014 VL 41 SU 1 MA M-032 BP S21 EP S21 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000033 ER PT J AU Rasmussen, TA Tolstrup, M Brinkmann, CR Olesen, R Erikstrup, C Solomon, A Winckelmann, A Palmer, S Dinarello, C Buzon, M Lichterfeld, M Lewin, SR Ostergaard, L Sogaard, OS AF Rasmussen, Thomas A. Tolstrup, Martin Brinkmann, Christel R. Olesen, Rikke Erikstrup, Christian Solomon, Ajantha Winckelmann, Anni Palmer, Sarah Dinarello, Charles Buzon, Maria Lichterfeld, Mathias Lewin, Sharon R. Ostergaard, Lars Sogaard, Ole S. TI Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial SO LANCET HIV LA English DT Article ID T-CELLS; REPLICATION; RESERVOIR; VORINOSTAT; ACTIVATION; EXPRESSION; ACID; VIVO AB Background Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. Methods In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. Findings We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p<0.0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3.5-fold (range 2.1-14.4). Panobinostat induced plasma viraemia with an odds ratio of 10.5 (95% CI2.2-50.3; p=0.0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. Interpretation Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir. C1 [Rasmussen, Thomas A.; Tolstrup, Martin; Brinkmann, Christel R.; Olesen, Rikke; Winckelmann, Anni; Ostergaard, Lars; Sogaard, Ole S.] Aarhus Univ Hosp, Dept Infect Dis, DK-8220 Aarhus N, Denmark. [Erikstrup, Christian] Aarhus Univ Hosp, Dept Clin Immunol, DK-8220 Aarhus N, Denmark. [Solomon, Ajantha; Lewin, Sharon R.] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia. [Solomon, Ajantha; Lewin, Sharon R.] Monash Univ, Melbourne, Vic 3004, Australia. [Palmer, Sarah] Univ Sydney, Westmead Millennium Inst Med Res, Westmead, NSW 2145, Australia. [Dinarello, Charles] Univ Colorado Denver, Dept Med, Div Infect Dis, Aurora, CO USA. [Buzon, Maria; Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Buzon, Maria; Lichterfeld, Mathias] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Lewin, Sharon R.] Burnet Inst, Ctr Biomed Res, Melbourne, Vic, Australia. RP Rasmussen, TA (reprint author), Aarhus Univ Hosp, Dept Infect Dis, Brendstrupgaardsvej 100, DK-8220 Aarhus N, Denmark. EM thomrasm@rm.dk RI Sogaard, Ole/P-6058-2016; OI Rasmussen, Thomas Aagaard/0000-0001-5354-2442; Olesen, Rikke/0000-0002-5157-080X; Lewin, Sharon Ruth/0000-0002-0330-8241 FU Australian National Health and Medical Research Council [1009533]; NHMRC Practitioner Fellowship; Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (Delaney AIDS Research Enterprise) [U19AI096109] FX We thank Carsten Schade Larsen, Alex Laursen, and Merete Storgaard for clinical guidance during the study and Henrik Stovring for biostatistical support. Amy Shaw provided technical support and Paul W Denton provided input to the drafting of the report. The study was primarily funded by The Danish Council For Strategic Research, but also received contributions from The Danish AIDS Foundation, The Augustinus Foundation, Frode V Nyegaard Foundation, SSAC Foundation, Aarhus University, Aarhus University Hospital, and the American Fund for AIDS Research. Novartis supplied panobinostat for use in the study. SRL's contribution was supported by an Australian National Health and Medical Research Council project grant 1009533, an NHMRC Practitioner Fellowship and the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (Delaney AIDS Research Enterprise; U19AI096109). We wish to express our sincere gratitude to the study patients for their participation in the study. NR 33 TC 99 Z9 100 U1 0 U2 6 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD OCT PY 2014 VL 1 IS 1 BP E13 EP E21 DI 10.1016/S2352-3018(14)70014-1 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CU8JC UT WOS:000363787300008 PM 26423811 ER PT J AU Pang, SC Wang, HP Li, KY Zhu, ZY Kang, JX Sun, YH AF Pang, Shao-Chen Wang, Hou-Peng Li, Kuo-Yu Zhu, Zuo-Yan Kang, Jing X. Sun, Yong-Hua TI Double Transgenesis of Humanized fat1 and fat2 Genes Promotes Omega-3 Polyunsaturated Fatty Acids Synthesis in a Zebrafish Model SO MARINE BIOTECHNOLOGY LA English DT Article DE Omega-3 fatty acids; Omega-6 fatty acids; Desaturase; Transgenic fish; Transcriptional regulation ID SALMON SALMO-SALAR; FISH-OIL; HETEROLOGOUS EXPRESSION; BIOSYNTHETIC-PATHWAY; MAMMALIAN-CELLS; DESATURASE GENE; VEGETABLE-OIL; N-3; MICE; GENERATION AB Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutrients for human health. However, vertebrates, including humans, have lost the abilities to synthesize EPA and DHA de novo, majorly due to the genetic absence of delta-12 desaturase and omega-3 desaturase genes. Fishes, especially those naturally growing marine fish, are major dietary source of EPA and DHA. Because of the severe decline of marine fishery and the decrease in n-3 LC-PUFA content of farmed fishes, it is highly necessary to develop alternative sources of n-3 LC-PUFA. In the present study, we utilized transgenic technology to generate n-3 LC-PUFA-rich fish by using zebrafish as an animal model. Firstly, fat1 was proved to function efficiently in fish culture cells, which showed an effective conversion of n-6 PUFA to n-3 PUFA with the n-6/n-3 ratio that decreased from 7.7 to 1.1. Secondly, expression of fat1 in transgenic zebrafish increased the 20:5n-3 and 22:6n-3 contents to 1.8- and 2.4-fold, respectively. Third, co-expression of fat2, a fish codon-optimized delta-12 desaturase gene, and fat1 in fish culture cell significantly promoted n-3 PUFA synthesis with the decreased n-6/n-3 ratio from 7.7 to 0.7. Finally, co-expression of fat1 and fat2 in double transgenic zebrafish increased the 20:5n-3 and 22:6n-3 contents to 1.7- and 2.8-fold, respectively. Overall, we generated two types of transgenic zebrafish rich in endogenous n-3 LC-PUFA, fat1 transgenic zebrafish and fat1/fat2 double transgenic zebrafish. Our results demonstrate that application of transgenic technology of humanized fat1 and fat2 in farmed fishes can largely improve the n-3 LC-PUFA production. C1 [Pang, Shao-Chen; Wang, Hou-Peng; Li, Kuo-Yu; Zhu, Zuo-Yan; Sun, Yong-Hua] Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan 430072, Peoples R China. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA USA. [Pang, Shao-Chen] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. RP Sun, YH (reprint author), Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan 430072, Peoples R China. EM yhsun@ihb.ac.cn RI Sun, Yong-Hua/B-5025-2012 OI Sun, Yong-Hua/0000-0001-9368-6969 FU China 863 High-Tech Program [2011AA100404]; China 973 Basic Research Program [2010CB126306, 2012CB944504]; National Science Fund for Excellent Young Scholars of NSFC [31222052]; FEBL [2011FBZ23] FX The authors thank Hanhua Hu, Xian-Tao Fang, Chun Cai, Junjie Zhang, and Guangzhao Chen for their technical support throughout the research project. This work was supported by the China 863 High-Tech Program Grant 2011AA100404, the China 973 Basic Research Program Grants 2010CB126306 and 2012CB944504, the National Science Fund for Excellent Young Scholars of NSFC Grant 31222052, and FEBL Grant 2011FBZ23 to Y. H. S. NR 54 TC 8 Z9 11 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1436-2228 EI 1436-2236 J9 MAR BIOTECHNOL JI Mar. Biotechnol. PD OCT PY 2014 VL 16 IS 5 BP 580 EP 593 DI 10.1007/s10126-014-9577-9 PG 14 WC Biotechnology & Applied Microbiology; Marine & Freshwater Biology SC Biotechnology & Applied Microbiology; Marine & Freshwater Biology GA AO7AL UT WOS:000341504200009 PM 24832481 ER PT J AU Rodriguez, CLR Szu, JI Eberle, MM Wang, Y Hsu, MS Binder, DK Park, BH AF Rodriguez, Carissa L. R. Szu, Jenny I. Eberle, Melissa M. Wang, Yan Hsu, Mike S. Binder, Devin K. Park, B. Hyle TI Decreased light attenuation in cerebral cortex during cerebral edema detected using optical coherence tomography SO NEUROPHOTONICS LA English DT Article DE cerebral edema; optical coherence tomography; brain swelling AB Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema. (C) The Authors. C1 [Rodriguez, Carissa L. R.; Eberle, Melissa M.; Park, B. Hyle] Univ Calif Riverside, Dept Bioengn, 900 Univ Ave, Riverside, CA 92521 USA. [Szu, Jenny I.; Hsu, Mike S.; Binder, Devin K.] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA. [Wang, Yan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wang, Yan] Harvard Med Sch, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Hsu, Mike S.; Binder, Devin K.] Umbrella Neurotechnol, Irvine, CA 92620 USA. RP Park, BH (reprint author), Univ Calif Riverside, Dept Bioengn, 900 Univ Ave, Riverside, CA 92521 USA. EM hylepark@engr.ucr.edu FU NIBIB NIH HHS [R00 EB007241] NR 19 TC 6 Z9 6 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD OCT-DEC PY 2014 VL 1 IS 2 AR 025004 DI 10.1117/1.NPh.1.2.025004 PG 7 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA V45SP UT WOS:000209836600006 PM 25674578 ER PT J AU Tunkel, DE Bauer, CA Sun, GH Rosenfeld, RM Chandrasekhar, SS Cunningham, ER Archer, SM Blakley, BW Carter, JM Granieri, EC Henry, JA Hollingsworth, D Khan, FA Mitchell, S Monfared, A Newman, CW Omole, FS Phillips, CD Robinson, SK Taw, MB Tyler, RS Waguespack, R Whamond, EJ AF Tunkel, David E. Bauer, Carol A. Sun, Gordon H. Rosenfeld, Richard M. Chandrasekhar, Sujana S. Cunningham, Eugene R., Jr. Archer, Sanford M. Blakley, Brian W. Carter, John M. Granieri, Evelyn C. Henry, James A. Hollingsworth, Deena Khan, Fawad A. Mitchell, Scott Monfared, Ashkan Newman, Craig W. Omole, Folashade S. Phillips, C. Douglas Robinson, Shannon K. Taw, Malcolm B. Tyler, Richard S. Waguespack, Richard Whamond, Elizabeth J. TI Clinical Practice Guideline: Tinnitus SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE amplification; hearing aids; hearing loss; quality of life; sound therapy; tinnitus AB Objective. Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. Purpose. The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. Action Statements. The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (>= 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (>= 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus. C1 [Tunkel, David E.] Johns Hopkins Outpatient Ctr, Otolaryngol Head & Neck Surg, 601 North Caroline St,Room 6231, Baltimore, MD 21287 USA. [Bauer, Carol A.] So Illinois Univ, Sch Med, Div Otolaryngol Head & Neck Surg, Springfield, IL USA. [Sun, Gordon H.] Partnership Hlth Analyt Res LLC, Los Angeles, CA USA. [Rosenfeld, Richard M.] Suny Downstate Med Ctr, Dept Otolaryngol, Brooklyn, NY 11203 USA. [Chandrasekhar, Sujana S.] New York Otol, New York, NY USA. [Cunningham, Eugene R., Jr.] Amer Acad Otolaryngol Head & Neck Surg Fdn, Dept Res & Qual Improvement, Alexandria, VA USA. [Archer, Sanford M.] Univ Kentucky, Div Rhinol & Sinus Surg, Lexington, KY USA. [Archer, Sanford M.] Univ Kentucky, Div Facial Plast & Reconstruct Surg, Lexington, KY USA. [Blakley, Brian W.] Univ Manitoba, Dept Otolaryngol, Winnipeg, MB, Canada. [Carter, John M.] Tulane Univ, Dept Otolaryngol, New Orleans, LA 70118 USA. [Granieri, Evelyn C.] Columbia Univ, Div Geriatr Med & Aging, New York, NY USA. [Henry, James A.] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. [Hollingsworth, Deena] ENT Specialists Northern Virginia, Falls Church, VA USA. [Khan, Fawad A.] Ochsner Hlth Syst, Kenner, LA USA. [Mitchell, Scott] Mitchell & Cavallo PC, Houston, TX USA. [Monfared, Ashkan] George Washington Univ, Dept Otol & Neurotol, Washington, DC USA. [Newman, Craig W.] Cleveland Clin, Lerner Coll Med, Dept Surg, Cleveland, OH 44106 USA. [Omole, Folashade S.] Morehouse Sch Med, East Point, GA USA. [Phillips, C. Douglas] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Head & Neck Imaging, New York, NY USA. [Robinson, Shannon K.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Taw, Malcolm B.] Univ Calif Los Angeles, Dept Med, Ctr East West Med, Los Angeles, CA 90024 USA. [Tyler, Richard S.] Univ Iowa, Dept Otolaryngol Head & Neck Surg, Iowa City, IA USA. [Waguespack, Richard] Univ Alabama Birmingham, Sch Med, Dept Surg, Birmingham, AL 35294 USA. [Whamond, Elizabeth J.] Consumers United Evidence Based Healthcare, Fredericton, NB, Canada. RP Tunkel, DE (reprint author), Johns Hopkins Outpatient Ctr, Otolaryngol Head & Neck Surg, 601 North Caroline St,Room 6231, Baltimore, MD 21287 USA. EM dtunkel@jhmi.edu OI Phillips, C. Douglas/0000-0003-1773-8899 FU American Academy of Otolaryngology-Head and Neck Surgery Foundation FX American Academy of Otolaryngology-Head and Neck Surgery Foundation. NR 263 TC 51 Z9 58 U1 3 U2 27 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2014 VL 151 SU 2 BP S1 EP S40 DI 10.1177/0194599814545325 PG 40 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA V43SX UT WOS:000209702200001 PM 25273878 ER PT J AU Joung, K AF Joung, Keith TI Targeted genome and epigenome editing using CRISPR-Cas and TALE technologies SO TRANSGENIC RESEARCH LA English DT Meeting Abstract C1 [Joung, Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Joung, Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. NR 0 TC 0 Z9 0 U1 1 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 EI 1573-9368 J9 TRANSGENIC RES JI Transgenic Res. PD OCT PY 2014 VL 23 IS 5 MA 26 BP 840 EP 840 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AO6BY UT WOS:000341434600038 ER PT J AU Chandra, A Lin, T Tribble, MB Zhu, J Altman, AR Tseng, WJ Zhang, YJ Akintoye, SO Cengel, K Liu, XS Qin, L AF Chandra, Abhishek Lin, Tiao Tribble, Mary Beth Zhu, Ji Altman, Allison R. Tseng, Wei-Ju Zhang, Yejia Akintoye, Sunday O. Cengel, Keith Liu, X. Sherry Qin, Ling TI PTH1-34 alleviates radiotherapy-induced local bone loss by improving osteoblast and osteocyte survival SO BONE LA English DT Article DE Parathyroid hormone; Radiotherapy; Image registration; Trabecular bone; Osteoblast; Apoptosis ID PARATHYROID-HORMONE 1-34; TRABECULAR BONE; MARROW MICROENVIRONMENT; IONIZING-RADIATION; BODY IRRADIATION; CANCELLOUS BONE; IN-VITRO; X-RAYS; MICE; CELLS AB Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1-34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1-34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1-34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1-34. Furthermore, histological analyses revealed that PTH1-34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R.; Tseng, Wei-Ju; Liu, X. Sherry; Qin, Ling] Univ Penn, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lin, Tiao] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Orthopaed Surg, Hangzhou 310009, Zhejiang, Peoples R China. [Zhang, Yejia] Univ Penn, Perelman Sch Med, Dept Phys Med & Rehabil, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Akintoye, Sunday O.] Univ Penn, Sch Dent Med, Dept Oral Med, Philadelphia, PA 19104 USA. [Cengel, Keith] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Qin, L (reprint author), Univ Penn, Dept Orthopaed Surg, 424A Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM qinling@mail.med.upenn.edu OI Zhang, Yejia/0000-0002-7484-8800; Liu, Xiaowei/0000-0001-7247-2232; Chandra, Abhishek/0000-0001-9423-9669 FU National Institute of Health [R01DK095803, K22CA169089]; Penn Center for Musculoskeletal Disorders [P30AR050950]; ASBMR Junior Faculty Osteoporosis Basic Research Award; McCabe Pilot Award FX This work was supported by the National Institute of Health (R01DK095803 to LQ and K22CA169089 to SOA), Penn Center for Musculoskeletal Disorders P30AR050950 (NIAMS/NIH), ASBMR Junior Faculty Osteoporosis Basic Research Award (to LQ) and McCabe Pilot Award (to XSL). NR 45 TC 15 Z9 18 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD OCT PY 2014 VL 67 BP 33 EP 40 DI 10.1016/j.bone.2014.06.030 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO3KJ UT WOS:000341227800005 PM 24998454 ER PT J AU Adeyemo, BO Biederman, J Zafonte, R Kagan, E Spencer, TJ Uchida, M Kenworthy, T Spencer, AE Faraone, SV AF Adeyemo, Bamidele O. Biederman, Joseph Zafonte, Ross Kagan, Elana Spencer, Thomas J. Uchida, Mai Kenworthy, Tara Spencer, Andrea E. Faraone, Stephen V. TI Mild Traumatic Brain Injury and ADHD: A Systematic Review of the Literature and Meta-Analysis SO JOURNAL OF ATTENTION DISORDERS LA English DT Review DE ADHD; traumatic brain injury; meta-analysis; review ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PROFESSIONAL FOOTBALL PLAYERS; CLOSED-HEAD INJURY; RECURRENT CONCUSSION; PSYCHIATRIC-ILLNESS; LEAGUE PLAYER; YOUNG-ADULTS; CHILDREN; ADOLESCENTS AB Objective: This study investigated the association between mild traumatic brain injury (mTBI) and ADHD, which increases risk of injuries and accidents. Method: We conducted a systematic review and meta-analysis of studies that examined the relationship between mTBI and ADHD. Results: Five studies, comprising 3,023 mTBI patients and 9,716 controls, fit our a priori inclusion and exclusion criteria. A meta-analysis found a significant association between ADHD and mTBI, which was significant when limited to studies that reported on ADHD subsequent to mTBI and when the direction of the association was not specified, but not for studies that reported mTBI subsequent to ADHD. Heterogeneity of effect size and publication biases were not evident. Conclusion: The literature documents a significant association between mTBI and ADHD. Further clarification of the relationship and direction of effect between mTBI and ADHD and treatment implications could have large clinical, scientific, and public health implications. C1 [Adeyemo, Bamidele O.; Zafonte, Ross] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. [Biederman, Joseph; Kenworthy, Tara; Spencer, Andrea E.] Massachusetts Gen Hosp, Res Program Autism Spectrum Disorders, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Spencer, Thomas J.; Uchida, Mai; Faraone, Stephen V.] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. [Kagan, Elana; Kenworthy, Tara] Massachusetts Gen Hosp, Pediat Psychopharmacol Program, Boston, MA 02114 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Res Program Autism Spectrum Disorders, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Pediatric Psychopharmacology Council Fund FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Pediatric Psychopharmacology Council Fund. NR 38 TC 9 Z9 9 U1 2 U2 27 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD OCT PY 2014 VL 18 IS 7 BP 576 EP 584 DI 10.1177/1087054714543371 PG 9 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA AN8VJ UT WOS:000340883000002 PM 25047040 ER PT J AU Balboni, MJ Puchalski, CM Peteet, JR AF Balboni, Michael J. Puchalski, Christina M. Peteet, John R. TI The Relationship between Medicine, Spirituality and Religion: Three Models for Integration SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Spirituality; Medicine; Integration; Pluralism ID PALLIATIVE CARE; HEALTH; QUALITY AB The integration of medicine and religion is challenging for historical, ethical, practical and conceptual reasons. In order to make more explicit the bases and goals of relating spirituality and medicine, we distinguish here three complementary perspectives: a whole-person care model that emphasizes teamwork among generalists and spiritual professionals; an existential functioning view that identifies a role for the clinician in promoting full health, including spiritual well-being; and an open pluralism view, which highlights the importance of differing spiritual and cultural traditions in shaping the relationship. C1 [Balboni, Michael J.; Peteet, John R.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Puchalski, Christina M.] George Washington Inst Spiritual & Hlth, Washington, DC 20036 USA. RP Peteet, JR (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. EM jpeteet@partners.org NR 40 TC 14 Z9 14 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD OCT PY 2014 VL 53 IS 5 BP 1586 EP 1598 DI 10.1007/s10943-014-9901-8 PG 13 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA AN4YE UT WOS:000340595100024 PM 24917445 ER PT J AU Takahashi, K Ohtani, K Larvie, M Moyo, P Chigweshe, L Van Cott, EM Wakamiya, N AF Takahashi, Kazue Ohtani, Katsuki Larvie, Mykol Moyo, Patience Chigweshe, Lorencia Van Cott, Elizabeth M. Wakamiya, Nobutaka TI Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC) SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Innate immunity; Collectin; Collectin kidney 1 (CL-K1); Disseminated intravascular coagulation; Respiratory diseases; Coagulation disorders; Vascular diseases ID MANNOSE-BINDING LECTIN; TRANSMITTANCE WAVE-FORM; C-REACTIVE PROTEIN; COLLECTIN 11 CL-11; EARLY IDENTIFICATION; COMPLEMENT; CLOT; LIPOPROTEIN; DEFICIENCY; ACTIVATION AB Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC. C1 [Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Ohtani, Katsuki; Wakamiya, Nobutaka] Asahikawa Med Univ, Dept Microbiol & Immunochem, Asahikawa, Hokkaido 0788510, Japan. [Larvie, Mykol] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Neuroradiol, Boston, MA 02114 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Van Cott, Elizabeth M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Takahashi, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, 55 Fruit St, Boston, MA 02114 USA. EM ktakahashi1@gmail.com FU NIH [U01-074503]; Japan of Ministry of Education, Culture, Sports, Science, and Technology [19390227]; Fuso Pharmaceutical Industry, Co.; Smoking Research Foundation; Mizutani foundation for glycoscience FX The authors thank laboratory personnel in the Coagulation Laboratory at the Massachusetts General Hospital. The work was supported in part by NIH Grant U01-074503 (K. T.) and Grants-in-Aid for Scientific Research of the Japan of Ministry of Education, Culture, Sports, Science, and Technology, 19390227 (N.W). This work was also supported by grants from Fuso Pharmaceutical Industry, Co., the Smoking Research Foundation, and the Mizutani foundation for glycoscience (N.W). NR 34 TC 11 Z9 11 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD OCT PY 2014 VL 38 IS 3 BP 331 EP 338 DI 10.1007/s11239-013-1042-5 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AO1PK UT WOS:000341085300007 PM 24474086 ER PT J AU Bierer, LM Bader, HN Daskalakis, NP Lehrner, AL Makotkine, I Seckl, JR Yehuda, R AF Bierer, Linda M. Bader, Heather N. Daskalakis, Nikolaos P. Lehrner, Amy L. Makotkine, Iouri Seckl, Jonathan R. Yehuda, Rachel TI Elevation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE 11 beta-Hydroxysterioddehydrogenase type 2; Cortisol; Gtucocorticoid metabolism; Developmental programming; Intergenerational; Holocaust; Offspring; Biomarkers; PTSD; HPA axis ID POSTTRAUMATIC-STRESS-DISORDER; BETA-HYDROXYSTEROID DEHYDROGENASE; MESSENGER-RIBONUCLEIC-ACID; GLUCOCORTICOID-RECEPTOR; PRENATAL STRESS; LOW CORTISOL; EPIGENETIC REGULATION; ADULT DISEASE; PARENTAL PTSD; EXPRESSION AB Background: Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring. Methods: Holocaust offspring (n = 85) and comparison subjects (n = 27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-h urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11 beta-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol. Results: Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p = .046), as had been shown for Holocaust survivors. However, 11 beta-HSD-2 activity was elevated for offspring compared to controls (p = .008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p = .032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample. Conclusions: The inverse association of offspring 11 beta-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a tong standing reduction in 11 beta-HSD-2 activity among survivors is readily interpreted, in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration. Published by Elsevier Ltd. C1 [Bierer, Linda M.; Bader, Heather N.; Daskalakis, Nikolaos P.; Lehrner, Amy L.; Makotkine, Iouri; Yehuda, Rachel] James J Peters VA Med Ctr, Bronx, NY USA. [Bierer, Linda M.; Bader, Heather N.; Daskalakis, Nikolaos P.; Lehrner, Amy L.; Makotkine, Iouri; Yehuda, Rachel] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Seckl, Jonathan R.] Univ Edinburgh, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland. RP Yehuda, R (reprint author), James J Peters Vet Affairs Med Ctr, Mental Hlth Care Ctr, Mt Sinai Sch Med, Traumat Stress Studies Div,Dept Psychiat, 526 OOMH PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM Rachel.yehuda@va.gov RI Daskalakis, Nikolaos/B-7930-2014 OI Daskalakis, Nikolaos/0000-0003-1660-9112 FU Identification of an Epigenetic Risk Marker for PTSD [1RC1MH088101-01]; NIMH [R01 MH 64675-01]; National Institute of Health [5 M01 RR00071] FX This work was supported by 1RC1MH088101-01 "Identification of an Epigenetic Risk Marker for PTSD" and NIMH R01 MH 64675-01 "Biology of Risk and PTSD in Holocaust Survivor Offspring" and in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institute of Health. The NIMH and NIH had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication. NR 48 TC 9 Z9 10 U1 3 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD OCT PY 2014 VL 48 BP 1 EP 10 DI 10.1016/j.psyneuen.2014.06.001 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA AN8JR UT WOS:000340851000001 PM 24971590 ER PT J AU Hodler, J Kransdorf, MJ Rosenthal, DI AF Hodler, Juerg Kransdorf, Mark J. Rosenthal, Daniel I. TI Polling the readers of Skeletal Radiology SO SKELETAL RADIOLOGY LA English DT Editorial Material C1 [Hodler, Juerg] Univ Zurich Hosp, AUFN C 18, CH-8091 Zurich, Switzerland. [Kransdorf, Mark J.] Mayo Clin, Phoenix, AZ USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosenthal, DI (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM juerg.hodler@usz.ch; kransdorf.mark@mayo.edu; DIRosenthal@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD OCT PY 2014 VL 43 IS 10 BP 1351 EP 1351 DI 10.1007/s00256-014-1942-2 PG 1 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA AO1TR UT WOS:000341098200001 PM 25073608 ER PT J AU Kamath, RS Lukina, E Watman, N Dragosky, M Pastores, GM Arreguin, EA Rosenbaum, H Zimran, A Aguzzi, R Puga, AC Norfleet, AM Peterschmitt, MJ Rosenthal, DI AF Kamath, Ravi S. Lukina, Elena Watman, Nora Dragosky, Marta Pastores, Gregory M. Avila Arreguin, Elsa Rosenbaum, Hanna Zimran, Ari Aguzzi, Rasha Puga, Ana Cristina Norfleet, Andrea M. Peterschmitt, M. Judith Rosenthal, Daniel I. TI Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat SO SKELETAL RADIOLOGY LA English DT Article DE Gaucher disease type 1; Bone disease; Drug therapy; Targeted molecular therapy; Magnetic resonance imaging; Dual-energy X-ray absorptiometry ID ENZYME REPLACEMENT THERAPY; BONE-DISEASE; TARTRATE GENZ-112638; GLUCOCEREBROSIDASE; MARROW; IMIGLUCERASE; MACROPHAGE; REDUCTION; MIGLUSTAT AB Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1. C1 [Kamath, Ravi S.; Rosenthal, Daniel I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kamath, Ravi S.; Rosenthal, Daniel I.] Harvard Univ, Sch Med, Boston, MA USA. [Lukina, Elena] Russian Acad Med Sci, Moscow, Russia. [Watman, Nora] Hosp Ramos Mejia, Buenos Aires, DF, Argentina. [Dragosky, Marta] Inst Mexicano Seguro Social Hosp Especialidades, Col La Raza, Mexico. [Pastores, Gregory M.] NYU, New York, NY USA. [Avila Arreguin, Elsa] Inst Argentino Diagnost & Tratamiento, Buenos Aires, DF, Argentina. [Rosenbaum, Hanna] Rambam Med Ctr, Haifa, Israel. [Zimran, Ari] Shaare Zedek Hebrew Univ, Jerusalem, Israel. [Zimran, Ari] Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. [Aguzzi, Rasha; Puga, Ana Cristina; Norfleet, Andrea M.; Peterschmitt, M. Judith] Genzyme, Cambridge, MA USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Rosenthal, DI (reprint author), Massachusetts Gen Hosp, Dept Radiol, 175 Cambridge St, Boston, MA 02114 USA. EM dirosenthal@partners.org FU Genzyme, a Sanofi company FX The eliglustat phase 2 trial was sponsored by Genzyme, a Sanofi company. NR 32 TC 21 Z9 22 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD OCT PY 2014 VL 43 IS 10 BP 1353 EP 1360 DI 10.1007/s00256-014-1891-9 PG 8 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA AO1TR UT WOS:000341098200002 PM 24816856 ER PT J AU Norris, RE Shusterman, S Gore, L Muscal, JA Macy, ME Fox, E Berkowitz, N Buchbinder, A Bagatell, R AF Norris, Robin E. Shusterman, Suzanne Gore, Lia Muscal, Jodi A. Macy, Margaret E. Fox, Elizabeth Berkowitz, Noah Buchbinder, Aby Bagatell, Rochelle TI Phase 1 Evaluation of EZN-2208, a Polyethylene Glycol Conjugate of SN38, in Children Adolescents and Young Adults With Relapsed or Refractory Solid Tumors SO PEDIATRIC BLOOD & CANCER LA English DT Article DE EZN-2208; pediatric cancer; pharmacokinetic; Phase 1 trial ID PROTRACTED IRINOTECAN SCHEDULE; ETIRINOTECAN PEGOL NKTR-102; TOPOISOMERASE-I INHIBITOR; PEDIATRIC-PATIENTS; ONCOLOGY-GROUP; RANDOMIZED PHASE-2; PEGYLATED SN-38; CANCER; TEMOZOLOMIDE; TRIALS AB Background. EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors. Procedure. EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2)). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination. Results. Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2). At dose levels above 16 mg/m(2), Grade >= 3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2). Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for >= 8 cycles. Conclusions. EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma. (C) 2014 Wiley Periodicals, Inc. C1 [Norris, Robin E.] Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Shusterman, Suzanne] Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. [Shusterman, Suzanne] Childrens Hosp Boston, Div Oncol, Boston, MA USA. [Gore, Lia; Macy, Margaret E.] Univ Colorado, Aurora, CO USA. [Gore, Lia; Macy, Margaret E.] Childrens Hosp Colorado, Aurora, CO USA. [Muscal, Jodi A.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Fox, Elizabeth; Bagatell, Rochelle] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Berkowitz, Noah; Buchbinder, Aby] Enzon Pharmaceut Inc, Bridgewater, NJ USA. RP Norris, RE (reprint author), Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, 11100 Euclid Ave,Mailstop RBC 6054, Cleveland, OH 44106 USA. EM robin.norris@uhhospitals.org FU Enzon Pharmaceuticals, Inc. FX Grant sponsor: Enzon Pharmaceuticals, Inc. NR 34 TC 3 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2014 VL 61 IS 10 BP 1792 EP 1797 DI 10.1002/pbc.25105 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4ET UT WOS:000340541100016 PM 24962521 ER PT J AU Nichols-Vinueza, DX Gutierrez, A Veintemilla, G Perez-Atayde, AR AF Nichols-Vinueza, Diana X. Gutierrez, Alejandro Veintemilla, Galo Perez-Atayde, Antonio R. TI Letter to The Editor: Pseudopapillary Tumor of The Pancreas in a Child With Hemihypertrophy and a History of Wilms Tumor SO PEDIATRIC BLOOD & CANCER LA English DT Letter ID BETA-CATENIN; GENE; WTX C1 [Nichols-Vinueza, Diana X.; Gutierrez, Alejandro] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Veintemilla, Galo] Inst Nacl Cancerol, Pediat Oncol Unit, Bogota, Colombia. [Perez-Atayde, Antonio R.] Harvard Univ, Sch Med, Dept Pathol, Boston Childrens Hosp, Boston, MA 02115 USA. RP Gutierrez, A (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM alejandro.gutierrez@childrens.harvard.edu; gveintemilla@cancer.gov.co NR 9 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2014 VL 61 IS 10 BP 1901 EP 1902 DI 10.1002/pbc.25112 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4ET UT WOS:000340541100040 PM 24962628 ER PT J AU Pan, J Palmateer, J Schallert, T Hart, M Pandya, A Vandenbark, AA Offner, H Hurn, PD AF Pan, Jie Palmateer, Julie Schallert, Timothy Hart, Madison Pandya, Arushi Vandenbark, Arthur A. Offner, Halina Hurn, Patricia D. TI Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Cerebral ischemia; Gender; Sex; Immunotherapy; Partial MHC class II constructs; Stroke; Ultrasonic vocalization ID MIGRATION INHIBITORY FACTOR; TREATS EXPERIMENTAL STROKE; CLASS-II CONSTRUCTS; ULTRASONIC VOCALIZATION; CEREBRAL-ISCHEMIA; CD74 EXPRESSION; IMMUNE-SYSTEM; RATS; MICE; INJURY AB Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal's recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DR alpha 1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females. C1 [Pan, Jie] Nanjing Univ, Sch Med, Nanjing 210008, Jiangsu, Peoples R China. [Pan, Jie; Palmateer, Julie; Hurn, Patricia D.] Univ Texas Austin, Dept Neurosci, Austin, TX 78712 USA. [Schallert, Timothy; Hart, Madison; Pandya, Arushi] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Vandenbark, Arthur A.; Offner, Halina] Oregon & Hlth Sci Univ, Dept Neurol, Portland, OR USA. [Vandenbark, Arthur A.; Offner, Halina] Neuroimmunol Res, Portland, OR USA. [Vandenbark, Arthur A.] Oregon & Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR USA. [Offner, Halina] Oregon & Hlth Sci Univ, Dept Anesthesiol & Perioperat Med, Portland Vet Affairs Med Ctr, Portland, OR USA. [Hurn, Patricia D.] Univ Texas Syst, Austin, TX USA. [Hurn, Patricia D.] Res & Innovat Univ Texas Syst, Austin, TX 78701 USA. RP Hurn, PD (reprint author), Res & Innovat Univ Texas Syst, 601 Colorado,Suite 211, Austin, TX 78701 USA. EM phurn@utsystem.edu FU NINDS NIH HHS [R42 NS065515] NR 40 TC 11 Z9 11 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2014 VL 5 IS 5 BP 577 EP 585 DI 10.1007/s12975-014-0345-y PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN1VV UT WOS:000340373000007 PM 24838614 ER PT J AU Zhu, WB Libal, NL Casper, A Bodhankar, S Offner, H Alkayed, NJ AF Zhu, Wenbin Libal, Nicole L. Casper, Amanda Bodhankar, Sheetal Offner, Halina Alkayed, Nabil J. TI Recombinant T Cell Receptor Ligand Treatment Improves Neurological Outcome in the Presence of Tissue Plasminogen Activator in Experimental Ischemic Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Ischemic stroke; Immunotherapy; Recombinant T cell receptor ligand; Tissue plasminogen activator; HLA-DR2 transgenic mice ID CEREBRAL-ARTERY; INFARCT SIZE; MICE; RECOMMENDATIONS; REPERFUSION; CLEARANCE; ANTIGEN; DESIGN AB RTL1000 is a partial human MHC molecule coupled to a human myelin peptide. We previously demonstrated that RTL1000 was protective against experimental ischemic stroke in HLA-DR2 transgenic (DR2-Tg) mice. Since thrombolysis with recombinant tissue plasminogen activator (t-PA) is a standard therapy for stroke, we determined if RTL1000 efficacy is altered when combined with t-PA in experimental stroke. Male DR2-Tg mice underwent 60 min of intraluminal middle cerebral artery occlusion (MCAO). t-PA or vehicle was infused intravenously followed by either a single or four daily subcutaneous injections of RTL1000 or vehicle. Infarct size was measured by 2, 3, 5-triphenyltetrazolium chloride staining at 24 or 96 h of reperfusion. Our data showed that t-PA alone reduced infarct size when measured at 24 h but not at 96 h after MCAO. RTL1000 alone reduced infarct size both at 24 and 96 h after MCAO. Combining RTL1000 with t-PA did not alter its ability to reduce infarct size at either 24 or 96 h after MCAO and provides additional protection in t-PA treated mice at 24 h after ischemic stroke. Taken together, RTL1000 treatment alone improves outcome and provides additional protection in t-PA-treated mice in experimental ischemic stroke. C1 [Zhu, Wenbin; Libal, Nicole L.; Casper, Amanda; Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. [Bodhankar, Sheetal; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Bodhankar, Sheetal; Offner, Halina] Portland VA Med Ctr, Portland, OR 97239 USA. RP Alkayed, NJ (reprint author), Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. EM alkayedn@ohsu.edu FU NIH [NS076013]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX This work was supported by NIH Grants #NS076013 (STTR) and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. NR 31 TC 11 Z9 11 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2014 VL 5 IS 5 BP 612 EP 617 DI 10.1007/s12975-014-0348-8 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN1VV UT WOS:000340373000011 PM 24953050 ER PT J AU Wilcox, T Hawkins, LB Hirshkowitz, A Boas, DA AF Wilcox, Teresa Hawkins, Laura B. Hirshkowitz, Amy Boas, David A. TI Cortical activation to object shape and speed of motion during the first year SO NEUROIMAGE LA English DT Article DE Object processing; Temporal cortex; Parietal cortex; Functional brain activation; Infants; Near-infrared spectroscopy ID NEAR-INFRARED SPECTROSCOPY; STRUCTURE-FROM-MOTION; MENTAL ROTATION; INFANT CORTEX; SPATIOTEMPORAL INFORMATION; NONHUMAN-PRIMATES; CEREBRAL-CORTEX; VISUAL-SYSTEM; BOLD ACTIVITY; PERCEPTION AB A great deal is known about the functional organization of cortical networks that mediate visual object processing in the adult. The current research is part of a growing effort to identify the functional maturation of these pathways in the developing brain. The current research used near-infrared spectroscopy to investigate functional activation of the infant cortex during the processing of featural information (shape) and spatiotemporal information (speed of motion) during the first year of life. Our investigation focused on two areas that were implicated in previous studies: anterior temporal cortex and posterior parietal cortex. Neuroimaging data were collected with 207 infants across three age groups: 3-6 months (Experiment 1), 7-8 months (Experiment 2), and 10-12 months (Experiments 3 and 4). The neuroimaging data revealed age-related changes in patterns of activation to shape and speed information, mostly involving posterior parietal areas, some of which were predicted and others that were not. We suggest that these changes reflect age-related differences in the perceptual and/or cognitive processes engaged during the task (C) 2014 Elsevier Inc. All rights reserved. C1 [Wilcox, Teresa; Hawkins, Laura B.; Hirshkowitz, Amy] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Wilcox, T (reprint author), Texas A&M Univ, Dept Psychol, 4235 TAMU, College Stn, TX 77843 USA. EM twilcox@tamu.edu FU [BCS-0642996]; [R01-HD057999]; [P41-RR14075] FX We thank Marisa Biondi, Tracy Smith Brower, Jennifer Armstrong Haslup, Melissa Wallace Klapuch, Mariam Massoud, Jennifer Moore Norvell, Jessica Stubbs, Kayla Boone Upshaw, Lesley Wheeler, and the staff of the Infant Cognition Lab at Texas A&M University for help with data collection and management, and the infants and parents who so graciously participated in the research. This work was support by grants BCS-0642996 and R01-HD057999 to TW and grant P41-RR14075 to DAB. DAB is an inventor on a technology licensed to TechEn, a company whose medical pursuits focus on noninvasive, optical brain monitoring. DAB's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 77 TC 5 Z9 5 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2014 VL 99 BP 129 EP 141 DI 10.1016/j.neuroimage.2014.04.082 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AM4XR UT WOS:000339860000014 PM 24821531 ER PT J AU Cryan, JB Haidar, S Ramkissoon, LA Bi, WL Knoff, DS Schultz, N Abedalthagafi, M Brown, L Wen, PY Reardon, DA Dunn, IF Folkerth, RD Santagata, S Lindeman, NI Ligon, AH Beroukhim, R Hornick, JL Alexander, BM Ligon, KL Ramkissoon, SH AF Cryan, Jane B. Haidar, Sam Ramkissoon, Lori A. Bi, Wenya Linda Knoff, David S. Schultz, Nikolaus Abedalthagafi, Malak Brown, Loreal Wen, Patrick Y. Reardon, David A. Dunn, Ian F. Folkerth, Rebecca D. Santagata, Sandro Lindeman, Neal I. Ligon, Azra H. Beroukhim, Rameen Hornick, Jason L. Alexander, Brian M. Ligon, Keith L. Ramkissoon, Shakti H. TI Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas SO ONCOTARGET LA English DT Article DE oligodendroglioma; astrocytoma; oligoastrocytoma; sequencing; IDH ID CENTRAL-NERVOUS-SYSTEM; LOW-GRADE GLIOMAS; ADJUVANT TEMOZOLOMIDE; DIFFUSE GLIOMAS; IDH2 MUTATIONS; TUMOR SAMPLES; CLASSIFICATION; GLIOBLASTOMA; RADIOTHERAPY; CONCOMITANT AB Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test. C1 [Cryan, Jane B.; Abedalthagafi, Malak; Folkerth, Rebecca D.; Santagata, Sandro; Lindeman, Neal I.; Ligon, Azra H.; Hornick, Jason L.; Ligon, Keith L.; Ramkissoon, Shakti H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Haidar, Sam; Ramkissoon, Lori A.; Knoff, David S.; Brown, Loreal; Wen, Patrick Y.; Reardon, David A.; Beroukhim, Rameen; Ligon, Keith L.; Ramkissoon, Shakti H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Santagata, Sandro; Ligon, Keith L.; Ramkissoon, Shakti H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bi, Wenya Linda; Dunn, Ian F.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Alexander, Brian M.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Kravis Ctr Mol Oncol, New York, NY 10021 USA. [Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Ramkissoon, SH (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM keith_ligon@dfci.harvard.edu; sramkissoon@partners.org OI Knoff, David/0000-0001-6233-2893 FU NCI NIH HHS [P01 CA142536, P50 CA165962, R01 CA170592]; NINDS NIH HHS [K08 NS087118] NR 26 TC 17 Z9 18 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8083 EP 8092 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900010 PM 25257301 ER PT J AU Nishi, M Akutsu, H Kudoh, A Kimura, H Yamamoto, N Umezawa, A Lee, SW Ryo, A AF Nishi, Mayuko Akutsu, Hidenori Kudoh, Ayumi Kimura, Hirokazu Yamamoto, Naoki Umezawa, Akihiro Lee, Sam W. Ryo, Akihide TI Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell SO ONCOTARGET LA English DT Article DE Cancer stem cell; p21Cip1; drug screening; senescence; tumor sphere formation ID EPITHELIAL-MESENCHYMAL TRANSITION; PREMATURE SENESCENCE; WITHANIA-SOMNIFERA; PROSTATE-CANCER; WITHAFERIN; INDUCTION; GEROCONVERSION; IDENTIFICATION; EXPRESSION; GENERATION AB Cancer stem cells (CSCs) retain the capacity to propagate themselves through self-renewal and to produce heterogeneous lineages of cancer cells constituting the tumor. Novel drugs that target CSCs can potentially eliminate the tumor initiating cell population therefore resulting in complete cure of the cancer. We recently established a CSC-like model using induced pluripotent stem cell (iPSC) technology to reprogram and partially differentiate human mammary epithelial MCF-10A cells. Using the induced CSC-like (iCSCL) model, we developed a phenotypic drug assay system to identify agents that inhibit the stemness and self-renewal properties of CSCs. The selectivity of the agents was assessed using three distinct assays characterized by cell viability, cellular stemness and tumor sphere formation. Using this approach, we found that withaferin A (WA), an Ayurvedic medicine constituent, was a potent inhibitor of CSC stemness leading to cellular senescence primarily via the induction of p21(Cip1) expression. Moreover, WA exhibited strong anti-tumorigenic activity against the iCSCL. These results indicate that our iCSCL model provides an innovative high throughput platform for a simple, easy, and cost-effective method to search for novel CSC-targeting drugs. Furthermore, our current study identified WA as a putative drug candidate for abrogating the stemness and tumor initiating ability of CSCs. C1 [Nishi, Mayuko; Kudoh, Ayumi; Ryo, Akihide] Yokohama City Univ, Sch Med, Dept Microbiol, Yokohama, Kanagawa 232, Japan. [Akutsu, Hidenori; Umezawa, Akihiro] Natl Res Inst Child Hlth & Dev, Dept Reprod Biol, Tokyo, Japan. [Kimura, Hirokazu] Natl Inst Infect Dis, Infect Dis Surveillance Ctr, Tokyo, Japan. [Yamamoto, Naoki] Natl Univ Singapore, Dept Microbiol, Singapore 117548, Singapore. [Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Ryo, A (reprint author), Yokohama City Univ, Sch Med, Dept Microbiol, Yokohama, Kanagawa 232, Japan. EM aryo@yokohama-cu.ac.jp FU Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program; Ministry of Education, Culture, Sports, Science and Technology of Japan FX We thank K Miyakawa, Y Watanabe, N Ikawa, H Nishikawa and N Kasuga for their excellent technical assistance. This work was supported in part by Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program and grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A.R. and M.N.). NR 57 TC 20 Z9 20 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8665 EP 8680 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900054 PM 25228591 ER PT J AU Moore, NF Azarova, AM Bhatnagar, N Ross, KN Drake, LE Frumm, S Liu, QS Christie, AL Sanda, T Chesler, L Kung, AL Gray, NS Stegmaier, K George, RE AF Moore, Nathan F. Azarova, Anna M. Bhatnagar, Namrata Ross, Kenneth N. Drake, Lauren E. Frumm, Stacey Liu, Qinsong S. Christie, Amanda L. Sanda, Takaomi Chesler, Louis Kung, Andrew L. Gray, Nathanael S. Stegmaier, Kimberly George, Rani E. TI Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma SO ONCOTARGET LA English DT Article DE ALK; neuroblastoma; crizotinib; mTOR inhibitor; MYCN ID TRANSLATION INITIATION; THERAPEUTIC TARGET; AKT; MYC; PHOSPHORYLATION; AMPLIFICATION; ACTIVATION; MECHANISM; CANCERS; TUMORS AB Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALK(F1174L) mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALK(F1174L)/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALK(F1174L)/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors. C1 [Moore, Nathan F.; Azarova, Anna M.; Bhatnagar, Namrata; Drake, Lauren E.; Frumm, Stacey; Sanda, Takaomi; Kung, Andrew L.; Stegmaier, Kimberly; George, Rani E.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Liu, Qinsong S.; Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Christie, Amanda L.; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Ross, Kenneth N.; Stegmaier, Kimberly] Broad Inst MIT & Harvard, Cambridge, MA USA. [Liu, Qinsong S.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. [Liu, Qinsong S.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. [Sanda, Takaomi] Inst Canc Res, Sutton, Surrey, England. [Chesler, Louis] Canc Sci Inst Singapore, Singapore, Singapore. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. EM rani_george@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU NIH [R01 CA148688]; Sidney Kimmel Translational Scholar Award [SKF-10-112]; Friends for Life Neuroblastoma Foundation FX This study was supported by NIH R01 CA148688 (R.E. George), a Sidney Kimmel Translational Scholar Award, SKF-10-112 (R.E. George) and the Friends for Life Neuroblastoma Foundation (R.E. George and K. Stegmaier). NR 32 TC 19 Z9 19 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8737 EP 8749 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900060 PM 25228590 ER PT J AU Kilbourne, AM Almirall, D Eisenberg, D Waxmonsky, J Goodrich, DE Fortney, JC Kirchner, JE Solberg, LI Main, D Bauer, MS Kyle, J Murphy, SA Nord, KM Thomas, MR AF Kilbourne, Amy M. Almirall, Daniel Eisenberg, Daniel Waxmonsky, Jeanette Goodrich, David E. Fortney, John C. Kirchner, Joann E. Solberg, Leif I. Main, Deborah Bauer, Mark S. Kyle, Julia Murphy, Susan A. Nord, Kristina M. Thomas, Marshall R. TI Protocol: Adaptive Implementation of Effective Programs Trial (ADEPT): cluster randomized SMART trial comparing a standard versus enhanced implementation strategy to improve outcomes of a mood disorders program SO IMPLEMENTATION SCIENCE LA English DT Article DE Adaptive intervention; Depression; Health behavior change; Care management ID MENTAL-HEALTH-SERVICES; CARDIOVASCULAR-DISEASE RISK; PRIMARY-CARE PRACTICES; REPLICATING EFFECTIVE PROGRAMS; HIV PREVENTION INTERVENTIONS; PAY-FOR-PERFORMANCE; OF-VETERANS-AFFAIRS; BIPOLAR DISORDER; QUALITY-IMPROVEMENT; COLLABORATIVE CARE AB Background: Despite the availability of psychosocial evidence-based practices (EBPs), treatment and outcomes for persons with mental disorders remain suboptimal. Replicating Effective Programs (REP), an effective implementation strategy, still resulted in less than half of sites using an EBP. The primary aim of this cluster randomized trial is to determine, among sites not initially responding to REP, the effect of adaptive implementation strategies that begin with an External Facilitator (EF) or with an External Facilitator plus an Internal Facilitator (IF) on improved EBP use and patient outcomes in 12 months. Methods/Design: This study employs a sequential multiple assignment randomized trial (SMART) design to build an adaptive implementation strategy. The EBP to be implemented is life goals (LG) for patients with mood disorders across 80 community-based outpatient clinics (N = 1,600 patients) from different U. S. regions. Sites not initially responding to REP (defined as <50% patients receiving >= 3 EBP sessions) will be randomized to receive additional support from an EF or both EF/IF. Additionally, sites randomized to EF and still not responsive will be randomized to continue with EF alone or to receive EF/IF. The EF provides technical expertise in adapting LG in routine practice, whereas the on-site IF has direct reporting relationships to site leadership to support LG use in routine practice. The primary outcome is mental health-related quality of life; secondary outcomes include receipt of LG sessions, mood symptoms, implementation costs, and organizational change. Discussion: This study design will determine whether an off-site EF alone versus the addition of an on-site IF improves EBP uptake and patient outcomes among sites that do not respond initially to REP. It will also examine the value of delaying the provision of EF/IF for sites that continue to not respond despite EF. C1 [Kilbourne, Amy M.; Goodrich, David E.; Kyle, Julia; Nord, Kristina M.] VA Ann Arbor Healthcare Syst, VA Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Kilbourne, Amy M.; Goodrich, David E.; Kyle, Julia; Nord, Kristina M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Almirall, Daniel; Murphy, Susan A.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48104 USA. [Eisenberg, Daniel] Univ Michigan, Sch Publ Hlth, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Waxmonsky, Jeanette; Thomas, Marshall R.] Colorado Access, Denver, CO 80231 USA. [Waxmonsky, Jeanette; Thomas, Marshall R.] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO 80045 USA. [Fortney, John C.] VA Puget Sound Hlth Care Syst, Seattle HSR&D Ctr Innovat Vet Ctr & Value Driven, Seattle, WA 98108 USA. [Kirchner, Joann E.] VA Mental Hlth Qual Enhancement Res Initiat MH QU, North Little Rock, AR 72114 USA. [Kirchner, Joann E.] Univ Arkansas Med Sci, Coll Med, Dept Psychiat, Little Rock, AR 72205 USA. [Solberg, Leif I.] HealthPartners Inst Educ & Res, Bloomington, MN 55425 USA. [Main, Deborah] Univ Colorado, Dept Hlth & Behav Sci, Denver, CO 80217 USA. [Bauer, Mark S.] VA Boston Healthcare Syst, VA Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. RP Kilbourne, AM (reprint author), VA Ann Arbor Healthcare Syst, VA Ctr Clin Management Res, 2215 Fuller Rd,Mailstop 152, Ann Arbor, MI 48105 USA. EM amykilbo@umich.edu OI Goodrich, David/0000-0003-3232-2189 FU National Institute of Mental Health [R01 099898] FX This research was supported by the National Institute of Mental Health (R01 099898). The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. NR 122 TC 2 Z9 2 U1 6 U2 11 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 SEP 30 PY 2014 VL 9 AR UNSP 132 DI 10.1186/s13012-014-0132-x PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU2GY UT WOS:000345435700001 PM 25267385 ER PT J AU Meagher, DJ Morandi, A Inouye, SK Ely, W Adamis, D Maclullich, AJ Rudolph, JL Neufeld, K Leonard, M Bellelli, G Davis, D Teodorczuk, A Kreisel, S Thomas, C Hasemann, W Timmons, S O'Regan, N Grover, S Jabbar, F Cullen, W Dunne, C Kamholz, B Van Munster, BC De Rooij, SE De Jonghe, J Trzepacz, PT AF Meagher, David J. Morandi, Alessandro Inouye, Sharon K. Ely, Wes Adamis, Dimitrios Maclullich, Alasdair J. Rudolph, James L. Neufeld, Karin Leonard, Maeve Bellelli, Giuseppe Davis, Daniel Teodorczuk, Andrew Kreisel, Stefan Thomas, Christine Hasemann, Wolfgang Timmons, Suzanne O'Regan, Niamh Grover, Sandeep Jabbar, Faiza Cullen, Walter Dunne, Colum Kamholz, Barbara Van Munster, Barbara C. De Rooij, Sophia E. De Jonghe, Jos Trzepacz, Paula T. TI Concordance between DSM-IV and DSM-5 criteria for delirium diagnosis in a pooled database of 768 prospectively evaluated patients using the delirium rating scale-revised-98 SO BMC MEDICINE LA English DT Article DE Delirium; Classification; Diagnosis; Cognition; Neurocognitive disorders; Dementia ID CONFUSION ASSESSMENT METHOD; MEDICAL INPATIENTS; SCALE REVISED-98; DEMENTIA; PHENOMENOLOGY; VALIDATION; BEDSIDE; COHORT; RISK; CARE AB Background: The Diagnostic and Statistical Manual fifth edition (DSM-5) provides new criteria for delirium diagnosis. We examined delirium diagnosis using these new criteria compared with the Diagnostic and Statistical Manual fourth edition (DSM-IV) in a large dataset of patients assessed for delirium and related presentations. Methods: Patient data (n = 768) from six prospectively collected cohorts, clinically assessed using DSM-IV and the Delirium Rating Scale-Revised-98 (DRS-R98), were pooled. Post hoc application of DRS-R98 item scores were used to rate DSM-5 criteria. 'Strict' and 'relaxed' DSM-5 criteria to ascertain delirium were compared to rates determined by DSM-IV. Results: Using DSM-IV by clinical assessment, delirium was found in 510/768 patients (66%). Strict DSM-5 criteria categorized 158 as delirious including 155 (30%) with DSM-IV delirium, whereas relaxed DSM-5 criteria identified 466 as delirious, including 455 (89%) diagnosed by DSM-IV (P < 0.001). The concordance between the different diagnostic methods was: 53% (kappa = 0.22) between DSM-IV and the strict DSM-5, 91% (kappa = 0.82) between the DSM-IV and relaxed DSM-5 criteria and 60% (kappa = 0.29) between the strict versus relaxed DSM-5 criteria. Only 155 cases were identified as delirium by all three approaches. The 55 (11%) patients with DSM-IV delirium who were not rated as delirious by relaxed criteria had lower mean DRS-R98 total scores than those rated as delirious (13.7 +/- 3.9 versus 23.7 +/- 6.0; P < 0.001). Conversely, mean DRS-R98 score (21.1 +/- 6.4) for the 70% not rated as delirious by strict DSM-5 criteria was consistent with suggested cutoff scores for full syndromal delirium. Only 11 cases met DSM-5 criteria that were not deemed to have DSM-IV delirium. Conclusions: The concordance between DSM-IV and the new DSM-5 delirium criteria varies considerably depending on the interpretation of criteria. Overly-strict adherence for some new text details in DSM-5 criteria would reduce the number of delirium cases diagnosed; however, a more 'relaxed' approach renders DSM-5 criteria comparable to DSM-IV with minimal impact on their actual application and is thus recommended. C1 [Meagher, David J.; Leonard, Maeve; Cullen, Walter; Dunne, Colum] Univ Limerick, Grad Entry Med Sch, Limerick, Ireland. [Meagher, David J.; Adamis, Dimitrios; Leonard, Maeve; Cullen, Walter; Dunne, Colum] Univ Limerick, Grad Entry Med Sch, Ctr Intervent Infect Inflammat & Immun 4i, Cognit Impairment Res Grp, Limerick, Ireland. [Meagher, David J.; Leonard, Maeve] Univ Hosp Limerick, Dept Psychiat, Limerick, Ireland. [Morandi, Alessandro] Rehabil & Aged Care Unit Hosp Ancelle, Cremona, Italy. [Morandi, Alessandro; Bellelli, Giuseppe] Geriatr Res Grp, Brescia, Italy. [Inouye, Sharon K.] Hebrew SeniorLife, Inst Aging Res, Aging Brain Ctr, Boston, MA USA. [Inouye, Sharon K.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gerontol,Dept Med, Boston, MA 02215 USA. [Ely, Wes] Vanderbilt Univ, Ctr Med, Nashville, TN 37232 USA. [Ely, Wes] Tennessee Valley VA Geriatr Res Educ Clin Ctr GRE, Nashville, TN USA. [Adamis, Dimitrios] Res & Acad Inst Athens, Athens 10677, Greece. [Adamis, Dimitrios] Sligo Mental Hlth Serv, Ballytivan, Sligo, Ireland. [Maclullich, Alasdair J.] Univ Edinburgh, Sch Clin Sci, Div Hlth Sci, Edinburgh Delirium Res Grp, Edinburgh, Midlothian, Scotland. [Maclullich, Alasdair J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Rudolph, James L.