FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Speliotes, EK AF Speliotes, Elizabeth K. TI Genetics of Common Obesity and Nonalcoholic Fatty Liver Disease SO GASTROENTEROLOGY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; NEUROTROPHIC FACTOR; BODY-WEIGHT; FTO GENE; LOCI; MICE; STEATOHEPATITIS; VARIANTS; TRAITS; SCAN C1 Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. RP Speliotes, EK (reprint author), Massachusetts Gen Hosp, Dept Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM espeliotes@partners.org FU NIDDK NIH HHS [K23 DK080145-01, F32 DK079466, K23 DK080145, F32 DK079466-01] NR 20 TC 11 Z9 11 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2009 VL 136 IS 5 BP 1492 EP 1495 DI 10.1053/j.gastro.2009.03.020 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 440WQ UT WOS:000265730800006 PM 19324104 ER PT J AU El-Serag, HB Johnson, ML Hachem, C Morgana, RO AF El-Serag, Hashem B. Johnson, Michael L. Hachem, Christine Morgana, Robert O. TI Statins Are Associated With a Reduced Risk of Hepatocellular Carcinoma in a Large Cohort of Patients With Diabetes SO GASTROENTEROLOGY LA English DT Article ID COA REDUCTASE INHIBITORS; COENZYME-A REDUCTASE; SCANDINAVIAN SIMVASTATIN SURVIVAL; COMBINATION THERAPY; PHARMACY RECORDS; FOLLOW-UP; CELLS; CANCER; APOPTOSIS; PROLIFERATION AB Background & Aims: Experimental studies indicate a potential cancer prevention effect for statins. Given the increasing prevalence of statin use, and the increasing incidence of hepatocellular carcinoma (HCC), the potential association between statins and HCC is an important issue to examine. Methods: We conducted a matched case-control study nested within a cohort of patients with diabetes. Cases comprised incident HCC at least 6 months after entry in the cohort. Controls were identified by incidence density sampling from patients who remained at risk at the date of the HCC diagnosis matched by age and sex. We identified fined statin prescriptions as well as several potential confounding conditions, medications, as well as propensity score to use statins. Odds ratios (ORs) as estimates of the relative risk for HCC associated with statin use and 95% confidence intervals were obtained using conditional logistic regression. Results: We examined 1303 cases and 5212 controls. The mean age was 72 years and 99% were men. A significantly smaller proportion of cases (34.3%) had at least one filled prescription for statins than controls (53.1%). There were no significant associations between HCC and nonstatin cholesterol- or triglyceride-lowering medications. The unadjusted OR for any statin prescription was 0.46 (9S% confidence interval, 0.40-0.517) and the adjusted OR was 0.74 (95% confidence interval, 0.64-0.87). To reduce the potential confounding effect of existing liver disease, we ran the analyses in a subgroup of patients without recorded liver disease; the ORs were slightly attenuated but remained highly significant for any statin prescription (0.63; 95% confidence interval, 0.50-0.78). Conclusions: Statin use is associated with a significant reduction in the risk of HCC among patients with diabetes. C1 [El-Serag, Hashem B.; Hachem, Christine; Morgana, Robert O.] Michael E DeBakey Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. [El-Serag, Hashem B.; Hachem, Christine; Morgana, Robert O.] Michael E DeBakey Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. [El-Serag, Hashem B.; Hachem, Christine; Morgana, Robert O.] Baylor Coll Med, Houston, TX 77030 USA. [Johnson, Michael L.] Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Gastroenterol Sect, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu FU Department of Veterans Affairs; Health Services Research and Development Service [IIR 02-081]; American College of Gastroenterology; National Institutes of Health [K24DK078154-03] FX This research was supported in part by the Department of Veterans Affairs, Health Services Research and Development Service (IIR 02-081), and by a grant from the American College of Gastroenterology. Dr EI-Serag is supported by a National Institutes of Health grant (K24DK078154-03). NR 28 TC 129 Z9 134 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2009 VL 136 IS 5 BP 1601 EP 1608 DI 10.1053/j.gastro.2009.01.053 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 440WQ UT WOS:000265730800023 PM 19208359 ER PT J AU Verzi, MP Stanfel, MN Moses, KA Kim, BM Zhang, Y Schwartz, RJ Shivdasani, RA Zimmer, WE AF Verzi, Michael P. Stanfel, Monique N. Moses, Kelvin A. Kim, Byeong-Moo Zhang, Yan Schwartz, Robert J. Shivdasani, Ramesh A. Zimmer, Warren E. TI Role of the Homeodomain Transcription Factor Bapx1 in Mouse Distal Stomach Development SO GASTROENTEROLOGY LA English DT Article ID EMBRYONAL GUT DEVELOPMENT; TARGETED DISRUPTION; AXIAL SKELETON; HOMEOBOX GENE; HOX GENES; SPLEEN; EXPRESSION; MICE; DROSOPHILA; BAGPIPE AB Background & Aims: Expansion and patterning of the endoderm generate a highly ordered, multiorgan digestive system in vertebrate animals. Among distal foregut derivatives, the gastric corpus, antrum, pylorus, and duodenum are distinct structures with sharp boundaries. Some homeodomain transcription factors expressed in gut mesenchyme convey positional information required for anterior-posterior patterning of the digestive tract. Barx1, in particular, controls stomach differentiation and morphogenesis. The Nirenberg and Kim homeobox gene Bapx1 (NW-2) has an established role in skeletal development, but its function in the mammalian gut is less clear. Methods: We generated a Bapx1(Cre) knock-in allele to fate map Bapx1-expressing cells and evaluate its function in gastrointestinal development. Results: Bapx1-expressing cells populate the gut mesenchyme with a rostral boundary in the hindstomach near the junction of the gastric corpus and antrum. Smooth muscle differentiation and distribution of early regional markers are ostensibly normal in Bapx1(Cre/Cre) gut, but there are distinctive morphologic abnormalities near this rostral Bapx1 domain: the antral segment of the stomach is markedly shortened, and the pyloric constriction is lost. Comparison of expression domains and examination of stomach phenotypes in single and compound Barx1 and Bapx1 mutant mice suggests a hierarchy between these 2 factors; Bapx1 expression is lost in the absence of Barx1. Conclusions: This study reveals the nonredundant requirement for Bapx1 in distal stomach development, places it within a Barx1-dependent pathway, and illustrates the pervasive influence of gut mesenchyme homeobox genes on endoderm differentiation and digestive organogenesis. C1 [Verzi, Michael P.; Kim, Byeong-Moo; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Verzi, Michael P.; Kim, Byeong-Moo; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Stanfel, Monique N.; Moses, Kelvin A.; Schwartz, Robert J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Zhang, Yan; Zimmer, Warren E.] Texas A&M Univ, Coll Med, Dept Syst Biol & Translat Med, College Stn, TX 77843 USA. [Schwartz, Robert J.; Zimmer, Warren E.] Texas A&M Univ, Coll Med, Ctr Environm & Rural Hlth, College Stn, TX 77843 USA. [Schwartz, Robert J.] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX USA. RP Zimmer, WE (reprint author), Texas A&M Hlth Sci, 310B Joe H Reynolds Bldg, College Stn, TX 77843 USA. EM ramesh_shivdasani@dfcl.harvard.edu; wezimmer@medicine.tamhsc.edu FU NCI NIH HHS [R01 CA095608, R01CA095608]; NHLBI NIH HHS [P01 HL067155, P01 HL049953, P01HL067155, P01HL49953]; NIDDK NIH HHS [R01 DK061139, R01 DK061139-04S1, R01DK061139, T32 DK007477, T32 DK007696, T32DK07477, T32DK07696]; NIEHS NIH HHS [P30 ES009106, P30 ES09106] NR 38 TC 27 Z9 29 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2009 VL 136 IS 5 BP 1701 EP 1710 DI 10.1053/j.gastro.2009.01.009 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 440WQ UT WOS:000265730800033 PM 19208343 ER PT J AU Plentz, R Park, JS Rhim, AD Abravanel, D Hezel, AF Sharma, SV Gurumurthy, S Deshpande, V Kenific, C Settleman, J Majumder, PK Stanger, BZ Bardeesy, N AF Plentz, Ruben Park, Ji-Sun Rhim, Andrew D. Abravanel, Daniel Hezel, Aram F. Sharma, Sreenath V. Gurumurthy, Sushma Deshpande, Vikram Kenific, Candia Settleman, Jeffrey Majumder, Pradip K. Stanger, Ben Z. Bardeesy, Nabeel TI Inhibition of gamma-Secretase Activity Inhibits Tumor Progression in a Mouse Model of Pancreatic Ductal Adenocarcinoma SO GASTROENTEROLOGY LA English DT Article ID CELL DIFFERENTIATION; INTRAEPITHELIAL NEOPLASIA; ENDOCRINE DEVELOPMENT; ACINAR-CELLS; NOTCH; CANCER; ACTIVATION; GROWTH; INDUCTION; FATE AB Background & Aim: The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression. Methods: We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice). Results: Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumorderived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P <.005, chi(2) test; compared with mice exposed to vehicle). Conclusions: These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy. C1 [Plentz, Ruben; Park, Ji-Sun; Hezel, Aram F.; Sharma, Sreenath V.; Gurumurthy, Sushma; Settleman, Jeffrey; Bardeesy, Nabeel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, Boston, MA 02114 USA. [Rhim, Andrew D.; Abravanel, Daniel; Stanger, Ben Z.] Univ Penn, Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Rhim, Andrew D.; Abravanel, Daniel; Stanger, Ben Z.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Sharma, Sreenath V.; Settleman, Jeffrey] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Therapeut, Boston, MA 02114 USA. [Deshpande, Vikram] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kenific, Candia] Merck Res Labs, Dept Neuropharmacol, Boston, MA USA. [Majumder, Pradip K.] Merck Res Labs, Dept Oncol Pharmacol, Boston, MA USA. RP Bardeesy, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, CPZN4216,185 Cambridge St, Boston, MA 02114 USA. EM bstanger@exchange.upenn.edu; Bardeesy.Nabeel@MGH.Harvard.edu FU NCI NIH HHS [5K01CA104647, 5P01CA117969, K01 CA104647, P01 CA117969, R01 CA133557]; NIDDK NIH HHS [T32-DK007066, T32 DK007066] NR 49 TC 88 Z9 89 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2009 VL 136 IS 5 BP 1741 EP 1749 DI 10.1053/j.gastro.2009.01.008 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 440WQ UT WOS:000265730800037 PM 19208345 ER PT J AU Taylor-Young, P Hildebrandt, E AF Taylor-Young, Patricia Hildebrandt, Eugenie TI The Multidimensional Burden of Hepatitis C and Its Treatment A Case Study SO GASTROENTEROLOGY NURSING LA English DT Article ID ANTIVIRAL TREATMENT; UNITED-STATES; DEPRESSION; PREVALENCE; MANAGEMENT; INFECTION; VETERANS AB The purpose of this case study was to gain an in-depth understanding of the mental, physical, and emotional burden of being infected with the hepatitis C virus (HCV) from the perspective of an individual living with the disease and undergoing antiviral treatment. Interviews were conducted during and after antiviral therapy with 1 participant chosen from a Midwest HCV clinic population. Interviews were audio recorded, transcribed verbatim, and coded. Content analysis and thematic analysis were performed. The participant reviewed and validated the themes and the interpretation of the themes. Ten categories were identified, which were subsequently integrated in 4 themes: (1) transition or process of change, (2) maintaining control over one's life, (3) social support and communication, and (4) side effects. The results of this study can assist healthcare providers to understand what individuals experience in the course of HCV infection and its treatment. This knowledge will assist them to provide effective patient-centered care. To provide such care, it is imperative that healthcare providers understand the physical, psychological, social, and professional impact that the diagnosis of HCV infection and antiviral therapy has on individuals. C1 [Taylor-Young, Patricia] Portland VA Med Ctr, Portland, OR 97239 USA. [Hildebrandt, Eugenie] Univ Wisconsin, Coll Nursing, Milwaukee, WI 53201 USA. RP Taylor-Young, P (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd P2NR, Portland, OR 97239 USA. EM patricia.tayloryoung@va.gov NR 28 TC 7 Z9 7 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1042-895X J9 GASTROENTEROL NURS JI Gastroenterol. Nurs. PD MAY-JUN PY 2009 VL 32 IS 3 BP 180 EP 187 PG 8 WC Gastroenterology & Hepatology; Nursing SC Gastroenterology & Hepatology; Nursing GA 458JV UT WOS:000267015300003 PM 19506434 ER PT J AU Fasanella, KE McGrath, KM Sanders, M Brody, D Domsic, R Khalid, A AF Fasanella, Kenneth E. McGrath, Kevin M. Sanders, Michael Brody, Debra Domsic, Robyn Khalid, Asif TI Pancreatic endocrine tumor EUS-guided FNA DNA microsatellite loss and mortality SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT Digestive Disease Week Meeting/109th Annual Meeting of the American-Gastroenterological-Association CY MAY 17-22, 2008 CL San Diego, CA SP Amer Gastroenterol Assoc ID CHROMOSOME 1Q; HETEROZYGOSITY; DIAGNOSIS; INSULINOMAS; PROGRESSION; MALIGNANCY; DELETION; CRITERIA; SYSTEM AB Background: The clinical course of pancreatic endocrine tumors (PET) depends on tumor size, the presence Of invasion or metastasis, the Ki-67 index, mitose's per high power field, and mutational damage. Most of this information is not available before surgery for clinical decision making or prognostication. Objective: To evaluate PET FUS-guided FNA (EUS-FNA) microsatellite loss analysis in the context of PET-related mortality. Design: A single institution retrospective cohort. Patients: Patients with PET diagnosed by EUS-FNA who underwent DNA microsatellite loss analysis and at least 1 year of follow-up or subsequent death. Intervention: PET microsatellite loss analysis and current clinical status were compared Results: Twenty-nine patients were included in the final analysis; the mean age of the patients was 57 years, and 10 were women (35%). The mean follow-up was 33.7 months (median 30 months, range 2-66 months). Twelve patients had disease progression, and 8 died, all from disease-specific causes. Malignant PET contained multiple microsatellite losses, with a median fractional allelic loss (FAL) of 0.37 (range 0.12-0.69, interquartile range [IQR] 0.23-0.42), significantly different from benign PET, median FAL 0 (range 0-0.18, IQR 0-0.08, P < .0001). Survival analysis revealed a significant difference in disease recurrence progression at 2 years (P < .0001) and in the 5-year survival between patients with FAL <= 0.2 compared with 0.2 (P <.0001). Logistic regression could not he performed because of the perfect association between an FAL > 0.2 of the perfect association between an FAL > 0.2 and disease status or mortality. Limitations: Retrospective design, referral bias, and DNA analysis availability. Conclusions: PET EUS-FNA microsatellite loss analysis provides preoperative prognostic information. An FAL > 0.2 is not only associated with disease progression but also with mortality (Gastrointest Endosc 2009:69:1074-80.) C1 [Khalid, Asif] Univ Pittsburgh, C Wing PUH, Dept Med, Med Ctr, Pittsburgh, PA 15213 USA. [Khalid, Asif] VA Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15213 USA. RP Khalid, A (reprint author), Univ Pittsburgh, C Wing PUH, Dept Med, Med Ctr, M2,200 Lothrop St, Pittsburgh, PA 15213 USA. EM khalida@upmc.edu RI Fasanella, Kenneth/I-2781-2012 NR 23 TC 10 Z9 10 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAY PY 2009 VL 69 IS 6 BP 1074 EP 1080 DI 10.1016/j.gie.2008.06.023 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 441KC UT WOS:000265766700014 PM 19152901 ER PT J AU Khalid, A Zahid, M Finkelstein, SD LeBlanc, JK Kaushik, N Ahmad, N Brugge, WR Edmundowicz, SA Hawes, RH McGrath, KM AF Khalid, Asif Zahid, Maliha Finkelstein, Sydney D. LeBlanc, Julia K. Kaushik, Neeraj Ahmad, Nuzhat Brugge, William R. Edmundowicz, Steven A. Hawes, Robert H. McGrath, Kevin M. TI Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT Digestive Disease Week Meeting/108th Annual Meeting of the American-Gastroenterological-Association CY MAY 19-24, 2007 CL Washington, DC SP Amer Gastroenterol Assoc, Amer Assoc Study Liver Dis, Amer Soc Gastrointestinal Endoscopy, Soc Surg Alimentary Tract ID PAPILLARY-MUCINOUS TUMORS; NEOPLASMS; ADENOCARCINOMA; PROGRESSION; EXPRESSION; LESIONS; P53 AB Background: The role of pancreatic cyst fluid DNA analysis in evaluating cysts remains unclear. Objective: Our purpose was to evaluate the utility of a detailed DNA analysis of pancreatic cyst fluid to diagnose mucinous and malignant cyst. Design: Prospective, multicenter study. Patients: Patients with pancreatic cysts presenting for EUS evaluation. Intervention: EUS-guided pancreatic cyst aspirates cytology evaluation, carcinoembryonic antigen (CEA) level determination, and a detailed DNA analysis; incorporating DNA quantification, k-ras mutation and multiple allelic has analysis, mutational amplitude, and sequence determination. Main Outcome Measurements: Cyst fluid analysis compared with surgical pathologic or malignant cytologic examination Results: The study cohort consisted of 113 patients with 40 malignant, 48 premalignant, and 25 benign cyst Cyst fluid k-ras mutation was helpful in the diagnosis of mucinous cysts (odds ratio 20.9, specificity 96%), whereas receiver-operator characteristic curve analysis indicated optimal cutoff points For allelic loss amplitude (area under the curve [AUC] 0.79; optimal value > 65%) and CEA (AUC 0.74; optimal value > 148 ng/ml). Components of DNA analysis detecting malignant cysts included allelic loss amplitude over 82% (AUC 0.9) and high DNA amount (optical density ratio > 10, AUC 0.79). The criteria of a high amplitude k-ras mutation followed by allelic loss showed maximum specificity (96%) for malignancy. All malignant cysts with negative cytology evaluation (10/40) could be diagnosed as malignant by using DNA analysis. Limitations: United follow-up, selection bias. Conclusions: Elevated amounts of pancreatic cyst fluid DNA hi,high-amplitude mutations, Mid specific mutation acquistion sequences we indicators of malignancy. The presence of a k-ras mutation is also indicative of a mucinous cyst. DNA analysis should be considered when cyst cytologic examination is negative for malignancy. (Gastrointest Endosc 2009;69:1095-102.) C1 [Khalid, Asif] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Zahid, Maliha] Univ Pittsburgh, Med Ctr, Dept Human Genet & Biochem, Pittsburgh, PA USA. [Finkelstein, Sydney D.] RedPath Integrated Pathol, Pittsburgh, PA USA. [LeBlanc, Julia K.] Indiana Univ Hosp, Dept Med, Indianapolis, IN 46202 USA. [Ahmad, Nuzhat] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Brugge, William R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Edmundowicz, Steven A.] Barnes Jewish Hosp, Dept Med, St Louis, MO 63110 USA. [Hawes, Robert H.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Khalid, A (reprint author), PUH, C Wing, M2,200 Lothrop St, Pittsburgh, PA 15213 USA. EM khalida@upmc.edu OI Edmundowicz, Steven/0000-0002-6541-3485 NR 11 TC 183 Z9 185 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAY PY 2009 VL 69 IS 6 BP 1095 EP 1102 DI 10.1016/j.gie.2008.07.033 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 441KC UT WOS:000265766700017 PM 19152896 ER PT J AU Sampaio, AS Miguel, EC Borcato, S Batistuzzo, M Fossaluza, V Geller, DA Hounie, AG AF Sampaio, Aline S. Miguel, Euripedes C. Borcato, Sonia Batistuzzo, Marcelo Fossaluza, Victor Geller, Daniel A. Hounie, Ana G. TI Perinatal risk factors and obsessive-compulsive spectrum disorders in patients with rheumatic fever SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article ID TOURETTES-SYNDROME; POLYMORPHISMS; ASSOCIATION; EXPRESSION; ALPHA C1 [Sampaio, Aline S.; Miguel, Euripedes C.; Borcato, Sonia; Batistuzzo, Marcelo; Fossaluza, Victor; Hounie, Ana G.] Univ Sao Paulo, Sch Med, Dept Psychiat, Hosp Clin, BR-05403010 Sao Paulo, Brazil. [Sampaio, Aline S.; Miguel, Euripedes C.; Borcato, Sonia; Batistuzzo, Marcelo; Fossaluza, Victor; Hounie, Ana G.] Univ Sao Paulo, Sch Med, Inst Psychiat, Hosp Clin, BR-05403010 Sao Paulo, Brazil. [Geller, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Sampaio, AS (reprint author), Univ Sao Paulo, PROTOC, Inst Psiquiatria, Fac Med, Rua Dr Ovidio Pires Campos 785,3 A,S 07,Cerqueira, BR-05403010 Sao Paulo, Brazil. EM alinestsampaio@gmail.com RI Miguel, Euripedes/B-2871-2008; SAMPAIO, ALINE/M-1229-2013; Fossaluza, Victor/B-3377-2014; Batistuzzo, Marcelo/H-7790-2015 OI SAMPAIO, ALINE/0000-0001-5568-6167; Fossaluza, Victor/0000-0002-9328-0210; FU CAPES/PRODOC, FAPESP [98/15013-9, 2005/55628-8]; CNPq FX This work was supported by grants from CAPES/PRODOC, FAPESP (grants 98/15013-9 and 2005/55628-8) and CNPq. NR 20 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAY-JUN PY 2009 VL 31 IS 3 BP 288 EP 291 DI 10.1016/j.genhosppsych.2008.08.003 PG 4 WC Psychiatry SC Psychiatry GA 445DF UT WOS:000266029200012 PM 19410109 ER PT J AU Burke, GV Wong, DA Saunders, CS Pierre, JM AF Burke, Guenevere V. Wong, Donovan A. Saunders, C. Scott Pierre, Joseph M. TI Self-limited erythema multiforme with risperidone SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article C1 [Wong, Donovan A.; Saunders, C. Scott; Pierre, Joseph M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Burke, Guenevere V.; Wong, Donovan A.; Saunders, C. Scott; Pierre, Joseph M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Pierre, JM (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 210, Los Angeles, CA 90073 USA. EM joseph.pierre2@va.gov NR 6 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 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAY-JUN PY 2009 VL 31 IS 3 BP 295 EP 296 DI 10.1016/j.genhosppsych.2008.08.008 PG 2 WC Psychiatry SC Psychiatry GA 445DF UT WOS:000266029200014 PM 19410111 ER PT J AU Liu, CY Yang, Q Cupples, LA Melgs, JB Dupuis, J AF Liu, Chunyu Yang, Qiong Cupples, L. Adrienne Melgs, James B. Dupuis, Josee TI Selection of the Most Informative Individuals From Families With Multiple Siblings for Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE linkage analysis; association study; linkage disequilibrium; identity-by-descent (IBD) ID QUANTITATIVE-TRAIT LOCI; LINKAGE DISEQUILIBRIUM; POWER; PAIRS AB Association analyses may follow an initial linkage analysis for mapping and identifying genes underlying complex quantitative traits and may be conducted on unrelated subsets of individuals where only one member of a family is included. We evaluate two methods to select one sibling per sibship when multiple siblings are available: (1) one sibling with the most extreme trait value; and (2) one sibling using a combination score statistic based on extreme trait values and identity-by-descent sharing information. We compare the type 1 error and power. Furthermore, we compare these selection strategies with a strategy that randomly selects one sibling per sibship and with an approach that includes all siblings, using both simulation Study and an application to fasting blood glucose in the Framingham Heart Study. When genetic effect is homogeneous, we find that using the combination score call increase power by 30-40% compared to a random selection strategy, and loses only 8-13% of power compared to the full sibship analysis, across all additive models considered, but offers at least 50% genotyping cost saving. In the presence of genetic heterogeneity, the score of fers a 50% increase in power over a random selection strategy, but there is substantial loss compared to the full sibship analysis. In application to fasting blood sample, two SNPs are found in common for the selection strategies and the full sample among the 10 highest ranked single nucleotide polymorphisms. The EV strategy tends to agree with the IBD-EV strategy and the analysis of the full sample. Genet. Epidemiol. 33:299-307, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Liu, Chunyu] Biogen Idec, Dept Drug Discovery, Genet & Genom, Cambridge, MA USA. [Yang, Qiong; Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Melgs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Melgs, James B.] Harvard Univ, Sch Med, Boston, MA USA. RP Liu, CY (reprint author), Biogen Idec, Dept Drug Discovery, Genet & Genom, 12 Cambridge Ctr, Cambridge, MA USA. EM chunyu.liu@biogenidec.com RI Yang, Qiong/G-5438-2014; OI Dupuis, Josee/0000-0003-2871-3603 FU NIH NCRR [1S10RR163736-01A1]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Diabetes Association FX Contract grant sponsor: NIH NCRR; Contract grant number: 1S10RR163736-01A1; Contract grant sponsor: National Heart, Lung and Blood Institute's Framingham Heart Study; Contract grant number: N01-HC-25195; Contract grant sponsor: American Diabetes Association. NR 18 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2009 VL 33 IS 4 BP 299 EP 307 DI 10.1002/gepi.20380 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 440UJ UT WOS:000265724900003 PM 19025786 ER PT J AU Norman, PJ Abi-Rached, L Gendzekhadze, K Hammond, JA Moesta, AK Sharma, D Graef, T McQueen, KL Guethlein, LA Carrington, CVF Chandanayingyong, D Chang, YH Crespi, C Saruhan-Direskeneli, G Hameed, K Kamkamidze, G Koram, KA Layrisse, Z Matamoros, N Mila, J Park, MH Pitchappan, RM Ramdath, DD Shiau, MY Stephens, HAF Struik, S Tyan, D Verity, DH Vaughan, RW Davis, RW Fraser, PA Riley, EM Ronaghi, M Parham, P AF Norman, Paul J. Abi-Rached, Laurent Gendzekhadze, Ketevan Hammond, John A. Moesta, Achim K. Sharma, Deepti Graef, Thorsten McQueen, Karina L. Guethlein, Lisbeth A. Carrington, Christine V. F. Chandanayingyong, Dasdayanee Chang, Yih-Hsin Crespi, Catalina Saruhan-Direskeneli, Guher Hameed, Kamran Kamkamidze, Giorgi Koram, Kwadwo A. Layrisse, Zulay Matamoros, Nuria Mila, Joan Park, Myoung Hee Pitchappan, Ramasamy M. Ramdath, D. Dan Shiau, Ming-Yuh Stephens, Henry A. F. Struik, Siske Tyan, Dolly Verity, David H. Vaughan, Robert W. Davis, Ronald W. Fraser, Patricia A. Riley, Eleanor M. Ronaghi, Mostafa Parham, Peter TI Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes SO GENOME RESEARCH LA English DT Article ID IG-LIKE RECEPTORS; MAJOR HISTOCOMPATIBILITY COMPLEX; COPY-NUMBER VARIATION; NATURAL-KILLER-CELLS; MODERN HUMAN ORIGINS; HUMAN COLOR-VISION; HLA-B; CUTTING EDGE; INHIBITORY RECEPTORS; STRUCTURAL VARIATION AB Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric "half'' was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family. C1 [Norman, Paul J.; Abi-Rached, Laurent; Gendzekhadze, Ketevan; Hammond, John A.; Moesta, Achim K.; Sharma, Deepti; Graef, Thorsten; McQueen, Karina L.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Norman, Paul J.; Abi-Rached, Laurent; Gendzekhadze, Ketevan; Hammond, John A.; Moesta, Achim K.; Sharma, Deepti; Graef, Thorsten; McQueen, Karina L.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Carrington, Christine V. F.; Ramdath, D. Dan] Univ W Indies, Fac Med Sci, Dept Preclin Sci, St Augustine, Trinid & Tobago. [Chandanayingyong, Dasdayanee] Mahidol Univ, Dept Transfus Med, Fac Med, Bangkok 10070, Thailand. [Chandanayingyong, Dasdayanee] Mahidol Univ, Siriraj Hosp, Bangkok 10070, Thailand. [Chang, Yih-Hsin] Chung Shan Med Univ, Sch Med Lab & Biotechnol, Taichung 402, Taiwan. [Crespi, Catalina; Mila, Joan] Hosp Univ Son Dureta, Serv Immunol, Palma De Mallorca 07014, Spain. [Saruhan-Direskeneli, Guher] Istanbul Univ, Istanbul Fac Med, Dept Physiol, TR-34093 Istanbul, Turkey. [Hameed, Kamran] Aga Khan Univ Hosp, Dept Med, Karachi 74800, Pakistan. [Kamkamidze, Giorgi] REA Ctr, Dept Clin Immunol, GE-0160 Tbilisi, Rep of Georgia. [Koram, Kwadwo A.] Univ Ghana, Noguchi Mem Inst Med Res, Legon LG581, Ghana. [Layrisse, Zulay] Venezuelan Res Inst IVIC, Ctr Med Expt Miguel Layrisse, Caracas 21827, Venezuela. [Park, Myoung Hee] Seoul Natl Univ, Coll Med, Dept Lab Med, Seoul 110744, South Korea. [Pitchappan, Ramasamy M.] Madurai Kamaraj Univ, Ctr Adv Studies Funct Genom, Sch Biol Sci, Madurai 625021, Tamil Nadu, India. [Shiau, Ming-Yuh] Hung Kuang Univ, Taichung 433, Taiwan. [Stephens, Henry A. F.] Royal Free & Univ Coll Med Sch, Ctr Nephrol, London NW3 2QG, England. [Stephens, Henry A. F.] Royal Free & Univ Coll Med Sch, Anthony Nolan Trust, London NW3 2QG, England. [Struik, Siske; Riley, Eleanor M.] London Sch Hyg & Trop Med, Dept Infect & Trop Med, London WC1E 7HT, England. [Tyan, Dolly] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Verity, David H.] Moorfields Eye Hosp, London EC1V 2PD, England. [Vaughan, Robert W.] Guys & St Thomas Fdn Trust & Kings Coll, Clin Transplantat Lab, London SE1 9RT, England. [Davis, Ronald W.; Ronaghi, Mostafa] Stanford Univ, Stanford Genome Technol Ctr, Sch Med, Palo Alto, CA 94304 USA. [Fraser, Patricia A.] Immune Dis Inst, Boston, MA 02115 USA. RP Parham, P (reprint author), Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. EM peropa@stanford.edu RI Abi-Rached, Laurent/H-7236-2012; Park, Myoung Hee/J-5483-2012; Riley, Eleanor/C-8960-2013; Crespi, Catalina/A-5543-2013; OI Riley, Eleanor/0000-0003-3447-3570; Crespi, Catalina/0000-0003-0781-9708; Moesta, Achim/0000-0001-9995-8398 FU NIAID NIH HHS [T32 AI007290] NR 79 TC 45 Z9 47 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2009 VL 19 IS 5 BP 757 EP 769 DI 10.1101/gr.085738.108 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 440AA UT WOS:000265668800009 PM 19411600 ER PT J AU Olawaiye, AB Boruta, DM AF Olawaiye, Alexander B. Boruta, David M., II TI Management of women with clear cell endometrial cancer A Society of Gynecologic Oncology (SGO) review SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Clear cell; Staging; Radiotherapy; Chemotherapy ID PEGYLATED LIPOSOMAL DOXORUBICIN; CLINICAL STAGE-I; PHASE-III TRIAL; PACLITAXEL PLUS FILGRASTIM; RADIATION-THERAPY; HIGH-RISK; 1ST-LINE CHEMOTHERAPY; CLINICOPATHOLOGICAL FEATURES; POSTOPERATIVE RADIATION; ADJUVANT TREATMENT AB Objective. Clear cell endometrial cancer (CCE) is an uncommon but important disease because of its aggressive behavior. Furthermore, prospective, randomized studies are either too difficult or impossible because of the small number of women affected. This review explores the differences between clear cell and endometrioid endometrial cancer. In addition, it uses available evidence to determine the best approach to management. Methods. Medline was searched between January 1, 1966 and December 31, 2008 for all publications in English where the studied population included women diagnosed with CCE. Qualifying studies must have had at least 30 patients. Results. Clear cell histology is diagnosed in less than 6% of all endometrial cancers and its incidence increases with age. Diagnosis can be made using the same tests that are used in the diagnosis of other types of endometrial cancer. Clear cell histology is morphologically and genetically different from the more prevalent endometrioid endometrial cancer histology. It shares many similarities with clear cell neoplasms of the ovary and kidney. Comprehensive surgical staging is critical in order to plan appropriate postoperative management. Adjuvant pelvic and/or whole abdominal radiotherapy have not been shown to be clearly beneficial ill women diagnosed with clear cell endometrial cancer. Adjuvant chemotherapy with cisplatinum, taxol and doxorubicin either in a doublet or triplet combination has demonstrated efficacy. Conclusions. Women diagnosed with CCE require comprehensive surgical staging. Platinum based adjuvant chemotherapy in a doublet or triplet format in combination with paclitaxel and/or doxorubicin should be considered as part of treatment of these women. Careful long term surveillance following treatment is indicated given the higher rate of recurrence compared to endometrioid endometrial cancer. (C) 2009 Elsevier Inc. All rights reserved. C1 [Olawaiye, Alexander B.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci,Div Gynecol Onco, Pittsburgh, PA 15213 USA. [Boruta, David M., II] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol,Div Gynecol Onc, Boston, MA 02114 USA. RP Olawaiye, AB (reprint author), Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci,Div Gynecol Onco, 300 Halket St, Pittsburgh, PA 15213 USA. EM olawaiyea@upmc.edu; DBORUTA@PARTNERS.ORG NR 60 TC 37 Z9 37 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2009 VL 113 IS 2 BP 277 EP 283 DI 10.1016/j.ygyno.2009.02.003 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 436GJ UT WOS:000265400400024 PM 19251307 ER PT J AU Pearson, SD Lieber, SR AF Pearson, Steven D. Lieber, Sarah R. TI Financial Penalties For The Unhealthy? Ethical Guidelines For Holding Employees Responsible For Their Health SO HEALTH AFFAIRS LA English DT Article AB As health care costs continue to rise, an increasing number of self-insured employers are using financial rewards or penalties to promote healthy behavior and control costs. These incentive programs have triggered a backlash from those concerned that holding employees responsible for their health, particularly through the use of penalties, violates individual liberties and discriminates against the unhealthy. This paper offers an ethical analysis of employee health incentive programs and presents an argument for a set of conditions under which penalties can be used in an ethical and responsible way to contain health care costs and encourage healthy behavior among employees. [Health Affairs 28, no. 3 (2009): 845-852; 10.1377/hlthaff.28.3.845] C1 [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Review, Boston, MA 02114 USA. RP Pearson, SD (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM spearson@icer-review.org; Lieber@post.harvard.edu FU National Institutes of Health (NIH) FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The opinions expressed are the authors' own. They do not represent any position or policy of the NIH, Public Health Service, or Department of Health and Human Services. NR 20 TC 22 Z9 23 U1 0 U2 4 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAY-JUN PY 2009 VL 28 IS 3 BP 845 EP 852 DI 10.1377/hlthaff.28.3.845 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 441OV UT WOS:000265779400030 PM 19414897 ER PT J AU Wolf, EJ Mori, DL AF Wolf, Erika J. Mori, DeAnna L. TI Avoidant Coping as a Predictor of Mortality in Veterans With End-Stage Renal Disease SO HEALTH PSYCHOLOGY LA English DT Article DE end-stage renal disease; avoidant coping; mortality; COPE ID URBAN HEMODIALYSIS-PATIENTS; BEHAVIORAL COMPLIANCE; PSYCHOLOGICAL-FACTORS; PATIENT ADHERENCE; PRACTICE PATTERNS; DEPRESSION; SURVIVAL; TRANSPLANTATION; STRATEGIES; DIALYSIS AB Objective: The aim of this study was to examine the role of active and avoidant coping strategies in predicting mortality in 61 veterans with end-stage renal disease. Design: Participants completed a self-report measure of coping strategies (The COPE; Carver, Scheier, & Weintraub, 1989) and were interviewed as part of a structured assessment to determine their appropriateness for renal transplant. On average, participants were then followed for 9 years via medical record review to determine mortality status. Main Outcome Measures: Mortality, as predicted by factor scores on active and avoidant coping factors estimated via confirmatory factor analysis of select COPE subscales. Results: A Cox regression revealed that a unit change in avoidant coping was associated with a 114% increase in odds of mortality, even after controlling for variance attributable to demographic variables. There was also a statistical trend indicating that this association might be mediated by poor attendance at medical appointments. Active coping did not predict mortality. Conclusion: Results demonstrate the importance of assessing coping style in this population; clinical implications of these findings and possible mechanisms of this effect are discussed. C1 [Wolf, Erika J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Mori, DeAnna L.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Wolf, Erika J.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. RP Mori, DL (reprint author), VA Boston Healthcare Syst 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM deanna.mori@va.gov OI Wolf, Erika/0000-0003-2666-2435 FU National Institute of Mental Health [5F31MH074267] FX This research was supported, in part, by National Institute of Mental Health Grant 5F31MH074267 awarded to Erika J. Wolf. NR 40 TC 13 Z9 14 U1 5 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD MAY PY 2009 VL 28 IS 3 BP 330 EP 337 DI 10.1037/a0013583 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 445XM UT WOS:000266084800009 PM 19450039 ER PT J AU Smith, JG Lowe, JK Kovvali, S Maller, JB Salit, J Daly, MJ Stoffel, M Altshuler, DM Friedman, JM Breslow, JL Newton-Cheh, C AF Smith, J. Gustav Lowe, Jennifer K. Kovvali, Sirisha Maller, Julian B. Salit, Jacqueline Daly, Mark J. Stoffel, Markus Altshuler, David M. Friedman, Jeffrey M. Breslow, Jan L. Newton-Cheh, Christopher TI Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae SO HEART RHYTHM LA English DT Article DE Conduction; Electrocardiography; Electrophysiology; Genetics; Ion channels ID SICK SINUS SYNDROME; CHANNEL GENE SCN5A; ATRIAL-FIBRILLATION; CARDIAC CONDUCTION; HEART-FAILURE; WHOLE-GENOME; VARIABILITY; MUTATIONS; VARIANTS; DISEASE AB BACKGROUND Cardiac conduction, as assessed by electrocardiographic PR interval and QRS duration, is an important electrophysiological trait and a determinant of arrhythmia risk. OBJECTIVE We sought to identify common genetic determinants of these measures. METHODS We examined 1604 individuals from the island of Kosrae, Federated States of Micronesia, an isolated founder population. We adjusted for covariates and estimated the heritability of quantitative electrocardiographic QRS duration and PR interval and, secondarily, its subcomponents, P-wave duration and PR segment. Finally, we performed a genome-wide association study (GWAS) in a subset of 1262 individuals genotyped using the Affymetrix GeneChip Human Mapping 500K microarray. RESULTS The heritability of PR interval was 34% (standard error [SE] 5%, P = 4 x 10(-18)); of PR segment, 31% (SE 6%, P = 3.2 x 10(-13)); and of P-wave duration, 17% (SE 5%, P = 5.8 x 10(-6)), but the heritablitity of QRS duration was only 3% (SE 4%, P = .20). Hence, GWAS was performed only for the PR interval and its subcomponents. A total of 338,049 single nucleotide polymorphisms (SNPs) passed quality filters. For the PR interval, the most significantly associated SNPs were located in and downstream of the alpha-subunit of the cardiac voltage-gated sodium channel gene SCN5A, with a 4.8 ms (SE 1.0) or 0.23 standard deviation increase in adjusted PR interval for each minor allele copy of rs7638909 (P = 1.6 x 10(-6), minor allele frequency 0.40). These SNPs were also associated with P-wave duration (P = 1.5 x 10(-4)) and PR segment (P = .01) but not with QRS duration (P >= .22). CONCLUSIONS The PR interval and its subcomponents showed substantial heritability in a South Pacific islander population and were associated with common genetic variation in SCN5A. C1 [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA. [Lowe, Jennifer K.; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Smith, J. Gustav; Lowe, Jennifer K.; Kovvali, Sirisha; Maller, Julian B.; Daly, Mark J.; Altshuler, David M.; Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. [Maller, Julian B.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Stoffel, Markus] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland. [Breslow, Jan L.] Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA. [Salit, Jacqueline; Friedman, Jeffrey M.] Rockefeller Univ, Mol Genet Lab, New York, NY 10021 USA. RP Newton-Cheh, C (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-242, Boston, MA 02114 USA. EM cnewtoncheh@chgr.mgh.harvard.edu RI Altshuler, David/A-4476-2009; Breslow, Jan/B-7544-2008; OI Altshuler, David/0000-0002-7250-4107; Maller, Julian/0000-0002-1565-9559 FU National Institutes of Health [NIH K23-HL-080025]; Doris Duke Charitable Foundation Clinical Scientist Development; Burroughs Wellcome Fund Career; Basic Research front the Massachusetts Biomedical Research Corporation; Burroughs Wellcome Fund Clinical Scholar in Translational Research and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation; Starr Foundation; Howard Hughes Medical Institute FX Dr. Newton-Cheh was supported by National Institutes of Health grant no, NIH K23-HL-080025. a Doris Duke Charitable Foundation Clinical Scientist Development Award. and a Burroughs Wellcome Fund Career Award for Medical Scientists. J.K. Lowe was supported by a Tosteson Post-Doctoral Fellowship for Basic Research front the Massachusetts Biomedical Research Corporation. Dr. Altshuler is a Burroughs Wellcome Fund Clinical Scholar in Translational Research and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. The genome-wide association scan on Kosrae was supported by grants from the Starr Foundation and Howard Hughes Medical Institute. NR 37 TC 35 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAY PY 2009 VL 6 IS 5 BP 634 EP 641 DI 10.1016/j.hrthm.2009.02.022 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 440VY UT WOS:000265729000011 PM 19389651 ER PT J AU Andersson, KL Chung, RT AF Andersson, Karin L. Chung, Raymond T. TI Monitoring During and After Antiviral Therapy for Hepatitis B SO HEPATOLOGY LA English DT Article; Proceedings Paper CT NIH Consensus Development Conference on Management of Hepatitis B Virus CY OCT 20-22, 2008 CL Bethesda, MD SP Natl Inst Hlth ID TERM-FOLLOW-UP; ALANINE AMINOTRANSFERASE LEVELS; VIRUS-DNA; LAMIVUDINE THERAPY; PEGINTERFERON ALPHA-2A; VIROLOGICAL RESPONSE; ADEFOVIR DIPIVOXIL; LIVER FIBROSIS; STIFFNESS MEASUREMENT; SUSTAINED RESPONSE AB Recent studies suggest that long-term suppression of viral replication is critical to reducing the complications of chronic hepatitis B virus (HBV) infection. Monitoring for continued virological response during and after treatment is essential because current treatment options have limited success in achieving durable endpoints, and antiviral resistance may emerge during long-term therapy. Methods of monitoring treatment response include tests for serum aminotransferase levels, HBV DNA level, hepatitis B e antigen (HBeAg) and antibody (anti-HBe), hepatitis B surface antigen (HBsAg) or antibody (anti-HBs), and liver histology. Virological suppression and loss of HBeAg or HBsAg with or without seroconversion play a prominent role in decision-making regarding the success and duration of antiviral therapy. Guidelines recommend that testing for serum markers be repeated every 12-24 weeks during antiviral therapy and every 6-12 months afterward. Recent data also suggest that serum HBV DNA levels should be assessed at weeks 12 and 24 of therapy, because early viral response may predict the likelihood of sustained response and antiviral resistance. The use of serum HBV DNA levels for this purpose requires an assay with a wide range of quantification, such as real-time polymerase chain reaction assays, which have a 7-8 log(10) dynamic range. Newer, investigational methods for monitoring treatment response include quantitative measurement of HBsAg, HBeAg, and intrahepatic covalently closed circular