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Rudolph, James L.] VA Boston Healthcare Syst, Div Geriatr & Palliat Care, Boston, MA USA. [Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rudolph, James L.] Harvard Univ, Sch Med, Boston, MA USA. [Neufeld, Karin] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Bellelli, Giuseppe] Univ Milano Bicocca, Monza, Italy. [Bellelli, Giuseppe] San Gerardo Hosp, Monza, Italy. [Davis, Daniel] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Teodorczuk, Andrew] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kreisel, Stefan] Bethel Evangel Krankenhaus, Dept Psychiat & Psychotherapy, Bielefeld, Germany. [Thomas, Christine] Klinikum Stuttgart, Ctr Mental Hlth, Dept Psychiat & Psychotherapy Aged, Stuttgart, Germany. [Hasemann, Wolfgang] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Timmons, Suzanne; O'Regan, Niamh] Natl Univ Ireland Univ Coll Cork, Sch Med, Ctr Gerontol & Rehabil, Cork, Ireland. [Grover, Sandeep] Postgrad Inst Med Educ & Res, Dept Psychiat, Chandigarh 160012, India. [Jabbar, Faiza] Univ Coll Hosp, Psychiat Later Life Serv, Galway, Ireland. [Kamholz, Barbara] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Van Munster, Barbara C.; De Rooij, Sophia E.] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, Geriatr Sect, NL-1105 AZ Amsterdam, Netherlands. [Van Munster, Barbara C.] Gelre Hosp, Dept Geriatr, Apeldoorn, Netherlands. [De Jonghe, Jos] Med Ctr Alkmaar, Dept Geriatr Med, Alkmaar, Netherlands. [Trzepacz, Paula T.] Lilly Res Labs, Indianapolis, IN USA. [Trzepacz, Paula T.] Univ Mississippi, Sch Med, Jackson, MS 39216 USA. [Trzepacz, Paula T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Trzepacz, Paula T.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Meagher, DJ (reprint author), Univ Limerick, Grad Entry Med Sch, Limerick, Ireland. EM david.meagher@ul.ie RI O'Regan, Niamh/I-6798-2016; Davis, Daniel/F-9995-2012; OI O'Regan, Niamh/0000-0003-2510-2495; Davis, Daniel/0000-0002-1560-1955; Cullen, Walter/0000-0003-1838-5052; Adamis, Dimitrios/0000-0003-1315-1695; Bellelli, Giuseppe/0000-0001-5430-0947; MacLullich, Alasdair/0000-0003-3159-9370; Teodorczuk, Andrew/0000-0003-0802-718X; Hasemann, Wolfgang/0000-0003-2417-3785 FU Johns Hopkins University from Ornim Medical LTD (PI Mandal); Wellcome Trust Research Training Fellowship [WT090661]; Health Research Board and All-Ireland Institute of Palliative Care; Swiss Alzheimer Association; Alzheimervereinigung beider Basel FX No specific funding was used to support this research. All of the authors are either members of the European Delirium Association or American Delirium Society, or both. PT is a salaried employee and shareholder of Eli Lilly and Company. Eli Lilly and Company do not presently have any product licensed for the treatment of delirium. Karin Neufeld receives Grant funding to Johns Hopkins University from Ornim Medical LTD (PI Mandal) for work exploring "The Relationship between NIRS and Delirium (Study of CerOx321F)" The purpose of this study is to understand the relationship between intraoperative cerebral autoregulation of blood pressure using the CerOx321F monitor and incidence of postoperative delirium in a group of older aged patients undergoing cardiac surgery who are free of delirium and major cognitive deficits in the preoperative setting. Daniel Davis was supported by a Wellcome Trust Research Training Fellowship (WT090661). David Meagher, Suzanne Timmons, Maeve Leonard and Niamh O'Regan are in receipt of project grants from the Health Research Board and All-Ireland Institute of Palliative Care. Wolfgang Hasemann has received funding from the Swiss Alzheimer Association and the Alzheimervereinigung beider Basel. The other authors declare that they have no competing interests. NR 39 TC 16 Z9 16 U1 5 U2 13 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 SEP 30 PY 2014 VL 12 AR 164 DI 10.1186/s12916-014-0164-8 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AT4DF UT WOS:000344889100001 PM 25266390 ER PT J AU Bhattacharyya, S Kim, M AF Bhattacharyya, Shamik Kim, Minjee TI Cervical spine fracture associated with ankylosing spondylitis SO NEUROLOGY LA English DT Editorial Material C1 [Bhattacharyya, Shamik] Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bhattacharyya, S (reprint author), Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. EM sbhattacharyya3@partners.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 30 PY 2014 VL 83 IS 14 BP 1297 EP 1297 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AT3UN UT WOS:000344860700018 PM 25267984 ER PT J AU Alshareef, M Krishna, V Ferdous, J Alshareef, A Kindy, M Kolachalama, VB Shazly, T AF Alshareef, Mohammed Krishna, Vibhor Ferdous, Jahid Alshareef, Ahmed Kindy, Mark Kolachalama, Vijaya B. Shazly, Tarek TI Effect of Spinal Cord Compression on Local Vascular Blood Flow and Perfusion Capacity SO PLOS ONE LA English DT Article ID NO-REFLOW PHENOMENON; CEREBROSPINAL-FLUID; FINITE-ELEMENT; CERVICAL-SPINE; INJURY MODEL; TRAUMA; MECHANISMS; PATHOPHYSIOLOGY; NOREPINEPHRINE; PRESSURE AB Spinal cord injury (SCI) can induce prolonged spinal cord compression that may result in a reduction of local tissue perfusion, progressive ischemia, and potentially irreversible tissue necrosis. Due to the combination of risk factors and the varied presentation of symptoms, the appropriate method and time course for clinical intervention following SCI are not always evident. In this study, a three-dimensional finite element fluid-structure interaction model of the cervical spinal cord was developed to examine how traditionally sub-clinical compressive mechanical loads impact spinal arterial blood flow. The spinal cord and surrounding dura mater were modeled as linear elastic, isotropic, and incompressible solids, while blood was modeled as a single-phased, incompressible Newtonian fluid. Simulation results indicate that anterior, posterior, and anteroposterior compressions of the cervical spinal cord have significantly different ischemic potentials, with prediction that the posterior component of loading elevates patient risk due to the concomitant reduction of blood flow in the arterial branches. Conversely, anterior loading compromises flow through the anterior spinal artery but minimally impacts branch flow rates. The findings of this study provide novel insight into how sub-clinical spinal cord compression could give rise to certain disease states, and suggest a need to monitor spinal artery perfusion following even mild compressive loading. C1 [Alshareef, Mohammed] Med Univ S Carolina, Coll Med, Charleston, SC 29425 USA. [Krishna, Vibhor; Kindy, Mark] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Ferdous, Jahid; Shazly, Tarek] Univ S Carolina, Biomed Engn Program, Columbia, SC 29208 USA. [Alshareef, Ahmed] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Kindy, Mark] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Kolachalama, Vijaya B.] Charles Stark Draper Lab, Cambridge, MA USA. [Shazly, Tarek] Univ S Carolina, Dept Mech Engn, Columbia, SC 29208 USA. RP Shazly, T (reprint author), Univ S Carolina, Biomed Engn Program, Columbia, SC 29208 USA. EM shazly@mailbox.sc.edu FU National Science Foundation [EPS-0903795, IIP-917987]; National Institutes of Health [R01 ES016774-01, 5 P20 RR016461, 8P20GM103444-04, P20RR021949-03]; VA Merit Award; Charles Stark Draper Laboratory [CSDL-29414-005] FX This work was supported by the National Science Foundation (EPS-0903795 and IIP-917987), the National Institutes of Health (R01 ES016774-01, 5 P20 RR016461, 8P20GM103444-04 and P20RR021949-03), a VA Merit Award, and a grant (CSDL-29414-005) from the Charles Stark Draper Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 1 U1 2 U2 4 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 SEP 30 PY 2014 VL 9 IS 9 AR e108820 DI 10.1371/journal.pone.0108820 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700170 PM 25268384 ER PT J AU Liao, J Jijon, HB Kim, IR Goel, G Sokol, H Bauer, H Herrmann, BG Lassen, KG Xavier, RJ AF Liao, Juan Jijon, Humberto B. Kim, Ira R. Goel, Gautam Sokol, Harry Bauer, Hermann Herrmann, Bernhard G. Lassen, Kara G. Xavier, Ramnik J. TI An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; GENOME-WIDE ASSOCIATION; NF-KAPPA-B; TOLL-LIKE RECEPTORS; RHEUMATOID-ARTHRITIS RISK; I INTERFERON-PRODUCTION; GAMMA-INTERFERON; RIG-I; INTERLEUKIN-27 EXPRESSION; SIGNALING PROTEIN AB The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-gamma) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-beta. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. C1 [Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Lassen, Kara G.; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Sokol, Harry; Lassen, Kara G.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Bauer, Hermann; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Ctr Study Inflammatory Bowe, Boston, MA USA. [Jijon, Humberto B.] Univ Calgary, Dept Med, Div Gastroenterol, Calgary, AB, Canada. [Sokol, Harry] St Antoine Hosp, AP HP, Dept Gastroenterol, Paris, France. [Bauer, Hermann; Herrmann, Bernhard G.] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. RP Xavier, RJ (reprint author), Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. EM xavier@molbio.mgh.harvard.edu OI sokol, harry/0000-0002-2914-1822 FU Leona M. and Harry B. Helmsley Charitable Trust; Juvenile Diabetes Research Foundation FX This research was funded by the Leona M. and Harry B. Helmsley Charitable Trust (www.helmsleytrust.org) and Juvenile Diabetes Research Foundation (www.jdrf.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 2 Z9 2 U1 2 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 SEP 30 PY 2014 VL 9 IS 9 AR e108777 DI 10.1371/journal.pone.0108777 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700162 PM 25268627 ER PT J AU Podrid, PJ AF Podrid, Philip J. TI Response to Letter Regarding Article, "ECG Response: May 20, 2014" SO CIRCULATION LA English DT Letter C1 [Podrid, Philip J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Podrid, Philip J.] Harvard Univ, Sch Med, Boston, MA USA. [Podrid, Philip J.] VA Boston Healthcare Syst, Boston, MA USA. RP Podrid, PJ (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 30 PY 2014 VL 130 IS 14 BP E128 EP E128 DI 10.1161/CIRCULATIONAHA.114.012965 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AQ8CA UT WOS:000343048800004 PM 25266866 ER PT J AU Gard, T Noggle, JJ Park, CL Vago, DR Wilson, A AF Gard, Tim Noggle, Jessica J. Park, Crystal L. Vago, David R. Wilson, Angela TI Potential self-regulatory mechanisms of yoga for psychological health SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE yoga; self-regulation; stress; executive control; viscerosomatic; top-down; bottom-up ID CARDIAC VAGAL TONE; POSTTRAUMATIC-STRESS-DISORDER; AUTONOMIC NERVOUS-SYSTEM; EMOTION-REGULATION; MEDITATION PRACTITIONERS; MINDFULNESS PRACTICE; COGNITIVE CONTROL; CHEMOREFLEX RESPONSE; PHYSICAL-ACTIVITY; BREATH AWARENESS AB Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga's potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. C1 [Gard, Tim] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gard, Tim] Univ Giessen, Bender Inst Neuroimaging, D-35390 Giessen, Germany. [Gard, Tim] Maastricht Univ, Fac Psychol & Neurosci, Maastricht, Netherlands. [Noggle, Jessica J.; Vago, David R.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Noggle, Jessica J.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02467 USA. [Park, Crystal L.] Univ Connecticut, Dept Psychol, Storrs, CT USA. [Vago, David R.] Brigham & Womens Hosp, Dept Psychiat, Funct Neuroimaging Lab, Boston, MA 02467 USA. [Wilson, Angela] Kripalu Ctr Yoga & Hlth, Inst Extraordinary Living, Stockbridge, MA USA. RP Vago, DR (reprint author), Brigham & Womens Hosp, Dept Psychiat, Funct Neuroimaging Lab, 824 Boylston St, Boston, MA 02467 USA. EM dvago@bics.bwh.harvard.edu OI Vago, David/0000-0002-6269-9027 NR 186 TC 30 Z9 31 U1 18 U2 73 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 30 PY 2014 VL 8 AR 770 DI 10.3389/fnhum.2014.00770 PG 20 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AP8PA UT WOS:000342339700001 PM 25368562 ER PT J AU Lepage, KQ Kramer, MA Chu, CJ AF Lepage, Kyle Q. Kramer, Mark A. Chu, Catherine J. TI A statistically robust EEG re-referencing procedure to mitigate reference effect SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article ID COMMON SPATIAL-PATTERNS; INFINITY REFERENCE; AVERAGE REFERENCE; ELECTROENCEPHALOGRAPHY; STANDARDIZE; POTENTIALS; COHERENCY; SIGNAL AB Background: The electroencephalogram (EEG) remains the primary tool for diagnosis of abnormal brain activity in clinical neurology and for in vivo recordings of human neurophysiology in neuroscience research. In EEG data acquisition, voltage is measured at positions on the scalp with respect to a reference electrode. When this reference electrode responds to electrical activity or artifact all electrodes are affected. Successful analysis of EEG data often involves re-referencing procedures that modify the recorded traces and seek to minimize the impact of reference electrode activity upon functions of the original EEG recordings. New method: We provide a novel, statistically robust procedure that adapts a robust maximum-likelihood type estimator to the problem of reference estimation, reduces the influence of neural activity from the re-referencing operation, and maintains good performance in a wide variety of empirical scenarios. Results: The performance of the proposed and existing re-referencing procedures are validated in simulation and with examples of EEG recordings. To facilitate this comparison, channel-to-channel correlations are investigated theoretically and in simulation. Comparison with existing methods: The proposed procedure avoids using data contaminated by neural signal and remains unbiased in recording scenarios where physical references, the common average reference (CAR) and the reference estimation standardization technique (REST) are not optimal. Conclusion: The proposed procedure is simple, fast, and avoids the potential for substantial bias when analyzing low-density EEG data. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lepage, Kyle Q.; Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Chu, Catherine J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lepage, KQ (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM lepage@math.bu.edu; mak@bu.edu FU Burroughs Welcome Fund; NIH [5K12NS066225-03]; [DMS-1042134] FX KQL is supported by DMS-1042134. MAK holds a career award at the scientific interface from the Burroughs Welcome Fund. CJC is supported by NIH 5K12NS066225-03. NR 39 TC 6 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 30 PY 2014 VL 235 BP 101 EP 116 DI 10.1016/j.jneumeth.2014.05.008 PG 16 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AP7PO UT WOS:000342269400012 PM 24975291 ER PT J AU Schmeidler, J Lazzeroni, LC Swerdlow, NR Ferreira, RP Braff, DL Calkins, ME Cadenhead, KS Freedman, R Green, MF Greenwood, TA Gur, RE Gur, RC Light, GA Olincy, A Nuechterlein, KH Radant, AD Seidman, LJ Siever, LJ Stone, WS Sprock, J Sugar, CA Tsuang, DW Tsuang, MT Turetsky, BI Silverman, JM AF Schmeidler, James Lazzeroni, Laura C. Swerdlow, Neal R. Ferreira, Rui P. Braff, David L. Calkins, Monica E. Cadenhead, Kristin S. Freedman, Robert Green, Michael F. Greenwood, Tiffany A. Gur, Raquel E. Gur, Ruben C. Light, Gregory A. Olincy, Ann Nuechterlein, Keith H. Radant, Allen D. Seidman, Larry J. Siever, Larry J. Stone, William S. Sprock, Joyce Sugar, Catherine A. Tsuang, Debby W. Tsuang, Ming T. Turetsky, Bruce I. Silverman, Jeremy M. TI Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings SO PSYCHIATRY RESEARCH LA English DT Article DE De novo mutations; Copy number variants; Genetic risk; Familial schizophrenia; Sporadic schizophrenia ID DE-NOVO MUTATIONS; AUDITORY WORKING-MEMORY; RISK; GENETICS; PERFORMANCE; CONSORTIUM; STARTLE AB We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes. Published by Elsevier Ireland Ltd. C1 [Schmeidler, James; Ferreira, Rui P.; Siever, Larry J.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Lazzeroni, Laura C.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Swerdlow, Neal R.; Braff, David L.; Cadenhead, Kristin S.; Greenwood, Tiffany A.; Light, Gregory A.; Sprock, Joyce; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Braff, David L.; Light, Gregory A.] VA San Diego Healthcare Syst, Educ & Clin Ctr, VISN Mental Illness Res 22, San Diego, CA USA. [Calkins, Monica E.; Gur, Raquel E.; Gur, Ruben C.; Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Freedman, Robert; Olincy, Ann] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Green, Michael F.; Nuechterlein, Keith H.; Sugar, Catherine A.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Geffen Sch Med, Los Angeles, CA 90024 USA. [Green, Michael F.; Sugar, Catherine A.] VA Greater Angeles Hlth Care Syst, Los Angeles, CA USA. [Radant, Allen D.; Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Seidman, Larry J.; Stone, William S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med,Dept Psychiat, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02215 USA. [Siever, Larry J.] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 3, New York, NY USA. [Tsuang, Debby W.] VA Puget Sound Hlth Care Syst, VISN Geriatr Res Educ & Clin Ctr 20, Seattle, WA USA. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Silverman, JM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM jeremy.silverman@mssm.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Lazzeroni, Laura/0000-0002-1846-6920; Greenwood, Tiffany/0000-0002-6080-6503 FU NIMH [R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, R01 MH65558] FX This material is based upon work supported by NIMH grants R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, and R01 MH65558. We are grateful to all the subjects who participated in this study. NR 25 TC 1 Z9 1 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2014 VL 219 IS 1 BP 67 EP 71 DI 10.1016/j.psychres.2014.05.035 PG 5 WC Psychiatry SC Psychiatry GA AL4ZQ UT WOS:000339143700006 PM 24913833 ER PT J AU Lynn, SK Hoge, EA Fischer, LE Barrett, LF Simon, NM AF Lynn, Spencer K. Hoge, Elizabeth A. Fischer, Laura E. Barrett, Lisa Feldman Simon, Naomi M. TI Gender differences in oxytocin-associated disruption of decision bias during emotion perception SO PSYCHIATRY RESEARCH LA English DT Article DE Signal detection theory; Face perception; Risk sensitivity; Behavioral economics ID INTRANASAL OXYTOCIN; FACIAL EXPRESSIONS; SOCIAL COGNITION; NEURAL CIRCUITRY; HUMANS; RECOGNITION; TRUST; METAANALYSIS; SENSITIVITY; DEPRESSION AB Oxytocin is associated with differences in the perception of and response to socially mediated information, such as facial expressions. Across studies, however, oxytocin's effect on emotion perception has been inconsistent. Outside the laboratory, emotion perception involves interpretation of perceptual uncertainty and assessment of behavioral risk. An account of these factors is largely missing from studies of oxytocin's effect on emotion perception and might explain inconsistent results across studies. Of relevance, studies of oxytocin's effect on learning and decision-making indicate that oxytocin attenuates risk aversion. We used the probability of encountering angry faces and the cost of misidentifying them as not angry to create a risky environment wherein bias to categorize faces as angry would maximize point earnings. Consistent with an underestimation of the factors creating risk (i.e., encounter rate and cost), men given oxytocin exhibited a worse (i.e., less liberal) response bias than men given placebo. Oxytocin did not influence women's performance. These results suggest that oxytocin may impair men's ability to adapt to changes in risk and uncertainty when introduced to novel or changing social environments. Because oxytocin also influences behavior in non-social realms, oxytocin pharmacotherapy could have unintended consequences (i.e., risk-prone decision-making) while nonetheless normalizing pathological social interaction. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Lynn, Spencer K.; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Hoge, Elizabeth A.; Fischer, Laura E.; Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, Boston, MA 02114 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Lynn, SK (reprint author), Northeastern Univ, Dept Psychol, 360 Huntington Ave, Boston, MA 02115 USA. EM s.lynn@neu.edu RI Hoge, Elizabeth/H-5879-2012 OI Hoge, Elizabeth/0000-0002-5513-2292 FU Highland Street Foundation; National Institutes of Health [R01MH093394, DP1OD 003312] FX We thank the members of the Interdisciplinary Affective Science Laboratory, Dept. Psychology, Northeastern University, for helpful feedback during the development of the manuscript. Preparation of this manuscript was supported by the Highland Street Foundation (Hoge, Simon, Fischer) and the National Institutes of Health (R01MH093394 to Lynn & Simon and DP1OD 003312 to Barrett). NR 41 TC 8 Z9 8 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2014 VL 219 IS 1 BP 198 EP 203 DI 10.1016/j.psychres.2014.04.031 PG 6 WC Psychiatry SC Psychiatry GA AL4ZQ UT WOS:000339143700026 PM 24814142 ER PT J AU Tan-McGrory, A Betancourt, J AF Tan-McGrory, Aswita Betancourt, Joseph TI Addressing language barriers and improving quality of transitions and discharge SO ISRAEL JOURNAL OF HEALTH POLICY RESEARCH LA English DT Editorial Material ID LENGTH-OF-STAY; READMISSIONS; DISPARITIES; CONCORDANCE; CARE AB The article by Rayan et al., "Transitions from Hospital to Community Care: the Role of Patient-Provider Language Concordance", highlights the importance of language-concordant communication and care during the hospital discharge process. These findings are completely in line with previous research on the impact of language barriers on quality of care. We strongly agree with Rayan et al. and the findings of this important research, and support efforts that help meet the cultural and linguistic needs of patients. Undoubtedly, patient-provider language concordance during the hospitalization discharge process and post discharge follow-up have important implications for health care transitions, quality, and costs. How can hospitals improve their performance in this area? Based on extensive research, there are currently two major hospital guides that were developed in the United States that focus on this area-improving communication and care for patients of diverse backgrounds and with language barriers. One, Project RED-or Re-Engineered Discharge, and the second, Improving Patient Safety Systems for Patients With Limited English Proficiency: A Guide for Hospitals, both aim to address these challenges. If we are to truly delivery high-quality, safe, cost-effective care, meeting the needs of patients who experience language barriers during health care will be essential as global migration and diversity increases every day. C1 [Tan-McGrory, Aswita; Betancourt, Joseph] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. RP Betancourt, J (reprint author), Massachusetts Gen Hosp, Dispar Solut Ctr, 50 Staniford St,9th Floor,Suite 901, Boston, MA 02114 USA. EM jbetancourt@partners.org NR 12 TC 0 Z9 0 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-4015 J9 ISR J HEALTH POLICY JI Isr. J. Health Policy Res. PD SEP 29 PY 2014 VL 3 AR 31 DI 10.1186/2045-4015-3-31 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AS1HG UT WOS:000344031000002 ER PT J AU Kai, X Chellappa, V Donado, C Reyon, D Sekigami, Y Ataca, D Louissaint, A Mattoo, H Joung, JK Pillai, S AF Kai, Xin Chellappa, Vasant Donado, Carlos Reyon, Deepak Sekigami, Yurie Ataca, Dalya Louissaint, Abner Mattoo, Hamid Joung, J. Keith Pillai, Shiv TI I kappa B Kinase beta(IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor kappa B (NF kappa B) Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MARGINAL ZONE LYMPHOMA; CELL LYMPHOMA; GENOME; LYMPHOCYTES; NOTCH2; PROLIFERATION; REGULATOR; MULTIPLE; PATHWAY; TALENS AB Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKK beta), the critical activating kinase in canonical (NF kappa B) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKK beta and K171T IKK beta represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKK beta contributes to lymphomagenesis. C1 [Kai, Xin; Chellappa, Vasant; Donado, Carlos; Sekigami, Yurie; Ataca, Dalya; Mattoo, Hamid; Pillai, Shiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02129 USA. [Reyon, Deepak; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. [Louissaint, Abner; Joung, J. Keith] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Louissaint, Abner; Joung, J. Keith] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Pillai, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02129 USA. EM pillai@helix.mgh.harvard.edu OI Ataca, Dalya/0000-0003-3964-5618 FU National Institutes of Health [AI 064930, AI 076505]; National Institutes of Health Director's Pioneer Award [DP1 GM105378] FX This work was supported, in whole or in part, by Grants AI 064930 and AI 076505 from the National Institutes of Health (to S. P.) and National Institutes of Health Director's Pioneer Award DP1 GM105378 (to J. K. J.). J. K. J. has a financial interest in Editas Medicine and Transposagen Biopharmaceuticals. J. K. J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 35 TC 5 Z9 6 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 26 PY 2014 VL 289 IS 39 BP 26960 EP 26972 DI 10.1074/jbc.M114.598763 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ5MS UT WOS:000342853900026 PM 25107905 ER PT J AU Bourgeois, EB Johnson, BN McCoy, AJ Trippa, L Cohen, AS Marsh, ED AF Bourgeois, Elliot B. Johnson, Brian N. McCoy, Almedia J. Trippa, Lorenzo Cohen, Akiva S. Marsh, Eric D. TI A Toolbox for Spatiotemporal Analysis of Voltage-Sensitive Dye Imaging Data in Brain Slices SO PLOS ONE LA English DT Article ID TEMPORAL-LOBE EPILEPSY; IN-VITRO; HIPPOCAMPUS; MUTATIONS; MODEL AB Voltage-sensitive dye imaging (VSDI) can simultaneously monitor the spatiotemporal electrical dynamics of thousands of neurons and is often used to identify functional differences in models of neurological disease. While the chief advantage of VSDI is the ability to record spatiotemporal activity, there are no tools available to visualize and statistically compare activity across the full spatiotemporal range of the VSDI dataset. Investigators commonly analyze only a subset of the data, and a majority of the dataset is routinely excluded from analysis. We have developed a software toolbox that simplifies visual inspection of VSDI data, and permits unaided statistical comparison across spatial and temporal dimensions. First, the three-dimensional VSDI dataset (x, y, time) is geometrically transformed into a two-dimensional spatiotemporal map of activity. Second, statistical comparison between groups is performed using a non-parametric permutation test. The result is a 2D map of all significant differences in both space and time. Here, we used the toolbox to identify functional differences in activity in VSDI data from acute hippocampal slices obtained from epileptic Arx conditional knock-out and control mice. Maps of spatiotemporal activity were produced and analyzed to identify differences in the activity evoked by stimulation of each of two axonal inputs to the hippocampus: the perforant pathway and the temporoammonic pathway. In mutant hippocampal slices, the toolbox identified a widespread decrease in spatiotemporal activity evoked by the temporoammonic pathway. No significant differences were observed in the activity evoked by the perforant pathway. The VSDI toolbox permitted us to visualize and statistically compare activity across the spatiotemporal scope of the VSDI dataset. Sampling error was minimized because the representation of the data is standardized by the toolbox. Statistical comparisons were conducted quickly, across the spatiotemporal scope of the data, without a priori knowledge of the character of the responses or the likely differences between them. C1 [Bourgeois, Elliot B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bourgeois, Elliot B.] Harvard Univ, Sch Med, Boston, MA USA. [Johnson, Brian N.; McCoy, Almedia J.; Cohen, Akiva S.; Marsh, Eric D.] Childrens Hosp Philadelphia, Dept Pediat, Div Pediat Neurol, Philadelphia, PA 19104 USA. [Trippa, Lorenzo] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cohen, Akiva S.; Marsh, Eric D.] Univ Penn, Dept Neurol, Div Pediat Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Bourgeois, EB (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM ebbourgeois@partners.org FU US National Institutes of Health [F32 NS080556, K02 NS065975, R01 NS082761, R01 HD059288, R01 NS069629, R01 NS046616] FX Funding for this work was provided by the US National Institutes of Health to EBB (F32 NS080556), EDM (K02 NS065975 and R01 NS082761), ASC (R01 HD059288 and R01 NS069629), and Jeffrey A. Golden (R01 NS046616). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 4 Z9 4 U1 1 U2 7 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 SEP 26 PY 2014 VL 9 IS 9 AR e108686 DI 10.1371/journal.pone.0108686 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3IP UT WOS:000342685600093 PM 25259520 ER PT J AU Pham-Kanter, G Zinner, DE Campbell, EG AF Pham-Kanter, Genevieve Zinner, Darren E. Campbell, Eric G. TI Codifying Collegiality: Recent Developments in Data Sharing Policy in the Life Sciences SO PLOS ONE LA English DT Article ID PATENTS AB Over the last decade, there have been significant changes in data sharing policies and in the data sharing environment faced by life science researchers. Using data from a 2013 survey of over 1600 life science researchers, we analyze the effects of sharing policies of funding agencies and journals. We also examine the effects of new sharing infrastructure and tools (i.e., third party repositories and online supplements). We find that recently enacted data sharing policies and new sharing infrastructure and tools have had a sizable effect on encouraging data sharing. In particular, third party repositories and online supplements as well as data sharing requirements of funding agencies, particularly the NIH and the National Human Genome Research Institute, were perceived by scientists to have had a large effect on facilitating data sharing. In addition, we found a high degree of compliance with these new policies, although noncompliance resulted in few formal or informal sanctions. Despite the overall effectiveness of data sharing policies, some significant gaps remain: about one third of grant reviewers placed no weight on data sharing plans in their reviews, and a similar percentage ignored the requirements of material transfer agreements. These patterns suggest that although most of these new policies have been effective, there is still room for policy improvement. C1 [Pham-Kanter, Genevieve] Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Philadelphia, PA 19104 USA. [Pham-Kanter, Genevieve] Harvard Univ, Edmond J Safra Ctr Eth, Boston, MA 02115 USA. [Zinner, Darren E.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA USA. RP Pham-Kanter, G (reprint author), Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Philadelphia, PA 19104 USA. EM gpkanter@drexel.edu OI Pham-Kanter, Genevieve/0000-0002-3044-7829 FU National Human Genome Research Institute [R01 HG006281]; Edmond J. Safra Center for Ethics at Harvard University; Brandeis University's Health Industry Forum FX This research was supported by the National Human Genome Research Institute (R01 HG006281). Genevieve Pham-Kanter is partially supported by the Edmond J. Safra Center for Ethics at Harvard University. Darren Zinner is partially supported by Brandeis University's Health Industry Forum, an independent policy consortium of major health care insurers, delivery systems, and biopharmaceutical and medical device firms. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 9 Z9 9 U1 1 U2 16 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 SEP 26 PY 2014 VL 9 IS 9 AR e108451 DI 10.1371/journal.pone.0108451 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3IP UT WOS:000342685600074 PM 25259842 ER PT J AU Saeed, S Quintin, J Kerstens, HHD Rao, NA Aghajanirefah, A Matarese, F Cheng, SC Ratter, J Berentsen, K van der Ent, MA Sharifi, N Janssen-Megens, EM Ter Huurne, M Mandoli, A van Schaik, T Ng, A Burden, F Downes, K Frontini, M Kumar, V Giamarellos-Bourboulis, EJ Ouwehand, WH van der Meer, JWM Joosten, LAB Wijmenga, C Martens, JHA Xavier, RJ Logie, C Netea, MG Stunnenberg, HG AF Saeed, Sadia Quintin, Jessica Kerstens, Hindrik H. D. Rao, Nagesha A. Aghajanirefah, Ali Matarese, Filomena Cheng, Shih-Chin Ratter, Jacqueline Berentsen, Kim van der Ent, Martijn A. Sharifi, Nilofar Janssen-Megens, Eva M. Ter Huurne, Menno Mandoli, Amit van Schaik, Tom Ng, Aylwin Burden, Frances Downes, Kate Frontini, Mattia Kumar, Vinod Giamarellos-Bourboulis, Evangelos J. Ouwehand, Willem H. van der Meer, Jos W. M. Joosten, Leo A. B. Wijmenga, Cisca Martens, Joost H. A. Xavier, Ramnik J. Logie, Colin Netea, Mihai G. Stunnenberg, Hendrik G. TI Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity SO SCIENCE LA English DT Article ID LIVER X RECEPTOR; NF-KAPPA-B; GENE-EXPRESSION; DENDRITIC CELLS; HOST-DEFENSE; TRANSCRIPTION FACTORS; REGULATORY ELEMENTS; HUMAN GENOME; IRAK-M; INFLAMMATION AB Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. C1 [Saeed, Sadia; Kerstens, Hindrik H. D.; Rao, Nagesha A.; Aghajanirefah, Ali; Matarese, Filomena; Berentsen, Kim; van der Ent, Martijn A.; Sharifi, Nilofar; Janssen-Megens, Eva M.; Ter Huurne, Menno; Mandoli, Amit; van Schaik, Tom; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Kerstens, Hindrik H. D.; Rao, Nagesha A.; Aghajanirefah, Ali; Matarese, Filomena; Berentsen, Kim; van der Ent, Martijn A.; Sharifi, Nilofar; Janssen-Megens, Eva M.; Ter Huurne, Menno; Mandoli, Amit; van Schaik, Tom; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Med, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Quintin, Jessica; Cheng, Shih-Chin; Ratter, Jacqueline; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Burden, Frances; Downes, Kate; Frontini, Mattia; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Burden, Frances; Downes, Kate; Frontini, Mattia; Ouwehand, Willem H.] Blood & Transplant Cambridge Ctr, Natl Hlth Serv, Cambridge CB0 2PT, England. [Kumar, Vinod; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med 1, Dept Internal Med 4, Athens 12462, Greece. RP Stunnenberg, HG (reprint author), Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. EM c.logie@ncmls.ru.nl; mihai.netea@radboudumc.nl; h.stunnenberg@ncmls.ru.nl RI Stunnenberg, Hendrik/D-6875-2012; Netea, Mihai/N-5155-2014; Ratter, Jacqueline/G-6301-2016; van der Meer, Jos/C-8521-2013; Wijmenga, Cisca/D-2173-2009; CHENG, SHIH-CHIN/H-4567-2015; Logie, Colin/A-1528-2010; Joosten, Leo/H-3138-2015 OI Ratter, Jacqueline/0000-0002-3807-9442; van der Meer, Jos/0000-0001-5120-3690; Wijmenga, Cisca/0000-0002-5635-1614; CHENG, SHIH-CHIN/0000-0003-1251-8774; Giamarellos-Bourboulis, Evangelos/0000-0003-4713-3911; Ouwehand, Willem/0000-0002-7744-1790; Logie, Colin/0000-0002-8534-6582; FU European Union [282510-BLUEPRINT]; Netherlands Organization for Scientific Research; ERC [310372] FX The authors are grateful to J. Stamatoyannopoulos for help with DNaseI-seq. We thank S. van Heeringen for access to his databases and expertise. The research leading to the results described in this manuscript has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282510-BLUEPRINT. M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant (no. 310372) and J.H.A.M by a VIDI grant of the Netherlands Organization for Scientific Research. All the genome-wide data generated and analyzed in this study, as well as the sequencing details, can be accessed via GEO accession no. GSE58310. NR 68 TC 180 Z9 181 U1 16 U2 80 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD SEP 26 PY 2014 VL 345 IS 6204 BP 1578 EP + AR 1251086 DI 10.1126/science.1251086 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP6CG UT WOS:000342164500033 PM 25258085 ER PT J AU Cheng, SC Quintin, J Cramer, RA Shepardson, KM Saeed, S Kumar, V Giamarellos-Bourboulis, EJ Martens, JHA Rao, NA Aghajanirefah, A Manjeri, GR Li, Y Ifrim, DC Arts, RJW van der Meer, BMJW Deen, PMT Logie, C O'Neill, LA Willems, P van de Veerdonk, FL van der Meer, JWM Ng, A Joosten, LAB Wijmenga, C Stunnenberg, HG Xavier, RJ Netea, MG AF Cheng, Shih-Chin Quintin, Jessica Cramer, Robert A. Shepardson, Kelly M. Saeed, Sadia Kumar, Vinod Giamarellos-Bourboulis, Evangelos J. Martens, Joost H. A. Rao, Nagesha Appukudige Aghajanirefah, Ali Manjeri, Ganesh R. Li, Yang Ifrim, Daniela C. Arts, Rob J. W. van der Meer, Brian M. J. W. Deen, Peter M. T. Logie, Colin O'Neill, Luke A. Willems, Peter van de Veerdonk, Frank L. van der Meer, Jos W. M. Ng, Aylwin Joosten, Leo A. B. Wijmenga, Cisca Stunnenberg, Hendrik G. Xavier, Ramnik J. Netea, Mihai G. TI mTOR- and HIF-1 alpha-mediated aerobic glycolysis as metabolic basis for trained immunity SO SCIENCE LA English DT Article ID INNATE IMMUNITY; BETA-GLUCAN; CELLS; MACROPHAGES; ACTIVATION; INFECTION; INFLAMMATION; REINFECTION; EXPRESSION; PROTECTION AB Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained immunity. C1 [Cheng, Shih-Chin; Quintin, Jessica; Ifrim, Daniela C.; Arts, Rob J. W.; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Cramer, Robert A.; Shepardson, Kelly M.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH 03755 USA. [Saeed, Sadia; Martens, Joost H. A.; Rao, Nagesha Appukudige; Aghajanirefah, Ali; Logie, Colin] Radboud Univ Nijmegen, Fac Sci, Nijmegen Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Rao, Nagesha Appukudige; Aghajanirefah, Ali; Logie, Colin] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Kumar, Vinod; Li, Yang; van der Meer, Brian M. J. W.; Wijmenga, Cisca; Stunnenberg, Hendrik G.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med, Dept Internal Med 4, Athens 12462, Greece. [Manjeri, Ganesh R.; Willems, Peter] Radboud Univ Nijmegen, Fac Sci, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6500 HB Nijmegen, Netherlands. [Manjeri, Ganesh R.; Willems, Peter] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6500 HB Nijmegen, Netherlands. [Deen, Peter M. T.] Radboud Univ Nijmegen, Dept Physiol, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [O'Neill, Luke A.] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. EM mihal.netea@radboudumc.nl RI Stunnenberg, Hendrik/D-6875-2012; Logie, Colin/A-1528-2010; Deen, P.M.T./H-8023-2014; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; Arts, Rob/P-8678-2015; van de Veerdonk, Frank/C-7256-2008; Willems, P.H.G.M./L-4759-2015; van der Meer, Jos/C-8521-2013; Wijmenga, Cisca/D-2173-2009; Cheng, Shih-Chin/H-4567-2015 OI Logie, Colin/0000-0002-8534-6582; Deen, P.M.T./0000-0002-7868-4655; Arts, Rob/0000-0002-6649-7190; van de Veerdonk, Frank/0000-0002-1121-4894; Willems, P.H.G.M./0000-0002-0915-1599; van der Meer, Jos/0000-0001-5120-3690; Cheng, Shih-Chin/0000-0003-1251-8774 FU Netherlands Organization of Scientific Research [863.13.011]; ERC [310372]; European Research Council under European Union [2012-322698]; National Institute of General Medical Sciences [5P30GM103415-03, 1P30GM106394-01]; National Institute of Allergy and Infectious Diseases [R01AI81838]; Helmsley Trust; JDRF; [DK43351]; [DK097485] FX S.-C. C., J.Q., and M.G.N. were supported by a Vici grant of the Netherlands Organization of Scientific Research and ERC Consolidator grant 310372 (both to M.G.N). C. W. is supported by funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC grant agreement 2012-322698). Y.L. is supported by Veni grant 863.13.011 of the Netherlands Organization for Scientific Research. R. A. C. and K. M. S. were supported by National Institute of General Medical Sciences grant 5P30GM103415-03 (William Green, PI) and 1P30GM106394-01 (Bruce Stanton, PI), and National Institute of Allergy and Infectious Diseases grant R01AI81838 (R. A. C., PI). R.A.C./K.M.S. thank B. Berwin for the S. aureus. R.J.X funded by DK43351, DK097485, Helmsley Trust, and JDRF. The detailed data have been deposited in the GEO database with accession number GSE57206. NR 46 TC 177 Z9 180 U1 21 U2 82 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD SEP 26 PY 2014 VL 345 IS 6204 BP 1579 EP + AR 1250684 DI 10.1126/science.1250684 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP6CG UT WOS:000342164500034 PM 25258083 ER PT J AU Chen, XY Spaeth, RB Retzepi, K Ott, D Kong, J AF Chen, Xiaoyan Spaeth, Rosa B. Retzepi, Kallirroi Ott, Daniel Kong, Jian TI Acupuncture modulates cortical thickness and functional connectivity in knee osteoarthritis patients SO SCIENTIFIC REPORTS LA English DT Article ID CHRONIC BACK-PAIN; SURFACE-BASED ANALYSIS; MEDIAL FRONTAL-CORTEX; CENTRAL SENSITIZATION; COGNITIVE CONTROL; BRAIN NETWORKS; ELECTROACUPUNCTURE STIMULATION; PERIAQUEDUCTAL GRAY; ADJUNCTIVE THERAPY; PLACEBO ANALGESIA AB In this study, we investigated cortical thickness and functional connectivity across longitudinal acupuncture treatments in patients with knee osteoarthritis (OA). Over a period of four weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before their first, third and sixth treatments. Clinical outcome showed a significantly greater Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (improvement) with verum acupuncture compared to the sham acupuncture. Longitudinal cortical thickness analysis showed that the cortical thickness at left posterior medial prefrontal cortex (pMPFC) decreased significantly in the sham group across treatment sessions as compared with verum group. Resting state functional connectivity (rsFC) analysis using the left pMPFC as a seed showed that after longitudinal treatments, the rsFC between the left pMPFC and the rostral anterior cingulate cortex (rACC), medial frontal pole (mFP) and periaquiduct grey (PAG) are significantly greater in the verum acupuncture group as compared with the sham group. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by preventing cortical thinning and decreases in functional connectivity in major pain related areas, therefore modulating pain in the descending pain modulatory pathway. C1 [Chen, Xiaoyan; Spaeth, Rosa B.; Retzepi, Kallirroi; Ott, Daniel; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. RP Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu FU NCCAM [R21AT004497, R01AT006364, R01AT005280, P01 AT006663]; NIDA [R03AT218317] FX This work was supported by R21AT004497 (NCCAM), R03AT218317 (NIDA), R01AT006364 (NCCAM) to Jian Kong, R01AT005280 (NCCAM) to Randy Gollub, and P01 AT006663 to Bruce Rosen. There is no conflict of interest for any of the authors. We thank Dr. Martin Reuter from Martino center at Massachusetts General Hospital for his technique support. NR 95 TC 9 Z9 11 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 26 PY 2014 VL 4 AR 6482 DI 10.1038/srep06482 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8XB UT WOS:000342361600002 PM 25258037 ER PT J AU Lovett, DH Chu, C Wang, GY Ratcliffe, MB Baker, AJ AF Lovett, David H. Chu, Charles Wang, Guanying Ratcliffe, Mark B. Baker, Anthony J. TI A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE contraction; heart failure; myofilament; Ca2+ transient; remodeling; MMP-2 ID ISCHEMIA-REPERFUSION INJURY; EXPRESSION; DYSFUNCTION; INFARCTION; MYOCYTES; DISEASE; TARGETS; RAT AB The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT-MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca2+ transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL-MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca2+ transients, indicating impaired activation. Conclusions: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca2+ transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes. C1 [Lovett, David H.; Chu, Charles; Wang, Guanying; Ratcliffe, Mark B.; Baker, Anthony J.] San Francisco VA Med Ctr, Div Cardiol, San Francisco, CA USA. [Lovett, David H.; Chu, Charles; Wang, Guanying; Baker, Anthony J.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.] Joint UC Berkeley UCSF Bioengn Grp, San Francisco, CA USA. RP Baker, AJ (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Div Cardiol, 111C,4150 Clement St, San Francisco, CA 94121 USA. EM anthony.baker@ucsf.edu FU Department of Veterans Affairs Merit Review Awards [I01BX000593, I01BX000740]; National Heart, Lung and Blood Institute [R01-HL-84431, R01-HL-63348]; American Heart Association [10GRNT3720074] FX This work was supported by Department of Veterans Affairs Merit Review Awards I01BX000593 (David H. Lovett), and I01BX000740 (Anthony J. Baker), National Heart, Lung and Blood Institute Grants R01-HL-84431 and R01-HL-63348 (Mark B. Ratcliffe), and an American Heart Association Grant-in-Aid 10GRNT3720074 (Anthony J. Baker). We thank Paul Wang, and Kevin V. Thai for expert technical assistance. NR 24 TC 6 Z9 6 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 25 PY 2014 VL 5 AR 363 DI 10.3389/fphys.2014.00363 PG 7 WC Physiology SC Physiology GA AX7JQ UT WOS:000347092800001 PM 25309453 ER PT J AU Mazumder, R Murchison, C Bourdette, D Cameron, M AF Mazumder, Rajarshi Murchison, Charles Bourdette, Dennis Cameron, Michelle TI Falls in People with Multiple Sclerosis Compared with Falls in Healthy Controls SO PLOS ONE LA English DT Article ID OLDER-ADULTS; RISK-FACTORS; ACCIDENTAL FALLS; COHORT; CONSEQUENCES; COMMUNITY; BALANCE AB Objective: To compare the risk, circumstances, consequences and causes of prospectively recorded falls between people with multiple sclerosis (PwMS) and healthy controls of similar age and gender. Methods: 58 PwMS and 58 healthy controls, who are community-dwelling, were recruited in this 6-month prospective cohort study. 90% of PwMS and 84% of healthy controls completed the study. Participants counted falls prospectively using fall calendars and noted fall location, fall-related injuries, and the cause of the falls. Kaplan Meier survival analysis and log-rank tests were performed to compare the distributions of survival without falling between PwMS and healthy controls. Results: 40.8% of controls and 71.2% of PwMS fell at least once. 48.1% of PwMS and 18.4% of healthy controls fell at least twice. 42.3% of PwMS and 20.4% of health controls sustained a fall-related injury. After adjusting for age and gender, the time to first fall (HR: 1.87, p = 0.033) and the time to recurrent falls (HR: 2.87, p = 0.0082) were significantly different between PwMS and healthy controls. PwMS reported an almost equal number of falls inside and outside, 86% of the falls in healthy controls were outside. Healthy controls were more likely to fall due to slipping on a slippery surface (39.5% vs 10.4%). PwMS more often attributed falls to distraction (31% vs 7%) and uniquely attributed falls to fatigue or heat. Conclusions: Fall risk, circumstances, consequences, and causes are different for PwMS than for healthy people of the same age and gender. PwMS fall more, are more likely to be injured by a fall, and often fall indoors. PwMS, but not healthy controls, frequently fall because they are distracted, fatigued or hot. C1 [Mazumder, Rajarshi] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Murchison, Charles; Bourdette, Dennis; Cameron, Michelle] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Bourdette, Dennis; Cameron, Michelle] Portland VA Med Ctr, Portland, OR USA. RP Mazumder, R (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97201 USA. EM mazumder.rajrishi@gmail.com FU Oregon Multidisciplinary Training Program in Health Services Research from the Agency for Healthcare Research and Quality (AHRQ) [T32 HS017582]; Foundation of the Consortium of Multiple Sclerosis Centers Workforce of the Future; Department of Veterans Affairs Rehabilitation Research & Development Service [CDA-2]; Oregon Clinical and Translational Research Institute [1 UL1 RR024140 01] FX Rajarshi Mazumder was supported by the Oregon Multidisciplinary Training Program in Health Services Research, grant number T32 HS017582 from the Agency for Healthcare Research and Quality (AHRQ), and by funding from the 2012 Foundation of the Consortium of Multiple Sclerosis Centers Workforce of the Future. To conduct this study, Michelle Cameron was supported by a CDA-2 from the Department of Veterans Affairs Rehabilitation Research & Development Service. Secure data storage was supported by the Oregon Clinical and Translational Research Institute grant support (1 UL1 RR024140 01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 8 Z9 8 U1 0 U2 7 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 SEP 25 PY 2014 VL 9 IS 9 AR e107620 DI 10.1371/journal.pone.0107620 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3UZ UT WOS:000344862300026 PM 25254633 ER PT J AU Win, AZ Aparici, CM AF Win, Aung Zaw Aparici, Carina Mari TI Normal SUV Values Measured from NaF18-PET/CT Bone Scan Studies SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; STANDARDIZED UPTAKE VALUES; F-18-FLUORIDE PET; FDG PET/CT; METABOLISM; METASTASES; FLUORIDE; SCINTIGRAPHY; RADIONUCLIDE; TECHNOLOGY AB Objectives: Cancer and metabolic bone diseases can alter the SUV. SUV values have never been measured from healthy skeletons in NaF18-PET/CT bone scans. The primary aim of this study was to measure the SUV values from normal skeletons in NaF18-PET/CT bone scans. Methods: A retrospective study was carried out involving NaF18-PET/CT bone scans that were done at our institution between January 2010 to May 2012. Our excluding criteria was patients with abnormal real function and patients with past history of cancer and metabolic bone diseases including but not limited to osteoporosis, osteopenia and Paget's disease. Eleven studies met all the criteria. Results: The average normal SUVmax values from 11 patients were: cervical vertebrae 6.84 (range 4.38-8.64), thoracic vertebrae 7.36 (range 6.99-7.66), lumbar vertebrae 7.27 (range 7.04-7.72), femoral head 2.22 (range 1.1-4.3), humeral head 1.82 (range 1.2-2.9), mid sternum 5.51 (range 2.6-8.1), parietal bone 1.71 (range 1.3-2.4). Conclusion: According to our study, various skeletal sites have different normal SUV values. SUV values can be different between the normal bones and bones with tumor or metabolic bone disease. SUV can be used to quantify NaF-18 PET/CT studies. If the SUV values of the normal skeleton are known, they can be used in the characterization of bone lesions and in the assessment of treatment response to bone diseases. C1 [Win, Aung Zaw] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. [Aparici, Carina Mari] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Win, AZ (reprint author), San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. EM aungzwin@gmail.com FU NCI NIH HHS [R01 CA094121] NR 30 TC 1 Z9 1 U1 0 U2 2 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 SEP 25 PY 2014 VL 9 IS 9 AR e108429 DI 10.1371/journal.pone.0108429 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3UZ UT WOS:000344862300081 PM 25254490 ER PT J AU Koppers-Lalic, D Hackenberg, M Bijnsdorp, IV van Eijndhoven, MAJ Sadek, P Sie, D Zini, N Middeldorp, JM Ylstra, B de Menezes, RX Wurdinger, T Meijer, GA Pegtel, DM AF Koppers-Lalic, Danijela Hackenberg, Michael Bijnsdorp, Irene V. van Eijndhoven, Monique A. J. Sadek, Payman Sie, Daud Zini, Nicoletta Middeldorp, Jaap M. Ylstra, Bauke de Menezes, Renee X. Wuerdinger, Thomas Meijer, Gerrit A. Pegtel, D. Michiel TI Nontemplated Nucleotide Additions Distinguish the Small RNA Composition in Cells from Exosomes SO CELL REPORTS LA English DT Article ID POTENTIAL REGULATORY FUNCTIONS; SMALL NONCODING RNA; 3' ADENYLATION; MIRNA ACTIVITY; VIRAL MIRNAS; MICRORNA; CANCER; STABILIZATION; TRANSFERASES; URIDYLATION AB Functional biomolecules, including small noncoding RNAs (ncRNAs), are released and transmitted between mammalian cells via extracellular vesicles (EVs), including endosome-derived exosomes. The small RNA composition in cells differs from exosomes, but underlying mechanisms have not been established. We generated small RNA profiles by RNA sequencing (RNA-seq) from a panel of human B cells and their secreted exosomes. A comprehensive bioinformatics and statistical analysis revealed nonrandomly distributed subsets of microRNA (miRNA) species between B cells and exosomes. Unexpectedly, 3' end adenylated miRNAs are relatively enriched in cells, whereas 3' end uridylated isoforms appear overrepresented in exosomes, as validated in naturally occurring EVs isolated from human urine samples. Collectively, our findings suggest that posttranscriptional modifications, notably 3' end adenylation and uridylation, exert opposing effects that may contribute, at least in part, to direct ncRNA sorting into EVs. C1 [Koppers-Lalic, Danijela; van Eijndhoven, Monique A. J.; Sadek, Payman; Sie, Daud; Middeldorp, Jaap M.; Ylstra, Bauke; Meijer, Gerrit A.; Pegtel, D. Michiel] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. [Koppers-Lalic, Danijela; van Eijndhoven, Monique A. J.; Sadek, Payman; Pegtel, D. Michiel] Vrije Univ Amsterdam, Med Ctr, Exosomes Res Grp, NL-1007 MB Amsterdam, Netherlands. [Hackenberg, Michael] Univ Granada, Dept Genet, Computat Genom & Bioinformat Grp, E-18071 Granada, Spain. [Bijnsdorp, Irene V.] Vrije Univ Amsterdam, Med Ctr, Dept Urol, NL-1007 MB Amsterdam, Netherlands. [Zini, Nicoletta] CNR Natl Res Council Italy, IGM, I-40136 Bologna, Italy. [Zini, Nicoletta] IOR, SC Lab Musculoskeletal Cell Biol, I-40136 Bologna, Italy. [de Menezes, Renee X.