DNA. Conclusions. Better methods for defining durable treatment endpoints are needed. Other areas requiring further research include the optimal treatment duration and the establishment of the optimal use of early viral kinetics for decision-making during antiviral therapy. (HEPATOLOGY 2009;49:S166-S173.) C1 [Andersson, Karin L.; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. RP Chung, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. EM rtchung@partners.org FU NIDDK NIH HHS [U01 DK082919-01, U01 DK082919, DK-82919] NR 49 TC 21 Z9 23 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2009 VL 49 IS 5 BP S166 EP S173 DI 10.1002/hep.22899 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 439ZZ UT WOS:000265668700020 PM 19399793 ER PT J AU Dienstag, JL AF Dienstag, Jules L. TI Benefits and Risks of Nucleoside Analog Therapy for Hepatitis B SO HEPATOLOGY LA English DT Article; Proceedings Paper CT NIH Consensus Development Conference on Management of Hepatitis B Virus CY OCT 20-22, 2008 CL Bethesda, MD SP Natl Inst Hlth ID SEVERELY DECOMPENSATED CIRRHOSIS; AWAITING LIVER-TRANSPLANTATION; TENOFOVIR DISOPROXIL FUMARATE; LONG-TERM THERAPY; ADEFOVIR DIPIVOXIL; LAMIVUDINE TREATMENT; VIROLOGICAL RESPONSE; ENTECAVIR THERAPY; HBV INFECTION; GLOBE TRIAL AB Five oral agents have been approved for the treatment of chronic hepatitis B, ranging in virological potency, clinical efficacy, barrier to resistance, and side-effect profile. The degree of histological, biochemical, and serological improvement with therapy generally corresponds to the degree of suppression of serum hepatitis B virus (HBV) DNA achieved with therapy. Conversely, for agents with a low barrier to resistance, the profundity of HBV DNA suppression in individual patients correlates inversely with the likelihood of resistance. The durability of hepatitis B e antigen (HBeAg) responses after a consolidation period of an additional 6-12 months of therapy is similar to 80% in western populations, lower in Asian populations. Loss of hepatitis B surface antigen (HBsAg) during a year of oral-agent therapy is limited, except with the most potent agents, but extending therapy for a second year and beyond can yield frequencies of HBsAg responses close to those reported in trials of interferon-based therapy. The oral agents are approved for 1-2 years of therapy, but treatment is continued indefinitely in the majority of patients (except for the similar to 20% of patients who are HBeAg-reactive who achieve a durable HBeAg response). HBeAg responses and virological/biochemical benefit continue to be maintained and to increase with continued therapy beyond the first year. Data continue to accumulate supporting the link between long-term HBV DNA suppression and reduction in hepatic fibrosis, hepatic decompensation, and liver-related mortality. All the benefits of a single year of injectable peginterferon therapy can be achieved with the newer, low-resistance oral agents continued beyond the first year, without interferon side effects. Future studies are needed to develop drug regimens that are even more effective in achieving clinical endpoints, that are not hampered by resistance, and that are more confined in treatment duration but are more durable. (HEPATOLOGY 2009;49: S112-S121.) C1 [Dienstag, Jules L.] Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Off Dean Med Educ, Boston, MA USA. RP Dienstag, JL (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Jackson 7,55 Fruit St, Boston, MA 02114 USA. EM jdienstag@partners.org FU NCRR NIH HHS [M01RR-01066]; NIDDK NIH HHS [1U01-DK08-2919, N01-DK-9-2319] NR 58 TC 51 Z9 55 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2009 VL 49 IS 5 BP S112 EP S121 DI 10.1002/hep.22920 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 439ZZ UT WOS:000265668700014 PM 19399795 ER PT J AU Bennetto-Hood, C Johnson, VA King, JR Hoesley, CJ Acosta, EP AF Bennetto-Hood, Chantelle Johnson, Victoria A. King, Jennifer R. Hoesley, Craig J. Acosta, Edward P. TI Novel Methodology for Antiretroviral Quantitation in the Female Genital Tract SO HIV CLINICAL TRIALS LA English DT Article DE antiretroviral; drug monitoring; women ID IMMUNODEFICIENCY-VIRUS TYPE-1; CERVICOVAGINAL SECRETIONS; HIV-1 RNA; HIV-1-INFECTED WOMEN; BLOOD; THERAPY; SEMEN; PLASMA; MEN AB Purpose: Challenges exist regarding antiretroviral quantitation in the female genital tract. Endocervical wicking using sterile tear flow test strips is an alternative to conventional methods due to the consistent sample volume obtained. Methods: A novel method for measuring antiretrovirals in cervicovaginal secretions using Sno-strip (R) wicking was developed and tested by spiking Sno-strips (R) with known concentrations of tenofovir, nevirapine, atazanavir, lopinavir, and ritonavir in blank cervicovaginal lavage fluid. Drug concentrations were determined by high-performance liquid chromatography with ultraviolet or mass spectrometry detection. Results: Mean extraction recoveries were 91% for tenofovir, 89% for nevirapine, 63% for atazanavir, 60% for lopinavir, and 61% for ritonavir relative to controls. Freezing spiked samples for 24 hours at -80 degrees C had no effect on recovery. Conclusions: Results suggest that the antiretrovirals tested can be efficiently extracted from Sno-strips (R), although a greater percentage of tenofovir and nevirapine was recovered. Storage of Sno-strip (R) samples up to 24 hours before analysis showed no difference in the percentage of drug recovered compared with immediate analysis. Quantitating antiretroviral penetration into the female genital tract may assist in determining optimal therapeutic antiretroviral regimens to both decrease the risk of HIV transmission and prevent development of HIV drug resistance. C1 [Bennetto-Hood, Chantelle; King, Jennifer R.; Acosta, Edward P.] Univ Alabama, Div Clin Pharmacol, Sch Med, Birmingham, AL 35294 USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Johnson, Victoria A.; Hoesley, Craig J.] Univ Alabama, Div Infect Dis, Sch Med, Birmingham, AL 35294 USA. RP Acosta, EP (reprint author), Univ Alabama, Div Clin Pharmacol, Sch Med, 1530 3rd Ave S,VH 116, Birmingham, AL 35294 USA. EM eacosta@uab.edu FU National Institute of Allergy and Infectious Diseases [U01AI38858]; Birmingham VA Medical Center; UAB CFAR core clinic and laboratory facilities; [P30 AI27767] FX This work was supported by Dr. Victoria A. Johnson's VA Merit Review entitled "Drug Resistance in Genital Tract Viruses Derived from HIV-Infected Women." The pharmacology laboratory was supported, in part, by the Adult: AIDS Clinical Trials Group Central Grant U01AI38858 of the National Institute of Allergy and Infectious Diseases. Dr. Johnson also acknowledges P30 AI27767 and the Birmingham VA Medical Center and UAB CFAR core clinic and laboratory facilities. NR 17 TC 3 Z9 3 U1 0 U2 0 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD MAY-JUN PY 2009 VL 10 IS 3 BP 193 EP 199 DI 10.1310/hct1003-193 PG 7 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 471SP UT WOS:000268078900008 PM 19632958 ER PT J AU Huppert, TJ Allen, MS Diamond, SG Boas, DA AF Huppert, Theodore J. Allen, Monica S. Diamond, Solomon G. Boas, David A. TI Estimating Cerebral Oxygen Metabolism From fMRI With a Dynamic Multicompartment Windkessel Model SO HUMAN BRAIN MAPPING LA English DT Article DE cerebral metabolism; functional neuroimaging; vascular modeling ID NEAR-INFRARED SPECTROSCOPY; MEAN TRANSIT-TIME; BLOOD-VOLUME; OXIDATIVE-METABOLISM; OPTICAL PATHLENGTH; HEMODYNAMIC-RESPONSE; FUNCTIONAL MRI; BRAIN-FUNCTION; BALLOON MODEL; BASE-LINE AB Stimulus evoked changes in cerebral blood flow, volume, and oxygenation arise from responses to underlying neuronally mediated changes in vascular tone and cerebral oxygen metabolism. There is increasing evidence that the magnitude and temporal characteristics of these evoked hemodynamic changes are additionally influenced by the local properties of the vasculature including the levels of baseline cerebral blood flow, volume, and blood oxygenation. In this work, we utilize a physiologically motivated vascular model to describe the temporal characteristics of evoked hemodynamic responses and their expected relationships to the structural and biomechanical properties of the underlying vasculature. We use this model in a temporal curve-fitting analysis of the high-temporal resolution functional MRI data to estimate the underlying cerebral vascular and metabolic responses in the brain. We present evidence for the feasibility of our model-based analysis to estimate transient changes in the cerebral metabolic rate of oxygen (CMRO(2)) in the human motor cortex from combined pulsed arterial spin labeling (ASL) and blood oxygen level dependent (BOLD) MRI. We examine both the numerical characteristics of this model and present experimental evidence to support this model by examining concurrently measured ASL, BOLD, and near-infrared spectroscopy to validate the calculated changes in underlying CMRO(2). Hum Brain Mapp 30:1548-1567, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Huppert, Theodore J.] Univ Pittsburgh, UPMC Presbyterian, Dept Radiol, Pittsburgh, PA 15213 USA. [Huppert, Theodore J.; Diamond, Solomon G.; Boas, David A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Allen, Monica S.] Univ Texas Arlington, Dept Elect Engn, Arlington, TX 76019 USA. [Diamond, Solomon G.] Dartmouth Coll, Thayer Sch Engn, Dept Engn, Hanover, NH 03755 USA. [Boas, David A.] MGH, HMS, Dept Radiol, Cambridge, MA USA. RP Huppert, TJ (reprint author), Univ Pittsburgh, UPMC Presbyterian, Dept Radiol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM huppertt@upmc.edu OI Diamond, Solomon/0000-0002-7589-2942 FU Howard Hughes Medical Institute predoctorial fellowship program; Rudolph Hermann Doctoral fellowship; National Institutes of Health [R01-EB002482, R01-EB000790, T32-CA09502, P41-RR14075]; NCRR, MIND Institute FX The Howard Hughes Medical Institute predoctorial fellowship program funded T.J.H. M.S.A. was funded by the Rudolph Hermann Doctoral fellowship at UTA. The authors thank Christiana Andre, Danny Joseph, Div Bolar, and Drs. Maria Franceschini, Rick Hoge for their assistance with the collection of this data. The authors also thank Heval Benav and Drs. Simon Arridge, Ville Kolehmainen, and Joe Mandeville for helpful discussion of this manuscript. NR 59 TC 28 Z9 28 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAY PY 2009 VL 30 IS 5 BP 1548 EP 1567 DI 10.1002/hbm.20628 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 440VK UT WOS:000265727600013 PM 18649348 ER PT J AU Taube, R Zhu, Q Marasco, WA AF Taube, R. Zhu, Q. Marasco, W. A. TI Lentivirus Display: Stable Expression of Human Antibodies on the Surface of Human Cells and Virus Particles SO HUMAN GENE THERAPY LA English DT Meeting Abstract CT 6th Annual Conference of the Israeli-Society-of-Gene-and-Cell-Therapy CY MAY 04, 2009 CL Ben Gurion Univ, Beer Sheva, ISRAEL SP Israel Soc Gene & Cell Therapy HO Ben Gurion Univ C1 [Zhu, Q.; Marasco, W. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Taube, R.] Ben Gurion Univ Negev, Div Basic Sci, IL-84105 Beer Sheva, Israel. EM rantaube@bgu.ac.il NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD MAY PY 2009 VL 20 IS 5 BP 537 EP 537 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 445DU UT WOS:000266030700027 ER PT J AU Kallio, SP Jakkula, E Purcell, S Suvela, M Koivisto, K Tienari, PJ Elovaara, I Pirttila, T Reunanen, M Bronnikov, D Viander, M Meri, S Hillert, J Lundmark, F Harbo, HF Lorentzen, AR De Jager, PL Daly, MJ Hafler, DA Palotie, A Peltonen, L Saarela, J AF Kallio, Suvi P. Jakkula, Eveliina Purcell, Shaun Suvela, Minna Koivisto, Keijo Tienari, Pentti J. Elovaara, Irina Pirttila, Tuula Reunanen, Mauri Bronnikov, Denis Viander, Markku Meri, Seppo Hillert, Jan Lundmark, Frida Harbo, Hanne F. Lorentzen, Aslaug R. De Jager, Philip L. Daly, Mark J. Hafler, David A. Palotie, Aarno Peltonen, Leena Saarela, Janna TI Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; TURKISH MULTIPLE-SCLEROSIS; COMPLEMENT-SYSTEM; FAMILIAL HYPERCHOLESTEROLEMIA; HAPLOTYPE RECONSTRUCTION; LINKAGE DISEQUILIBRIUM; INTERLEUKIN-7 RECEPTOR; DIAGNOSTIC-CRITERIA; GENOME SCREEN; AXONAL INJURY AB Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles. C1 [Kallio, Suvi P.; Jakkula, Eveliina; Suvela, Minna; Bronnikov, Denis; Peltonen, Leena] Biomedicum, FIMM, Helsinki, Finland. [Kallio, Suvi P.; Jakkula, Eveliina; Bronnikov, Denis; Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Tienari, Pentti J.] Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland. [Meri, Seppo] Univ Helsinki, Dept Bacteriol & Immunol, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Finnish Genome Ctr, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, FIMM, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland. [Kallio, Suvi P.; Jakkula, Eveliina; Suvela, Minna; Bronnikov, Denis; Peltonen, Leena; Saarela, Janna] Biomedicum, Natl Inst Hlth & Welf, Helsinki, Finland. [Jakkula, Eveliina; Purcell, Shaun; De Jager, Philip L.; Daly, Mark J.; Hafler, David A.; Palotie, Aarno; Peltonen, Leena] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Purcell, Shaun; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [De Jager, Philip L.; Daly, Mark J.] Harvard Univ, Sch Med, Partners Healthcare Ctr Genet & Genom, Boston, MA USA. [Koivisto, Keijo] Seinajoki Cent Hosp, Dept Neurol, Seinajoki, Finland. [Elovaara, Irina] Tampere Univ Hosp, Dept Neurol, Tampere, Finland. [Elovaara, Irina; Saarela, Janna] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Pirttila, Tuula] Kuopio Univ Hosp, Dept Neurol & Neurosci, SF-70210 Kuopio, Finland. [Reunanen, Mauri] Oulu Univ Hosp, Dept Neurol, Oulu, Finland. [Viander, Markku] Univ Turku, Dept Med Microbiol & Immunol, Turku, Finland. [Hillert, Jan; Lundmark, Frida] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Lorentzen, Aslaug R.] Univ Oslo, Ulleval Univ Hosp, Dept Neurol, Fac Div, Oslo, Norway. [Lorentzen, Aslaug R.] Univ Oslo, Rikshosp, Univ Hosp, Inst Immunol, N-0027 Oslo, Norway. [De Jager, Philip L.; Hafler, David A.] Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. [Palotie, Aarno; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Peltonen, L (reprint author), Biomedicum, FIMM, Helsinki, Finland. EM leena@sanger.ac.uk RI Tienari, Pentti/A-4893-2012; Saarela, Janna/E-5369-2014; OI Saarela, Janna/0000-0002-0853-6219 FU National Institutes of Health [RO1 NS 43559]; Center of Excellence for Disease Genetics of the Academy of Finland; Sigrid Juselius Foundation; Biocentrum Helsinki Foundation; Helsinki University Central Hospital Research Foundation; Multiple Sclerosis Foundation of USA; Harry Weaver Neuroscience Scholar Award; National Multiple Sclerosis Society; Neuropromise EU project [LSHMCT2005-018637]; National Center for Research Resources [U54 RR020278]; SGENE EU project [LSHM-CT-2006-037761]; Simons Foundation [R01MH71425-01A1] FX This work was supported by National Institutes of Health ( grant RO1 NS 43559), Center of Excellence for Disease Genetics of the Academy of Finland, the Sigrid Juselius Foundation, the Biocentrum Helsinki Foundation, Helsinki University Central Hospital Research Foundation, the Multiple Sclerosis Foundation of USA, a Harry Weaver Neuroscience Scholar Award from National Multiple Sclerosis Society ( P. L. D.) and the Neuropromise EU project ( grant LSHMCT2005-018637). The Broad Institute Center for Genotyping and Analysis is supported by the National Center for Research Resources ( grant U54 RR020278). The genotyping of the Health 2000 controls was funded by the SGENE EU project (LSHM-CT-2006-037761) and Simons Foundation (R01MH71425-01A1). NR 60 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 1 PY 2009 VL 18 IS 9 BP 1670 EP 1683 DI 10.1093/hmg/ddp073 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 431WS UT WOS:000265096100013 PM 19221116 ER PT J AU Velez, JCQ Ryan, KJ Harbeson, CE Bland, AM Budisavljevic, MN Arthur, JM Fitzgibbon, WR Raymond, JR Janech, MG AF Velez, Juan Carlos Q. Ryan, Kevin J. Harbeson, Caroline E. Bland, Alison M. Budisavljevic, Milos N. Arthur, John M. Fitzgibbon, Wayne R. Raymond, John R. Janech, Michael G. TI Angiotensin I Is Largely Converted to Angiotensin (1-7) and Angiotensin (2-10) by Isolated Rat Glomeruli SO HYPERTENSION LA English DT Article; Proceedings Paper CT 62nd Annual Fall Conference and Scientific Sessions of the American-Heart-Association-Council-for-High-Blood-Pressure-Research CY SEP 17-20, 2008 CL Atlanta, GA SP Amer Heart Assoc Council High Blood Presure Res DE renin-angiotensin system; neprilysin; aminopeptidase A; angiotensin-converting enzyme; angiotensin II; podocytes; des-Asp (1)-angiotensin I ID RENOVASCULAR HYPERTENSION; FLUID CONCENTRATIONS; ANESTHETIZED RATS; PROXIMAL TUBULES; AMINOPEPTIDASE-A; MESANGIAL CELLS; KIDNEY; CONVERSION; ENZYME; CHYMASE AB Intraglomerular renin-angiotensin system enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (Ang) II detection, ignoring the generation of other Ang I-derived metabolites, some of which may cross-react with Ang II. Therefore, our aim was to examine the metabolism of Ang I in freshly isolated intact glomeruli using matrix-assisted laser desorption ionization time of flight mass spectrometry as an analytic method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 mu mol/L of Ang I for 15 to 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by matrix-assisted laser desorption ionization time of flight tandem mass spectrometry or linear-trap-quadrupole mass spectrometry. Peaks were quantified using customized valine-(13)C(center dot 15)N-labeled peptides as standards. The most prominent peaks resulting from Ang I cleavage were 899 and 1181 m/z, corresponding with Ang (1-7) and Ang (2-10), respectively. Smaller peaks for Ang II, Ang (1-9), and Ang (3-10) also were detected. The disappearance of Ang I was significantly reduced during inhibition of aminopeptidase A or neprilysin. In contrast, captopril did not alter Ang I degradation. Furthermore, during simultaneous inhibition of aminopeptidase A and neprilysin, the disappearance of Ang I was markedly attenuated compared with all of the other conditions. These results suggest that there is prominent intraglomerular conversion of Ang I to Ang (2-10) and Ang (1-7), mediated by aminopeptidase A and neprilysin, respectively. Formation of these alternative Ang peptides may be critical to counterbalance the local actions of Ang II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for Ang II-mediated glomerular diseases. (Hypertension. 2009; 53: 790-797.) C1 [Velez, Juan Carlos Q.; Ryan, Kevin J.; Harbeson, Caroline E.; Bland, Alison M.; Budisavljevic, Milos N.; Arthur, John M.; Fitzgibbon, Wayne R.; Raymond, John R.; Janech, Michael G.] Med Univ S Carolina, Div Nephrol, Dept Med, Charleston, SC 29425 USA. [Velez, Juan Carlos Q.; Budisavljevic, Milos N.; Arthur, John M.; Raymond, John R.; Janech, Michael G.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Med & Res Serv, Charleston, SC 29425 USA. RP Velez, JCQ (reprint author), Med Univ S Carolina, Div Nephrol, Dept Med, 96 Jonathan Lucas St,CSB,Room 829, Charleston, SC 29425 USA. EM velezj@musc.edu RI Velez, Juan Carlos/N-3782-2016; OI Janech, Michael/0000-0002-3202-4811 FU NIDDK NIH HHS [K08 DK080944-01, K08 DK080944] NR 35 TC 25 Z9 26 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2009 VL 53 IS 5 BP 790 EP 797 DI 10.1161/HYPERTENSIONAHA.109.128819 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 436XW UT WOS:000265450400010 PM 19289651 ER PT J AU Sun, N Liu, Y Lee, H Weissleder, R Ham, D AF Sun, Nan Liu, Yong Lee, Hakho Weissleder, Ralph Ham, Donhee TI CMOS RF Biosensor Utilizing Nuclear Magnetic Resonance SO IEEE JOURNAL OF SOLID-STATE CIRCUITS LA English DT Article; Proceedings Paper CT IEEE Radio Frequency Integrated Circuits Symposium (RFIC) CY JUN 15-17, 2008 CL Atlanta, GA DE Biosensor; CMOS integrated circuit; low noise amplifier; nuclear magnetic resonance; RF transceiver ID NOISE AB We report on a CMOS RF transceiver designed for detection of biological objects such as cancer marker proteins. Its main function is to manipulate and monitor RF dynamics of protons in water via nuclear magnetic resonance (NMR). Target objects alter the proton dynamics, which is the basis for our biosensing. The RF transceiver has a measured receiver noise figure of 0.7 dB. This high sensitivity enabled construction of an entire NMR system around the RF transceiver in a 2-kg portable platform, which is 60 times lighter, 40 times smaller, yet 60 times more mass sensitive than a state-of-the-art commercial benchtop system. Sensing 20 fmol and 1.4 ng of avidin (protein) in a 5 mu L sample volume, our system represents a circuit designer's approach to pursue low-cost diagnostics in a portable platform. C1 [Sun, Nan; Ham, Donhee] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Lee, Hakho; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Sun, N (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM nansun@seas.har-vard.edu; donhee@seas.harvard.edu RI Liu, Yong/J-3636-2014 NR 19 TC 52 Z9 52 U1 1 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9200 J9 IEEE J SOLID-ST CIRC JI IEEE J. Solid-State Circuit PD MAY PY 2009 VL 44 IS 5 BP 1629 EP 1643 DI 10.1109/JSSC.2009.2017007 PG 15 WC Engineering, Electrical & Electronic SC Engineering GA 443UP UT WOS:000265936600028 ER PT J AU Cai, GF Freeman, GJ AF Cai, Guifang Freeman, Gordon J. TI The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation SO IMMUNOLOGICAL REVIEWS LA English DT Review DE CD160; BTLA; HVEM; LIGHT; coinhibition; costimulation ID HERPESVIRUS ENTRY MEDIATOR; TUMOR-NECROSIS-FACTOR; LYMPHOTOXIN-BETA-RECEPTOR; GPI-ANCHORED PROTEINS; TNF FAMILY MEMBER; MHC CLASS-I; CHRONIC VIRAL-INFECTION; NEWLY IDENTIFIED MEMBER; LYMPHOCYTE ATTENUATOR; B-LYMPHOCYTE AB CD160 is a newly identified ligand for HVEM (herpes virus entry mediator). Previously identified HVEM ligands include BTLA (B- and T-lymphocyte attenuator), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and LT alpha (lymphotoxin-alpha). The binding of LIGHT or LT alpha to HVEM delivers a costimulatory signal, whereas the binding of BTLA or CD160 to HVEM delivers a coinhibitory signal. Thus, HVEM is a bidirectional switch regulating T-cell activation in a costimulatory or coinhibitory fashion whose outcome depends on the ligand engaged. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of coinhibitory ligands CD160 and BTLA but not costimulatory ligand LIGHT. Deletion or blockade of HVEM CRD1 abolishes the binding of CD160 and BTLA, but not LIGHT, and converts HVEM to a dominant costimulatory molecule, possibly through the loss of negative signaling by CD160/BTLA. Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding are being developed to enhance immune responses and vaccination. C1 [Cai, Guifang; Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst,Dept Med, Boston, MA 02115 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst,Dept Med, Boston, MA 02115 USA. EM gordon_freeman@dfci.harvard.edu NR 145 TC 94 Z9 103 U1 1 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD MAY PY 2009 VL 229 BP 244 EP 258 DI 10.1111/j.1600-065X.2009.00783.x PG 15 WC Immunology SC Immunology GA 436JG UT WOS:000265409800016 PM 19426226 ER PT J AU Kinsey, BM Jackson, DC Orson, FM AF Kinsey, Berma M. Jackson, David C. Orson, Frank M. TI Anti-drug vaccines to treat substance abuse SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE anti drug; drugs; vaccine; substance abuse ID NICOTINE CONJUGATE VACCINE; MONOCLONAL-ANTIBODIES; ACTIVE IMMUNIZATION; TOBACCO DEPENDENCE; COCAINE ADDICTION; METHAMPHETAMINE; RATS; IMMUNOGENICITY; PROTECTS; EFFICACY AB Substance abuse is a growing world-wide problem. The big four drugs of abuse that might lend themselves to immunotherapy are nicotine, cocaine, morphine/heroin and methamphetamine. Tobacco abuse has a well-known enormous impact on major chronic cardiovascular and pulmonary diseases, while the last three, aside from their neuropsychological effects, are illegal, leading to crime and incarceration as well as the transmission of viral diseases. Having an efficient vaccine that would generate antibodies to sequester the drug and prevent its access to the brain could go a long way toward helping a motivated addict quit the addiction. This review will discuss what has been done to bring such vaccines to human use, and what the challenges are for the future of this promising intervention. Immunology and Cell Biology ( 2009) 87, 309-314; doi:10.1038/icb.2009.17; published online 31 March 2009 C1 [Kinsey, Berma M.] Baylor Coll Med, MEDVAMC, Dept Internal Med, Houston, TX 77030 USA. [Kinsey, Berma M.; Orson, Frank M.] Michael E DeBakey Vet Affairs Med Ctr, Res Serv, Houston, TX USA. [Jackson, David C.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. [Orson, Frank M.] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. [Orson, Frank M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Kinsey, BM (reprint author), Baylor Coll Med, MEDVAMC, Dept Internal Med, Room 221,Bldg 109,2002 Holcombe Blvd, Houston, TX 77030 USA. EM bkinsey@bcm.tmc.edu OI Jackson, David/0000-0001-7255-270X FU Department of Veterans Affairs (VA) Merit Review Program FX This study was supported by the Department of Veterans Affairs (VA) Merit Review Program. NR 53 TC 33 Z9 35 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD MAY-JUN PY 2009 VL 87 IS 4 BP 309 EP 314 DI 10.1038/icb.2009.17 PG 6 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 447RF UT WOS:000266208800008 PM 19333250 ER PT J AU Bhuiyan, TR Lundin, SB Khan, AI Lundgren, A Harris, JB Calderwood, SB Qadri, F AF Bhuiyan, Taufiqur Rahman Lundin, Samuel B. Khan, Ashraful Islam Lundgren, Anna Harris, Jason B. Calderwood, Stephen B. Qadri, Firdausi TI Cholera Caused by Vibrio cholerae O1 Induces T-Cell Responses in the Circulation SO INFECTION AND IMMUNITY LA English DT Article ID IMMUNE-RESPONSES; INFLAMMATORY MEDIATORS; HELICOBACTER-PYLORI; ANTIBODY-RESPONSES; TOXIN; DISEASE; HEMAGGLUTININ; BANGLADESH; CHILDREN; DIARRHEA AB Considerable effort is being made to understand the acute and memory antibody responses in natural cholera infection, while rather less is known about the roles of cellular immune responses involving T and B lymphocytes. We studied responses in adult patients hospitalized with cholera caused by Vibrio cholerae O1. Peripheral blood mononuclear cells from patients (n = 15) were analyzed by flow cytometry after stimulation with V. cholerae O1 membrane protein (MP) or toxin-coregulated pilus antigen (TcpA). The gamma interferon (IFN-gamma) and interleukin-13 (IL-13) responses in stimulated-lymphocyte supernatants were studied. The responses were compared with those of healthy controls (n = 10). Patients responded with increased frequencies of gut-homing CD4(+) T cells (CD4(+) beta 7(+)), gut-homing CD8(+) T cells (CD8(+) beta 7(+)), and gut-homing B cells (CD19(+) beta 7(+)) at the early and/or late convalescent stages compared to the acute stage. After stimulation with MP or TcpA, proliferation of CD4(+) and CD8(+) T cells was increased at the acute stage and/or early convalescent stage compared to healthy controls. Increased IL-13 and IFN-gamma responses were observed after antigenic stimulation at the acute and convalescent stages compared to healthy controls. Thus, increases in the levels of gut-homing T and B cells, as well as involvement of CD8 and CD4 Th1-mediated (IFN-gamma) and CD4 Th2-mediated (IL-13) cytokine responses, take place in acute dehydrating disease caused by V. cholerae O1. Further studies are needed to determine if such responses are also stimulated after immunization with oral cholera vaccines and if these responses play a role in protection following exposure to cholera. C1 [Bhuiyan, Taufiqur Rahman; Khan, Ashraful Islam; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Div Sci Lab, Immunol Lab, Dhaka 1000, Bangladesh. [Bhuiyan, Taufiqur Rahman; Lundin, Samuel B.; Lundgren, Anna] Univ Gothenburg, Inst Biomed, Dept Microbiol & Immunol, S-40530 Gothenburg, Sweden. [Harris, Jason B.; Calderwood, Stephen B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Qadri, F (reprint author), Int Ctr Diarrhoeal Dis Res, Div Sci Lab, Immunol Lab, GPO Box 128, Dhaka 1000, Bangladesh. EM fqadri@icddrb.org FU Swedish Agency; Sida-SAREC [INT-ICDDR, B-HN-01-AV]; National Institutes of Health [U01 AI058935] FX This study was conducted at the ICDDR, B Centre for Health and Population Research with support from grants from the Swedish Agency for Research Cooperation with Developing Countries (Sida-SAREC grant INT-ICDDR, B-HN-01-AV) and the National Institutes of Health (grant U01 AI058935). NR 26 TC 19 Z9 19 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2009 VL 77 IS 5 BP 1888 EP 1893 DI 10.1128/IAI.01101-08 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 434MX UT WOS:000265279900017 PM 19237532 ER PT J AU Stein, DJ Lydiard, RB Herman, BK Mandel, FS AF Stein, Dan J. Lydiard, R. Bruce Herman, Barry K. Mandel, Francine S. TI Impact of gastrointestinal symptoms on response to pregabalin in generalized anxiety disorder: results of a six-study combined analysis SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE gastrointestinal symptoms; generalized anxiety disorder; pregabalin ID IRRITABLE-BOWEL-SYNDROME; DOUBLE-BLIND; PRIMARY-CARE; DEPRESSION; MULTICENTER; VENLAFAXINE; PREVALENCE; MANAGEMENT; EFFICACY AB The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GO symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4-6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300-450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.5 mg/day; lorazepam, 6 mg/day). A GI-high subgroup (high GI symptomatology) was defined by a baseline HAM-A item-11 (G 1) score of 3 or greater (severe/very severe). At baseline, 301 patients (16.2%) met criteria for the GI-high subgroup. Baseline characteristics were approximately similar for the four study treatments in the GI-high subgroup. For the GI-high subgroup, last observation carried forward (LOCF) endpoint reduction in HAM-A was significantly higher on PGB-300/450-13.8 +/- 1.2 and PGB-600 - 14.7 +/- 1.0 compared with PBO - 10.1 +/- 0.9 (P< 0.01 for both comparisons); but the difference on PGB-150 did not achieve significance (- 13.5 +/- 11.6; P=0.083). Also in the GI-high subgroup, endpoint reduction in HAM-A item-11 was significantly higher on PGB-300/450 compared with PBO (- 1.93 +/- 0.16 vs. - 1.52 +/- 0.13; P= 0.04), but did not achieve significance on PG B-600 mg (- 1.89 +/- 0.14; P= 0.06), or PG B-150 mg (- 1.90 +/- 0.23; P= 0.16). In the GI-high subgroup, treatment with a benzodiazepine was not associated with significant endpoint reduction in either the HAM-A total score or the HAM-A item-11 score. Patients in the GI-high subgroup had higher discontinuation rates when treated with benzodiazepines, whereas treatment with PGB 300-600 mg/day was not associated with treatment-emergent worsening in GI symptoms compared with placebo. Treatment with PGB improved overall levels of anxiety, as well as specifically improving GI symptoms. Int Clin Psychopharmacol 24:126-132 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Herman, Barry K.; Mandel, Francine S.] Pfizer Inc, Pfizer Global Pharmaceut, New York, NY 10017 USA. [Stein, Dan J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Lydiard, R. Bruce] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Herman, BK (reprint author), Pfizer Inc, Pfizer Global Pharmaceut, 235 E 42nd St,9th Floor,Off 101,Mailstop 235-9-39, New York, NY 10017 USA. EM barry.herman@pfizer.com RI Stein, Dan/A-1752-2008 OI Stein, Dan/0000-0001-7218-7810 FU Pfizer Inc. FX The study was funded by Pfizer Inc., and editorial support was provided by Edward Schweizer, MD and funded by Pfizer Inc. NR 23 TC 9 Z9 9 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD MAY PY 2009 VL 24 IS 3 BP 126 EP 132 DI 10.1097/YIC.0b013e3283249c7b PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 438FH UT WOS:000265540800003 PM 19352198 ER PT J AU Flavin, R Smyth, P Barrett, C Russell, S Wen, H Wei, JJ Laios, A O'Toole, S Ring, M Denning, K Li, J Aherne, S Sammarae, D Aziz, NA Alhadi, A Finn, SP Loda, M Sheppard, B Sheils, O O'Leary, JJ AF Flavin, Richard Smyth, Paul Barrett, Ciara Russell, S. Wen, Hannah Wei, Jianjun Laios, Alex O'Toole, Sharon Ring, M. Denning, K. Li, J. Aherne, S. Sammarae, D. Aziz, N. A. Alhadi, A. Finn, Sephen P. Loda, M. Sheppard, B. Sheils, Orla O'Leary, John J. TI miR-29b Expression Is Associated With Disease-Free Survival in Patients With Ovarian Serous Carcinoma SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Micro-RNA; Ovarian serous carcinoma; Biomarkers ID CHRONIC LYMPHOCYTIC-LEUKEMIA; HUMAN LUNG CANCERS; MICRORNA EXPRESSION; REDUCED EXPRESSION; GENE-EXPRESSION; POOR-PROGNOSIS; GROWTH-FACTOR; CELL-LINES; SIGNATURE; PROFILES AB Micro-RNAs are a group of small noncoding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature micro-RNAs in human cancers. We characterized the alteration in expression of miR-29b in ovarian serous carcinoma. miR-29b expression was analyzed using quantitative stem-loop reverse transcriptase polymerase chain reaction on a set of 50 formal in-fixed, paraffin-embedded ovarian serous carcinoma samples. Protein expression of p53, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, and insulinlike growth factor I was quantified in the corresponding tissue microarray. The expression profile of miR-29b was correlated with clinicopathological and patient survival data. We provide definitive evidence that miR-29b is down-regulated in a significant proportion of ovarian serous carcinomas and is associated with specific clinicopathological features, most notably high miR-29b expression being associated with reduced disease-free survival. C1 [Flavin, Richard] St James Hosp, Dept Histopathol, Trinity Coll, Phase Trinity Ctr Hlth Sci 3, Dublin 8, Ireland. [Wen, Hannah] Trinity Coll Dublin, Dept Obstet & Gynaecol, Dublin, Ireland. [Wei, Jianjun] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA. [Laios, Alex; O'Toole, Sharon; Sammarae, D.; Aziz, N. A.; Alhadi, A.; Sheppard, B.] NYU, Dept Pathol, New York, NY 10016 USA. [Finn, Sephen P.; Loda, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Flavin, R (reprint author), St James Hosp, Dept Histopathol, Trinity Coll, Phase Trinity Ctr Hlth Sci 3, Jamess St, Dublin 8, Ireland. EM flavinr@tcd.ie RI Sheils, Orla Sheils/B-8461-2015; OI Sheils, Orla Sheils/0000-0002-4493-9496; Finn, Stephen/0000-0002-8628-5814; o toole, sharon/0000-0002-9260-3225 FU HRB Ireland Clinical Research Fellowship [CRT/2006/10]; The Emer Casey Foundation Ireland FX Dr Richard Flavin is funded by an HRB Ireland Clinical Research Fellowship Under Grant No. CRT/2006/10. The authors would like to acknowledge The Emer Casey Foundation Ireland. NR 69 TC 36 Z9 40 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAY PY 2009 VL 19 IS 4 BP 641 EP 647 DI 10.1111/IGC.0b013e3181a48cf9 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 457ZF UT WOS:000266976800024 PM 19509563 ER PT J AU Nam, SW Jo, YS Eun, JW Song, JY Ryu, KS Lee, JY Lee, JM MacLaughlin, DT Kim, JH AF Nam, Suk Woo Jo, Yun Sung Eun, Jung Woo Song, Jae Yen Ryu, Ki Sung Lee, Jung Young Lee, Joon Mo MacLaughlin, David T. Kim, Jang Heub TI Identification of large-scale characteristic genes of Mullerian inhibiting substance in human ovarian cancer cells SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE Mullerian inhibiting substance; OVCAR-8 cell line; DNA microarray; cell cycle ID II RECEPTOR; HEPATOCELLULAR-CARCINOMA; INDEPENDENT MECHANISM; SEXUAL DEVELOPMENT; MOLECULAR-CHANGES; IN-VIVO; EXPRESSION; GROWTH; TARGET; DIFFERENTIATION AB The purpose of this study was to investigate the large-scale characteristic molecular signature of Mullerian inhibiting substance (MIS) in human ovarian cancer cells through expression genomics. To understand the comprehensive molecular mechanisms by which MIS inhibits ovarian cancer cell growth, we identified the large-scale characteristic molecular changes elicited by MIS in the human ovarian cancer cell line OVCAR-8, using DNA microarray analysis. Combined serial gene expression analysis from 0 to 96 h after MIS treatment of OVCAR-8 cells resulted in 759 genes which showed at least a 2-fold change in overexpression or underexpression compared to non-treatment groups. Of the 759 outlier genes, 498 genes were mapped to known biological cellular processes, and the resultant major pathways included metabolism, signal transduction, cell growth and apoptosis. Among these pathways, 68 genetic elements were dissected as cell cycle-related genes induced by MIS. Although cellular phenotypic changes by MIS were observed after 24 h of treatment, the characteristic large-scale molecular changes were observed from 48 to 96 h of exposure to MIS. This finding may imply that the suppressive role of MIS on ovarian cancer cells could be cumulative in that the metabolic disturbance of MIS is followed by arrest at the G1/S cell cycle checkpoint. We suggest 759 outlier genes comprise the characteristic molecular signature of MIS, which may be responsible for the suppressive effect on OVCAR-8 cells. Although the precise biological mechanisms underlying these outlier genes should be validated, the genetic elements described herein provide promising therapeutic interventions for ovarian cancer. C1 [Jo, Yun Sung; Song, Jae Yen; Ryu, Ki Sung; Lee, Joon Mo; Kim, Jang Heub] Catholic Univ Korea, Coll Med, Dept Obstet & Gynecol, Seoul 150713, South Korea. [Nam, Suk Woo; Eun, Jung Woo; Lee, Jung Young] Catholic Univ Korea, Microdissect Genom Res Inst, Dept Pathol, Seoul 150713, South Korea. [MacLaughlin, David T.] Massachusetts Gen Hosp, Pediat Surg Res Lab, Boston, MA 02114 USA. [MacLaughlin, David T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kim, JH (reprint author), Catholic Univ Korea, Coll Med, Dept Obstet & Gynecol, 62 Yeouido Dong, Seoul 150713, South Korea. EM janghkim@catholic.ac.kr FU Korea Ministry of Environment; Korea Science & Engineering Foundation (KOSEF) through the Cell Death Disease Research Center FX This work was supported by the Korea Ministry of Environment as 'The Eco-technopia 21 project' and by the Korea Science & Engineering Foundation (KOSEF) through the Cell Death Disease Research Center at The Catholic University of Korea. NR 36 TC 4 Z9 5 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 EI 1791-244X J9 INT J MOL MED JI Int. J. Mol. Med. PD MAY PY 2009 VL 23 IS 5 BP 589 EP 596 DI 10.3892/ijmm_00000168 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 434FU UT WOS:000265261400003 PM 19360316 ER PT J AU Warden, D Rush, AJ Wisniewski, SR Lesser, IM Kornstein, SG Balasubramani, GK Thase, ME Preskorn, SH Nierenberg, AA Young, EA Shores-Wilson, K Trivedi, MH AF Warden, Diane Rush, A. John Wisniewski, Stephen R. Lesser, Ira M. Kornstein, Susan G. Balasubramani, G. K. Thase, Michael E. Preskorn, Sheldon H. Nierenberg, Andrew A. Young, Elizabeth A. Shores-Wilson, Kathy Trivedi, Madhukar H. TI What predicts attrition in second step medication treatments for depression?: a STAR*D Report SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 4th Biennial Conference of the International-Society-of-Affective-Disorders CY MAR 14-17, 2008 CL Cape Town, SOUTH AFRICA SP Int Soc Affect Disorders DE Adherence; attrition; antidepressants; depression; predictors ID SEQUENCED TREATMENT ALTERNATIVES; DIAGNOSTIC SCREENING QUESTIONNAIRE; MEASUREMENT-BASED CARE; ILLNESS RATING-SCALE; REPORT QIDS-SR; QUICK INVENTORY; PSYCHOMETRIC EVALUATION; CLINICAL-PRACTICE; SYMPTOMATOLOGY; OUTPATIENTS AB Attrition rates are high during treatment for major depressive disorder (MDD), and patients who drop out are less likely to reach remission. This report evaluates the incidence, timing, and predictors of attrition during second-step medication treatment. Outpatients in the multisite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study receiving a medication augmentation (n=563) or medication switch (n=723) for non-psychotic MDD after an unsatisfactory outcome with citalopram were evaluated to determine attrition rates and pretreatment sociodemographic or clinical predictors of attrition. Twenty percent of participants receiving a medication augmentation and 27% receiving a medication switch dropped Out before 12 wk in the second treatment step. Remission rates were lower for dropouts [7% vs. 43%, (medication augmentation); 12% vs. 31% (medication switch)]. For medication augmentation, Black and other non-Caucasian races, Hispanic ethnicity, younger age, family history of drug abuse, concurrent drug abuse, sociodemographic disadvantage, less symptom improvement with initial citalopram treatment, and greater symptom severity when beginning augmentation were associated with attrition. For medication switch, Black and other non-Caucasian races, younger age, more melancholic features, and lower exit doses but more severe side-effects with citalopram treatment were associated with attrition. Minority status, younger age, and greater difficulty with the first treatment step are risk factors for attrition in the second treatment step. Focus on patients with attrition risk factors for medication augmentation or switch strategies may enhance retention and improve outcomes. C1 [Warden, Diane; Rush, A. John; Shores-Wilson, Kathy; Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Wisniewski, Stephen R.; Balasubramani, G. K.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Lesser, Ira M.] UCLA Med Ctr, Dept Psychiat, Torrance, CA USA. [Lesser, Ira M.] UCLA Med Ctr, Los Angeles Biomed Res Inst Harbor, Torrance, CA USA. [Kornstein, Susan G.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Thase, Michael E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Preskorn, Sheldon H.] Univ Kansas, Sch Med, Dept Psychiat & Behav Sci, Wichita, KS 67214 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. [Young, Elizabeth A.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Young, Elizabeth A.] Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI 48109 USA. RP Warden, D (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Diane.Warden@UTSouthwestern.edu RI Preskorn, Sheldon/L-9839-2016; OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Goundappa K, Balasubramani/0000-0001-7221-1825 FU NIMH NIH HHS [N01MH90003] NR 42 TC 42 Z9 43 U1 3 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2009 VL 12 IS 4 BP 459 EP 473 DI 10.1017/S1461145708009073 PG 15 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 449BM UT WOS:000266305800003 PM 18611293 ER PT J AU Herrera, VM Casas, JP Miranda, JJ Perel, P Pichardo, R Gonzalez, A Sanchez, JR Ferreccio, C Aguilera, X Silva, E Orostegui, M Gomez, LF Chirinos, JA Medina-Lezama, J Perez, CM Suarez, E Ortiz, AP Rosero, L Schapochnik, N Ortiz, Z Ferrante, D Diaz, M Bautista, LE AF Herrera, V. M. Casas, J. P. Miranda, J. J. Perel, P. Pichardo, R. Gonzalez, A. Sanchez, J. R. Ferreccio, C. Aguilera, X. Silva, E. Orostegui, M. Gomez, L. F. Chirinos, J. A. Medina-Lezama, J. Perez, C. M. Suarez, E. Ortiz, A. P. Rosero, L. Schapochnik, N. Ortiz, Z. Ferrante, D. Diaz, M. Bautista, L. E. CA Latin Amer Consortium Studies TI Interethnic differences in the accuracy of anthropometric indicators of obesity in screening for high risk of coronary heart disease SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE coronary heart disease; screening; ethnic group; Latin America; NHANES ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; METABOLIC SYNDROME; MYOCARDIAL-INFARCTION; MULTIPLE IMPUTATION; CARDIOVASCULAR RISK; AFRICAN-AMERICANS; FAT DISTRIBUTION; PREVALENCE AB Background: Cut points for defining obesity have been derived from mortality data among Whites from Europe and the United States and their accuracy to screen for high risk of coronary heart disease (CHD) in other ethnic groups has been questioned. Objective: To compare the accuracy and to define ethnic and gender-specific optimal cut points for body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) when they are used in screening for high risk of CHD in the Latin-American and the US populations. Methods: We estimated the accuracy and optimal cut points for BMI, WC and WHR to screen for CHD risk in Latin Americans (n = 18 976), non-Hispanic Whites (Whites; n = 8956), non-Hispanic Blacks (Blacks; n 5205) and Hispanics (n = 5803). High risk of CHD was defined as a 10-year risk >= 20% (Framingham equation). The area under the receiver operator characteristic curve (AUC) and the misclassification-cost term were used to assess accuracy and to identify optimal cut points. Results: WHR had the highest AUC in all ethnic groups (from 0.75 to 0.82) and BMI had the lowest (from 0.50 to 0.59). Optimal cut point for BMI was similar across ethnic/gender groups (27 kg/m(2)). In women, cut points for WC (94 cm) and WHR (0.91) were consistent by ethnicity. In men, cut points for WC and WHR varied significantly with ethnicity: from 91cm in Latin Americans to 102cm in Whites, and from 0.94 in Latin Americans to 0.99 in Hispanics, respectively. Conclusion: WHR is the most accurate anthropometric indicator to screen for high risk of CHD, whereas BMI is almost uninformative. The same BMI cut point should be used in all men and women. Unique cut points for WC and WHR should be used in all women, but ethnic-specific cut points seem warranted among men. International Journal of Obesity (2009) 33, 568-576; doi:10.1038/ijo.2009.35; published online 24 February 2009 C1 [Herrera, V. M.; Bautista, L. E.] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Casas, J. P.; Miranda, J. J.; Perel, P.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Pichardo, R.] Inst Dominicano Cardiol, Santo Domingo, Dominican Rep. [Sanchez, J. R.] Inst Nacl Salud, Ctr Nacl Alimentac & Nutr, Lima, Peru. [Ferreccio, C.] Pontificia Univ Catolica Chile, Dept Salud Publ, Santiago, Chile. [Aguilera, X.] Minist Salud Chile, Santiago, Chile. [Silva, E.] Univ Zulia, Fac Med, Inst Invest & Estudios Enfermedades Cardiovasc, Maracaibo 4011, Venezuela. [Orostegui, M.] Univ Ind Santander, Epidemiol Res Ctr, Cardiovasc Dis Epidemiol Observ, Bucaramanga, Colombia. [Gomez, L. F.] Fdn FES Social, Hlth Div, Bogota, Colombia. [Chirinos, J. A.] Univ Penn, Sch Med, Div Cardiol, Philadelphia, PA 19104 USA. [Chirinos, J. A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Medina-Lezama, J.] Santa Maria Catholic Univ, Arequipa, Peru. [Medina-Lezama, J.] Santa Maria Res Inst, Arequipa, Peru. [Perez, C. M.; Suarez, E.; Ortiz, A. P.] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Biostat & Epidemiol, San Juan, PR 00936 USA. [Rosero, L.] Univ Costa Rica, Ctr Ctr Amer Poblac, San Jose, Costa Rica. [Schapochnik, N.] Minist Salud Prov Tierra Fuego, Ushuaia, Argentina. [Ortiz, Z.] Acad Nacl Med Buenos Aires, Inst Invest Epidemiol, Buenos Aires, DF, Argentina. [Ferrante, D.] Minist Salud & Ambiente, Buenos Aires, DF, Argentina. [Diaz, M.] Ctr Invest Med Acad, Montevideo, Uruguay. RP Bautista, LE (reprint author), Univ Wisconsin, Dept Populat Hlth Sci, 610 Walnut St,703 WARF, Madison, WI 53726 USA. EM lebautista@wisc.edu RI Herrera, Victor/C-5602-2008; Miranda, J. Jaime/A-8482-2008; Aguilera, Ximena/D-9861-2014 OI Miranda, J. Jaime/0000-0002-4738-5468; Aguilera, Ximena/0000-0002-8153-6733 FU NCRR NIH HHS [P20 RR 011126, G12 RR 03051, G12 RR003051, P20 RR011126]; NIMHD NIH HHS [G12 MD007600]; Wellcome Trust [074833] NR 49 TC 35 Z9 36 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2009 VL 33 IS 5 BP 568 EP 576 DI 10.1038/ijo.2009.35 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 443DF UT WOS:000265889700008 PM 19238159 ER PT J AU Gizani, S Papaioannou, W Haffajee, AD Kavvadia, K Quirynen, M Papagiannoulis, L AF Gizani, Sotiria Papaioannou, William Haffajee, Anne D. Kavvadia, Katerina Quirynen, Marc Papagiannoulis, Liza TI Distribution of selected cariogenic bacteria in five different intra-oral habitats in young children SO INTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY LA English DT Article ID DENTAL PLAQUE; ORAL-CAVITY; CARIES; FLORA; PERIODONTOPATHOGENS; MICROFLORA; SURFACES; SAMPLES; SALIVA; TOOTH AB Knowledge of the colonization patterns and composition of the oral microbiota can lead to a better understanding of disease initiation. The aim of this study was to examine the distribution of selected cariogenic bacteria in samples from five different oral habitats in young Greek children. Ninety-three children 3-12 years old (mean + SD 7.9 +/- 2.5) (60.2% male, 39.8% female) participated and split into three different age groups: primary (3-6 years), early mixed (6-9 years), and mixed dentition (9-12 years). Samples for bacterial enumeration were taken from saliva, supragingival and subgingival plaque, tongue dorsum, and soft tissues from each child, and were further analysed using checkerboard DNA-DNA hybridization. Mean counts and proportions of all the test bacteria differed significantly among sample locations. Cariogenic bacteria were present in almost all healthy children. Mean proportions of Streptococcus mutans isolated from soft tissue and Streptococcus sanguinis from soft tissue, subgingival and saliva samples increased significantly with age, whereas the opposite was seen for Lactobacillus acidophilus. Cariogenic bacteria were present in almost all young children. Soft tissues, saliva, and tongue were more often colonized by cariogenic streptococcal species than teeth. These surfaces may serve as reservoirs for oral pathogens, requiring attention during preventive interventions. C1 [Gizani, Sotiria; Kavvadia, Katerina; Papagiannoulis, Liza] Univ Athens, Dept Padiatr Dent, Athens, Greece. [Haffajee, Anne D.] Forsyth Insitutue, Dept Periodontol, Boston, MA USA. [Quirynen, Marc] Catholic Univ Louvain, Dept Periodontol, B-3000 Leuven, Belgium. [Papaioannou, William] Univ Athens, Dept Prevent & Community Dent, Athens, Greece. RP Gizani, S (reprint author), El Venizelou 199, N Smyrni 17123, Greece. EM periowp@hol.gr FU University of Athens Special Account for Research Grants [70/4/8887] FX The authors would like to acknowledge the invaluable assistance provided by E. Mandelou and T. Yaskell in the preparation and analysis of the samples, as well as S. Poulopoulou and Assoc. Professor U. Dafni for their statistical advice. The study was partially funded by the University of Athens Special Account for Research Grants: 'Kapodistrias' programme (#70/4/8887). NR 27 TC 13 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0960-7439 J9 INT J PAEDIATR DENT JI Int. J. Paediatr. Dent. PD MAY PY 2009 VL 19 IS 3 BP 193 EP 200 DI 10.1111/j.1365-263X.2008.00956.x PG 8 WC Dentistry, Oral Surgery & Medicine; Pediatrics SC Dentistry, Oral Surgery & Medicine; Pediatrics GA 430UA UT WOS:000265013200006 PM 19207737 ER PT J AU Nguyen, PL Chen, MH Hoffman, KE Katz, MS D'Amico, AV AF Nguyen, Paul L. Chen, Mlng-Hui Hoffman, Karen E. Katz, Matthew S. D'Amico, Anthony V. TI PREDICTING THE RISK OF PELVIC NODE INVOLVEMENT AMONG MEN WITH PROSTATE CANCER IN THE CONTEMPORARY ERA SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Pelvic lymph nodes; Prostate cancer; Prediction model; Roach formula ID ADEQUATE STAGING PROCEDURE; RADICAL PROSTATECTOMY; GLEASON SCORE; NEEDLE-BIOPSY; DISSECTION; LYMPHADENECTOMY; METASTASIS; SPECIMENS; ANTIGEN AB Purpose: The "Roach formula" for the risk of pelvic lymph node metastases [(2/3) * PSA + (Gleason score - 6) * 10] was developed in the early prostate-specific antigen (PSA) era. We examined the accuracy of this formula in contemporary patients. Methods: We included men in the Surveillance, Epidemiology, and End Results Registry with a diagnosis of clinical T1c-T4 prostate cancer in 2004 who had a surgical lymph node evaluation, Gleason score (typically from prostatectomy), and baseline PSA level (n = 9,387). Expected and observed rates of node positivity were compared. Results: Ninety-eight percent were clinical T1c/T2, and 97% underwent prostatectomy. Overall, 309 patients (3.291%) had positive lymph nodes. Roach scores overestimated the actual rate of positive lymph nodes in the derivation set by 16-fold for patients with Roach score less than or equal to 10%, by 7-fold for scores greater than 10-20%, and by approximately 2.5-fold for scores greater than 20%. Applying these adjustment factors to Roach scores in the validation data set yielded accurate predictions of risk. For those with Roach score less than or equal to 10%, adjusted expected risk was 0.2% and observed risk was 0.2%. For Roach score greater than 10-20%, adjusted expected risk was 2.0% and observed risk was 2.1%. For Roach score greater than 20-30%, adjusted expected risk was 9.7% and observed risk was 6.5%. For Roach score greater than 30-40%, adjusted expected risk was 13.9% and observed risk was 13.9%. Conclusion: Applied to contemporary patients with mainly T1c/T2 disease, the Roach formula appears to overestimate pelvic lymph node risk. The adjustment factors presented here should be validated by using biopsy Gleason scores and extended lymphadenectomies. (C) 2009 Elsevier Inc. C1 [Nguyen, Paul L.] Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Chen, Mlng-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Katz, Matthew S.] St Med Ctr, Div Radiat Oncol, Lowell, MA USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 20 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAY 1 PY 2009 VL 74 IS 1 BP 104 EP 109 DI 10.1016/j.ijrobp.2008.07.053 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 436GW UT WOS:000265401700016 PM 19286330 ER PT J AU Kozak, KR Adams, J Krejcarek, SJ Tarbell, NJ Yock, TI AF Kozak, Kevin R. Adams, Judith Krejcarek, Stephanie J. Tarbell, Nancy J. Yock, Torunn I. TI A DOSIMETRIC COMPARISON OF PROTON AND INTENSITY-MODULATED PHOTON RADIOTHERAPY FOR PEDIATRIC PARAMENINGEAL RHABDOMYOSARCOMAS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Comparison; Intensity-modulated radiation therapy; Parameningeal rhabdomyosarcoma; Pediatric; Protons ID CONFORMAL RADIATION-THERAPY; EXTERNAL-BEAM IRRADIATION; NECK-CANCER-PATIENTS; INTERGROUP RHABDOMYOSARCOMA; CHILDHOOD-CANCER; HEARING-LOSS; NASOPHARYNGEAL CARCINOMA; CRANIAL IRRADIATION; CHILDREN; HEAD AB Purpose: We compared tumor and normal tissue dosimetry of proton radiation therapy with intensity-modulated radiation therapy (IMRT) for pediatric parameningeal rhabdomyosarcomas (PRMS). Methods and Materials: To quantify dosimetric differences between contemporary proton and photon treatment for pediatric PRMS, proton beam plans were compared with IMRT plans. Ten patients treated with proton radiation therapy at Massachusetts General Hospital had IMRT plans generated. To facilitate dosimetric comparisons, clinical target volumes and normal tissue volumes were held constant. Plans were optimized for target volume coverage and normal tissue sparing. Results: Proton and IMRT plans provided acceptable and comparable target volume coverage, with at least 99% of the CTV receiving 95% of the prescribed dose in all cases. Improved dose conformality provided by proton therapy resulted in significant sparing of all examined normal tissues except for ipsilateral cochlea and mastoid; ipsilateral parotid gland sparing was of borderline statistical significance (p = 0.05). More profound sparing of contralateral structures by protons resulted in greater dose asymmetry between ipsilateral and contralateral retina, optic nerves, cochlea, and mastoids; dose asymmetry between ipsilateral and contralateral parotids was of borderline statistical significance (p = 0.05). Conclusions: For pediatric PRMS, superior normal tissue sparing is achieved with proton radiation therapy compared with IMRT. Because of enhanced conformality, proton plans also demonstrate greater normal tissue dose distribution asymmetry. Longitudinal studies assessing the impact of proton radiotherapy and IMRT on normal tissue function and growth symmetry are necessary to define the clinical consequences of these differences. (C) 2009 Elsevier Inc. C1 [Kozak, Kevin R.; Adams, Judith; Krejcarek, Stephanie J.; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM tyock@partners.org NR 38 TC 46 Z9 47 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAY 1 PY 2009 VL 74 IS 1 BP 179 EP 186 DI 10.1016/j.ijrobp.2008.06.1942 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 436GW UT WOS:000265401700027 PM 19019562 ER PT J AU Patel, AA Wolfgang, JA Niemierko, A Hong, TS Yock, T Choi, NC AF Patel, Abhijit A. Wolfgang, John A. Niemierko, Andrzej Hong, Theodore S. Yock, Torunn Choi, Noah C. TI IMPLICATIONS OF RESPIRATORY MOTION AS MEASURED BY FOUR-DIMENSIONAL COMPUTED TOMOGRAPHY FOR RADIATION TREATMENT PLANNING OF ESOPHAGEAL CANCER SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Esophageal cancer; Tumor motion; Four-dimensional CT; Lymph nodes; Internal target volume ID INTERNAL TARGET VOLUME; LUNG-CANCER; CONFORMAL RADIOTHERAPY; MOVEMENT; THERAPY; CHEMOTHERAPY; MOBILITY; MARGINS; TUMORS AB Purpose: To evaluate the respiratory motion of primary esophageal cancers and pathologic celiac-region lymph nodes using time-resolved four-dimensional computed tomography (4D CT). Methods and Materials: Respiration-synchronized 41) CT scans were obtained to quantify the motion of primary tumors located in the proximal, mid-, or distal thoracic esophagus, as well as any involved celiac-region lymph nodes. Respiratory motion was measured in the superior-inferior (SI), anterior-posterior (AP), and left-right (LR) directions and was analyzed for correlation with anatomic location. Recommended margin expansions were determined for both primary and nodal targets. Results: Thirty patients underwent 4D CT scans at Massachusetts General Hospital for planned curative treatment of esophageal cancer. Measurements of respiratory tumor motion were obtained for I proximal, 4 mid-, and 25 distal esophageal tumors, as well as 12 involved celiac-region lymph nodes. The mean (SD) peak-to-peak displacements of all primary tumors in the SI, AP, and LR dimensions were 0.80 (0.45) cm, 0.28 (0.20) cm, and 0.22 (0.23) cm, respectively. Distal tumors were found to have significantly greater SI and AP motion than proximal or mid-esophageal tumors. The mean (SD) SI, AP, and LR peak-to-peak displacements of the celiac-region lymph nodes were 0.92 (0.56) cm, 0.46 (0.27) cm, and 0.19 (0.26) cm, respectively. Conclusions: Margins of 1.5 cm SI, 0.75 cm AP, and 0.75 cm LR would account for respiratory tumor motion of >95% of esophageal primary tumors in the dataset. All celiac-region lymph nodes would be adequately covered with SI, AP, and LR margins of 2.25 cm, 1.0 cm, and 0.75 cm, respectively. (C) 2009 Elsevier Inc. C1 [Choi, Noah C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Choi, NC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM nchoi@partners.org NR 21 TC 34 Z9 43 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAY 1 PY 2009 VL 74 IS 1 BP 290 EP 296 DI 10.1016/j.ijrobp.2008.12.060 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 436GW UT WOS:000265401700041 PM 19362248 ER PT J AU Downes, J Vartoukian, SR Dewhirst, FE Izard, J Chen, T Yu, WH Sutcliffe, IC Wade, WG AF Downes, Julia Vartoukian, Sonia R. Dewhirst, Floyd E. Izard, Jacques Chen, Tsute Yu, Wen-Han Sutcliffe, Iain C. Wade, William G. TI Pyramidobacter piscolens gen. nov., sp nov., a member of the phylum 'Synergistetes' isolated from the human oral cavity SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article ID MOBILE SP NOV.; ENDODONTIC INFECTIONS; BACTERIAL DIVERSITY; EMENDED DESCRIPTION; COMB. NOV; THERMANAEROVIBRIO; ACIDAMINOVORANS; PHYLOTYPES; SEQUENCES; SULFUR AB Four strains of anaerobic, Gram-negative bacilli isolated from the human oral cavity were subjected to a comprehensive range of phenotypic and genotypic tests and were found to comprise a homogeneous group distinct from any species with validly published names. 16S rRNA and 23S rRNA gene sequence analyses and DNA-DNA reassociation data revealed that the strains constituted a novel group within the phylum 'Synergistetes' and were most closely related to Jonquetella anthropi. Two libraries of randomly cloned DNA were prepared from strain W5455(T) and were sequenced to provide a genome survey as a resource for metagenomic studies. A new genus and novel species, Pyramidobacter piscolens gen. nov., sp. nov., is proposed to accommodate these strains. The genus Pyramidobacter comprises strains that are anaerobic, non-motile, asaccharolytic bacilli that produce acetic and isovaleric acids and minor to trace amounts of propionic, isobutyric, succinic and phenylacetic acids as end products of metabolism. P. piscolens gen. nov., sp. nov. produced hydrogen sulphide but was otherwise largely biochemically unreactive. Growth was stimulated by the addition of glycine to broth media. The G + C content of the DNA of the type strain was 59 mol%. The type strain of Pyramidobacter piscolens sp. nov. is W5455(T) (=DSM 21147(T)=CCUG 55836(T)). C1 [Downes, Julia; Vartoukian, Sonia R.; Wade, William G.] Kings Coll London, Inst Dent, Infect Res Grp, London SE1 9RT, England. [Dewhirst, Floyd E.; Izard, Jacques; Chen, Tsute; Yu, Wen-Han; Wade, William G.] Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. [Sutcliffe, Iain C.] Northumbria Univ, Div Biomed Sci, Sch Appl Sci, Newcastle Upon Tyne NE1 8ST, Tyne & Wear, England. RP Wade, WG (reprint author), Kings Coll London, Inst Dent, Infect Res Grp, London SE1 9RT, England. EM william.wade@kcl.ac.uk RI Sutcliffe, Iain/A-5354-2009; Izard, Jacques/A-6074-2012; OI Sutcliffe, Iain/0000-0002-9036-2683; Izard, Jacques/0000-0002-5904-5436; Wade, William/0000-0003-2685-826X FU NIH [DE-10374, DE-16937, DE-17106]; National Institute for Dental and Craniofacial Research; Guy's and St Thomas' Charity [R050724]; NSF [0228651] FX This research was Supported by NIH grants (DE-10374, DE-16937 and DE-17106) from the National Institute for Dental and Craniofacial Research and a grant from the Guy's and St Thomas' Charity (ref. R050724). Professor Hans Truper is thanked for his expert advice oil the construction of the species name. We thank Janet Cheong, Sara Barbuto and Erin Klein for their technical assistance with 23S rRNA gene sequencing, and Derek Spencer for making the second genomic library. We thank Jonathan Eisen for allowing us to use the 23S rRNA gene sequence of S. jonesii. The genome sequencing of S. jonesii was supported by an NSF 'Assembling the Tree of Life' grant (0228651) to Jonathan Eisen and Naomi Ward. NR 43 TC 39 Z9 40 U1 0 U2 4 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAY PY 2009 VL 59 BP 972 EP 980 DI 10.1099/ijs.0.000364-0 PG 9 WC Microbiology SC Microbiology GA 450UL UT WOS:000266426400008 PM 19406777 ER PT J AU Seddon, JM Reynolds, R Maller, J Fagerness, JA Daly, MJ Rosner, B AF Seddon, Johanna M. Reynolds, Robyn Maller, Julian Fagerness, Jesen A. Daly, Mark J. Rosner, Bernard TI Prediction Model for Prevalence and Incidence of Advanced Age-Related Macular Degeneration Based on Genetic, Demographic, and Environmental Variables SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BODY-MASS INDEX; FACTOR-H POLYMORPHISM; RISK-FACTORS; VITAMIN-C; CIGARETTE-SMOKING; VARIANT; DIETARY; SUSCEPTIBILITY; ASSOCIATION; CFH AB PURPOSE. The joint effects of genetic, ocular, and environmental variables were evaluated and predictive models for prevalence and incidence of AMD were assessed. METHODS. Participants in the multicenter Age-Related Eye Disease Study (AREDS) were included in a prospective evaluation of 1446 individuals, of which 279 progressed to advanced AMD (geographic atrophy or neovascular disease) and 1167 did not progress during 6.3 years of follow-up. For prevalent AMD, 509 advanced cases were compared with 222 controls. Covariates for the incidence analysis included age, sex, education, smoking, body mass index (BMI), baseline AMD grade, and the AREDS vitamin-mineral treatment assignment. DNA specimens were evaluated for six variants in five genes related to AMD. Unconditional logistic regression analyses were performed for prevalent and incident advanced AMD. An algorithm was developed and receiver operating characteristic curves and C statistics were calculated to assess the predictive ability of risk scores to discriminate progressors from nonprogressors. RESULTS. All genetic polymorphisms were independently related to prevalence of advanced AMD, controlling for genetic factors, smoking, BMI, and AREDS treatment. Multivariate odds ratios (ORs) were 3.5 (95% confidence interval [CI], 1.7-7.1) for CFH Y402H; 3.7 (95% CI, 1.6-8.4) for CFH rs1410996; 25.4 (95% CI, 8.6-75.1) for LOC387715 A69S (ARMS2); 0.3 (95% CI, 0.1-0.7) for C2 E318D; 0.3 (95% CI, 0.1-0.5) for CFB; and 3.6 (95% CI, 1.4-9.4) for C3 R102G, comparing the homozygous risk/protective genotypes to the referent genotypes. For incident AMD, all these variants except CFB were significantly related to progression to advanced AMD, after controlling for baseline AMD grade and other factors, with ORs from 1.8 to 4.0 for presence of two risk alleles and 0.4 for the protective allele. An interaction was seen between CFH402H and treatment, after controlling for all genotypes. Smoking was independently related to AMD, with a multiplicative joint effect with genotype on AMD risk. The C statistic for the full model with all variables was 0.831 for progression to advanced AMD. CONCLUSIONS. Factors reflective of nature and nurture are independently related to prevalence and incidence of advanced AMD, with excellent predictive power. (Invest Ophthalmol Vis Sci. 2009;50:2044-2053) DOI:10.1167/iovs.08-3064 C1 [Maller, Julian; Fagerness, Jesen A.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Maller, Julian; Fagerness, Jesen A.; Daly, Mark J.] Broad Inst Harvard, Program Med & Populat Genet, Boston, MA USA. [Maller, Julian; Fagerness, Jesen A.; Daly, Mark J.] MIT, Boston, MA USA. [Rosner, Bernard] Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. [Seddon, Johanna M.] Tufts Univ, Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, New England Eye Ctr,Sch Med, Boston, MA 02111 USA. RP Seddon, JM (reprint author), Tufts Univ, Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, New England Eye Ctr,Sch Med, 800 Washington St 450, Boston, MA 02111 USA. EM jseddon@tuftsmedicalcenter.org OI Maller, Julian/0000-0002-1565-9559 FU National Institutes of Health (NIH) National Eye Institute [R01-EY11309]; Foundation Fighting Blindness, Owing Mills, MD; Age-Related Macular Degeneration Research Fund; Ophthalmic Epidemiology and Genetics Service; Tufts Medical Center; Tufts University School of Medicine; Massachusetts Lions Eye Research Fund Inc., Northboro, MA; National Center for Research Resources to the Broad Institute Center for Genotyping and Analysis [U54 RR020278]; Research to Prevent Blindness Inc., New York, NY FX Supported by Grant R01-EY11309 from the National Institutes of Health (NIH) National Eye Institute; the Foundation Fighting Blindness, Owing Mills, MD; the Age-Related Macular Degeneration Research Fund, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Tufts University School of Medicine; the Massachusetts Lions Eye Research Fund Inc., Northboro, MA; Grant U54 RR020278 from the National Center for Research Resources to the Broad Institute Center for Genotyping and Analysis; and unrestricted grants from Research to Prevent Blindness Inc., New York, NY. NR 38 TC 165 Z9 172 U1 2 U2 20 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2009 VL 50 IS 5 BP 2044 EP 2053 DI 10.1167/iovs.08-3064 PG 10 WC Ophthalmology SC Ophthalmology GA 436YC UT WOS:000265451000011 PM 19117936 ER PT J AU Mavandadi, S Zanjani, F Ten Have, TR Oslin, DW AF Mavandadi, Shahrzad Zanjani, Faika Ten Have, Thomas R. Oslin, David W. TI Psychological Well-Being Among Individuals Aging With HIV: The Value of Social Relationships SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 01-04, 2007 CL New Orleans, LA SP Amer Assoc Geriat Psychiat DE aging; depressive symptoms; HIV positive; positive affect; social support ID HUMAN-IMMUNODEFICIENCY-VIRUS; QUALITY-OF-LIFE; DEPRESSIVE SYMPTOMS; SOCIOEMOTIONAL SELECTIVITY; ECONOMIC CIRCUMSTANCES; OLDER-ADULTS; HEALTH-CARE; SHORT-FORM; SUPPORT; AGE AB Objective: Utilizing a heterogenous sample of adults diagnosed with HIV infection, the current study sought to explore associations among age, various dimensions of social support, and psychological and functional well-being. Methods: Cross-sectional data capturing subjective and instrumental support, social interaction, behavioral health service utilization, and psychological well-being (ie, positive affect and depressive symptomatology), and physical functioning, wet e collected from 109 men and women living with HIV To explore a;e group differences, participants were stratified by age (<54 vs. 55- years). Results: Despite endorsing greater medical comorbidity, older adults reported significantly lower depressive symptomatology and greater positive affect and were less likely to report seeing a behavioral health specialist than their younger counterparts. No age group differences emerged for instrumental support or amount of social interaction. However, older adults reported higher subjective Support, which in turn was associated with lower depressive symptomatology, greater positive affect, and nonutilization of behavioral health services. Conclusions: More attention should be paid to the social environment of individuals diagnosed with HIV as tic quality of social relationships may be particularly important for successful psychological adaptation to HIV C1 [Mavandadi, Shahrzad; Oslin, David W.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA 19104 USA. [Zanjani, Faika] Univ Kentucky, Dept Gerontol, Lexington, KY USA. [Ten Have, Thomas R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Oslin, David W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Mavandadi, S (reprint author), Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, 3900 Woodland Ave,116A, Philadelphia, PA 19104 USA. EM shahrzad.mavandadi@va.gov FU NIAID NIH HHS [P30 AI045008, P30 AI045008-10, 5P30AI045008]; NIMH NIH HHS [P30 MH066270-05] NR 54 TC 22 Z9 22 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAY 1 PY 2009 VL 51 IS 1 BP 91 EP 98 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 438WD UT WOS:000265585800014 PM 19282781 ER PT J AU Hayashi, A Naseri, A Pennesi, ME de Juan, E AF Hayashi, Atsushi Naseri, Ayman Pennesi, Mark E. de Juan, Eugene, Jr. TI Subretinal delivery of immunoglobulin G with gold nanoparticles in the rabbit eye SO JAPANESE JOURNAL OF OPHTHALMOLOGY LA English DT Article DE IgG; gold nanoparticle; rabbit; retina; subretinal delivery ID NANOGOLD; CANCER; CELLS; TIME AB To examine the feasibility of subretinal delivery of immunoglobulin G (IgG) adsorbed onto gold nanoparticles (GNPs) and its histologic distribution in the rabbit retina after the injection. Goat IgG was adsorbed onto GNPs electrostatically. Goat IgG-adsorbed GNPs or buffer with goat IgG was injected into the subretinal space of rabbit eyes and followed up for 3 months by examination of fundus photographs, immunohistochemistry against goat IgG, and transmission electron microscopy (TEM). Human retinal pigment epithelial cells (ARPE-19 cells) were cultured, and cell proliferation with or without GNPs was assayed. At 1 week after the subretinal injection of goat IgG-adsorbed GNPs, retinal degeneration was observed in the outer retina, and goat IgG was immunolabeled in the retinal pigment epithelium (RPE) and the photoreceptor cells. TEM showed GNPs located in the outer segments and in the lysosomes in the RPE at 1 month and no apparent cytotoxicity of the RPE. There were no inhibitory effects of GNPs on proliferation of ARPE-19 cells. Goat IgG was successfully delivered into photoreceptor cells and RPE using GNPs, though retinal degeneration in the outer retina occurred in this model. This might be an alternative drug delivery method to photoreceptors and RPE. C1 [Hayashi, Atsushi; Naseri, Ayman; Pennesi, Mark E.; de Juan, Eugene, Jr.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Naseri, Ayman] San Francisco VA Med Ctr, Dept Ophthalmol, San Francisco, CA USA. RP Hayashi, A (reprint author), Toyama Univ, Dept Ophthalmol, 2630 Sugitani, Toyama 9300194, Japan. EM ganka@med.u-toyama.ac.jp NR 18 TC 14 Z9 14 U1 0 U2 7 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0021-5155 J9 JPN J OPHTHALMOL JI Jpn. J. Ophthalmol. PD MAY PY 2009 VL 53 IS 3 BP 249 EP 256 DI 10.1007/s10384-009-0655-x PG 8 WC Ophthalmology SC Ophthalmology GA 451ZS UT WOS:000266510000011 PM 19484444 ER PT J AU Sitnikova, T Goff, D Kuperberg, GR AF Sitnikova, Tatiana Goff, Donald Kuperberg, Gina R. TI Neurocognitive Abnormalities During Comprehension of Real-World Goal-Directed Behaviors in Schizophrenia SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Review DE schizophrenia; ERPs; real-world knowledge; comprehension of goal-directed actions; behavior abnormalities ID EVENT-RELATED POTENTIALS; PSYCHIATRIC RATING-SCALE; PREFRONTAL CORTEX DYSFUNCTION; CONTEXT-PROCESSING DEFICITS; NEGATIVE SYMPTOMS; BRAIN POTENTIALS; WORKING-MEMORY; SENTENCE COMPREHENSION; CLINICAL SYMPTOMS; NEURAL MECHANISMS AB Origins of impaired adaptive functioning in schizophrenia remain poorly understood. Behavioral disorganization may arise from an abnormal reliance on common combinations between concepts stored in semantic memory. Avolition-apathy may be related to deficits in using goal-related requirements to flexibly plan behavior. The authors recorded event-related potentials (ERPs) in 16 patients with medicated schizophrenia and 16 healthy controls in a novel video paradigm presenting congruous or incongruous objects in real-world activities. All incongruous objects were contextually inappropriate, but the incongruous scenes varied in comprehensibility. Psychopathology was assessed with the Scales for the Assessment of Positive and Negative Symptoms (SAPS/SANS) and the Brief Psychiatric Rating Scale. In patients, an N400 ERP, thought to index activity in semantic memory, was abnormally enhanced to less comprehensible incongruous scenes, and larger N400 priming was associated with disorganization severity. A P600 ERP, which may index flexible object-action integration based on goal-related requirements, was abnormally attenuated in patients, and its smaller magnitude was associated with the SANS rating of impersistence at work or school (goal-directed behavior). Thus, distinct neurocognitive abnormalities may underlie disorganization and goal-directed behavior deficits in schizophrenia. C1 [Sitnikova, Tatiana] Massachusetts Gen Hosp, AthinoulaA Martinos Ctr Biomed Imaging, Dept Psychiat, Charlestown, MA 02129 USA. [Kuperberg, Gina R.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Sitnikova, Tatiana] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Sch Med, Charlestown, MA 02129 USA. RP Sitnikova, T (reprint author), Massachusetts Gen Hosp, AthinoulaA Martinos Ctr Biomed Imaging, Dept Psychiat, Bldg 149 2301,13th St, Charlestown, MA 02129 USA. EM tatiana@nmr.mgh.harvard.edu FU NIMH NIH HHS [K23 MH002034, K23 MH002034-05, MH02034, MH071635, R01 MH071635, R01 MH071635-01A1, R01 MH071635-02] NR 177 TC 13 Z9 14 U1 3 U2 8 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD MAY PY 2009 VL 118 IS 2 BP 256 EP 277 DI 10.1037/a0015619 PG 22 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 443EP UT WOS:000265893300002 PM 19413402 ER PT J AU Wojnar, M Ilgen, MA Czyz, E Strobbe, S Klimkiewicz, A Jakubczyk, A Glass, J Brower, KJ AF Wojnar, Marcin Ilgen, Mark A. Czyz, Ewa Strobbe, Stephen Klimkiewicz, Anna Jakubczyk, Andrzej Glass, Jennifer Brower, Kirk J. TI Impulsive and non-impulsive suicide attempts in patients treated for alcohol dependence SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Suicide; Attempt; Alcohol dependence; Impulsive behavior; Poland ID USE-DISORDER TREATMENT; ILLICIT DRUG-USE; RISK-FACTORS; PERSONALITY-DISORDER; INHIBITORY CONTROL; HISTORY; AGGRESSION; BEHAVIOR; INDIVIDUALS; ADOLESCENCE AB Background: Suicidal behavior has been recognized as an increasing problem among alcohol-dependent subjects. The aim of the study was to identify correlates of impulsive and non-impulsive suicide attempts among a treated population of alcohol-dependent patients. Methods: A total of 154 patients with alcohol dependence consecutively admitted for addiction treatment participated in the study. Suicidal behavior was assessed together with severity of alcohol dependence, childhood abuse, impulsivity, and family history. A stop-signal procedure was used as a behavioral measure of impulsivity. Results and conclusions: Lifetime suicide attempts were reported by 43% of patients in alcohol treatment; of which 62% were impulsive. Compared to patients without a suicide attempt, those with a non-impulsive attempt were more likely to have a history of sexual abuse (OR=7.17), a family history of suicide (OR=4.09), and higher scores on a personality measure of impulsiveness (OR=2.27). The only significant factor that distinguished patients with impulsive suicide attempts from patients without a suicide attempt and from patients with a non-impulsive suicide attempt was a higher level of behavioral impulsivity (OR=1.84-2.42). Limitations: Retrospective self-report of suicide attempts and family history. Lack of diagnostic measure. (C) 2008 Elsevier B.V. All rights reserved. C1 [Wojnar, Marcin] Univ Michigan, Addict Res Ctr, Dept Psychiat, Ann Arbor, MI 48109 USA. [Wojnar, Marcin; Klimkiewicz, Anna; Jakubczyk, Andrzej] Med Univ Warsaw, Dept Psychiat, Warsaw, Poland. [Ilgen, Mark A.] US Dept Vet Affairs, Hlth Serv Res & Dev, Ann Arbor, MI USA. [Glass, Jennifer] Univ Michigan, Inst Social Res, Ann Arbor, MI 48109 USA. RP Wojnar, M (reprint author), Univ Michigan, Addict Res Ctr, Dept Psychiat, Rachel Upjohn Bldg,4250 Plymouth Rd, Ann Arbor, MI 48109 USA. EM mwojnar@umich.edu FU Fogarty International Center/NIDA International Substance Abuse Research Program [D43 TW05818]; Fogarty International Center/NLAAA International Collaborative Alcohol & Injury Research Training Program [D43 TW007569]; NIAAA [R21 AA016104]; Polish Ministry of Science and Higher Education [2P05D 004 29] FX Authors have not signed an agreement with any sponsor of the study reported in this paper that has a clause which prevents them from publishing both positive and negative results, from collaborating with other investigators to pool data across sites, or that forbids them from publishing without the approval of the sponsor. The views expressed in this report are those of the authors and do not necessarily represent those of the Supporting agencies. The supporting agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 58 TC 39 Z9 41 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY PY 2009 VL 115 IS 1-2 BP 131 EP 139 DI 10.1016/j.jad.2008.09.001 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 435CC UT WOS:000265319900015 PM 18835498 ER PT J AU Meeker, JD Calafat, AM Hauser, R AF Meeker, John D. Calafat, Antonia M. Hauser, Russ TI Urinary Metabolites of Di(2-ethylhexyl) Phthalate Are Associated With Decreased Steroid Hormone Levels in Adult Men SO JOURNAL OF ANDROLOGY LA English DT Article DE Androgen; biomarker; endocrine; environment; human; estrogen; male reproduction; testosterone ID MALE REPRODUCTIVE-SYSTEM; RAT GRANULOSA-CELLS; MONO-(2-ETHYLHEXYL) PHTHALATE; QUANTITATIVE DETECTION; OXIDATIVE METABOLITES; TEMPORAL VARIABILITY; ESTRADIOL PRODUCTION; MALE-INFERTILITY; DNA-DAMAGE; IN-UTERO AB Experimental animal studies have demonstrated that exposure to some phthalates may be associated with altered endocrine function and adverse effects on male reproductive development and function, but human studies are limited. In the present study, urine and serum samples were collected from 425 men recruited through a US infertility clinic. Urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites were measured, along with serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle-stimulating hormone, luteinizing hormone, inhibin B, and prolactin. Two oxidized urinary metabolites of DEHP were also measured in urine from 221 of the men. In multiple regression models adjusted for potential confounders, MEHP was inversely associated with testosterone, estradiol, and free androgen index (FAI). An interquartile range increase in MEHP was associated with 3.7% (95% confidence interval [CI], -6.8% to -0.5%) and 6.8% (95% Cl, -11.2% to -2.4%) declines in testosterone and estradiol, respectively, relative to the population median hormone levels. There was limited evidence for effect modification of the inverse association between MEHP and FAI by the proportion of DEHP metabolites in the urine measured as MEHP (MEHP%), which is considered a phenotypic marker of less efficient metabolism of DEHP to its oxidized metabolites. Finally, the ratio of testosterone to estradiol was positively associated with MEHP (P = .07) and MEHP% (P = .007), suggesting potential relationships with aromatase suppression. In conclusion, these results suggest that urinary metabolites of DEHP are inversely associated with circulating steroid hormone levels in adult men. However, additional research is needed to confirm these findings. C1 [Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 6635 SPH Tower,109 S Observ St, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Meeker, John/0000-0001-8357-5085 FU National Institute of Environmental Health Sciences (NIEHS) [ES009718, ES00002]; National Institutes of Health (NIH) FX Supported by grants ES009718 and ES00002 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). NR 51 TC 90 Z9 91 U1 0 U2 8 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD MAY-JUN PY 2009 VL 30 IS 3 BP 287 EP 297 DI 10.2164/jandrol.108.006403 PG 11 WC Andrology SC Endocrinology & Metabolism GA 439IO UT WOS:000265621000011 PM 19059903 ER PT J AU Luga, A Lerner, E Shedd, TR van der Schalie, WH AF Luga, Aurel Lerner, Ethan Shedd, Tommy R. van der Schalie, William H. TI Rapid responses of a melanophore cell line to chemical contaminants in water SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Xenopus laevis; melanophore; chromatophore; toxicity; sensor; drinking water ID TOXICITY AB We have evaluated a Xenopus cell line as a potential sensor for detecting toxins in water. X. laevis melanophores responded rapidly by dispersing melanosomes following exposure to six (ammonia, arsenic, copper, mercury, pentachlorophenol and phenol) of 12 tested chemicals in the desired sensitivity range. For two additional chemicals (nicotine and paraquat) the melanophore response improved upon the response capabilities of several available toxicity sensors. These results suggest that a melanophore-based sensor could be useful for the rapid assessment of chemical toxicity in drinking water. Published 2009 by John Wiley and Sons, Ltd. C1 [Shedd, Tommy R.; van der Schalie, William H.] USA, Ctr Environm Hlth Res, Ft Detrick, MD 21702 USA. [Luga, Aurel; Lerner, Ethan] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Shedd, TR (reprint author), USA, Ctr Environm Hlth Res, 568 Doughten Dr, Ft Detrick, MD 21702 USA. EM Tommy.Shedd@us.army.mil FU US Army Medical Research and Materiel Command; National Institutes of Health [SU01AI061420] FX We thank Bill Dennis and Alan Rosencrance for analytical chemistry and sample preparation support that was critical to the success of the effort. Elgin Perry provided the statistical analysis. The views, opinions and/or findings contained in this short communication are those of the authors and should not be construed as official Department of the Army position, policy or decision, unless so designated by other official documentation. Citations of commercial organizations or trade names in this paper do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations. This work was supported by the US Army Medical Research and Materiel Command and by the National Institutes of Health (grant no. SU01AI061420). NR 15 TC 3 Z9 3 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0260-437X J9 J APPL TOXICOL JI J. Appl. Toxicol. PD MAY PY 2009 VL 29 IS 4 BP 346 EP 349 DI 10.1002/jat.1416 PG 4 WC Toxicology SC Toxicology GA 451YU UT WOS:000266507600010 ER PT J AU Venkatesh, J Kawabata, D Kim, S Xu, XN Chinnasamy, P Paul, E Diamond, B Grimaldi, CM AF Venkatesh, Jeganathan Kawabata, Daisuke Kim, Sunjung Xu, Xiaonan Chinnasamy, Prameladevi Paul, Elahna Diamond, Betty Grimaldi, Christine M. TI Selective regulation of autoreactive B cells by Fc gamma RIIB SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Antibodies; Autoimmunity; Lupus; B cells; Fc receptor ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INTERFERON-INDUCIBLE GENE; AUTOIMMUNE-PRONE MICE; DENDRITIC CELLS; LIPID RAFTS; NEGATIVE SELECTION; IMMUNE-COMPLEXES; DEFICIENT MICE; DNA ANTIBODIES; UP-REGULATION AB Fc gamma RIIB is an inhibitory receptor which plays a role in limiting B cell and DC activation. Since Fc gamma RIIB is known to dampen the signaling strength of the BCR, vie wished to determine the impact of Fc gamma RIIB on the regulation of BCRs which differ in their affinity for DNA. For these studies, Fc gamma RIIB deficient BALB/c mice were bred with mice expressing the transgene-encoded H chain of the R4A anti-DNA antibody which gives rise to BCRs which express high, low or no affinity for DNA. The deletion of Fc gamma RIIB in R4A BALB/c mice led to an alteration in the B cell repertoire, allowing for the expansion and activation of high affinity DNA-reactive B cells. By 6-8 months of age, R4A x Fc gamma RIIB(-/-) BALB/c mice spontaneously developed anti-DNA antibody titers. These mice also displayed an induction of IFN-inducible genes and an elevation in levels of the B cell survival factor, BAFF. These data demonstrate that Fc gamma RIIB preferentially limits activation of high affinity autoreactive B cells and can influence the activation of DC through an immune complex-mediated mechanism. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Venkatesh, Jeganathan; Kawabata, Daisuke; Kim, Sunjung; Chinnasamy, Prameladevi; Diamond, Betty; Grimaldi, Christine M.] Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. [Xu, Xiaonan] Feinstein Inst Med Res, Ctr Oncol & Cell Biol, Manhasset, NY 11030 USA. [Paul, Elahna] Massachusetts Gen Hosp, Dept Pediat Nephrol, Boston, MA 02114 USA. RP Grimaldi, CM (reprint author), Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. EM cgrimaldi@nshs.edu FU NIAMS FX This work was supported by grants from NIAMS (BD and CMG). We wish to thank Alla Tashmukhamedova for technical assistance and Sylvia Jones for help with the preparation of this manuscript. NR 64 TC 16 Z9 18 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD MAY-JUN PY 2009 VL 32 IS 3-4 BP 149 EP 157 DI 10.1016/j.jaut.2009.02.009 PG 9 WC Immunology SC Immunology GA 451ZV UT WOS:000266510300001 PM 19327966 ER PT J AU Lee, DH Shi, JJ Jeoung, NH Kim, MS Zabolotny, JM Lee, SW White, MF Wei, L Kim, YB AF Lee, Dae Ho Shi, Jianjian Jeoung, Nam Ho Kim, Min Seon Zabolotny, Janice M. Lee, Sam W. White, Morris F. Wei, Lei Kim, Young-Bum TI Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING PROTEIN RHO; SERINE/THREONINE KINASE; PATHWAY; GTPASE; GLUT4; PHOSPHORYLATION; TRANSLOCATION; CYTOSKELETON; ADIPOCYTES; ACTIVATION AB Insulin signaling is essential for normal glucose homeostasis. Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. To investigate the physiological role of ROCK1 in the regulation of whole body glucose homeostasis and insulin sensitivity in vivo, we studied mice with global disruption of ROCK1. Here we show that, at 16 - 18 weeks of age, ROCK1-deficient mice exhibited insulin resistance, as revealed by the failure of blood glucose levels to decrease after insulin injection. However, glucose tolerance was normal in the absence of ROCK1. These effects were independent of changes in adiposity. Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. To determine the mechanism(s) by which deletion of ROCK1 causes insulin resistance, we measured the ability of insulin to activate phosphatidylinositol 3-kinase and multiple distal pathways in skeletal muscle. Insulin-stimulated phosphatidylinositol 3-kinase activity associated with IRS-1 or phospho-tyrosine was also reduced similar to 40% without any alteration in tyrosine phosphorylation of insulin receptor in skeletal muscle. Concurrently, serine phosphorylation of IRS-1 at serine 632/635, which is phosphorylated by ROCK in vitro, was also impaired in these mice. Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes. C1 [Shi, Jianjian; Wei, Lei] Indiana Univ, Sch Med, Wells Ctr Pediat Res, Riley Heart Res Ctr,Dept Pediat, Indianapolis, IN 46202 USA. [Lee, Dae Ho; Zabolotny, Janice M.; Kim, Young-Bum] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Lee, Dae Ho; Zabolotny, Janice M.; Kim, Young-Bum] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Jeoung, Nam Ho] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Jeoung, Nam Ho] Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. [Kim, Min Seon] Univ Ulsan, Coll Med, Asan Inst Life Sci, Dept Internal Med, Seoul 138736, South Korea. [Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [White, Morris F.] Childrens Hosp, Div Endocrinol, Howard Hughes Med Inst, Boston, MA 02115 USA. [White, Morris F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Wei, L (reprint author), Indiana Univ, Sch Med, Wells Ctr Pediat Res, Riley Heart Res Ctr,Dept Pediat, 1044 W Walnut St,R4-370, Indianapolis, IN 46202 USA. EM lewei@iupui.edu; ykim2@bidmc.harvard.edu OI Jeoung, Nam Ho/0000-0002-7584-3761 FU National Institutes of Health [DK43051, DK38712, CA127247, HL072897, HL085098]; American Diabetes Association [7-05-PPG-02, 1-09-RA-87]; Showalter Trust [89829]; Korean Ministry of Health and Welfare Grant [A06-2363]; Korea Science and Engineering Foundation [R-01-2006-000-108060-0] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK43051 (to Y.B.K.), DK38712 (to M. F. W.), CA127247 (to S. W. L.), and HL072897 and HL085098 (to L. W.). This work was also supported by American Diabetes Association Grants 7-05-PPG-02 and 1-09-RA-87 (to Y.B.K.), Showalter Trust Grant 89829 (to J.S.), Korean Ministry of Health and Welfare Grant A06-2363 (to M. S. K.), and Korea Science and Engineering Foundation Grant R-01-2006-000-108060-0 (to M. S. K.). NR 34 TC 58 Z9 62 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 1 PY 2009 VL 284 IS 18 BP 11776 EP 11780 DI 10.1074/jbc.C900014200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NQ UT WOS:000265494600009 PM 19276091 ER PT J AU Cogan, SF Ehrlich, J Plante, TD Smirnov, A Shire, DB Gingerich, M Rizzo, JF AF Cogan, Stuart F. Ehrlich, Julia Plante, Timothy D. Smirnov, Anton Shire, Douglas B. Gingerich, Marcus Rizzo, Joseph F. TI Sputtered Iridium Oxide Films for Neural Stimulation Electrodes SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE neural stimulation; neural recording; microelectrode; iridium oxide; sputtering ID CHARGE-INJECTION LIMITS; ELECTRICAL-STIMULATION; INTRACORTICAL MICROSTIMULATION; MICROELECTRODE ARRAYS; PERCEPTUAL THRESHOLDS; RETINAL PROSTHESIS; MORPHOLOGY; CAPACITY; PULSES; SALINE AB Sputtered iridium (oxide films (SIROFs) deposited by DC reactive sputtering from an iridium metal target have been characterized in vitro for their potential as neural recording and stimulation electrodes. SIROFs were deposited over gold metallization oil flexible multielectrode arrays fabricated oil thin (15 mu m) polyimide substrates. SIROF thickness and electrode areas of 200-1300 nm and 1960-125,600 mu m(2), respectively, were investigated. The charge-injection capacities of the SIROFs were evaluated in an inorganic interstitial fluid model in response to charge-balanced, cathodal-first current pulses. Charge injection capacities were measured as a function of cathodal pulse width (0.2-1 ins) and potential bias in the interpulse period (0.0 to 0.7 V vs. Ag/AgCl). Depending on the pulse parameters and electrode area, charge-injection capacities ranged from 1-9 mC/cm(2), comparable with activated iridium oxide films (AIROFs) pulsed under similar conditions. Other parameters relevant to the use of SIROF oil nerve electrodes, including the thickness dependence of impedance (0.05-10(5) Hz) and the current necessary to maintain a bias in the interpulse region were also determined. (C) 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 89B: 353-361, 2009 C1 [Cogan, Stuart F.; Ehrlich, Julia; Plante, Timothy D.; Smirnov, Anton] EIC Labs, Norwood, MA 02062 USA. [Shire, Douglas B.; Gingerich, Marcus] Cornell Univ, Dept Vet Affairs, Ctr Innovat Visual Rehabil, Ithaca, NY 14853 USA. [Shire, Douglas B.; Gingerich, Marcus] Cornell Univ, Cornell NanoScale Sci & Technol Facil, Ithaca, NY 14853 USA. [Rizzo, Joseph F.] Ctr Innovat Visual Rehabil, Dept Vet Affairs, Boston, MA 02062 USA. [Rizzo, Joseph F.] Massachusetts Eye & Ear Infirm, Boston, MA 02062 USA. RP Cogan, SF (reprint author), EIC Labs, Norwood, MA 02062 USA. EM scogan@eiclabs.com FU National Institutes of Health [C4266-C, 5R44HL071395] FX Contract grant sponsor: Department of Veterans Affairs: Rehabilitation Research and Development service: National Institutes of Health; Contract grant numbers: C4266-C, 5R44HL071395 NR 38 TC 50 Z9 50 U1 2 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD MAY PY 2009 VL 89B IS 2 BP 353 EP 361 DI 10.1002/jbm.b.31223 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 436VU UT WOS:000265445000010 PM 18837458 ER PT J AU Hernandez-Montes, MDS Furlong, C Rosowski, JJ Hulli, N Harrington, E Cheng, JT Ravicz, ME Santoyo, FM AF del Socorro Hernandez-Montes, Maria Furlong, Cosme Rosowski, John J. Hulli, Nesim Harrington, Ellery Cheng, Jeffrey Tao Ravicz, Michael E. Mendoza Santoyo, Fernando TI Optoelectronic holographic otoscope for measurement of nano-displacements in tympanic membranes SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE tympanic membrane; optoelectronic holography; interferometry; otoscope ID HUMAN MIDDLE-EAR; TIME-AVERAGED HOLOGRAPHY; FINITE-ELEMENT METHOD; DYNAMIC-BEHAVIOR; VIBRATION MEASUREMENT; CAT EARDRUM; INTERFEROMETRY; TYMPANOMETRY; ADULTS; MODEL AB Current methodologies for characterizing tympanic membrane (TM) motion are usually limited to either average acoustic estimates (admittance or reflectance) or single-point mobility measurements, neither of which suffices to characterize the detailed mechanical response of the TM to sound. Furthermore, while acoustic and single-point measurements may aid in diagnosing some middle-ear disorders, they are not always useful. Measurements of the motion of the entire TM surface can provide more information than these other techniques and may be superior for diagnosing pathology. We present advances in our development of a new compact optoelectronic holographic otoscope (OEHO) system for full field-of-view characterization of nanometer-scale sound-induced displacements of the TM surface at video rates. The OEHO system consists of a fiber optic subsystem, a compact otoscope head, and a high-speed image processing computer with advanced software for recording and processing holographic images coupled to a computer-controlled sound-stimulation and recording system. A prototype OEHO system is in use in a medical research environment to address basic science questions regarding TM function. The prototype provides real-time observation of sound-induced TM displacement patterns over a broad frequency range. Representative time-averaged and stroboscopic holographic interferometry results in animals and human cadaver samples are shown, and their potential utility is discussed. (C) 2009 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3153898] C1 [del Socorro Hernandez-Montes, Maria; Hulli, Nesim; Harrington, Ellery] Worcester Polytech Inst, Dept Mech Engn, Worcester, MA USA. [Furlong, Cosme] Worcester Polytech Inst, Ctr Holog Studies & Laser MicromechaTron, Worcester, MA USA. [del Socorro Hernandez-Montes, Maria; Mendoza Santoyo, Fernando] Ctr Invest Opt AC, Guanajuato 37150, Mexico. [Furlong, Cosme; Rosowski, John J.; Cheng, Jeffrey Tao; Ravicz, Michael E.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Furlong, Cosme; Rosowski, John J.] MIT, Harvard Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. [Rosowski, John J.; Cheng, Jeffrey Tao; Ravicz, Michael E.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Hernandez-Montes, MDS (reprint author), AC Metrol, Ctr Invest Opt, Loma Bosque 115, Guanajuato 37150, Mexico. EM mhernandez@cio.mx OI Mendoza-Santoyo, Fernando/0000-0002-4596-3316 FU U. S. National Institute for Deafness and other Communicative Disorders (NIDCD); Worcester Polytechnic Institute (WPI); Centro de Investigaciones en Optica; Massachusetts Eye and Ear Infirmary (MEEI); Lakshmi Mittal FX This research was supported by the U. S. National Institute for Deafness and other Communicative Disorders (NIDCD), Worcester Polytechnic Institute (WPI), Centro de Investigaciones en Optica, A. C. (CIO), Massachusetts Eye and Ear Infirmary (MEEI), and Lakshmi Mittal. We thank Chris Scarpino of the MEEI, an alumni of WPI, for facilitating the interactions between our two research groups. Thanks also go to Christian Wester, Benjamin Dwyer, and Marty Maccaferri for their contributions to this work. NR 39 TC 27 Z9 27 U1 2 U2 5 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAY-JUN PY 2009 VL 14 IS 3 AR 034023 DI 10.1117/1.3153898 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 477RN UT WOS:000268536300032 PM 19566316 ER PT J AU Deliolanis, NC Dunham, J Wurdinger, T Figueiredo, JL Tannous, BA Ntziachristos, V AF Deliolanis, Nikolaos C. Dunham, Joshua Wurdinger, Thomas Figueiredo, Jose-Luiz Bakhos A., Tannous Ntziachristos, Vasilis TI In-vivo imaging of murine tumors using complete-angle projection fluorescence molecular tomography SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE fluorescence; tomography; in vivo; molecular imaging; cancer; tumor; fluorescent proteins ID DIFFUSE OPTICAL TOMOGRAPHY; BREAST-CANCER; RECONSTRUCTION AB We interrogate the ability of free-space fluorescence tomography to image small animals in vivo using charge-coupled device (CCD) camera measurements over 360-deg noncontact projections. We demonstrate the performance of normalized dual-wavelength measurements that are essential for in-vivo use, as they account for the heterogeneous distribution of photons in tissue. In-vivo imaging is then showcased on mouse lung and brain tumors cross-validated by x-ray microcomputed tomography and histology. (C) 2009 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3149854] C1 [Deliolanis, Nikolaos C.; Ntziachristos, Vasilis] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, D-85764 Neuherberg, Germany. [Deliolanis, Nikolaos C.; Dunham, Joshua; Wurdinger, Thomas; Figueiredo, Jose-Luiz; Bakhos A., Tannous; Ntziachristos, Vasilis] Harvard Univ, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Wurdinger, Thomas; Bakhos A., Tannous] Harvard Univ, Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. RP Deliolanis, NC (reprint author), Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany. EM n.deliolanis@helmholtz-muenchen.de OI Deliolanis, Nikolaos/0000-0002-6392-3035 FU Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme; National Institutes of Health [RO1 EB004382-01, RO1 EB000750-01, R43-ES012360] FX The authors would like to thank Tobias Lasser and Damon Hyde for helpful discussions. This research was supported by a Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme, and by National Institutes of Health grants RO1 EB004382-01, RO1 EB000750-01, and R43-ES012360. NR 14 TC 27 Z9 28 U1 0 U2 5 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAY-JUN PY 2009 VL 14 IS 3 AR 030509 DI 10.1117/1.3149854 PG 3 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 477RN UT WOS:000268536300006 PM 19566290 ER PT J AU Wu, JY Scadden, DT Kronenberg, HM AF Wu, Joy Y. Scadden, David T. Kronenberg, Henry M. TI Role of the Osteoblast Lineage in the Bone Marrow Hematopoietic Niches SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article ID STEM-CELL NICHE; PROGENITOR CELLS; SELF-RENEWAL; IN-VIVO; DIFFERENTIATION; MICROENVIRONMENT; MICE; RECEPTOR; GENE; QUIESCENCE C1 [Wu, Joy Y.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. EM hkronenberg@partners.org FU NIH [AR053781, AR054741, HL081030, DK117940] FX The authors thank Drs. Cristina Lo Celso, Louise Purton, and Sean Wu for thoughtful comments on this manuscript. This work was supported by NIH Grants AR053781 and AR054741 (to J.Y.W.), HL081030 (to H.M.K. and D.T.S.), and DK117940 (to H.M.K.). NR 75 TC 58 Z9 60 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2009 VL 24 IS 5 BP 759 EP 764 DI 10.1359/JBMR.090225 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 438IV UT WOS:000265550000001 PM 19257832 ER PT J AU Wu, HP Xu, GL Li, YP AF Wu, Haiping Xu, Guoliang Li, Yi-Ping TI Atp6v0d2 Is an Essential Component of the Osteoclast-Specific Proton Pump That Mediates Extracellular Acidification in Bone Resorption SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE Atp6v0d2; vacuolar-ATPases; osteoclasts; bone resorption; extracellular acidification ID VACUOLAR H+-ATPASE; V-ATPASE; TRANSLOCATING ATPASE; D-SUBUNIT; C-SUBUNIT; STIMULATING FACTOR; MOLECULAR-CLONING; GENE-EXPRESSION; A3 ISOFORM; DIFFERENTIATION AB Bone resorption relies on the extracellular acidification function of vacuolar (V-) ATPase proton pump(s) present in the plasma membrane of osteoclasts. The exact configuration of osteoclast-specific V-ATPases remains largely unknown. In this study, we found that Atp6v0d2 (d2), an isoform of the d subunit in the V-ATPase, showed 5-fold higher expression than that of Atp6v0d1. (d1) in mature osteoclasts, indicating a potential function in osteoclastic bone resorption. When d2 was depleted at an earl), stage of RANKL-induced osteoclast differentiation in vitro, formation of multinucleated cells was severely impaired. However, depletion of d2 at a late differentiation stage did not affect osteoclast fusion but did abolish the activity of extracellular acidification and bone resorption of mature osteoclasts. We also showed the association of the two tagged-proteins d2 and a3 when co-expressed in mammalian cells with a co-immunoprecipitation assay. Moreover, glutathione-S-transferase (GST) pull-down assay showed the direct interaction of d2 with the N terminus of Atp6v0a3 (0), which is the functionally identified osteoclast-specific component of V-ATPase. Therefore, our results show the dual function of d2 as a regulator of cell fusion in osteoclast differentiation and as an essential component of the osteoclast-specific proton pump that mediates extracellular acidification in bone resorption. C1 [Li, Yi-Ping] Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. [Li, Yi-Ping] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Wu, Haiping] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China. [Wu, Haiping; Xu, Guoliang] Chinese Acad Sci, Grad Sch, Shanghai, Peoples R China. RP Li, YP (reprint author), Forsyth Inst, Dept Cytokine Biol, 140 Fenway, Boston, MA 02115 USA. EM ypli@forsyth.org FU China National Science Foundation; Ministry of Science and Technology of China [2005CB522400]; Shanghai Municipal Commission for Science and Technology,; Max-Planck-Gesellschaft zur Forderung der Wissenschaften; NIH [AR-44741] FX We thank Christie Taylor and Carrie Soltanoff for manuscript assistance; Dr. Shengmei Feng and Dr. Wei Chen for critical discussion and technical assistance of this work; Dr. Jiuhong Kang (Institute of Biochemistry and Cell Biology, Chinese Academy of Science, Shanghai, China) for kindly providing the lentivirus vector and packaging plasmids; Yihui Tu for assistance of confocal microscopy and Aqin Li for SEM assistance. Work in G-L.X.'s laboratory is supported by grants from the China National Science Foundation, the Ministry of Science and Technology of China (National Basic Research Program 2005CB522400), the Shanghai Municipal Commission for Science and Technology, and the Max-Planck-Gesellschaft zur Forderung der Wissenschaften (the Max Planck Society for the Advancement of Science). The work in Y-P.L.'s laboratory is supported by NIH Grant AR-44741. NR 56 TC 45 Z9 50 U1 0 U2 5 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2009 VL 24 IS 5 BP 871 EP 885 DI 10.1359/JBMR.081239 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 438IV UT WOS:000265550000014 PM 19113919 ER PT J AU Goyal, S Gupta, P Ryan, CM Kazlas, M Noviski, N Sheridan, RL AF Goyal, Sunali Gupta, Punkaj Ryan, Colleen M. Kazlas, Melanie Noviski, Natan Sheridan, Robert L. TI Toxic Epidermal Necrolysis in Children: Medical, Surgical, and Ophthalmologic Considerations SO JOURNAL OF BURN CARE & RESEARCH LA English DT Review ID STEVENS-JOHNSON-SYNDROME; COLONY-STIMULATING FACTOR; DOSE INTRAVENOUS IMMUNOGLOBULINS; SCALDED SKIN SYNDROME; NECROSIS-FACTOR-ALPHA; CYTOTOXIC T-CELLS; ERYTHEMA MULTIFORME; BURN CENTER; PULMONARY COMPLICATIONS; FAS LIGAND AB Toxic epidermal necrolysis is a rare acute inflammatory multisystem life-threatening condition characterized by widespread epidermal necrosis and profound toxic systemic reaction. Implicated etiologic agents in children include drugs, infections, and autoimmune diseases. The pathophysiology includes separation of the epidermis at the dermal-epidermal junction of both skin and extracutaneous epithelium and mucous membranes. The general consensus is that expeditious transfer to a burn center, maintenance of fluid and electrolyte: balance, temperature maintenance, control of evaporative losses, avoidance of use of complicating drugs as corticosteroids and topical sulfa compounds, aggressive septic surveillance, vigorous nutritional support via nasoenteric tube, early ophthalmologic consultation, and appropriate wound care with a regimen of therapy relying on basic principles of treatment of partial-thickness epidermal wounds predict better outcome in the treatment of this disease process. The course of toxic epidermal necrolysis in children, even though dramatic at onset, leads to low mortality when managed appropriately. The current limited published evidence does not clearly delineate differences in epidemiology, pathogenesis, and prognosis of severe skin reactions in children as compared with adults. In this article, we review the available literature oil the pathogenesis, clinical features, pathophysiology, treatment, and complications of this rare disease in children. (J Burn Care Res 2009;30:437-449) C1 [Goyal, Sunali] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Schepens Eye Res Inst, Boston, MA USA. [Gupta, Punkaj; Noviski, Natan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Crit Care, Boston, MA USA. [Gupta, Punkaj; Noviski, Natan] Shriners Burns Hosp Childrens, Boston, MA USA. [Kazlas, Melanie] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Pediat Ophthalmol & Strabismus Serv, Boston, MA USA. RP Gupta, P (reprint author), 20 Staniford St, Boston, MA 02114 USA. NR 142 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD MAY-JUN PY 2009 VL 30 IS 3 BP 437 EP 449 DI 10.1097/BCR.0b013e3181a28c82 PG 13 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA 444BJ UT WOS:000265954600011 PM 19349890 ER PT J AU Jain, V Pineda, R AF Jain, Vandana Pineda, Roberto TI Reactivated herpetic keratitis following laser in situ keratomileusis SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID SIMPLEX-VIRUS KERATITIS; LASIK AB A 40-year-old woman presented with an unusual form of corneal herpetic reactivation 5 weeks after laser in situ keratomileusis. The cornea showed diffuse edema and a stromal ring infiltrate (disciform in appearance). Oral antiviral and topical steroids in tapered dosages were administered. The infiltrate disappeared within 6 weeks. Progressive improvement was also seen in all the parameters on Pentacam scans, including the pachymetry, keratometry readings, and elevation on the anterior float. Herpetic reactivation may occur in many forms after excimer laser ablation. Timely diagnosis and management is crucial to maintain good structural and visual outcomes. Pentacam analysis may serve as a useful adjunct in following the progression of herpetic reactivation cases. J Cataract Refract Surg 2009; 35.