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. [Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Dept Neurosurg, Neurooncol Res Grp, NL-1007 MB Amsterdam, Netherlands. [Wuerdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Wuerdinger, Thomas] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Koppers-Lalic, D (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. EM d.koppers@vumc.nl; d.pegtel@vumc.nl RI Hackenberg, Michael/A-2503-2009; Pegtel, Dirk/M-8393-2015; Ylstra, Bauke/D-2906-2012; OI Hackenberg, Michael/0000-0003-2248-3114; Pegtel, Dirk/0000-0002-7357-4406; Ylstra, Bauke/0000-0001-9479-3010; Sie, Daoud/0000-0001-6762-2582; ZINI, NICOLETTA/0000-0002-4442-7079; Middeldorp, Jaap/0000-0002-0765-4125 FU VIDI [91711366]; Dutch Cancer Society research award [KWF-5510]; AICR [11-0157]; NWO-VENI [91696087] FX We thank P.P. Eijk, F. Rustenburg, and Y. Sabogal Pineros for their technical assistance and J. Berenguer de Felipe for inspiring discussions. T.W. is supported by VIDI 91711366. D.M.P. is supported by personal Dutch Cancer Society research award (KWF-5510). This work was funded by AICR grant 11-0157 and NWO-VENI 91696087 awarded to D.M.P. NR 46 TC 98 Z9 100 U1 2 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 SEP 25 PY 2014 VL 8 IS 6 BP 1649 EP 1658 DI 10.1016/j.celrep.2014.08.027 PG 10 WC Cell Biology SC Cell Biology GA AR9BZ UT WOS:000343867400006 PM 25242326 ER PT J AU Ting, DT Wittner, BS Ligorio, M Jordan, NV Shah, AM Miyamoto, DT Aceto, N Bersani, F Brannigan, BW Xega, K Ciciliano, JC Zhu, HL MacKenzie, OC Trautwein, J Arora, KS Shahid, M Ellis, HL Qu, N Bardeesy, N Rivera, MN Deshpande, V Ferrone, CR Kapur, R Ramaswamy, S Shioda, T Toner, M Maheswaran, S Haber, DA AF Ting, David T. Wittner, Ben S. Ligorio, Matteo Jordan, Nicole Vincent Shah, Ajay M. Miyamoto, David T. Aceto, Nicola Bersani, Francesca Brannigan, Brian W. Xega, Kristina Ciciliano, Jordan C. Zhu, Huili MacKenzie, Olivia C. Trautwein, Julie Arora, Kshitij S. Shahid, Mohammad Ellis, Haley L. Qu, Na Bardeesy, Nabeel Rivera, Miguel N. Deshpande, Vikram Ferrone, Cristina R. Kapur, Ravi Ramaswamy, Sridhar Shioda, Toshi Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI Single-Cell RNA Sequencing Identifies Extracellular Matrix Gene Expression by Pancreatic Circulating Tumor Cells SO CELL REPORTS LA English DT Article ID FACTOR BINDING PROTEIN-5; BREAST-CANCER; CLINICAL-RELEVANCE; COLON-CARCINOMA; STEM-CELLS; ADENOCARCINOMA; METASTASIS; STROMA; MOUSE; MICROARRAY AB Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genomewide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stemcell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs. C1 [Ting, David T.; Wittner, Ben S.; Ligorio, Matteo; Jordan, Nicole Vincent; Miyamoto, David T.; Aceto, Nicola; Bersani, Francesca; Brannigan, Brian W.; Xega, Kristina; Ciciliano, Jordan C.; Zhu, Huili; MacKenzie, Olivia C.; Trautwein, Julie; Arora, Kshitij S.; Shahid, Mohammad; Ellis, Haley L.; Qu, Na; Bardeesy, Nabeel; Rivera, Miguel N.; Deshpande, Vikram; Ferrone, Cristina R.; Ramaswamy, Sridhar; Shioda, Toshi; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Shah, Ajay M.; Kapur, Ravi; Toner, Mehmet] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Ting, David T.; Wittner, Ben S.; Jordan, Nicole Vincent; Aceto, Nicola; Bersani, Francesca; Brannigan, Brian W.; Xega, Kristina; Ciciliano, Jordan C.; Zhu, Huili; MacKenzie, Olivia C.; Trautwein, Julie; Ellis, Haley L.; Qu, Na; Bardeesy, Nabeel; Ramaswamy, Sridhar; Shioda, Toshi; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Ligorio, Matteo; Shah, Ajay M.; Arora, Kshitij S.; Shahid, Mohammad; Ferrone, Cristina R.; Toner, Mehmet; Maheswaran, Shyamala] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. [Miyamoto, David T.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Arora, Kshitij S.; Shahid, Mohammad; Rivera, Miguel N.; Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Ligorio, Matteo] Univ Genoa, Dept Hlth Sci, I-16126 Genoa, Italy. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Maheswaran, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM maheswaran@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu RI Aceto, Nicola/O-2484-2014; OI Aceto, Nicola/0000-0001-9579-6918; Shahid, Mohammad/0000-0003-2615-9848; Ting, David/0000-0002-3261-2322 FU Stand Up to Cancer; Howard Hughes Medical Institute; NIBIB Quantum [5R01EB008047, NCI 2R01CA129933]; National Foundation for Cancer Research; Burroughs Wellcome Fund [K12CA087723-11A1]; Department of Defense; Affymetrix, Inc; Warshaw Institute for Pancreatic Cancer Research; Verville Family Pancreatic Cancer Research Fund FX We are grateful to Laura Libby for mouse colony care, Lev Silberstein for providing technical assistance in single-cell RNA sequencing, Linda Nieman for microscopy expertise, and engineering techs for their help in running samples on the CTC-iChip. This work was supported by Stand Up to Cancer (D.A.H., M.T., and S.M.), Howard Hughes Medical Institute (D.A.H. and M.N.R.), NIBIB Quantum grant 5R01EB008047 (M.T.), NCI 2R01CA129933 (D.A.H.), National Foundation for Cancer Research (D.A.H.), the Burroughs Wellcome Fund (D.T.T. and M.N.R.), K12CA087723-11A1 (D.T.T.), Department of Defense (D.T.M. and D.T.T.), Affymetrix, Inc. (D.T.T., M.N.R., and V.D.), the Warshaw Institute for Pancreatic Cancer Research (D.T.T.), and the Verville Family Pancreatic Cancer Research Fund (D.T.T.). NR 49 TC 58 Z9 59 U1 5 U2 40 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 SEP 25 PY 2014 VL 8 IS 6 BP 1905 EP 1918 DI 10.1016/j.celrep.2014.08.029 PG 14 WC Cell Biology SC Cell Biology GA AR9BZ UT WOS:000343867400029 PM 25242334 ER PT J AU Passingham, RE Chung, A Goparaju, B Cowey, A Vaina, LM AF Passingham, R. E. Chung, A. Goparaju, B. Cowey, A. Vaina, L. M. TI Using action understanding to understand the left inferior parietal cortex in the human brain SO BRAIN RESEARCH LA English DT Article DE Inferior parietal cortex; Human brain; Action understanding; Action observation; Pantomime; Apraxia; Cerebral dominance ID TRACTOGRAPHY-BASED PARCELLATION; SURFACE-BASED ANALYSIS; PREFRONTAL CORTEX; MACAQUE MONKEY; PREMOTOR CORTEX; TOOL USE; VENTRAL PREMOTOR; FRONTAL-CORTEX; NEURONS; FMRI AB Humans have a sophisticated knowledge of the actions that can be performed with objects. In an fMRI study we tried to establish whether this depends on areas that are homologous with the inferior parietal cortex (area PFG) in macaque monkeys. Cells have been described in area PFG that discharge differentially depending upon whether the observer sees an object being brought to the mouth or put in a container. In our study the observers saw videos in which the use of different objects was demonstrated in pantomime; and after viewing the videos, the subject had to pick the object that was appropriate to the pantomime. We found a cluster of activated voxels in parietal areas PFop and PFt and this cluster was greater in the left hemisphere than in the right. We suggest a mechanism that could account for this asymmetry, relate our results to handedness and suggest that they shed light on the human syndrome of apraxia. Finally, we suggest that during the evolution of the hominids, this same pantomime mechanism could have been used to 'name' or request objects. (C) 2014 Elsevier B.V. All rights reserved. C1 [Passingham, R. E.; Cowey, A.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Chung, A.; Goparaju, B.; Vaina, L. M.] Boston Univ, Brain & Vis Res Lab, Dept Biomed Engn, Boston, MA 02215 USA. [Vaina, L. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Radiol, Boston, MA 02114 USA. RP Vaina, LM (reprint author), Boston Univ, Brain & Vis Res Lab, Dept Biomed Engn, 44 Cummington Mall, Boston, MA 02215 USA. EM vaina@bu.edu FU NIH [RO1NS064100] FX We thank Steve Wise for very detailed comments on a draft of this paper. We thank Rogier Mars for help with identifying the areas that were activated in parietal cortex and for comments on a draft of this paper. Finally, we thank Michael Nahhas for help with the imaging figures. This work was supported in part by the NIH grant RO1NS064100 to LMV. NR 65 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 25 PY 2014 VL 1582 BP 64 EP 76 DI 10.1016/j.brainres.2014.07.035 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AR1PM UT WOS:000343357100007 PM 25086203 ER PT J AU Erkan, EP Strobel, T Lewandrowski, G Tannous, B Madlener, S Czech, T Saydam, N Saydam, O AF Erkan, E. P. Stroebel, T. Lewandrowski, G. Tannous, B. Madlener, S. Czech, T. Saydam, N. Saydam, O. TI Depletion of minichromosome maintenance protein 7 inhibits glioblastoma multiforme tumor growth in vivo SO ONCOGENE LA English DT Article DE glioblastoma multiforme; minichromosome maintenance; MCM7; the cancer genome atlas; prognostic marker ID CELL LUNG-CANCER; MCM PROTEINS; DNA-REPLICATION; PROGNOSTIC-SIGNIFICANCE; PHOSPHORYLATION; IDENTIFICATION; MARKER; FAMILY; PROLIFERATION; INITIATION AB Minichromosome maintenance (MCM) proteins are key elements that function as a part of the pre-replication complex to initiate DNA replication in eukaryotes. Consistent with their roles in initiating DNA replication, overexpression of MCM family members has been observed in several malignancies. Through bioinformatic analysis of The Cancer Genome Atlas's data on glioblastoma multiforme (GBM), we found that the genomic region containing MCM7 gene was amplified in more than 80% of the present cases. To validate this finding and to identify the possible contribution of the remaining members of the MCM family to GBM progression, we used quantitative real-time PCR to analyze the gene expression profiles of all MCM family members in Grade IV (GBM) tissue samples and observed a significant upregulation in GBM samples compared with normal white matter tissues. In addition, we compared the observed gene expression profiles with those of Grade II and Grade III astrocytoma samples and determined that the observed upregulation was restricted and specific to Grade IV. MCM7 was the most upregulated gene in the gene set we analyzed, and therefore we wanted to identify the role of MCM7 in GBM progression. We determined that siRNA-mediated knockdown of MCM7 expression reduced GBM cell proliferation and also inhibited tumor growth in both xenograft and orthotopic mouse models of GBM. Taken together, our data suggest that MCM7 can be a potential prognostic marker and a novel therapeutic target in GBM therapy. C1 [Erkan, E. P.; Madlener, S.; Saydam, N.; Saydam, O.] Med Univ Vienna, Dept Pediat, Mol Neurooncol Res Unit, A-1090 Vienna, Austria. [Stroebel, T.] Med Univ Vienna, Inst Neurol, A-1090 Vienna, Austria. [Lewandrowski, G.; Tannous, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Expt Therapeut & Mol Imaging Lab, Boston, MA USA. [Czech, T.] Med Univ Vienna, Dept Neurosurg, A-1090 Vienna, Austria. RP Saydam, O (reprint author), Med Univ Vienna, Dept Pediat, Mol Neurooncol Res Unit, A-1090 Vienna, Austria. EM okay.saydam@meduniwien.ac.at OI Madlener, Sibylle/0000-0001-7099-9997 FU Forschungsgesellschaft for Brain Tumors; EU-FP7-PEOPLE-CIG; Association for Conduct of Scientific Research in the Field of Neonatology and Pediatric Intensive Care: 'Unser Kind' FX This work was supported, in part, by Forschungsgesellschaft for Brain Tumors (OS, NS), EU-FP7-PEOPLE-2011-CIG (OS) and Association for Conduct of Scientific Research in the Field of Neonatology and Pediatric Intensive Care: 'Unser Kind' (OS and NS). NR 39 TC 7 Z9 7 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD SEP 25 PY 2014 VL 33 IS 39 BP 4778 EP 4785 DI 10.1038/onc.2013.423 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AR0ED UT WOS:000343239500008 PM 24166506 ER PT J AU Mayeur, C Leyton, PA Kolodziej, SA Yu, BL Bloch, KD AF Mayeur, Claire Leyton, Patricio A. Kolodziej, Starsha A. Yu, Binglan Bloch, Kenneth D. TI BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism SO BLOOD LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; MORPHOGENETIC PROTEIN BMP; TARGETED DISRUPTION; DEFICIENCY; OVERLOAD; CELLS; MICE; GASTRULATION; INDUCTION; INSIGHTS AB Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2(+/-)), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2(+/-) mice, and mice in which either BMPR2 or ActR2a was deficient. Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism. C1 [Mayeur, Claire; Leyton, Patricio A.; Kolodziej, Starsha A.; Yu, Binglan; Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Kenneth D.] Harvard Univ, Sch Med, Boston, MA USA. RP Mayeur, C (reprint author), Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM cmayeur@mgh.harvard.edu FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01DK082971]; Fondation LeDucq FX This work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082971) and by a grant from the Fondation LeDucq. NR 40 TC 9 Z9 11 U1 2 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 25 PY 2014 VL 124 IS 13 BP 2116 EP 2123 DI 10.1182/blood-2014-04-572644 PG 8 WC Hematology SC Hematology GA AQ4JY UT WOS:000342763500018 PM 25075125 ER PT J AU Dotson, AL Zhu, WB Libal, N Alkayed, NJ Offner, H AF Dotson, Abby L. Zhu, Wenbin Libal, Nicole Alkayed, Nabil J. Offner, Halina TI Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE experimental stroke; aging; RTL1000; therapy; immune response; neuroinflammation ID REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TUMOR-NECROSIS-FACTOR; TREATS EXPERIMENTAL STROKE; ISCHEMIC BRAIN-INJURY; CEREBRAL-ISCHEMIA; RECEPTOR LIGANDS; INTERFERON-GAMMA; MULTIPLE-SCLEROSIS; CNS INFLAMMATION AB Stroke is a leading cause of death and disability in the United States. The lack of clinical success in stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from experimental stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to stroke that allow unique targeting of stroke immunotherapies. C1 [Dotson, Abby L.; Offner, Halina] VA Med Ctr, Portland, OR USA. [Dotson, Abby L.; Alkayed, Nabil J.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Zhu, Wenbin; Libal, Nicole; Alkayed, Nabil J.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH Grant [NS065515-02A1]; Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research and Development FX The authors wish to thank Gail Kent for assistance with manuscript submission. This work was supported by NIH Grants # NS065515-02A1 (STTR) and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. Dr. Offner discloses US patent #8,491,913 B2 for the use of recombinant molecules in treatment of stroke. NR 68 TC 4 Z9 4 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD SEP 25 PY 2014 VL 8 AR 284 DI 10.3389/fncel.2014.00284 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AP5NE UT WOS:000342125100001 PM 25309326 ER PT J AU Hunt, DP Sahani, DV Corey, KE Masia, R AF Hunt, Daniel P. Sahani, Dushyant V. Corey, Kathleen E. Masia, Ricard TI Case 30-2014: A 29-Year-Old Man with Diarrhea, Nausea, and Weight Loss SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ELEVATED SERUM FERRITIN; AUTOIMMUNE HEPATITIS; WILSONS-DISEASE; FEATURES; EXPERIENCE; DIAGNOSIS; LIVER; MANAGEMENT; CIRRHOSIS C1 [Hunt, Daniel P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Corey, Kathleen E.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Masia, Ricard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hunt, Daniel P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sahani, Dushyant V.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Corey, Kathleen E.] Harvard Univ, Sch Med, Boston, MA USA. [Masia, Ricard] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hunt, DP (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 26 TC 1 Z9 1 U1 2 U2 7 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 SEP 25 PY 2014 VL 371 IS 13 BP 1238 EP 1247 DI 10.1056/NEJMcpc1405218 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AP4WH UT WOS:000342079700012 PM 25251619 ER PT J AU Peterson, JR De La Rosa, S Eboda, O Cilwa, KE Agarwal, S Buchman, SR Cederna, PS Xi, CW Morris, MD Herndon, DN Xiao, WZ Tompkins, RG Krebsbach, PH Wang, SC Levi, B AF Peterson, Jonathan R. De La Rosa, Sara Eboda, Oluwatobi Cilwa, Katherine E. Agarwal, Shailesh Buchman, Steven R. Cederna, Paul S. Xi, Chuanwu Morris, Michael D. Herndon, David N. Xiao, Wenzhong Tompkins, Ronald G. Krebsbach, Paul H. Wang, Stewart C. Levi, Benjamin TI Treatment of heterotopic ossification through remote ATP hydrolysis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID OSTEOGENIC DIFFERENTIATION; STEM-CELLS; ADIPOCYTE DIFFERENTIATION; ENDOCHONDRAL OSSIFICATION; BONE-FORMATION; IN-VITRO; PROGRESSIVA; MODEL; TRAUMA; BURNS AB Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation. C1 [Peterson, Jonathan R.; De La Rosa, Sara; Eboda, Oluwatobi; Agarwal, Shailesh; Buchman, Steven R.; Cederna, Paul S.; Wang, Stewart C.; Levi, Benjamin] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA. [Cilwa, Katherine E.] Naval Med Res Ctr, Dept Regenerat Med, Silver Spring, MD 20910 USA. [Cederna, Paul S.] Univ Michigan Hlth Syst, Dept Biomed Engn, Sect Plast Surg, Ann Arbor, MI 48109 USA. [Xi, Chuanwu] Univ Michigan, Sch Publ Hlth, Dept Environm & Hlth Sci, Ann Arbor, MI 48109 USA. [Morris, Michael D.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Herndon, David N.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA. [Herndon, David N.] Shriners Hosp Children, Galveston, TX 77550 USA. [Xiao, Wenzhong; Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Krebsbach, Paul H.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Levi, B (reprint author), Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA. EM blevi@med.umich.edu RI Cilwa, Katherine/N-3840-2016 OI Cilwa, Katherine/0000-0003-3828-884X FU Plastic Surgery Foundation National Endowment Award; NIH [R01GM098350-02, R01 AR055222, P50-GM60338, R01-GM56687, T32-GM8256, U54-GM062119]; National Institute on Disability and Rehabilitation Research [H133A070026, H133A70019]; Shriners Hospitals for Children [85500, 71008]; [1K08GM109105-01]; [R24-GM102656] FX B.L. was funded by 1K08GM109105-01 and Plastic Surgery Foundation National Endowment Award. This research was partially supported by NIH grant R01GM098350-02 to C.X. and S.C.W.; NIH grant R01 AR055222 to M.D.M.; National Institute on Disability and Rehabilitation Research (grants H133A070026 and H133A70019), NIH (grants P50-GM60338, R01-GM56687, and T32-GM8256), and Shriners Hospitals for Children (grants 85500 and 71008) to D.N.H.; and NIH grant U54-GM062119 to R.G.T. and its legacy grant R24-GM102656 to W.X. for the Trauma-Related Database (TRDB). NR 33 TC 31 Z9 31 U1 1 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 24 PY 2014 VL 6 IS 255 AR 255ra132 DI 10.1126/scitranslmed.3008810 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AR1BY UT WOS:000343316800008 PM 25253675 ER PT J AU Braverman, ER Han, D Oscar-Berman, M Karikh, T Truesdell, C Dushaj, K Kreuk, F Li, M Stratton, D Blum, K AF Braverman, Eric R. Han, David Oscar-Berman, Marlene Karikh, Tatiana Truesdell, Courtney Dushaj, Kristina Kreuk, Florian Li, Mona Stratton, Danielle Blum, Kenneth TI Menopause Analytical Hormonal Correlate Outcome Study (MAHCOS) and the Association to Brain Electrophysiology (P300) in a Clinical Setting SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; PLASMA LEPTIN LEVELS; INCIDENT ALZHEIMER-DISEASE; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; LUTEINIZING-HORMONE; OLDER-ADULTS; RISK-FACTORS; MOUSE MODEL; WEIGHT-LOSS AB Various studies have demonstrated that increased leptin levels and obesity are inversely related to cognitive decline in menopausal women. It is hypothesized that adiposity is inversely correlated with cognitive decline, as women with increased weight are less vulnerable to diminishing cognition. However, it is increasingly observed that menopausal women, even with increased adiposity, experience significant cognitive decline. Positron emission tomography (PET) has been used to analyze cognitive function and processing in menopausal women. Evoked potentials (P300) and neurophysiologic tests have validated brain metabolism in cognitively impaired patients. Post-hoc analyses of 796 female patients entering PATH Medical Clinic, between January 4, 2009 and February 24, 2013, were performed as part of the "Menopause Analytical Hormonal Correlate Outcome Study" (MAHCOS). Patient age range was 39-76 years (46.7 +/- 0.2). P300 latency and amplitude correlated with a number of hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, estrone, estriol, DHEA, pregnenolone, progesterone, free and total testosterone, thyroid stimulating hormone (TSH), Vitamins D 1.25 and D 25OH, leptin, and insulin-like growth factor-binding protein 3 (IGF-BP3). Corrected statistics did not reveal significant associations with P300 latency or amplitude for these hormones except for leptin plasma levels. However, factor analysis showed that FSH and LH clustered together with Vitamin D1.25 and Vitamin D25OH, P300 latency (not amplitude), and log leptin were found to be associated in the same cluster. Utilizing regression analysis, once age adjusted, leptin was the only significant predictor for latency or speed (p = 0.03) with an effect size of 0.23. Higher plasma leptin levels were associated with abnormal P300 speed (OR = 0.98). Our findings show a significant relationship of higher plasma leptin levels, potentially due to leptin resistance, and prolonged P300 latency. This suggests leptin resistance may delay electrophysiological processing of memory and attention, which appears to be the first of such an association. C1 [Braverman, Eric R.; Karikh, Tatiana; Truesdell, Courtney; Dushaj, Kristina; Kreuk, Florian; Li, Mona; Stratton, Danielle; Blum, Kenneth] PATH Fdn NY, Dept Clin Neurol, New York, NY 10016 USA. [Braverman, Eric R.; Blum, Kenneth] Univ Florida, Coll Med, Dept Psychiat, Gainesville, FL USA. [Braverman, Eric R.; Blum, Kenneth] McKnight Brain Inst, Gainesville, FL USA. [Han, David] Univ Texas San Antonio, Dept Management Sci & Stat, San Antonio, TX USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Psychiat, Dept Neurol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston VA Healthcare Syst, Boston, MA USA. [Blum, Kenneth] Univ Vermont, Ctr Clin & Translat Sci, Dept Psychiat, Human Integrated Serv Unit, Burlington, VT USA. [Blum, Kenneth] Inst Integrat Omics & Appl Biotechnol, Medinipur, W Bengal, India. [Blum, Kenneth] Domin Diagnost LLC, North Kingstown, RI USA. RP Blum, K (reprint author), PATH Fdn NY, Dept Clin Neurol, New York, NY 10016 USA. EM drd2gene@gmail.com FU Life Extension Foundation FX The authors are grateful to the Life Extension Foundation for their generous financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 0 Z9 0 U1 1 U2 7 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 SEP 24 PY 2014 VL 9 IS 9 AR e105048 DI 10.1371/journal.pone.0105048 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0SJ UT WOS:000342492700006 PM 25251414 ER PT J AU Dohi, K Kraemer, BC Erickson, MA McMillan, PJ Kovac, A Flachbartova, Z Hansen, KM Shah, GN Sheibani, N Salameh, T Banks, WA AF Dohi, Kenji Kraemer, Brian C. Erickson, Michelle A. McMillan, Pamela J. Kovac, Andrej Flachbartova, Zuzana Hansen, Kim M. Shah, Gul N. Sheibani, Nader Salameh, Therese Banks, William A. TI Molecular Hydrogen in Drinking Water Protects against Neurodegenerative Changes Induced by Traumatic Brain Injury SO PLOS ONE LA English DT Article ID INDUCED OXIDATIVE DAMAGE; TNF-ALPHA; BARRIER; TRANSPORT; PERICYTES; MATRIX-METALLOPROTEINASE-9; LIPOPOLYSACCHARIDE; PERMEABILITY; CYCLOPHILIN; EXPRESSION AB Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI. C1 [Dohi, Kenji; Kraemer, Brian C.; Erickson, Michelle A.; Kovac, Andrej; Hansen, Kim M.; Salameh, Therese; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Dohi, Kenji] Jikei Univ, Sch Med, Dept Emergency Med, Tokyo, Japan. [Kraemer, Brian C.; Kovac, Andrej; Hansen, Kim M.; Salameh, Therese; Banks, William A.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Kraemer, Brian C.; McMillan, Pamela J.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [McMillan, Pamela J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Flachbartova, Zuzana] Univ Vet Med & Pharm, Dept Microbiol & Immunol, Lab Biomed Microbiol & Immunol, Kosice, Slovakia. [Shah, Gul N.] St Louis Univ, Sch Med, Edward Doisy Res Ctr, Div Endocrinol,Dept Internal Med, St Louis, MO USA. [Sheibani, Nader] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU Kiban C grant [23592683]; VA Merit Review [RO-1 AG029839, R0-1 NS064131]; [RO-1 DK083485] FX KD was supported by Kiban C grant number 23592683. WAB was supported by VA Merit Review; RO-1 AG029839. WAB and GNS was supported by RO-1 DK083485. BCK was supported by VA Merit Review; R0-1 NS064131. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 3 Z9 4 U1 1 U2 14 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 SEP 24 PY 2014 VL 9 IS 9 AR e108034 DI 10.1371/journal.pone.0108034 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0SJ UT WOS:000342492700070 PM 25251220 ER PT J AU Singhal, AB Lo, W AF Singhal, Aneesh B. Lo, Warren TI Life after stroke Beyond medications SO NEUROLOGY LA English DT Editorial Material ID YOUNG-ADULTS; ISCHEMIC-STROKE; EVENTS C1 [Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lo, Warren] Nationwide Childrens Hosp, Dept Neurol, Columbus, OH USA. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM asinghal@mgh.harvard.edu FU NINDS NIH HHS [U10NS0867290, R01NS051412, R21NS077442] NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 23 PY 2014 VL 83 IS 13 BP 1128 EP 1129 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AT3TE UT WOS:000344856400006 PM 25128181 ER PT J AU Falcone, GJ Radmanesh, F Brouwers, HB Battey, TWK Devan, WJ Valant, V Raffeld, MR Chitsike, LP Ayres, AM Schwab, K Goldstein, JN Viswanathan, A Greenberg, SM Selim, M Meschia, JF Brown, DL Worrall, BB Silliman, SL Tirschwell, DL Flaherty, ML Martini, SR Deka, R Biffi, A Kraft, P Woo, D Rosand, J Anderson, CD AF Falcone, Guido J. Radmanesh, Farid Brouwers, H. Bart Battey, Thomas W. K. Devan, William J. Valant, Valerie Raffeld, Miriam R. Chitsike, Lennox P. Ayres, Alison M. Schwab, Kristin Goldstein, Joshua N. Viswanathan, Anand Greenberg, Steven M. Selim, Magdy Meschia, James F. Brown, Devin L. Worrall, Bradford B. Silliman, Scott L. Tirschwell, David L. Flaherty, Matthew L. Martini, Sharyl R. Deka, Ranjan Biffi, Alessandro Kraft, Peter Woo, Daniel Rosand, Jonathan Anderson, Christopher D. CA Int Stroke Genetics Consortium TI APOE epsilon variants increase risk of warfarin-related intracerebral hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; ATRIAL-FIBRILLATION; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; CLINICAL-DIAGNOSIS; GENE-ENVIRONMENT; STROKE; ASSOCIATION; ANTICOAGULATION; METAANALYSIS AB Objective: We aimed to assess the effect of APOE epsilon variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH. Methods: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE epsilon variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE epsilon and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE epsilon and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power. Results: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE epsilon 2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas epsilon 4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with epsilon 2 (p = 0.03) and e4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE epsilon variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20). Conclusions: APOE epsilon variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted. C1 [Falcone, Guido J.; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Valant, Valerie; Raffeld, Miriam R.; Chitsike, Lennox P.; Ayres, Alison M.; Schwab, Kristin; Viswanathan, Anand; Greenberg, Steven M.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Valant, Valerie; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Falcone, Guido J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Selim, Magdy] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Devin L.] Univ Michigan Hlth Syst, Dept Neurol, Stroke Program, Ann Arbor, MI USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. [Silliman, Scott L.] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. [Tirschwell, David L.] Univ Washington, Harborview Med Ctr, Stroke Ctr, Seattle, WA 98104 USA. [Flaherty, Matthew L.; Martini, Sharyl R.; Deka, Ranjan; Woo, Daniel] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM cdanderson@partners.org RI Lee, Chaeyoung/C-7929-2012; Goldstein, Joshua/H-8953-2016; Falcone, Guido/L-2287-2016 OI Lee, Chaeyoung/0000-0002-2940-1778; Falcone, Guido/0000-0002-6407-0302 FU NIH; National Institute for Neurological Disorders and Stroke (NINDS) [R01NS059727, P50NS061343, NS36695, NS30678]; NIH-NINDS SPOTRIAS fellowship [P50NS061343]; American Brain Foundation; Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care FX Supported by the NIH and the National Institute for Neurological Disorders and Stroke (NINDS) through grants R01NS059727 and P50NS061343 (GOCHA Study), NS36695 (Genetic and Environmental Risk Factors for Hemorrhagic Stroke), and NS30678 (Hemorrhagic and Ischemic Stroke among Blacks and Whites). Drs. Falcone and Brouwers were supported by the NIH-NINDS SPOTRIAS fellowship grant P50NS061343. Dr. Anderson was supported by the American Brain Foundation, and received support from the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care for his cerebrovascular disease research. NR 26 TC 10 Z9 11 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 23 PY 2014 VL 83 IS 13 BP 1139 EP 1146 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AT3TE UT WOS:000344856400009 PM 25150286 ER PT J AU Gkotzamanidou, M Sfikakis, PP Kyrtopoulos, SA Bamia, C Dimopoulos, MA Souliotis, VL AF Gkotzamanidou, M. Sfikakis, P. P. Kyrtopoulos, S. A. Bamia, C. Dimopoulos, M. A. Souliotis, V. L. TI Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma SO BRITISH JOURNAL OF CANCER LA English DT Article DE multiple myeloma; melphalan; epigenetic changes; DNA damage response; transcription-coupled repair; clinical outcome; malignant bone marrow plasma cells; peripheral blood mononuclear cells ID INTERSTRAND CROSS-LINKS; HISTONE DEACETYLASE INHIBITORS; STEM-CELL TRANSPLANTATION; HIGH-DOSE MELPHALAN; GENOMIC INSTABILITY; NITROGEN MUSTARDS; DAMAGE RESPONSE; BONE-MARROW; IN-VITRO; CANCER AB Background: Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown. Methods: Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n = 57) or non-responders (n = 28) to melphalan therapy. PBMCs from healthy controls (n = 25) were also included in the study. Results: In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001). Conclusions: Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy. C1 [Gkotzamanidou, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Gkotzamanidou, M.; Dimopoulos, M. A.] Univ Athens, Sch Med, Dept Clin Therapeut, Athens 11528, Greece. [Sfikakis, P. P.] Univ Athens, Sch Med, Dept Propedeut Med 1, GR-11527 Athens, Greece. [Kyrtopoulos, S. A.; Souliotis, V. L.] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens 11635, Greece. [Bamia, C.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. RP Souliotis, VL (reprint author), Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, 48 Vassileos Constantinou Ave, Athens 11635, Greece. EM vls@eie.gr FU ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union [513943] FX We would like to thank Professor Kenneth C Anderson (Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA) and Dr Evangelos Terpos (Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece) for their helpful comments and suggestions. This work was partly supported by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943). NR 51 TC 2 Z9 2 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 23 PY 2014 VL 111 IS 7 BP 1293 EP 1304 DI 10.1038/bjc.2014.410 PG 12 WC Oncology SC Oncology GA AR1DT UT WOS:000343323100007 PM 25051404 ER PT J AU Hara, T Truelove, J Tawakol, A Wojtkiewicz, GR Hucker, WJ MacNabb, MH Brownell, AL Jokivarsi, K Kessinger, CW Jaff, MR Henke, PK Weissleder, R Jaffer, FA AF Hara, Tetsuya Truelove, Jessica Tawakol, Ahmed Wojtkiewicz, Gregory R. Hucker, William J. MacNabb, Megan H. Brownell, Anna-Liisa Jokivarsi, Kimmo Kessinger, Chase W. Jaff, Michael R. Henke, Peter K. Weissleder, Ralph Jaffer, Farouc A. TI F-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Enables the Detection of Recurrent Same-Site Deep Vein Thrombosis by Illuminating Recently Formed, Neutrophil-Rich Thrombus SO CIRCULATION LA English DT Article DE fluorodeoxyglucose F18; inflammation; neutrophils; positron-emission tomography; venous thrombosis ID CATHETER-DIRECTED THROMBOLYSIS; VENOUS THROMBOSIS; POSTTHROMBOTIC SYNDROME; ATHEROSCLEROTIC PLAQUES; VASCULAR INFLAMMATION; F-18-FDG PET; MOUSE MODEL; THROMBOEMBOLISM; RESOLUTION; FDG AB Background-Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT. Methods and Results-We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/computed tomography (CT) was performed at DVT time points of day 2, 4, 7, 14, or 2+ 16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice before DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (P<0.05). Histological analyses demonstrated that thrombus neutrophils (P<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT in comparison with controls (P=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (P=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (P<0.01). Conclusions-Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT. C1 [Hara, Tetsuya; Kessinger, Chase W.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Truelove, Jessica; Wojtkiewicz, Gregory R.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Tawakol, Ahmed; Hucker, William J.; MacNabb, Megan H.; Jaff, Michael R.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Brownell, Anna-Liisa; Jokivarsi, Kimmo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Biomed Imaging Ctr, Boston, MA USA. [Henke, Peter K.] Univ Michigan, Dept Surg, Vasc Surg Sect, Ann Arbor, MI 48109 USA. RP Jaffer, FA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,Room 3206, Boston, MA 02114 USA. EM fjaffer@mgh.harvard.edu FU National Institutes of Health grant [HL108229]; Wagner-Torizuka Society of Nuclear Medicine Fellowship; American Heart Association Founders postdoctoral fellowship [13POST14640021]; [13GRNT17060040] FX This study was supported by National Institutes of Health grant HL108229 (to Dr Jaffer), Wagner-Torizuka Society of Nuclear Medicine Fellowship (to Dr Hara), American Heart Association Founders postdoctoral fellowship #13POST14640021 (to Dr Hara), and Grant-in-Aid #13GRNT17060040 (to Dr Jaffer). NR 47 TC 11 Z9 11 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 23 PY 2014 VL 130 IS 13 BP 1044 EP + DI 10.1161/CIRCULATIONAHA.114.008902 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AQ3IK UT WOS:000342685100009 PM 25070665 ER PT J AU Quan, JH Adelmant, G Marto, JA Look, AT Yusufzai, T AF Quan, Jinhua Adelmant, Guillaume Marto, Jarrod A. Look, A. Thomas Yusufzai, Timur TI The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1 SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE; TUMOR-SUPPRESSOR; NEUROBLASTOMA-CELLS; PHD FINGERS; DNA-DAMAGE; COMPLEXES; GENE; EXPRESSION; CANCER; RECOGNITION AB Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression. C1 [Quan, Jinhua; Yusufzai, Timur] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Quan, Jinhua; Adelmant, Guillaume; Marto, Jarrod A.; Yusufzai, Timur] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Dept Canc Biol, Boston, MA 02115 USA. [Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Yusufzai, T (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM timur_yusufzai@dfci.harvard.edu FU Dana-Farber Cancer Institute; William F. Milton Fund; Claudia Adams Barr Program FX This work was supported by the Dana-Farber Cancer Institute, the William F. Milton Fund, and the Claudia Adams Barr Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 6 Z9 6 U1 0 U2 1 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 SEP 23 PY 2014 VL 9 IS 9 AR e108066 DI 10.1371/journal.pone.0108066 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8TL UT WOS:000342351800059 PM 25247294 ER PT J AU Ghosh, D Bagley, AF Na, YJ Birrer, MJ Bhatia, SN Belcher, AM AF Ghosh, Debadyuti Bagley, Alexander F. Na, Young Jeong Birrer, Michael J. Bhatia, Sangeeta N. Belcher, Angela M. TI Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer imaging; fluorescence-guided surgery; M13 bacteriophage ID NEAR-INFRARED WINDOW; IN-VIVO; QUANTUM DOTS; FLUORESCENCE; CANCER; NANOPARTICLES; PHAGE; MICE; LIBRARIES; LIGANDS AB Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery. C1 [Ghosh, Debadyuti; Bagley, Alexander F.; Bhatia, Sangeeta N.; Belcher, Angela M.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Ghosh, Debadyuti; Belcher, Angela M.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Belcher, Angela M.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Bagley, Alexander F.] Harvard Univ, Biophys Program, Boston, MA 02115 USA. [Bagley, Alexander F.] Harvard Univ, Sch Med, MD PhD Program, Boston, MA 02115 USA. [Na, Young Jeong; Birrer, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Bhatia, SN (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sbhatia@mit.edu; belcher@mit.edu FU National Institutes of Health (NIH) Center for Cancer Nanotechnology Excellence [U54-CA119349-04, U54-CA151884]; Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund; Marie D. & Pierre Casimir-Lambert Fund; Professor Amar G. Bose Research Grant; NIH/Medical Scientist Training Program; [P30-ES002109] FX The authors thank Dr. Rod Bronson for tumor scoring, Mike Brown and the Koch Institute Tang Histology Facility for assistance with histology, and Heather Fleming for excellent assistance with editing of the manuscript. The authors acknowledge the Koch Institute Swanson Biotechnology Center for DNA sequencing. This work was supported by the National Institutes of Health (NIH) Center for Cancer Nanotechnology Excellence Grants U54-CA119349-04 and U54-CA151884 (to S.N.B. and A. M. B.). This work was supported in part by the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund. This work was funded in part by Grant P30-ES002109, the Marie D. & Pierre Casimir-Lambert Fund, and a Professor Amar G. Bose Research Grant. A. F. B. is supported by the NIH/Medical Scientist Training Program. S.N.B. is a Howard Hughes Medical Institute Investigator. NR 36 TC 43 Z9 43 U1 10 U2 64 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 SEP 23 PY 2014 VL 111 IS 38 BP 13948 EP 13953 DI 10.1073/pnas.1400821111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP3PC UT WOS:000341988200064 PM 25214538 ER PT J AU Lysaght, AC Yuan, Q Fan, Y Kalwani, N Caruso, P Cunnane, M Lanske, B Stankovic, KM AF Lysaght, Andrew C. Yuan, Quan Fan, Yi Kalwani, Neil Caruso, Paul Cunnane, MaryBeth Lanske, Beate Stankovic, Konstantina M. TI FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice SO PLOS ONE LA English DT Article ID OTITIS-MEDIA; VITAMIN-D; INNER-EAR; HYPOPHOSPHATEMIC RICKETS; TUMORAL CALCINOSIS; KLOTHO PROTEIN; EXPRESSION; PHOSPHATE; HYPERPHOSPHATEMIA; OTOTOXICITY AB Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf23(+/-) mice are profoundly deaf. Fgf23(+/-) mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf23(-/-) mice demonstrate dysplastic bulla and ossicles; Fgf23(+/-) mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf23(-/-) mice do not match the auditory phenotype of Kl(-/-) mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media. C1 [Lysaght, Andrew C.] Harvard MIT Joint Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Lysaght, Andrew C.; Kalwani, Neil; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Yuan, Quan; Fan, Yi; Lanske, Beate] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Caruso, Paul; Cunnane, MaryBeth] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Caruso, Paul; Cunnane, MaryBeth] Harvard Univ, Sch Med, Boston, MA USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Lysaght, AC (reprint author), Harvard MIT Joint Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. EM andrew_lysaght@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [K08 DC010419]; Bertarelli Foundation; National Institute of Diabetes and Digestive and Kidney Diseases grant [DK097105] FX The authors are grateful for support from National Institute on Deafness and Other Communication Disorders grant K08 DC010419 (KMS), the Bertarelli Foundation (KMS) and National Institute of Diabetes and Digestive and Kidney Diseases grant DK097105 (BL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 10 Z9 11 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2014 VL 9 IS 9 AR e107681 DI 10.1371/journal.pone.0107681 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6FX UT WOS:000343679800043 PM 25243481 ER PT J AU Massimini, DF Warner, JJP Li, GA AF Massimini, Daniel F. Warner, Jon J. P. Li, Guoan TI Glenohumeral joint cartilage contact in the healthy adult during scapular plane elevation depression with external humeral rotation SO JOURNAL OF BIOMECHANICS LA English DT Article DE Shoulder; Kinematics; Fluoroscopy; Orthopaedics; Mechanics ID LATE PREPARATORY PHASE; SHOULDER ARTHROPLASTY; BICIPITAL GROOVE; IN-VIVO; SCAPULOHUMERAL RHYTHM; NATURAL-HISTORY; CUFF TEARS; KINEMATICS; ORIENTATION; MOTION AB The shoulder (glenohumeral) joint has the greatest range of motion of all human joints; as a result, it is particularly vulnerable to dislocation and injury. The ability to non-invasively quantify in-vivo articular cartilage contact patterns of joints has been and remains a difficult biomechanics problem. As a result, little is known about normal in-vivo glenohumeral joint contact patterns or the consequences that surgery has on altering them. In addition, the effect of quantifying glenohumeral joint contact patterns by means of proximity mapping, both with and without cartilage data, is unknown. Therefore, the objectives of this study are to (1) describe a technique for quantifying in-vivo glenohumeral joint contact patterns during dynamic shoulder motion, (2) quantify normal glenohumeral joint contact patterns in the young healthy adult during scapular plane elevation depression with external humeral rotation, and (3) compare glenohumeral joint contact patterns determined both with and without articular cartilage data. Our results show that the inclusion of articular cartilage data when quantifying in-vivo glenohumeral joint contact patterns has significant effects on the anterior-posterior contact centroid location, the superior-inferior contact centroid range of travel, and the total contact path length. As a result, our technique offers an advantage over glenohumeral joint contact pattern measurement techniques that neglect articular cartilage data. Likewise, this technique may be more sensitive than traditional 6-Degree-of-Freedom (6-DOF) joint kinematics for the assessment of overall glenohumeral joint health. Lastly, for the shoulder motion tested, we found that glenohumeral joint contact was located on the anterior-inferior glenoid surface. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Massimini, Daniel F.; Warner, Jon J. P.; Li, Guoan] Massachusetts Gen Hosp, Shoulder Biomot Lab, Boston, MA 02114 USA. [Warner, Jon J. P.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Massimini, Daniel F.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Shoulder Biomot Lab, 55 Fruit St,GRJ-1223, Boston, MA 02114 USA. EM gli1@partners.org FU Massachusetts General Hospital research funds in the Department of Orthopaedics FX Funding for this project was provided from unrestricted internal Massachusetts General Hospital research funds in the Department of Orthopaedics. No external funding sources were used for any part of this study. All study design elements, data analysis and manuscript preparation were performed exclusively by the authors without any input from hospital or external sources. NR 40 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD SEP 22 PY 2014 VL 47 IS 12 BP 3100 EP 3106 DI 10.1016/j.jbiomech.2014.06.034 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AR2CU UT WOS:000343392000038 PM 25047740 ER PT J AU Shingai, M Donau, OK Plishka, RJ Buckler-White, A Mascola, JR Nabel, GJ Nason, MC Montefiori, D Moldt, B Poignard, P Diskin, R Bjorkman, PJ Eckhaus, MA Klein, F Mouquet, H Lorenzi, JCC Gazumyan, A Burton, DR Nussenzweig, MC Martin, MA Nishimura, Y AF Shingai, Masashi Donau, Olivia K. Plishka, Ronald J. Buckler-White, Alicia Mascola, John R. Nabel, Gary J. Nason, Martha C. Montefiori, David Moldt, Brian Poignard, Pascal Diskin, Ron Bjorkman, Pamela J. Eckhaus, Michael A. Klein, Florian Mouquet, Hugo Lorenzi, Julio Cesar Cetrulo Gazumyan, Anna Burton, Dennis R. Nussenzweig, Michel C. Martin, Malcolm A. Nishimura, Yoshiaki TI Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RHESUS-MONKEYS; ENVELOPE GLYCOPROTEIN; RATIONAL DESIGN; ENV TRIMERS; IN-VITRO; CHALLENGE; MUCOSAL; PROTECTION; VACCINE AB It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (similar to 1:100) and potentially achievable by vaccination. C1 [Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Martin, Malcolm A.; Nishimura, Yoshiaki] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mascola, John R.; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Montefiori, David] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Diskin, Ron] Weizmann Inst Sci, Dept Biol Struct, IL-7610001 Rehovot, Israel. [Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.; Nussenzweig, Michel C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Eckhaus, Michael A.] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20892 USA. [Klein, Florian; Lorenzi, Julio Cesar Cetrulo; Gazumyan, Anna; Nussenzweig, Michel C.] Rockefeller Univ,New, Lab Mol Immunol, New York, NY 10065 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Burton, Dennis R.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov; ynishimura@niaid.nih.gov RI Cetrulo Lorenzi, Julio Cesar/B-5264-2008; poignard, pascal/N-6678-2013 OI Cetrulo Lorenzi, Julio Cesar/0000-0003-2492-3961; FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 62 TC 83 Z9 84 U1 1 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 22 PY 2014 VL 211 IS 10 BP 2061 EP 2074 DI 10.1084/jem.20132494 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4EC UT WOS:000342744800013 PM 25155019 ER PT J AU Simon, RA Shirani, H Aslund, KOA Back, M Haroutunian, V Gandy, S Nilsson, KPR AF Simon, Rozalyn A. Shirani, Hamid Aslund, K. O. Andreas Back, Marcus Haroutunian, Vahram Gandy, Sam Nilsson, K. Peter R. TI Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-beta and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism ID LUMINESCENT CONJUGATED OLIGOTHIOPHENES; THIOFLAVIN-T BINDING; CONFORMATIONAL STATES; MOLECULAR-MECHANISM; PROBES; POLYMERS; ASSIGNMENT; DERIVATIVES; DEPOSITS; FIBRILS AB A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (A beta) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer's disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate A beta and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of A beta and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates. C1 [Simon, Rozalyn A.; Shirani, Hamid; Aslund, K. O. Andreas; Back, Marcus; Nilsson, K. Peter R.] Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden. [Haroutunian, Vahram; Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, Vahram; Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Haroutunian, Vahram; Gandy, Sam] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Nilsson, KPR (reprint author), Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden. EM petni@ifm.liu.se FU Swedish Foundation for Strategic Research; Alzheimer Disease Research Center (ADRC) (NIH) [NIH-AG05138]; ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council FX Our work is supported by the Swedish Foundation for Strategic Research (K.P.R.N, R. S.) and the Alzheimer Disease Research Center (ADRC) (NIH grantNIH-AG05138; V. H., S. G.). K.P.R.N is financed by an ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council. R. S. is enrolled in the doctoral program Forum Scientum. NR 36 TC 7 Z9 7 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD SEP 22 PY 2014 VL 20 IS 39 BP 12537 EP 12543 DI 10.1002/chem.201402890 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA AQ2OL UT WOS:000342626200026 PM 25111601 ER PT J AU Buckholtz, JW Faigman, DL AF Buckholtz, Joshua W. Faigman, David L. TI Promises, promises for neuroscience and law SO CURRENT BIOLOGY LA English DT Editorial Material ID FUNCTIONAL MRI; LIE DETECTION; SCIENCE; DIRECTIONS; COURT; RISK C1 [Buckholtz, Joshua W.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Ctr Law Brain & Behav, Boston, MA 02114 USA. [Faigman, David L.] Univ Calif San Francisco, Hastings Coll Law, San Francisco, CA 94102 USA. [Faigman, David L.] Univ Calif San Francisco, Dept Psychiat, Sch Med, San Francisco, CA 94102 USA. [Faigman, David L.] UCSF UC Hastings Consortium Law Sci & Hlth Policy, San Francisco, CA 94102 USA. RP Buckholtz, JW (reprint author), Harvard Univ, Dept Psychol, 52 Oxford St, Cambridge, MA 02138 USA. EM joshua_buckholtz@harvard.edu NR 25 TC 4 Z9 4 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD SEP 22 PY 2014 VL 24 IS 18 BP R861 EP R867 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP9JU UT WOS:000342396900015 PM 25247363 ER PT J AU Gelfand, MV Hagan, N Tata, A Oh, WJ Lacoste, B Kang, KT Kopycinska, J Bischoff, J Wang, JH Gu, C AF Gelfand, Maria V. Hagan, Nellwyn Tata, Aleksandra Oh, Won-Jong Lacoste, Baptiste Kang, Kyu-Tae Kopycinska, Justyna Bischoff, Joyce Wang, Jia-Huai Gu, Chenghua TI Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding SO ELIFE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PATHOLOGICAL ANGIOGENESIS; VASCULAR DEVELOPMENT; HEPARIN-BINDING; SEMAPHORIN-III; TUMOR-GROWTH; RECEPTOR; ISOFORMS; MICE; PHOSPHORYLATION AB During development, tissue repair, and tumor growth, most blood vessel networks are generated through angiogenesis. Vascular endothelial growth factor (VEGF) is a key regulator of this process and currently, both VEGF and its receptors, VEGFR1, VEGFR2, and Neuropilin1 (NRP1), are targeted in therapeutic strategies for vascular disease and cancer. NRP1 is essential for vascular morphogenesis, but how NRP1 functions to guide vascular development has not been completely elucidated. Here, we generated a mouse line harboring a point mutation in the endogenous Nrp1 locus that selectively abolishes VEGF-NRP1 binding (Nrp1(VEGF-)). Nrp1(VEGF-) mutants survive to adulthood with normal vasculature revealing that NRP1 functions independent of VEGF-NRP1 binding during developmental angiogenesis. Moreover, we found that Nrp1-deficient vessels have reduced VEGFR2 surface expression in vivo demonstrating that NRP1 regulates its co-receptor, VEGFR2. Given the resources invested in NRP1 targeted anti-angiogenesis therapies, our results will be integral for developing strategies to re-build vasculature in disease. C1 [Gelfand, Maria V.; Hagan, Nellwyn; Tata, Aleksandra; Oh, Won-Jong; Lacoste, Baptiste; Kopycinska, Justyna; Gu, Chenghua] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Oh, Won-Jong] Korea Brain Res Inst, Taegu, South Korea. [Kang, Kyu-Tae; Bischoff, Joyce] Harvard Univ, Boston Childrens Hosp, Sch Med, Vasc Biol Program, Boston, MA USA. [Kang, Kyu-Tae; Bischoff, Joyce] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Surg, Boston, MA USA. [Kang, Kyu-Tae] Duksung Womens Univ, Coll Pharm, Seoul, South Korea. [Wang, Jia-Huai] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gu, C (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM chenghua_gu@hms.harvard.edu OI Bischoff, Joyce/0000-0002-6367-1974 FU Neural Imaging Center NINDS P30 Core Center grant [NS072030]; National Institutes of Health Fundamental Neurobiology Training grant [T32 NS007484-12]; Alice and Joseph Brooks Fund Postdoctoral Fellowship; Harvard Mahoney Neuroscience Institute Fund Postdoctoral Fellowship; National Institutes of Health [R01 HL096384, R01 NS064583]; Sloan research fellowship; Armenise junior faculty award; Genise Goldenson fund FX We thank members of the Gu laboratory for helpful comments on the manuscript, Lauren Byrnes for technical support, and both the Flow Cytometry Facility in the Systems Biology Department and the Neurobiology Imaging Facility in the Neurobiology Department of Harvard Medical School for consultation and instrument availability that facilitated this work. The Neurobiology Imaging Facility is supported in part by the Neural Imaging Center as part of an NINDS P30 Core Center grant #NS072030. This study was supported by the National Institutes of Health Fundamental Neurobiology Training grant T32 NS007484-12 (N. Hagan), the Alice and Joseph Brooks Fund Postdoctoral Fellowship (A. Tata), Harvard Mahoney Neuroscience Institute Fund Postdoctoral Fellowship (B. Lacoste), National Institutes of Health grant R01 HL096384 (K. Kang and J. Bischoff), and the following grants to C. Gu: Sloan research fellowship, Armenise junior faculty award, the Genise Goldenson fund, and National Institutes of Health grant R01 NS064583. NR 34 TC 25 Z9 25 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 22 PY 2014 VL 3 AR e03720 DI 10.7554/eLife.03720 PG 40 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AP4ZN UT WOS:000342089600001 PM 25244320 ER PT J AU Lowalekar, SK Treanor, PR Thatte, HS AF Lowalekar, Samar K. Treanor, Patrick R. Thatte, Hemant S. TI Cardioplegia at subnormothermia facilitates rapid functional resuscitation of hearts preserved in SOMAH for transplants SO JOURNAL OF CARDIOTHORACIC SURGERY LA English DT Article DE Cardioplegia; Transplantation; Reperfusion injury; High energy phosphates ID MYOCARDIAL PROTECTION; CRYSTALLOID CARDIOPLEGIA; CARDIOCIRCULATORY DEATH; REPERFUSION INJURY; CARDIAC-SURGERY; DONOR HEARTS; BLOOD; METAANALYSIS; PERFUSION; STORAGE AB Objectives: Hearts preserved ex vivo at 4 degrees C undergo time-dependent irreversible injury due to extreme hypothermia. Studies using novel organ preservative solution SOMAH, suggest that hearts are optimally 'preserved' at subnormothermic temperature of 21 degrees C. Present study evaluates relative efficacy of SOMAH 'cardioplegia' at 4 and 21 degrees C in preservation of optimum heart function after in vitro storage at subnormothermia. Methods: Porcine hearts arrested with SOMAH cardioplegia at 4 or 21 degrees C were stored in SOMAH for 5-hour at 21 degrees C (n = 5). At the end of storage, the weight of hearts was recorded and biopsies taken for cardiac tissue high energy phosphate level measurements. The hearts were then attached to a reperfusion apparatus and biochemical parameters including cardiac enzyme release and myocardial oxygen consumption and lactate production were determined in perfusate samples at regular intervals during ex vivo perfusion experiment. Functional evaluation of the hearts intraoperatively and ex vivo was performed by 2D echocardiography using trans-esophageal echocardiography probe. Results: Post-storage heart weights were unaltered in both groups, while available high-energy phosphates (HEP) were greater in the 21 degrees C group. Upon ex vivo reperfusion, coronary flow was significantly greater (p < 0.05) in 21 degrees C group. 2D echo revealed a greater cardiac output, fractional area change and ejection fraction in 21 degrees C group that was not significantly different than the 4 degrees C group. However, unlike 4 degrees C hearts, 21 degrees C hearts did not require inotropic intervention. Upon reperfusion, rate of cardiac enzyme release temporally resolved in 21 degrees C group, but not in the 4 degrees C group. 21 degrees C working hearts maintained their energy state during the experimental duration but not the 4 degrees C group; albeit, both groups demonstrated robust metabolism and function during this period. Conclusions: Rapid metabolic switch, increased synthesis of HEP, decreased injury and optimal function provides evidence that hearts arrested at 21 degrees C remain viably and functionally superior to those arrested at 4 degrees C when stored in SOMAH at ambient temperature pre-transplant. C1 [Lowalekar, Samar K.; Thatte, Hemant S.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Div Cardiothorac Surg, Boston, MA 02132 USA. [Lowalekar, Samar K.; Thatte, Hemant S.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Surg, Boston, MA 02115 USA. [Lowalekar, Samar K.; Treanor, Patrick R.; Thatte, Hemant S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Thatte, HS (reprint author), Brigham & Womens Hosp, VA Boston Healthcare Syst, Div Cardiothorac Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM hemant_thatte@hms.harvard.edu FU VA Merit Review grant; Department of Veterans Affairs, Office of Research and Development, Washington DC FX This work was supported by VA Merit Review grant (Dr. Thatte), Department of Veterans Affairs, Office of Research and Development, Washington DC, and an unrestricted gift from Somahlution (Jupiter, Fl) to Boston VA Research Institute for research (Dr. Thatte). NR 27 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8090 J9 J CARDIOTHORAC SURG JI J. Cardiothorac. Surg. PD SEP 20 PY 2014 VL 9 AR 155 DI 10.1186/s13019-014-0155-z PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS9LE UT WOS:000344563400001 PM 25238790 ER PT J AU Robert, C Ribas, A Wolchok, JD Hodi, FS Hamid, O Kefford, R Weber, JS Joshua, AM Hwu, WJ Gangadhar, TC Patnaik, A Dronca, R Zarour, H Joseph, RW Boasberg, P Chmielowski, B Mateus, C Postow, MA Gergich, K Elassaiss-Schaap, J Li, XN Iannone, R Ebbinghaus, SW Kang, SP Daud, A AF Robert, Caroline Ribas, Antoni Wolchok, Jedd D. Hodi, F. Stephen Hamid, Omid Kefford, Richard Weber, Jeffrey S. Joshua, Anthony M. Hwu, Wen-Jen Gangadhar, Tara C. Patnaik, Amita Dronca, Roxana Zarour, Hassane Joseph, Richard W. Boasberg, Peter Chmielowski, Bartosz Mateus, Christine Postow, Michael A. Gergich, Kevin Elassaiss-Schaap, Jeroen Li, Xiaoyun Nicole Iannone, Robert Ebbinghaus, Scot W. Kang, S. Peter Daud, Adil TI Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial SO LANCET LA English DT Article ID METASTATIC MELANOMA; RESPONSE CRITERIA; IMPROVED SURVIVAL; BRAF INHIBITORS; MEK INHIBITION; OPEN-LABEL; SAFETY; MUTATION; PD-1; IMMUNOTHERAPY AB Background The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. Methods In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged >= 18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. Findings 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses-21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. Interpretation The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. C1 [Robert, Caroline; Mateus, Christine] Gustave Roussy, Paris, France. [Robert, Caroline; Mateus, Christine] INSERM, U981, Paris, France. [Ribas, Antoni; Chmielowski, Bartosz] Univ Calif Los Angeles, Los Angeles, CA USA. [Wolchok, Jedd D.; Postow, Michael A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamid, Omid; Boasberg, Peter] Angeles Clin & Res Inst, Los Angeles, CA USA. [Kefford, Richard] Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW 2145, Australia. [Kefford, Richard] Melanoma Inst Australia, Westmead, NSW 2145, Australia. [Kefford, Richard] Univ Sydney, Sydney, NSW 2006, Australia. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gangadhar, Tara C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Patnaik, Amita] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Dronca, Roxana] Mayo Clin, Rochester, MN USA. [Zarour, Hassane] Univ Pittsburgh, Pittsburgh, PA USA. [Joseph, Richard W.] Mayo Clin, Jacksonville, FL 32224 USA. [Gergich, Kevin; Elassaiss-Schaap, Jeroen; Li, Xiaoyun Nicole; Iannone, Robert; Ebbinghaus, Scot W.; Kang, S. Peter] Merck, Whitehouse Stn, NJ USA. [Daud, Adil] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Robert, C (reprint author), Inst Gustave Roussy, 114 Rue Edouard Vaillant, F-94805 Villejuif Paris Sud, France. EM caroline.robert@gustaveroussy.fr RI Li, Xiaoyun/P-8265-2014; Elassaiss-Schaap , Jeroen/Q-5451-2016; OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Merck Sharp and Dohme FX Merck Sharp and Dohme. NR 32 TC 534 Z9 553 U1 16 U2 100 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD SEP 20 PY 2014 VL 384 IS 9948 BP 1109 EP 1117 DI 10.1016/S0140-6736(14)60958-2 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2PU UT WOS:000342630600031 PM 25034862 ER PT J AU Nannini, M Astolfi, A Urbini, M Indio, V Santini, D Heinrich, MC Corless, CL Ceccarelli, C Saponara, M Mandrioli, A Lolli, C Ercolani, G Brandi, G Biasco, G Pantaleo, MA AF Nannini, Margherita Astolfi, Annalisa Urbini, Milena Indio, Valentina Santini, Donatella Heinrich, Michael C. Corless, Christopher L. Ceccarelli, Claudio Saponara, Maristella Mandrioli, Anna Lolli, Cristian Ercolani, Giorgio Brandi, Giovanni Biasco, Guido Pantaleo, Maria A. TI Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST) SO BMC CANCER LA English DT Article DE Gastrointestinal stromal tumors (GIST); Wild-type; KIT; PDGFRA; Succinate dehydrogenase; SDHA; RAS; Quadruple(WT) ID GASTROINTESTINAL STROMAL TUMORS; DIFFERENTIAL EXPRESSION ANALYSIS; SUCCINATE-DEHYDROGENASE SUBUNIT; FAMILY TRANSCRIPTION FACTOR; TYROSINE-KINASE INHIBITOR; RECEPTOR-LIKE RECEPTOR; PHASE-I TRIAL; SDHA MUTATIONS; ANTITUMOR-ACTIVITY; DEFICIENT GISTS AB Background: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet derived growth factor receptor alpha (PDGFRA) mutations Clin Oncol 223813-3825, 2004; Hematol Oncol Clin North Am 23:15-34,2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate clehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (HAS pathway or RAS-P). In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild -type GIST (quadruple(WT) or KITWT /PDGFRA(WT)/SDHWT/RAS-P-WT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT /PDGFRA(WT)/SDHWT/RAS-P-WT GIST, by using a massively parallel sequencing and ruicroarray approach, and compare it with the genoruic profile of other GIST subtypes. Methods: We performed El whole genome analysis using a massively parallel sequencing approuch on a total of 16 GIST cases (2 KITWT/PDGFRA(WT)/SDFWT and SDHBIHC+/SDHA(IHC+), 2 KITWT/PDGFRA(WT)/SDHA(mut) arid SDHBIHC-/SDHA(IHC-) and 12 cases of KITmut or PDGFRAM(mut) GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFHA(WT) SDHA(mut) GIST and 19 KITmut or PDGFRA(mut) GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. Results: We found that both cases of quadruple(WT) GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadruple(WT) GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). Conclusion: We report for the first e an integrated genomic picture of KITWT/PDGFRA(WT)/SDHWT/RAS-P-WT GIST, using massively parallel sequencing and gene expression analyses, and found that quadruple(WT) GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadruple(WT) GIST represent another unique group within the family of gastrointestintal stromal tumors. C1 [Nannini, Margherita; Mandrioli, Anna; Lolli, Cristian; Brandi, Giovanni; Biasco, Guido; Pantaleo, Maria A.] Univ Bologna, St Orsola Malpighi Hosp, Dept Specialized Expt & Diagnost Med, I-40138 Bologna, Italy. [Astolfi, Annalisa; Urbini, Milena; Indio, Valentina; Saponara, Maristella; Biasco, Guido; Pantaleo, Maria A.] Univ Bologna, Giorgio Prodi Canc Res Ctr, I-40138 Bologna, Italy. [Santini, Donatella; Ceccarelli, Claudio] Univ Bologna, S Orsola Malpighi Hosp, Pathol Unit, I-40138 Bologna, Italy. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Div Hematol & Oncol, Portland, OR 97201 USA. [Corless, Christopher L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Ercolani, Giorgio] Univ Bologna, S Orsola Malpighi Hosp, Transplant Gen & Emergency Surg Dept, I-40138 Bologna, Italy. RP Pantaleo, MA (reprint author), Univ Bologna, St Orsola Malpighi Hosp, Dept Specialized Expt & Diagnost Med, Via Massarenti 9, I-40138 Bologna, Italy. EM maria.pantaleo@unibo.it RI Urbini, Milena/K-1351-2016; nannini, margherita/J-9866-2016; OI Urbini, Milena/0000-0002-3364-9098; PANTALEO, MARIA ABBONDANZA/0000-0002-0177-6957; Ceccarelli, Claudio/0000-0003-0743-2087; NANNINI, MARGHERITA/0000-0002-2103-1960; astolfi, annalisa/0000-0002-2732-0747; Indio, Valentina/0000-0002-8854-3821 FU Novartis Oncology, Italy; My First Grant, AIRC FX The present work was done with a financial contribution by Novartis Oncology, Italy, and with funds by My First Grant 2013, AIRC 2013. NR 64 TC 21 Z9 22 U1 2 U2 14 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 SEP 20 PY 2014 VL 14 AR 685 DI 10.1186/1471-2407-14-685 PG 12 WC Oncology SC Oncology GA AQ0HW UT WOS:000342464900001 PM 25239601 ER PT J AU Adams, S Gray, RJ Demaria, S Goldstein, L Perez, EA Shulman, LN Martino, S Wang, M Jones, VE Saphner, TJ Wolff, AC Wood, WC Davidson, NE Sledge, GW Sparano, JA Badve, SS AF Adams, Sylvia Gray, Robert J. Demaria, Sandra Goldstein, Lori Perez, Edith A. Shulman, Lawrence N. Martino, Silvana Wang, Molin Jones, Vicky E. Saphner, Thomas J. Wolff, Antonio C. Wood, William C. Davidson, Nancy E. Sledge, George W. Sparano, Joseph A. Badve, Sunil S. TI Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN-RECEPTOR; CHEMOTHERAPY; CELLS AB Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin-stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence-free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter. (C) 2014 by American Society of Clinical Oncology C1 [Adams, Sylvia; Demaria, Sandra] NYU, Sch Med, New York, NY 10016 USA. [Sparano, Joseph A.] Albert Einstein Med Ctr, Bronx, NY USA. [Shulman, Lawrence N.; Wang, Molin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldstein, Lori] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Davidson, Nancy E.] Univ Pittsburgh, Pittsburgh, PA USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Jones, Vicky E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Saphner, Thomas J.] St Vincent Reg Canc, Green Bay, WI USA. [Wolff, Antonio C.] Johns Hopkins Univ, Baltimore, MD USA. [Wood, William C.] Emory Univ, Atlanta, GA 30322 USA. [Sledge, George W.; Badve, Sunil S.] Indiana Univ, Indianapolis, IN 46204 USA. RP Adams, S (reprint author), NYU, Inst Canc, Dept Med, 160 East 34th St, New York, NY 10016 USA. EM sylvia.adams@nyumc.org OI Wolff, Antonio/0000-0003-3734-1063; Demaria, Sandra/0000-0003-4426-0499 FU Public Health Service [CA23318, CA66636, CA21115, CA27525, CA21076, CA16116, CA39229, CA49883, CA14958, CA114737, CA32102, CA25224, CA31946, CA11789]; National Cancer Institute (NCI), National Institutes of Health; Department of Health and Human Services; sanofi-aventis; NCI [R01CA161891]; Komen Scholar Award [SAC110004]; Breast Cancer Research Foundation FX Coordinated by the Eastern Cooperative Oncology Group (ECOG) and supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA27525, CA21076, CA16116, CA39229, CA49883, CA14958, CA114737, CA32102, CA25224, CA31946, and CA11789; National Cancer Institute (NCI), National Institutes of Health; Department of Health and Human Services; grants from sanofi-aventis and Breast Cancer Research Foundation; NCI Grant No. R01CA161891 (S.A.); and Komen Scholar Award No. SAC110004 (S.S.B.). Biospecimens provided by ECOG Pathology Coordinating Office and Reference Laboratory. NR 25 TC 176 Z9 183 U1 9 U2 21 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 2959 EP + DI 10.1200/JCO.2013.55.0491 PG 9 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200008 PM 25071121 ER PT J AU Rosenberg, AR Orellana, L Kang, TI Geyer, JR Feudtner, C Dussel, V Wolfe, J AF Rosenberg, Abby R. Orellana, Liliana Kang, Tammy I. Geyer, J. Russell Feudtner, Chris Dussel, Veronica Wolfe, Joanne TI Differences in Parent-Provider Concordance Regarding Prognosis and Goals of Care Among Children With Advanced Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PHYSICIAN-ASSISTED SUICIDE; PALLIATIVE CARE; ONCOLOGY-GROUP; LIFE; END; COMMUNICATION; ATTITUDES; IMPACT; TRANSPLANTATION AB Purpose Concordance between parents of children with advanced cancer and health care providers has not been described. We aimed to describe parent-provider concordance regarding prognosis and goals of care, including differences by cancer type. Patients and Methods A total of 104 pediatric patients with recurrent or refractory cancer were enrolled at three large children's hospitals. On enrollment, their parents and providers were invited to complete a survey assessing perceived prognosis and goals of care. Patients' survival status was retrospectively abstracted from medical records. Concordance was assessed via discrepancies in perceived prognosis, kappa statistics, and McNemar's test. Distribution of categorical variables and survival rates across cancer type were compared with Fisher's exact and log-rank tests, respectively. Results Data were available from 77 dyads (74% of enrolled). Parent-provider agreement regarding prognosis and goals of care was poor (kappa, 0.12 to 0.30). Parents were more likely to report cure was likely (P < .001). The frequency of perceived likelihood of cure and the goal of cure varied by cancer type for both parents and providers (P < .001 to .004). Relatively optimistic responses were more common among parents and providers of patients with hematologic malignancies, although there were no differences in survival. Conclusion Parent-provider concordance regarding prognosis and goals in advanced pediatric cancer is generally poor. Perceptions of prognosis and goals of care vary by cancer type. Understanding these differences may inform parent-provider communication and decision making. C1 [Rosenberg, Abby R.; Geyer, J. Russell] Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Rosenberg, Abby R.; Geyer, J. Russell] Univ Washington, Seattle, WA 98195 USA. [Rosenberg, Abby R.] Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Orellana, Liliana; Dussel, Veronica] Natl Canc Inst, Buenos Aires, DF, Argentina. [Dussel, Veronica] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Kang, Tammy I.; Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wolfe, Joanne] Boston Childrens Hosp, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu RI Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337 FU National Cancer Institute, National Institutes of Health [1K07 CA096746-01]; Charles H. Hood Foundation Child Health Research Award; American Cancer Society Pilot and Exploratory Project; St Baldrick's Foundation FX Supported by Grant No. 1K07 CA096746-01 from the National Cancer Institute, National Institutes of Health; a Charles H. Hood Foundation Child Health Research Award; an American Cancer Society Pilot and Exploratory Project Award in palliative care of cancer patients and their families; and a St Baldrick's Foundation Fellow Award (A.R.R.). NR 32 TC 6 Z9 6 U1 1 U2 13 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 3005 EP + DI 10.1200/JCO.2014.55.4659 PG 8 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200014 PM 25024073 ER PT J AU Siddiqui, MM Wilson, KM Epstein, MM Rider, JR Martin, NE Stampfer, MJ Giovannucci, EL Mucci, LA AF Siddiqui, Mohummad Minhaj Wilson, Kathryn M. Epstein, Mara M. Rider, Jennifer R. Martin, Neil E. Stampfer, Meir J. Giovannucci, Edward L. Mucci, Lorelei A. TI Vasectomy and Risk of Aggressive Prostate Cancer: A 24-Year Follow-Up Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES MEN; TRICHOMONAS-VAGINALIS; PLASMA ANTIBODIES; COHORT; HEALTH; ASSOCIATION AB Purpose Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. Patients and Methods Among 49,405 US men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. Results Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. Conclusion Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely. (C) 2014 by American Society of Clinical Oncology C1 [Siddiqui, Mohummad Minhaj; Wilson, Kathryn M.; Epstein, Mara M.; Rider, Jennifer R.; Martin, Neil E.; Stampfer, Meir J.; Giovannucci, Edward L.; Mucci, Lorelei A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilson, Kathryn M.; Epstein, Mara M.; Rider, Jennifer R.; Stampfer, Meir J.; Giovannucci, Edward L.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Martin, Neil E.] Dana Farber Canc Inst, Boston, MA USA. [Epstein, Mara M.] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Mucci, LA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM lmucci@hsph.harvard.edu RI Martin, Neil/E-2193-2014; OI Martin, Neil/0000-0002-8164-8516; Rider, Jennifer/0000-0002-2637-6036; Siddiqui, Mohummad/0000-0002-4484-6820 FU National Cancer Institute/National Institutes of Health [P01 CA055075, CA133891, CA141298, UM1CA167552-01, T32 CA09001] FX Supported by Grants No. P01 CA055075, CA133891, CA141298, and UM1CA167552-01 and by Training Grant No. T32 CA09001 (K.M.W., J.R.R., and M.M.E.) from the National Cancer Institute/National Institutes of Health. L.A.M., J.R.R., and N.E.M. are Young Investigators of the Prostate Cancer Foundation. NR 32 TC 15 Z9 17 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 3033 EP + DI 10.1200/JCO.2013.54.8446 PG 7 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200017 PM 25002716 ER PT J AU Campigotto, F Weller, E AF Campigotto, Federico Weller, Edie TI Impact of Informative Censoring on the Kaplan-Meier Estimate of Progression-Free Survival in Phase II Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; DEPENDENT COMPETING RISKS; MULTIPLE-MYELOMA PATIENTS; SINGLE-CENTER EXPERIENCE; WALDENSTROMS MACROGLOBULINEMIA; AUTOLOGOUS TRANSPLANTATION; INTERNATIONAL WORKSHOP; INVERSE PROBABILITY; PROGNOSTIC-FACTORS; CHEMOTHERAPY AB Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate. C1 [Campigotto, Federico; Weller, Edie] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Campigotto, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02115 USA. EM federico@jimmy.harvard.edu FU National Cancer Institute [5P50CA100707, 5P01CA078378] FX Supported by Grants No. 5P50CA100707 and 5P01CA078378 from the National Cancer Institute. NR 39 TC 6 Z9 6 U1 2 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 3068 EP 3074 DI 10.1200/JCO.2014.55.6340 PG 7 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200021 PM 25113767 ER PT J AU Wang, JN Xu, LH Zeng, WG Hu, P Zeng, MS Rabkin, SD Liu, RB AF Wang, Jiani Xu, Lihua Zeng, Weigen Hu, Pan Zeng, Musheng Rabkin, Samuel D. Liu, Renbin TI Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta SO CANCER CELL INTERNATIONAL LA English DT Article DE Hepatocellular carcinoma; Oncolytic herpes simplex virus; Cytotoxicity; Subcutaneous model ID REPLICATION-COMPETENT; MALIGNANT GLIOMA; VIRAL THERAPY; GENE-THERAPY; RISK-FACTORS; CANCER; MUTANT; MODEL; TUMORS; G207 AB Background: Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells while sparing the adjacent normal tissue. Hepatocellular carcinoma (HCC) is amongst the most common and lethal cancers, especially in Third World countries. In this study, the cytotoxicity of a third-generation oncolytic HSV, G47 Delta, was investigated in different human HCC cell lines and in an immortalized human hepatic cell line. Additionally, subcutaneous models of HCC were established to evaluate the in vivo anti-tumor efficacy of G47 Delta. Methods: The HepG2, HepB, SMMC-7721, BEL-7404, and BEL-7405 human HCC cell lines and the HL-7702 human hepatic immortalized cell lines were infected with G47 Delta at different multiplicities of infection (MOIs). The viability of infected cells was determined, and the G47 Delta replication was identified by X-gal staining for LacZ expression. Two subcutaneous (s.c.) HCC tumor models of HCC were also established in Balb/c nude mice, which were intratumorally (i.t.) treated with either G47 Delta or mock virus. Tumor volume and mouse survival times were documented. Results: More than 95% of the HepG2, Hep3B, and SMMC-7721 HCC cells were killed on by day 5 after infection with a MOI's of 0.01. For the HL-7702 human hepatic immortalized cells, 100% of the cells were killed on by day 5 after infection with a MOI's of 0.01. The BEL-7404 HCC cell line was less susceptible with about 70% cells were killed by day 5 after infection with a MOI's of 0.01. Whereas the BEL-7405 HCC cells were the least susceptible, with only 30% of the cells were killed. Both the SMMC-7721 and BEL-7404 cells form aggressive sc tumor models. G47 Delta replicates in the tumors, such that most of the tumors regressed after the G47 Delta-treatment, and treated tumor-bearing mice survived much longer than the control animals. Conclusions: G47 Delta effectively kills human HCC cells and an immortalized hepatic cell line at low MOI. Intra-tumor injection of G47 Delta can induce a therapeutic effect and prolong the survival of treated mice bearing SMMC-7721 and BEL-7404 subcutaneously (s.c.) tumors. Thus, G47 Delta may be useful as a novel therapeutic agent for HCC. C1 [Wang, Jiani; Zeng, Weigen; Hu, Pan; Liu, Renbin] Sun Yat Sen Univ, Affiliated Hosp 3, Breast Canc Ctr, Guangzhou 510630, Guangdong, Peoples R China. [Xu, Lihua] Guangzhou Med Univ, Affiliated Hosp 1, Dept Hematol & Oncol, Guangzhou, Guangdong, Peoples R China. [Zeng, Weigen] Chinese Acad Med Sci, Peking Union Med Coll, Canc Hosp, Dept Colorectal Surg, Beijing 100021, Peoples R China. [Zeng, Musheng] Sun Yat Sen Univ, State Key Lab Oncol South China, Guangzhou 510630, Guangdong, Peoples R China. [Rabkin, Samuel D.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Rabkin, Samuel D.] Harvard Univ, Sch Med, Boston, MA USA. RP Liu, RB (reprint author), Sun Yat Sen Univ, Affiliated Hosp 3, Breast Canc Ctr, 600 Tianhe Rd, Guangzhou 510630, Guangdong, Peoples R China. EM liur@vip.163.com OI rabkin, samuel/0000-0003-2344-2795 FU National Natural Science Foundation of China [81372815, 81172523] FX Our work is supported by the National Natural Science Foundation of China (No. 81372815, 81172523). NR 43 TC 3 Z9 3 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2867 J9 CANCER CELL INT JI Cancer Cell Int. PD SEP 19 PY 2014 VL 14 AR 83 DI 10.1186/s12935-014-0083-y PG 9 WC Oncology SC Oncology GA AW3PL UT WOS:000346198700001 PM 25360068 ER PT J AU Tierney, DB Franke, MF Becerra, MC Viru, FAA Bonilla, CA Sanchez, E Guerra, D Munoz, M Llaro, K Palacios, E Mestanza, L Hurtado, RM Furin, JJ Shin, S Mitnick, CD AF Tierney, Dylan B. Franke, Molly F. Becerra, Mercedes C. Alcantara Viru, Felix A. Bonilla, Cesar A. Sanchez, Epifanio Guerra, Dalia Munoz, Maribel Llaro, Karim Palacios, Eda Mestanza, Lorena Hurtado, Rocio M. Furin, Jennifer J. Shin, Sonya Mitnick, Carole D. TI Time to Culture Conversion and Regimen Composition in Multidrug-Resistant Tuberculosis Treatment SO PLOS ONE LA English DT Article ID PREDICTORS AB Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31-92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs. C1 [Tierney, Dylan B.; Becerra, Mercedes C.; Shin, Sonya; Mitnick, Carole D.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Tierney, Dylan B.; Franke, Molly F.; Becerra, Mercedes C.; Alcantara Viru, Felix A.; Guerra, Dalia; Munoz, Maribel; Llaro, Karim; Shin, Sonya; Mitnick, Carole D.] Partners Hlth, Boston, MA USA. [Tierney, Dylan B.; Franke, Molly F.; Becerra, Mercedes C.; Alcantara Viru, Felix A.; Guerra, Dalia; Munoz, Maribel; Llaro, Karim; Shin, Sonya; Mitnick, Carole D.] Socios Salud Sucursal Peru, Lima, Peru. [Franke, Molly F.; Becerra, Mercedes C.; Mitnick, Carole D.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Bonilla, Cesar A.] Minist Hlth, Natl TB Strategy, Lima, Peru. [Sanchez, Epifanio] Hosp Nacl Sergio E Bernales, Lima, Peru. [Palacios, Eda; Mestanza, Lorena] Asociac Visionarios, Lima, Peru. [Hurtado, Rocio M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Hurtado, Rocio M.] Global Hlth Comm, Boston, MA USA. [Furin, Jennifer J.] Case Western Reserve Univ, TB Res Unit, Cleveland, OH 44106 USA. RP Tierney, DB (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. EM dtierney@partners.org FU Research Core of the Department of Global Health and Social Medicine at Harvard Medical School; Janssen Pharmaceuticals, Inc. FX This work was supported by the Research Core of the Department of Global Health and Social Medicine at Harvard Medical School. The fee for open access publication of this report was paid by a philanthropic contribution to Harvard Medical School from Janssen Pharmaceuticals, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 6 Z9 6 U1 0 U2 2 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 SEP 19 PY 2014 VL 9 IS 9 AR e108035 DI 10.1371/journal.pone.0108035 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0RY UT WOS:000342491600080 PM 25238411 ER PT J AU Duan, ZF Zhang, JM Ye, SA Shen, J Choy, E Cote, G Harmon, D Mankin, H Hua, YQ Zhang, Y Gray, NS Hornicek, FJ AF Duan, Zhenfeng Zhang, Jianming Ye, Shunan Shen, Jacson Choy, Edwin Cote, Gregory Harmon, David Mankin, Henry Hua, Yingqi Zhang, Yu Gray, Nathanael S. Hornicek, Francis J. TI A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells SO BMC CANCER LA English DT Article DE Osteosarcoma; MDR; Src kinase; Doxorubicin ID TYROSINE KINASE INHIBITOR; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; CANCER-CELLS; CHEMOTHERAPEUTIC-AGENTS; ALLOGRAFT-REJECTION; INORGANIC-PHOSPHATE; DRUG-RESISTANCE; SARCOMA-CELLS; LUNG-CANCER AB Background: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances. Methods: We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel. Results: We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OS(MR) and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OS(MR) and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay. Conclusions: These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma. C1 [Duan, Zhenfeng; Ye, Shunan; Shen, Jacson; Choy, Edwin; Cote, Gregory; Harmon, David; Mankin, Henry; Hornicek, Francis J.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Zhang, Jianming] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Hua, Yingqi] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Shanghai 200080, Peoples R China. [Zhang, Yu] Liu Hua Qiao Hosp, Dept Orthoped Surg, Guangzhou 510010, Guangdong, Peoples R China. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Sarcoma Foundation of America (SFA); Gategno and Wechsler funds; NIH [U54 HG006097]; Jennifer Hunter Yates Foundation; Kenneth Stanton Fund FX This project was supported, in part, by a grant from Sarcoma Foundation of America (SFA), grants from the Gategno and Wechsler funds, and NIH U54 HG006097 (NSG and JZ). Support has also been provided by the Jennifer Hunter Yates Foundation and the Kenneth Stanton Fund. NR 45 TC 8 Z9 8 U1 0 U2 8 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 SEP 19 PY 2014 VL 14 AR 681 DI 10.1186/1471-2407-14-681 PG 11 WC Oncology SC Oncology GA AP5JN UT WOS:000342115600001 PM 25236161 ER PT J AU Kendall, RT Lee, MH Pleasant, DL Robinson, K Kuppuswamy, D McDermott, PJ Luttrell, LM AF Kendall, Ryan T. Lee, Mi-Hye Pleasant, Dorea L. Robinson, Katherine Kuppuswamy, Dhandapani McDermott, Paul J. Luttrell, Louis M. TI Arrestin-dependent Angiotensin AT(1) Receptor Signaling Regulates Akt and mTor-mediated Protein Synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; BETA-ARRESTIN; CARDIAC MYOCYTES; S6 KINASE; IN-VIVO; PHOSPHORYLATION; ACTIVATION; PATHWAY; ERK; COMPLEX AB Control of protein synthesis is critical to both cell growth and proliferation. The mammalian target of rapamycin (mTOR) integrates upstream growth, proliferation, and survival signals, including those transmitted via ERK1/2 and Akt, to regulate the rate of protein translation. The angiotensin AT(1) receptor has been shown to activate both ERK1/2 and Akt in arrestin-based signalsomes. Here, we examine the role of arrestin-dependent regulation of ERK1/2 and Akt in the stimulation of mTOR-dependent protein translation by the AT(1) receptor using HEK293 and primary vascular smooth muscle cell models. Nascent protein synthesis stimulated by both the canonical AT(1) receptor agonist angiotensin II (AngII), and the arrestin pathway-selective agonist [Sar(1)-Ile(4)-Ile(8)] AngII (SII), is blocked by shRNA silencing of beta arrestin1/2 or pharmacological inhibition of Akt, ERK1/2, or mTORC1. In HEK293 cells, SII activates a discrete arrestin-bound pool of Akt and promotes Akt-dependent phosphorylation of mTOR and its downstream effector p70/p85 ribosomal S6 kinase (p70/85S6K). In parallel, SII-activated ERK1/2 helps promote mTOR and p70/85S6K phosphorylation, and is required for phosphorylation of the known ERK1/2 substrate p90 ribosomal S6 kinase (p90RSK). Thus, arrestins coordinate AT(1) receptor regulation of ERK1/2 and Akt activity and stimulate protein translation via both Akt-mTOR-p70/85S6K and ERK1/2-p90RSK pathways. These results suggest that in vivo, arrestin pathway-selective AT(1) receptor agonists may promote cell growth or hypertrophy through arrestin-mediated mechanisms despite their antagonism of G protein signaling. C1 [Kendall, Ryan T.; Lee, Mi-Hye; Pleasant, Dorea L.; Robinson, Katherine; Kuppuswamy, Dhandapani; McDermott, Paul J.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Kuppuswamy, Dhandapani; McDermott, Paul J.; Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Luttrell, LM (reprint author), Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, 96 Jonathan Lucas St, Charleston, SC 29425 USA. EM luttrell@musc.edu FU National Institutes of Health [5K12GM081265, 5R01DK055524]; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center FX This work was supported by National Institutes of Health Grants 5K12GM081265 (to R. T. K.) and 5R01DK055524 (to L. M. L.), and the Research Service of the Ralph H. Johnson Veterans Affairs Medical Center. NR 44 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2014 VL 289 IS 38 BP 26155 EP 26166 DI 10.1074/jbc.M114.595728 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800012 PM 25081544 ER PT J AU Zhao, YL Xiao, M Sun, BG Zhang, ZM Shen, T Duan, XY Yu, PB Feng, XH Lin, X AF Zhao, Yulan Xiao, Mu Sun, Baoguo Zhang, Zhengmao Shen, Tao Duan, Xueyan Yu, Paul Borchyung Feng, Xin-Hua Lin, Xia TI C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL SELF-RENEWAL; BETA; PATHWAY; IDENTIFICATION; NUCLEUS AB The bone morphogenetic protein (BMP) signaling pathway regulates a wide range of cellular responses in metazoans. A key step in the canonical BMP signaling is the phosphorylation and activation of transcription factors Smad1, Smad5, and Smad8 (collectively Smad1/5/8) by the type I BMP receptors. We previously identified PPM1A as a phosphatase toward dephosphorylation of all receptor-regulated Smads (R-Smads), including Smad1/5/8. Here we report another nuclear phosphatase named SCP4/CTDSPL2, belonging to the FCP/SCP family, as a novel Smad phosphatase in the nucleus. SCP4 physically interacts with and specifically dephosphorylates Smad1/5/8, and as a result attenuates BMP-induced transcriptional responses. Knockdown of SCP4 in multipotent mesenchymal C2C12 cells leads to increased expression of BMP target genes and consequently promotes BMP-induced osteogenic differentiation. Collectively, our results demonstrate that SCP4, as a Smad phosphatase, plays a critical role in BMP-induced signaling and cellular functions. C1 [Zhao, Yulan; Xiao, Mu; Feng, Xin-Hua] Zhejiang Univ, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. [Zhao, Yulan; Xiao, Mu; Feng, Xin-Hua] Zhejiang Univ, Innovat Ctr Cell Biol, Hangzhou 310058, Zhejiang, Peoples R China. [Sun, Baoguo; Zhang, Zhengmao; Shen, Tao; Feng, Xin-Hua; Lin, Xia] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Sun, Baoguo; Feng, Xin-Hua] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Duan, Xueyan; Feng, Xin-Hua] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Shen, Tao] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA. [Yu, Paul Borchyung] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Feng, XH (reprint author), Zhejiang Univ, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. EM xhfeng@zju.edu.cn; xialin@bcm.edu RI Huang, Xiaoyan/N-2561-2014; OI Yu, Paul/0000-0003-2145-4944 FU Ministry of Science and Technology [2012CB966600]; National Natural Science Foundation of China [31090360]; National Institutes of Health [R01GM63773, R01AR053591, R01CA108454, R01DK073932]; Project 111 [B13026]; Project 985; Fundamental Research Funds for the Central Universities FX This research was partly supported by grants from the Ministry of Science and Technology (2012CB966600); the National Natural Science Foundation of China (31090360); the National Institutes of Health (R01GM63773, R01AR053591, and R01CA108454 to X.-H. F., and R01DK073932 to X. L.); Project 111 (B13026); Project 985; and the Fundamental Research Funds for the Central Universities. NR 32 TC 6 Z9 6 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2014 VL 289 IS 38 BP 26441 EP 26450 DI 10.1074/jbc.M114.568964 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800035 PM 25100727 ER PT J AU Kabrhel, C Rempell, JS Avery, LL Dudzinski, DM Weinberg, I AF Kabrhel, Christopher Rempell, Joshua S. Avery, Laura L. Dudzinski, David M. Weinberg, Ido TI Case 29-2014: A 60-Year-Old Woman with Syncope SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC VENOUS THROMBOEMBOLISM; MASSIVE PULMONARY-EMBOLISM; EMERGENCY PHYSICIANS; SURGICAL-TREATMENT; METAANALYSIS; RISK; ECHOCARDIOGRAPHY; MANAGEMENT; THROMBOSIS; DIAGNOSIS C1 [Kabrhel, Christopher] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Avery, Laura L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Dept Echocardiog, Boston, MA 02114 USA. [Dudzinski, David M.; Weinberg, Ido] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Rempell, Joshua S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Kabrhel, Christopher] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. [Avery, Laura L.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Dudzinski, David M.] Harvard Univ, Sch Med, Dept Echocardiog, Boston, MA USA. [Dudzinski, David M.; Weinberg, Ido] Harvard Univ, Sch Med, Dept Cardiol, Boston, MA USA. RP Kabrhel, C (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. FU Diagnostica Stago; Siemens Healthcare; Sanofi; Advantage Health Care; VIVA Physicians FX Dr. Kabrhel reports receiving consulting fees from Diagnostica Stago and grant support to his institution from Diagnostica Stago and Siemens Healthcare; Dr. Dudzinski, consulting fees from Sanofi and Advantage Health Care; and Dr. Weinberg, consulting fees from VIVA Physicians. No other potential conflict of interest relevant to this article was reported. NR 22 TC 4 Z9 4 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 18 PY 2014 VL 371 IS 12 BP 1143 EP 1150 DI 10.1056/NEJMcpc1403307 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300011 PM 25229919 ER PT J AU Azab, AK Sahin, I Azab, F Moschetta, M Mishima, Y Burwick, N Zimmermann, J Romagnoli, B Patel, K Chevalier, E Roccaro, AM Ghobrial, IM AF Azab, Abdel Kareem Sahin, Ilyas Azab, Feda Moschetta, Michele Mishima, Yuji Burwick, Nicholas Zimmermann, Johann Romagnoli, Barbara Patel, Kalpana Chevalier, Eric Roccaro, Aldo M. Ghobrial, Irene M. TI CXCR7-dependent angiogenic mononuclear cell trafficking regulates tumor progression in multiple myeloma SO BLOOD LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; BONE-MARROW MICROENVIRONMENT; MEDIATED DRUG-RESISTANCE; CHEMOKINE RECEPTOR; CXCR7; RDC1; ADHESION; CXCL12; PROLIFERATION; BEVACIZUMAB AB The CXCR4/stromal cell-derived factor-1 (SDF-1) axis is essential for cell trafficking and has been shown to regulate tumor progression and metastasis in many tumors including multiple myeloma (MM). A second chemokine receptor for SDF-1, CXCR7 was discovered recently and found on activated endothelial cells. We examined the role of CXCR7 in angiogenic mononuclear cells (AMCs) trafficking in MM. Our data demonstrate that AMCs are circulating in patients with MM and in vivo studies show that they specifically home to areas of MM tumor growth. CXCR7 expression is important for regulating trafficking and homing of AMCs into areas of MM tumor growth and neoangiogenesis. We demonstrate that the CXCR7 inhibitor, POL6926, abrogated trafficking of AMCs to areas of MM tumor progression leading to a significant inhibition of tumor progression. These effects were through regulation of endothelial cells and not through a direct tumor effect, indicating that targeting a bone marrow microenvironmental cell can lead to a delay in MM tumor progression. In conclusion, our studies demonstrate that CXCR7 may play an important role in the regulation of tumor progression in MM through an indirect effect on the recruitment of AMCs to areas of MM tumor growth in the bone marrow niche. C1 [Azab, Abdel Kareem; Sahin, Ilyas; Azab, Feda; Moschetta, Michele; Mishima, Yuji; Burwick, Nicholas; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Azab, Abdel Kareem; Azab, Feda] Washington Univ, Div Canc Biol, Dept Radiat Oncol, St Louis, MO USA. [Zimmermann, Johann; Romagnoli, Barbara; Patel, Kalpana; Chevalier, Eric] Polyphor Ltd, Allschwil, Switzerland. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu OI Roccaro, Aldo/0000-0002-1872-5128 FU National Cancer Institute [R01CA154648, R01CA125690]; Leukemia and Lymphoma Society FX This study was supported in part by the National Cancer Institute (R01CA154648 and R01CA125690), and the Leukemia and Lymphoma Society. NR 42 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 18 PY 2014 VL 124 IS 12 BP 1905 EP 1914 DI 10.1182/blood-2014-02-558742 PG 10 WC Hematology SC Hematology GA AQ4JT UT WOS:000342762800012 PM 25079359 ER PT J AU Ferrao, R Zhou, H Shan, YB Liu, Q Li, QB Shaw, DE Li, XX Wu, H AF Ferrao, Ryan Zhou, Hao Shan, Yibing Liu, Qun Li, Qiubai Shaw, David E. Li, Xiaoxia Wu, Hao TI IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly SO MOLECULAR CELL LA English DT Article ID PYOGENIC BACTERIAL-INFECTIONS; RECEPTOR-ASSOCIATED KINASE-4; TOLL-LIKE RECEPTORS; KAPPA-B ACTIVATION; STRUCTURAL INSIGHTS; PROTEIN-KINASES; COMPLEX; MECHANISM; MYD88; CONFORMATION AB trans-autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane-proximal adaptor MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-kappa B activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a K-D of 2.5 mu M and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-K-D concentrations. The crystal structure of the unphosphorylated IRAK4(KD) dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show that dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation. C1 [Ferrao, Ryan; Li, Qiubai; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ferrao, Ryan; Li, Qiubai; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Ferrao, Ryan; Wu, Hao] Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA. [Zhou, Hao; Li, Xiaoxia] Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA. [Shan, Yibing; Shaw, David E.] DE Shaw Res, New York, NY 10036 USA. [Liu, Qun] Brookhaven Natl Lab, Natl Synchrotron Light Source X4, New York Struct Biol Ctr, Upton, NY 11961 USA. [Shaw, David E.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM hao.wu@childrens.harvard.edu RI Liu, Qun/A-8757-2011 OI Liu, Qun/0000-0002-1179-290X FU National Institutes of Health [AI050872] FX We thank Dr. Wayne Hendrickson for suggesting the use of X4A beamline of NSLS for sulfur anomalous diffraction, Dr. Venkatesh Mysore for assistance in performing the MD simulation, Dr. Stewart Shuman and Dr. Heather Ordonez for their technical support and advice involving radiolabeled kinase assays, Dr. Stephen Harrison and Dr. Yoana Dimitrova for access to the SE-AUC equipment and assistance with the experiment, and the National Institutes of Health for funding support (AI050872 to H.W.). NR 39 TC 18 Z9 18 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 18 PY 2014 VL 55 IS 6 BP 891 EP 903 DI 10.1016/j.molcel.2014.08.006 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ2MA UT WOS:000342619200010 PM 25201411 ER PT J AU Smith-Bindman, R Aubin, C Bailitz, J Bengiamin, RN Camargo, CA Corbo, J Dean, AJ Goldstein, RB Griffey, RT Jay, GD Kang, TL Kriesel, DR Ma, OJ Mallin, M Manson, W Melnikow, J Miglioretti, DL Miller, SK Mills, LD Miner, JR Moghadassi, M Noble, VE Press, GM Stoller, ML Valencia, VE Wang, J Wang, RC Cummings, SR AF Smith-Bindman, R. Aubin, C. Bailitz, J. Bengiamin, R. N. Camargo, C. A., Jr. Corbo, J. Dean, A. J. Goldstein, R. B. Griffey, R. T. Jay, G. D. Kang, T. L. Kriesel, D. R. Ma, O. J. Mallin, M. Manson, W. Melnikow, J. Miglioretti, D. L. Miller, S. K. Mills, L. D. Miner, J. R. Moghadassi, M. Noble, V. E. Press, G. M. Stoller, M. L. Valencia, V. E. Wang, J. Wang, R. C. Cummings, S. R. TI Ultrasonography versus Computed Tomography for Suspected Nephrolithiasis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RADIATION-EXPOSURE; UROLITHIASIS; CHILDHOOD; DIAGNOSIS; SCANS; RISK; PAIN; CT AB BACKGROUND There is a lack of consensus about whether the initial imaging method for patients with suspected nephrolithiasis should be computed tomography (CT) or ultrasonography. METHODS In this multicenter, pragmatic, comparative effectiveness trial, we randomly assigned patients 18 to 76 years of age who presented to the emergency department with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physician (point-of-care ultrasonography), ultrasonography performed by a radiologist (radiology ultrasonography), or abdominal CT. Subsequent management, including additional imaging, was at the discretion of the physician. We compared the three groups with respect to the 30-day incidence of high-risk diagnoses with complications that could be related to missed or delayed diagnosis and the 6-month cumulative radiation exposure. Secondary outcomes were serious adverse events, related serious adverse events (deemed attributable to study participation), pain (assessed on an 11-point visual-analogue scale, with higher scores indicating more severe pain), return emergency department visits, hospitalizations, and diagnostic accuracy. RESULTS A total of 2759 patients underwent randomization: 908 to point-of-care ultrasonography, 893 to radiology ultrasonography, and 958 to CT. The incidence of high-risk diagnoses with complications in the first 30 days was low (0.4%) and did not vary according to imaging method. The mean 6-month cumulative radiation exposure was significantly lower in the ultrasonography groups than in the CT group (P<0.001). Serious adverse events occurred in 12.4% of the patients assigned to point-of-care ultrasonography, 10.8% of those assigned to radiology ultrasonography, and 11.2% of those assigned to CT (P = 0.50). Related adverse events were infrequent (incidence, 0.4%) and similar across groups. By 7 days, the average pain score was 2.0 in each group (P = 0.84). Return emergency department visits, hospitalizations, and diagnostic accuracy did not differ significantly among the groups. CONCLUSIONS Initial ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high-risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits, or hospitalizations. C1 [Smith-Bindman, R.; Goldstein, R. B.; Moghadassi, M.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Smith-Bindman, R.; Stoller, M. L.; Valencia, V. E.; Wang, R. C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smith-Bindman, R.; Stoller, M. L.; Valencia, V. E.; Wang, R. C.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. [Kriesel, D. R.; Cummings, S. R.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Bengiamin, R. N.] UCSF, Dept Emergency Med, Fresno, CA USA. [Kang, T. L.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Melnikow, J.] Univ Calif Davis, Ctr Healthcare Policy & Res, Davis, CA 95616 USA. [Miglioretti, D. L.] Univ Calif Davis, Div Biostat, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Mills, L. D.] Univ Calif Davis, Dept Emergency Med, Davis, CA 95616 USA. [Aubin, C.; Griffey, R. T.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO 63130 USA. [Bailitz, J.] Rush Univ, Med Ctr, Dept Emergency Med, Jr Hosp Cook Cty, Chicago, IL 60612 USA. [Bailitz, J.] Rush Univ, Med Ctr, Dept Emergency Med, Chicago, IL 60612 USA. [Camargo, C. A., Jr.; Noble, V. E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, C. A., Jr.; Noble, V. E.] Harvard Univ, Sch Med, Boston, MA USA. [Corbo, J.; Wang, J.] Jacobi Med Ctr, Dept Emergency Med, Bronx, NY USA. [Dean, A. J.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Jay, G. D.] Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. [Jay, G. D.] Brown Univ, Dept Emergency Med, Providence, RI 02912 USA. [Ma, O. J.] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Miglioretti, D. L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Mallin, M.] Univ Utah, Salt Lake City, UT USA. [Manson, W.] Emory Univ, Sch Med, Atlanta, GA USA. [Miller, S. K.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Press, G. M.] Univ Texas Houston, Houston Med Sch, Houston, TX USA. [Miner, J. R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. EM rebecca.smith-bindman@ucsf.edu RI Griffey, Richard/I-5256-2015 OI Jay, Gregory/0000-0003-1517-8488; Wang, Ralph/0000-0001-5382-9486; FU Agency for Healthcare Research and Quality through its Clinical and Health Outcomes Initiative in Comparative Effectiveness [R01HS019312] FX Supported by a grant (R01HS019312) from the Agency for Healthcare Research and Quality through its Clinical and Health Outcomes Initiative in Comparative Effectiveness. NR 18 TC 112 Z9 112 U1 1 U2 13 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 SEP 18 PY 2014 VL 371 IS 12 BP 1100 EP 1110 DI 10.1056/NEJMoa1404446 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300005 PM 25229916 ER PT J AU Boehmerle, W Huehnchen, P Peruzzaro, S Balkaya, M Endres, M AF Boehmerle, Wolfgang Huehnchen, Petra Peruzzaro, Sarah Balkaya, Mustafa Endres, Matthias TI Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED PERIPHERAL NEUROPATHY; MULTIPLE-MYELOMA; TAXOL NEUROPATHY; CHEMOTHERAPY; MODELS; CANCER; RESPONSES; SYSTEM; NERVES AB Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine-and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies. C1 [Boehmerle, Wolfgang; Huehnchen, Petra; Peruzzaro, Sarah; Balkaya, Mustafa; Endres, Matthias] Charite, Klin & Hochschulambulanz Neurol, D-13353 Berlin, Germany. [Boehmerle, Wolfgang; Huehnchen, Petra; Endres, Matthias] Charite, Cluster Excellence NeuroCure, D-13353 Berlin, Germany. [Balkaya, Mustafa; Endres, Matthias] Charite, Ctr Stroke Res, D-13353 Berlin, Germany. [Endres, Matthias] German Ctr Neurodegenerat Dis DZNE, Berlin, Germany. [Balkaya, Mustafa] Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, Boston, MA 02114 USA. [Balkaya, Mustafa] Harvard Univ, Sch Med, Boston, MA USA. RP Boehmerle, W (reprint author), Charite, Klin & Hochschulambulanz Neurol, D-13353 Berlin, Germany. EM wolfgang.boehmerle@charite.de OI Boehmerle, Wolfgang/0000-0001-7195-3894; Huehnchen, Petra/0000-0002-6825-7270 FU federal ministry of education and research via center for stroke research Berlin [01 EO 0801]; Volkswagen foundation (Lichtenberg program); Deutsche Forschungsgemeinschaft DFG (NeuroCure); Charite Universitatsmedizin Berlin; Berlin Institute of Health FX We would like to thank Catherine Aubel for thoughtful text editing, Heather L. More for the Matlab routine used to perform semi-automatic nerve morphometry and Petra Loge for excellent technical assistance. The research leading to these results has received funding from the federal ministry of education and research via the grant center for stroke research Berlin (01 EO 0801), the Volkswagen foundation (Lichtenberg program to Matthias Endres), and Deutsche Forschungsgemeinschaft DFG (NeuroCure). W. Boehmerle is participant in the Charite Clinical Scientist Program funded by the Charite Universitatsmedizin Berlin and the Berlin Institute of Health. NR 39 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 18 PY 2014 VL 4 AR 6370 DI 10.1038/srep06370 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP2YH UT WOS:000341941600001 PM 25231679 ER PT J AU Pugach, MK Gibson, CW AF Pugach, Megan K. Gibson, Carolyn W. TI Analysis of enamel development using murine model systems: approaches and limitations SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE enamel development; transgenic; knockout; knockin; amelogenin; mineralization ID AMELOGENESIS IMPERFECTA PHENOTYPE; MICRO-COMPUTED TOMOGRAPHY; TRANSGENIC MICE; REPORTER GENE; DENTAL ENAMEL; PEPTIDE ALTERS; RAT INCISOR; TOOTH COLOR; IN-VIVO; EXPRESSION AB A primary goal of enamel research is to understand and potentially treat or prevent enamel defects related to amelogenesis imperfecta (AI). Rodents are ideal models to assist our understanding of how enamel is formed because they are easily genetically modified, and their continuously erupting incisors display all stages of enamel development and mineralization. While numerous methods have been developed to generate and analyze genetically modified rodent enamel, it is crucial to understand the limitations and challenges associated with these methods in order to draw appropriate conclusions that can be applied translationally, to AI patient care. We have highlighted methods involved in generating and analyzing rodent enamel and potential approaches to overcoming limitations of these methods: (1) generating transgenic, knockout, and knockin mouse models, and (2) analyzing rodent enamel mineral density and functional properties (structure and mechanics) of mature enamel. There is a need for a standardized workflow to analyze enamel phenotypes in rodent models so that investigators can compare data from different studies. These methods include analyses of gene and protein expression, developing enamel histology, enamel pigment, degree of mineralization, enamel structure, and mechanical properties. Standardization of these methods with regard to stage of enamel development and sample preparation is crucial, and ideally investigators can use correlative and complementary techniques with the understanding that developing mouse enamel is dynamic and complex. C1 [Pugach, Megan K.] Harvard Univ, Sch Dent Med, Dept Mineralized Tissue Biol, Forsyth Inst, Cambridge, MA 02142 USA. [Gibson, Carolyn W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. RP Pugach, MK (reprint author), Harvard Univ, Sch Dent Med, Dept Mineralized Tissue Biol, Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. EM mpugach@forsyth.org FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [R00DE022624, R01DE011089] FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health, grants R00DE022624 (Megan K. Pugach) and R01DE011089 (Carolyn W. Gibson). NR 70 TC 6 Z9 6 U1 0 U2 8 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 17 PY 2014 VL 5 AR 313 DI 10.3389/fphys.2014.00313 PG 10 WC Physiology SC Physiology GA AX7IH UT WOS:000347089300001 PM 25278900 ER PT J AU Hansen, VJ Greene, ME Bragdon, MA Nebergall, AK Barr, CJ Huddleston, JI Bragdon, CR Malchau, H AF Hansen, Victor J. Greene, Meredith E. Bragdon, Marc A. Nebergall, Audrey K. Barr, Christopher J. Huddleston, J. I. Bragdon, Charles R. Malchau, Henrik TI Registries Collecting Level-I through IV Data: Institutional and Multicenter Use SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID TOTAL HIP-ARTHROPLASTY; MOLECULAR-WEIGHT POLYETHYLENE; JOINT REPLACEMENT REGISTRY; CROSS-LINKED POLYETHYLENE; KNEE ARTHROPLASTY; UNITED-STATES; FOLLOW-UP; JOHN-CHARNLEY; WEAR; OSTEOLYSIS C1 [Hansen, Victor J.; Greene, Meredith E.; Bragdon, Marc A.; Nebergall, Audrey K.; Barr, Christopher J.; Huddleston, J. I.; Bragdon, Charles R.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. RP Hansen, VJ (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St,GRJ 1121, Boston, MA 02114 USA. EM viktor.j.hansen@gmail.com NR 50 TC 3 Z9 3 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD SEP 17 PY 2014 VL 96A IS 18 AR e160 DI 10.2106/JBJS.M.01458 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AR8BF UT WOS:000343799800007 PM 25232090 ER PT J AU Gandy, S Ikonomovic, MD Mitsis, E Elder, G Ahlers, ST Barth, J Stone, JR DeKosky, ST AF Gandy, Sam Ikonomovic, Milos D. Mitsis, Effie Elder, Gregory Ahlers, Stephen T. Barth, Jeffrey Stone, James R. DeKosky, Steven T. TI Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis SO MOLECULAR NEURODEGENERATION LA English DT Review ID AMYLOID-BETA-PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; POSTTRAUMATIC-STRESS-DISORDER; FOOTBALL-LEAGUE PLAYER; PITTSBURGH COMPOUND-B; MILD HEAD-INJURY; BRAIN-INJURY; DEMENTIA-PUGILISTICA; NEUROFIBRILLARY TANGLES; PROFESSIONAL BOXERS AB Background: Chronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name "dementia pugilistica" (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e. g., [F-18] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE. Methods: Major academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland. Results: The major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [F-18] T807 tauopathy imaging, are also introduced and their significance has been explained. Conclusion: Recent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults. C1 [Gandy, Sam; Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam; Mitsis, Effie; Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Gandy, Sam; Mitsis, Effie; Elder, Gregory] Icahn Sch Med Mt Sinai, Mt Sinai Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, Sam; Elder, Gregory] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Ikonomovic, Milos D.] Univ Pittsburgh, Dept Neurol, VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. [Ikonomovic, Milos D.] Univ Pittsburgh, Dept Psychiat, VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. [Ahlers, Stephen T.] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Barth, Jeffrey] Univ Virginia, Dept Psychiat, Charlottesville, VA 22908 USA. [Barth, Jeffrey] Univ Virginia, Dept Neurobehav Sci, Charlottesville, VA 22908 USA. [Stone, James R.] Univ Virginia, Dept Radiol, Charlottesville, VA 22908 USA. [DeKosky, Steven T.] Univ Virginia, Coll Med, Off Dean, Charlottesville, VA 22908 USA. [DeKosky, Steven T.] Univ Virginia, Dept Nerurol, Charlottesville, VA 22908 USA. RP Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, One Gustave L Levy Pl, New York, NY 10029 USA. EM samuel.gandy@mssm.edu RI Meijer, Anna/K-5118-2016 FU NIH [P01NS30318, P01AG14449, P50AG05133, P01AG25204]; VA MERIT [1I01BX000348, 1 I01 RX000684, 1 I01RX000511, 1I01RX000179, 1I01RX000996-01, I01 CX000190]; Mount Sinai School of Medicine CTSA [UL1-RR-029887]; Cure Alzheimer's Fund; US NIH [P50 AG05138]; Pittsburgh Foundation [M2010-0041]; Office of Naval Research [0601153 N.0000.00A0702]; Defense Health Program-US Army MRMC [W81XWH-09-2-0055, W81XWH-11-2-0109, W81XWH-09-2-0160]; USUHS [HU0001-08-1-0001] FX The authors gratefully acknowledge the support of NIH grants P01NS30318, P01AG14449 and P50AG05133 (S. T. DeKosky and M. D. Ikonomovic), P01AG25204 (M. Ikonomovic), and VA MERIT review grants 1I01BX000348 (S. Gandy), 1 I01 RX000684 (S. Gandy), 1 I01RX000511 (M. D. Ikonomovic), 1I01RX000179 (G. Elder), 1I01RX000996-01 (G. Elder), and I01 CX000190 (E. Mitsis). E. Mitsis was also supported by the Mount Sinai School of Medicine CTSA grant UL1-RR-029887. Gandy also acknowledges the support of the Cure Alzheimer's Fund and of US NIH P50 AG05138. Ikonomovic also acknowledges support from The Pittsburgh Foundation grant M2010-0041. Ahlers acknowledges support from the Office of Naval Research: 0601153 N.0000.00A0702. The authors also acknowledge Defense Health Program-US Army MRMC contracts W81XWH-09-2-0055 (J. Stone), W81XWH-11-2-0109 (J. Stone), W81XWH-09-2-0160 (S. Ahlers, J. Stone), and USUHS award HU0001-08-1-0001 (S. Ahlers, J. Stone). The authors thank P. Davies (North Shore-Hofstra) for helpful discussions. The authors also thank Corey Fernandez for outstanding administrative support. The opinions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or of the Naval Service at large. NR 119 TC 18 Z9 18 U1 3 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD SEP 17 PY 2014 VL 9 AR UNSP 37 DI 10.1186/1750-1326-9-37 PG 21 WC Neurosciences SC Neurosciences & Neurology GA AP3BZ UT WOS:000341951300001 PM 25231386 ER PT J AU Brilakis, E Banerjee, S Karmpaliotis, D Lombardi, W Tsai, TT Shunk, K Kennedy, KF Spertus, J Holmes, D Grantham, JA AF Brila