-946-948 (C) 2009 ASCRS and ESCRS C1 [Jain, Vandana; Pineda, Roberto] Massachusetts Eye & Ear Infirm, Dept Cornea, Boston, MA 02114 USA. [Jain, Vandana] Aditya Jyot Eye Hosp, Dept Cornea & External Dis, Bombay, Maharashtra, India. RP Pineda, R (reprint author), Massachusetts Eye & Ear Infirm, Dept Cornea, 243 Charles St, Boston, MA 02114 USA. EM Roberto_pineda@MEEI.harvard.edu NR 9 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD MAY PY 2009 VL 35 IS 5 BP 946 EP 948 DI 10.1016/j.jcrs.2008.11.065 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 445LY UT WOS:000266053500031 PM 19393899 ER PT J AU Cai, J Yi, FF Bian, ZY Shen, DF Yang, L Yan, L Tang, QZ Yang, XC Li, HL AF Cai, Jun Yi, Fang-Fang Bian, Zhou-Yan Shen, Di-Fei Yang, Long Yan, Ling Tang, Qi-Zhu Yang, Xin-Chun Li, Hongliang TI Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE crocetin; reactive oxygen species; cardiac remodelling; fibrosis; NF-kappa B; ERK1/2 ID ANGIOTENSIN-II; OXIDATIVE STRESS; PRESSURE-OVERLOAD; HEART-FAILURE; REDOX REGULATION; GENE-EXPRESSION; ATHEROSCLEROSIS; GATA4; RATS; NOREPINEPHRINE AB Oxidative stress plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. Because crocetin represses oxidative stress in vitro and in vivo, we have suggested that crocetin would repress cardiac hypertrophy by targeting oxidative stress-dependent signalling. We tested this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. The results showed that crocetin (1-10 mu M) dose-dependently blocked cardiac hypertrophy induced by angiogensin II (Ang II; 1 mu M) in vitro. Our data further revealed that crocetin (50 mg/kg/day) both prevented and reversed cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters and gene expression of hypertrophic markers. The inhibitory effect of crocetin on cardiac hypertrophy is mediated by blocking the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 (MEK/ERK1/2) pathway and GATA binding protein 4 (GATA-4) activation. Further investigation demonstrated that crocetin inhibited inflammation by blocking nuclear factor kappa B (NF-kappa B) signalling and attenuated fibrosis and collagen synthesis by abrogating MEK-ERK1/2 signalling. Overall, our results indicate that crocetin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis by suppression of ROS-dependent signalling pathways. C1 [Cai, Jun; Yi, Fang-Fang; Yang, Long; Yang, Xin-Chun] Capital Med Univ, Beijing Chaoyang Hosp, Dept Cardiol, Beijing 100020, Peoples R China. [Cai, Jun] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Cai, Jun] Harvard Univ, Sch Med, Boston, MA USA. [Bian, Zhou-Yan; Shen, Di-Fei; Yan, Ling; Tang, Qi-Zhu; Li, Hongliang] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430072, Peoples R China. [Bian, Zhou-Yan; Shen, Di-Fei; Yan, Ling; Tang, Qi-Zhu; Li, Hongliang] Wuhan Univ, Cardiovasc Res Inst, Wuhan 430072, Peoples R China. RP Yang, XC (reprint author), Capital Med Univ, Beijing Chaoyang Hosp, Dept Cardiol, 8 Baijiazhuang Rd, Beijing 100020, Peoples R China. EM yangxc@medmail.com.cn FU National Natural Science Foundation of China [30600337, 30770875] FX The authors thank Dr. Michael Raher (Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School) for review of the manuscript and helpful comments. This work was supported by grants from the National Natural Science Foundation of China (No. 30600337 and No. 30770875) to Dr. Yang Xin-Chun. NR 49 TC 28 Z9 32 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD MAY PY 2009 VL 13 IS 5 BP 909 EP 925 DI 10.1111/j.1582-4934.2008.00620.x PG 17 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 458AB UT WOS:000266980300008 PM 19413885 ER PT J AU Venugopal, B Mesires, NT Kennedy, JC Curcio-Morelli, C Laplante, JM Dice, JF Slaugenhaupt, SA AF Venugopal, Bhuvarahamurthy Mesires, Nicholas T. Kennedy, John C. Curcio-Morelli, Cyntia Laplante, Janice M. Dice, J. Fred Slaugenhaupt, Susan A. TI Chaperone-Mediated Autophagy is Defective in Mucolipidosis Type IV SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID RAT-LIVER LYSOSOMES; PROTEIN TRANSLOCATION; MEMBRANE-PROTEIN; PROTECTIVE PROTEIN; CATION CHANNEL; LATE ENDOSOMES; DEGRADATION; GENE; IDENTIFICATION; TRAFFICKING AB Mucolipidosis type IV (MLIV) is a lysosomal storage disorder caused by mutations in the MCOLN1 gene, a member of the transient receptor potential (TRP) cation channel gene family. The encoded protein, transient receptor potential mucolipin-1 (TRPML1), has been localized to lysosomes and late endosomes but the pathogenic mechanism by which loss of TRPML1 leads to abnormal cellular storage and neuronal cell death is still poorly understood. Yeast two-hybrid and co-immunoprecipitation (coIP) experiments identified interactions between TRPML1 and Hsc70 as well as TRPML1 and Hsp40. Hsc70 and Hsp40 are members of a molecular chaperone complex required for protein transport into the lysosome during chaperone-mediated autophagy (CMA). To determine the functional relevance of this interaction, we compared fibroblasts from MLIV patients to those from sex- and age-matched controls and show a defect in CMA in response to serum withdrawal. This defect in CMA was subsequently confirmed in purified lysosomes isolated from control and MLIV fibroblasts. We further show that the amount of lysosomal-associated membrane protein type 2A (LAMP-2A) is reduced in lysosomal membranes of MLIV fibroblasts. As a result of decreased CMA, MLIV fibroblasts have increased levels of oxidized proteins compared to control fibroblasts. We hypothesize that TRPML1 may act as a docking site for intralysosomal Hsc70 (Iy-Hsc70) allowing it to more efficiently pull in substrates for CMA. It is also possible that TRPML1 channel activity may be required for CMA. Understanding the role of TRPML1 in CMA will undoubtedly help to characterize the pathogenesis of MLIV. C1 [Venugopal, Bhuvarahamurthy; Kennedy, John C.; Curcio-Morelli, Cyntia; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Venugopal, Bhuvarahamurthy; Kennedy, John C.; Curcio-Morelli, Cyntia; Laplante, Janice M.; Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Boston, MA USA. [Mesires, Nicholas T.; Dice, J. Fred] Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. [Laplante, Janice M.] Brigham & Womens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. RP Slaugenhaupt, SA (reprint author), 185 Cambridge St, Boston, MA 02114 USA. EM slaugenhaupt@chgr.mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke [NS39995]; MLIV Foundation FX This study was supported by National Institute of Neurological Disorders and Stroke Grant NS39995 (S.A.S.) and the MLIV Foundation. NR 68 TC 51 Z9 57 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD MAY PY 2009 VL 219 IS 2 BP 344 EP 353 DI 10.1002/jcp.21676 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 425VO UT WOS:000264666000014 PM 19117012 ER PT J AU Luong, MX Tam, J Lin, Q Hagendoorn, J Moore, KJ Padera, TP Seed, B Fukumura, D Kucherlapati, R Jain, RK AF Luong, Mai X. Tam, Joshua Lin, Qingcong Hagendoorn, Jeroen Moore, Kathryn J. Padera, Timothy P. Seed, Brian Fukumura, Dai Kucherlapati, Raju Jain, Rakesh K. TI Lack of Lymphatic Vessel Phenotype in LYVE-1/CD44 Double Knockout Mice SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID HYALURONAN RECEPTOR LYVE-1; VASCULAR ENDOTHELIAL-CELLS; TUMOR-METASTASIS; GENE-EXPRESSION; PAW EDEMA; CD44; LYMPHANGIOGENESIS; INFLAMMATION; ANGIOGENESIS; MACROPHAGES AB Lymphatic vessels play a key role in maintaining tissue-fluid homeostasis, immune surveillance and metastasis. The hyaluronan receptor, LYVE-1, is widely used as a molecular marker for adult and embryonic lymphatic endothelium, but its physiological functions have not yet been established in vivo. In agreement with a recent report, LYVE-1(-/-) mice, which are healthy and fertile, do not display any defects related to congenital abnormalities of the lymphatic system. One hypothesis for the absence of a phenotype in LYVE-1 null mice is that other hyaluronan receptors, such as CD44, may compensate for LYVE-1. To test this hypothesis, we created LYVE-1/CD44 double knockout mice with appropriate littermate controls. Lymphatic vessel structure and function, as determined by histological methods and intravital microscopy, show that LYVE-1(-/-), CD44(-/-) and LYVE-1(-/-)/CD44(-/-) mice are indistinguishable from wild-type mice under normal conditions. Furthermore, resolution of carrageenan-induced paw edema is comparable in all genotypes. However, LYVE-1(-/-)/CD44-/- mice exhibit increased edema formation in a carrageenan-induced paw inflammation model compared to wild-type mice, but not to LYVE(-/-) or CD44(-/-) mice. These data suggest that LYVE-1 and CD44 are not required for the formation or function of lymphatics, but do not rule out a role for LYVE-1 in inflammation. C1 [Luong, Mai X.; Tam, Joshua; Hagendoorn, Jeroen; Padera, Timothy P.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA USA. [Tam, Joshua] Massachusetts Gen Hosp, Harvard MIT Div Hlth Sci & Technol, Charlestown, MA USA. [Lin, Qingcong] Wyeth Res, Biol Technol, Mol Genet, Cambridge, MA USA. [Moore, Kathryn J.] Massachusetts Gen Hosp, Dept Lipid Metab, Boston, MA USA. [Seed, Brian] Massachusetts Gen Hosp, Dept Genet, Boston, MA USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Partners Healthcare Ctr Genet & Genom, Boston, MA 02115 USA. RP Kucherlapati, R (reprint author), Harvard Univ, Sch Med, Ctr Genet & Genom 250, 77 Louis Pasteur Ave, Boston, MA 02115 USA. EM rkucherlapati@partners.org; jain@steele.mgh.harvard.edu OI Moore, kathryn/0000-0003-2505-2547; Padera, Timothy/0000-0002-3453-9384 FU NCI NIH HHS [R01 CA085140-08, P01 CA080124, P01 CA080124-05, P01 CA080124-06A2, P01 CA080124-07, P01 CA080124-08, P01-CA80124, R01 CA085140, R01 CA085140-06, R01 CA085140-07, R01 CA096915, R01-CA85140, T32 CA073479, T32 CA073479-07, T32 CA073479-08, T32 CA073479-09, U01 CA084301, U01 CA084301-07, U01 CA084301-08, U01 CA084301-09, U01 CA084301-10, U01-CA84301]; NIDDK NIH HHS [P30 DK043351] NR 39 TC 13 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD MAY PY 2009 VL 219 IS 2 BP 430 EP 437 DI 10.1002/jcp.21686 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 425VO UT WOS:000264666000023 PM 19170073 ER PT J AU Rosell, A Arai, K Lok, J He, TR Guo, SZ Navarro, M Montaner, J Katusic, ZS Lo, EH AF Rosell, Anna Arai, Ken Lok, Josephine He, Tongrong Guo, Shuzhen Navarro, Miriam Montaner, Joan Katusic, Zvonimir S. Lo, Eng H. TI Interleukin-1 beta augments angiogenic responses of murine endothelial progenitor cells in vitro SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE angiogenesis; cytokine; MAP kinase; neuroinflammation; spleen; stroke ID CEREBRAL ISCHEMIA-REPERFUSION; INDUCED MOBILIZATION; CD34(+) CELLS; BRAIN-INJURY; BLOOD; NEOVASCULARIZATION; EXPRESSION; STROKE; DIFFERENTIATION; TRANSPLANTATION AB Endothelial progenitor cells (EPCs) may provide novel opportunities for therapeutic angiogenesis after ischemic diseases. However, it is unclear how the angiogenic potential of EPCs might be affected by an inflammatory environment. We examine how the potent cytokine interleukin-1 beta (IL-1 beta) affects angiovasculogenic responses in EPCs in culture. Mononuclear cells isolated from mouse spleen were plated on fibronectin-coated wells and grown in EGM-2MV media. Endothelial progenitor cells were phenotyped using multiple markers (UEA-Lectin, ac-LDL, CD133, CD34, vWillebrand Factor, Flk-1) and to identify the IL-1 Receptor-I. We quantified cell and colony counts and performed MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide) and Matrigel assays, in vitro, under control and IL-1 beta (10 ng/mL) conditions. Endothelial progenitor cells exposed to IL-1 beta increased in the number of cells and colonies compared with untreated cells, without any effect on cell metabolic integrity. Furthermore, IL-1 beta treatment augmented EPC angiogenic function, significantly increasing the number of vessel-like structures in the Matrigel assay. An early phosphorylation of ERK1/2 occurred after IL-1 beta stimulation, and this pathway was inhibited if IL-1 Receptor-I was blocked. Our results suggest that IL-1 beta is a potent stimulator of in vitro angiogenesis through ERK signaling in mouse EPCs. Further studies are warranted to assess how interactions between proinflammatory environments and EPC responses may be leveraged to enhance therapeutic angiogenesis. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 933-943; doi:10.1038/jcbfm.2009.17; published online 25 February 2009 C1 [Rosell, Anna; Arai, Ken; Lok, Josephine; Guo, Shuzhen; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab,Med Sch, Charlestown, MA 02129 USA. [He, Tongrong; Katusic, Zvonimir S.] Mayo Clin, Coll Med, Dept Anesthesiol, Rochester, MN USA. [Navarro, Miriam; Montaner, Joan] Univ Autonoma Barcelona, Vall Hebron Hosp, Dept Neurol, Neurovasc Res Lab, E-08193 Barcelona, Spain. RP Lo, EH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab,Med Sch, MGH E 149-2401, Charlestown, MA 02129 USA. EM anna.rosell@gmail.com; Lo@helix.mgh.harvard.edu RI Montaner, Joan/D-3063-2015; IBIS, NEUROVASCULAR/O-1855-2015 FU NIH [P01-NS55104, P50-NS10828, R37-NS37074, R01-NS48422, R01NS53560]; American Heart Association; Ministerio de Educacion y Ciencia [EXT2006/766]; Fondo de Investigacion Sanitaria [FIS06/471] FX Supported in part by NIH grants P01-NS55104, P50-NS10828, R37-NS37074, R01-NS48422, R01NS53560, and a Bugher award from the American Heart Association. AR is the recipient of a postdoctoral grant from Ministerio de Educacion y Ciencia (EXT2006/766) and MN is the recipient of a predoctoral grant from Fondo de Investigacion Sanitaria (FIS06/471). NR 45 TC 33 Z9 37 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAY PY 2009 VL 29 IS 5 BP 933 EP 943 DI 10.1038/jcbfm.2009.17 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 439PU UT WOS:000265640300007 PM 19240740 ER PT J AU Foerch, C Arai, K Van Cott, EM van Leyen, K Lo, EH AF Foerch, Christian Arai, Ken Van Cott, Elizabeth Merrill van Leyen, Klaus Lo, Eng H. TI Rapid reversal of anticoagulation reduces hemorrhage volume in a mouse model of Warfarin-associated intracerebral hemorrhage SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE anticoagulation; intracerebral hemorrhage; mouse model; warfarin ID PROTHROMBIN COMPLEX CONCENTRATE; FRESH-FROZEN PLASMA; ATRIAL-FIBRILLATION; EMERGENCY REVERSAL; VITAMIN-K; THERAPY; RATS; MANAGEMENT; BERIPLEX; EFFICACY AB Warfarin-associated intracerebral hemorrhage (W-ICH) is a severe type of stroke. There is no consensus on the optimal treatment for W-ICH. Using a mouse model, we tested whether the rapid reversal of anticoagulation using human prothrombin complex concentrate (PCC) can reduce hemorrhagic blood volume. Male CD-1 mice were treated with warfarin (2 mg/kg over 24 h), resulting in a mean (+/- s.d.) International Normalized Ratio of 3.5 +/- 0.9. First, we showed that an intravenous administration of human PCC rapidly reversed anticoagulation in mice. Second, a stereotactic injection of collagenase was administered to induce hemorrhage in the right striatum. Forty-five minutes later, the animals were randomly treated with PCC (100 U/kg) or saline IV (n = 12 per group). Twenty-four hours after hemorrhage induction, hemorrhagic blood volume was quantified using a photometric hemoglobin assay. The mean hemorrhagic blood volume was reduced in PCC-treated animals (6.5 +/- 3.1 mu L) compared with saline controls (15.3 +/- 11.2 mu L, P = 0.015). In the saline group, 45% of the mice developed large hematomas (i.e., > 15 mu L). In contrast, such extensive lesions were never found in the PCC group. We provide experimental data suggesting PCC to be an effective acute treatment for W-ICH in terms of reducing hemorrhagic blood volume. Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1015-1021; doi:10.1038/jcbfm.2009.27; published online 25 March 2009 C1 [Foerch, Christian; Arai, Ken; van Leyen, Klaus; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med,Neuroprotect Res Lab, Boston, MA 02129 USA. [Van Cott, Elizabeth Merrill] Harvard Univ, Massachusetts Gen Hosp, Dept Pathol, Sch Med, Boston, MA 02129 USA. RP Foerch, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med,Neuroprotect Res Lab, Room 2414,149 13th St, Boston, MA 02129 USA. EM foerch@em.uni-frankfurt.de RI van Leyen, Klaus/C-9126-2013 FU 'Deutsche Forschungsgemeinschaft' (DFG); NIH [R37-NS37074, R01-NS48422, R01-NS56458, R01-NS3560, P01NS55104] FX Christian Foerch received the medication used in this study (the Prothrombin Complex Concentrate 'Beriplex') as a donation from CSL Behring, Marburg, Germany. This study was in part funded by the 'Deutsche Forschungsgemeinschaft' (DFG) and by NIH-grants R37-NS37074, R01-NS48422, R01-NS56458, R01-NS3560 and P01NS55104. All the other authors declare no conflicts of interest. NR 25 TC 25 Z9 25 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAY PY 2009 VL 29 IS 5 BP 1015 EP 1021 DI 10.1038/jcbfm.2009.27 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 439PU UT WOS:000265640300015 PM 19319147 ER PT J AU Kahle, KT Barnett, SN Sassower, KC Staley, KJ AF Kahle, Kristopher T. Barnett, Sarah N. Sassower, Kenneth C. Staley, Kevin J. TI Decreased Seizure Activity in a Human Neonate Treated With Bumetanide, an Inhibitor of the Na(+)-K(+)-2Cl(-) Cotransporter NKCC1 SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE neonatal seizures; bumetanide; Na(+)-K(+)-2Cl cotransporter NKCC1 ID CATION-CHLORIDE COTRANSPORTERS; DEVELOPING BRAIN; NEURONAL COMMUNICATION; GABA; EEG; PHARMACOKINETICS; DRUGS AB Neonatal seizures have devastating consequences for brain development and are inadequately treated by available antiepileptics. In neonates, gamma-aminobutyric acid (GABA) is an excitatory neurotransmitter due to elevated levels of intraneuronal chloride achieved by robust activity of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). This depolarizing action of GABA likely contributes to the lowered seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants among infants. The diuretic bumetanide inhibits NKCC1 and silences seizure activity in rodent models of neonatal seizures, but its effect on seizures in human neonates is unknown. Continuous electroencephalography (EEG) monitoring was used to quantify the number, duration, and frequency of seizures 2 hours before and after the administration of bumetanide in a neonate with intractable multifocal seizures. Significant reductions in mean seizure duration and frequency were noted following treatment, with no associated clinical side effects or metabolic imbalances. These results suggest bumetanide may exert antiepileptic effects in human neonates. C1 [Staley, Kevin J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Div Pediat Neurol, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Staley, KJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Div Pediat Neurol, 55 Fruit St, Boston, MA 02114 USA. EM kstaley@partners.org NR 26 TC 60 Z9 63 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD MAY PY 2009 VL 24 IS 5 BP 572 EP 576 DI 10.1177/0883073809333526 PG 5 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 437RW UT WOS:000265505600007 PM 19406757 ER PT J AU Kunisawa, T Nagata, O Nagashima, M Mitamura, S Ueno, M Suzuki, A Takahata, O Iwasaki, H AF Kunisawa, Takayuki Nagata, Osamu Nagashima, Michio Mitamura, Sayuri Ueno, Megumi Suzuki, Akihiro Takahata, Osamu Iwasaki, Hiroshi TI Dexmedetomidine suppresses the decrease in blood pressure during anesthetic induction and blunts the cardiovascular response to tracheal intubation SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article CT Annual Meeting of the Japan-Society-for-Clinical-Anesthesia CY OCT 27, 2006 CL Asahikawa, JAPAN SP Japan Soc Clin Anesthesia DE Anesthesia induction; Adjuvant anesthetic sparing effect; Dexmedetomidine ID PERIOPERATIVE HEMODYNAMICS; ABDOMINAL HYSTERECTOMY; CARDIAC-ARREST; REQUIREMENTS; INFUSION; HUMANS; AGONIST; ARTERY AB Study Objective: To evaluate the effect of dexmedetomidine combined with fentanyl on hemodynamics. Design: Prospective, double-blinded, randomized study. Setting: Operating room of a university hospital. Patients: 30 ASA physical status II and III patients with mild-to-moderate cardiovascular disease. Interventions: Patients were assigned to one of three groups: Group D-F2 [dexmedetomidine, effect-site concentration (ESC) of fentanyl = two ng/mL]; Group F2 (placebo, ESC of fentanyl = two ng/mL), or Group F4 (placebo, ESC of fentanyl = 4 ng/mL). Measurements: Dexmedetomidine (an initial dose of 1.0 mu g/kg for 10 min, followed by a continuous infusion of 0.7 mu g-kg(-1.)hr(-1)) or placebo saline was administered 15 minutes before anesthetic induction. Anesthesia was induced with propofal and fentanyl using a target-controlled infusion system. Hemodynamic parameters: systolic (SBP) and diastolic blood pressures (DBP), and heart rate (HR) during anesthetic induction were measured and the percent changes were calculated for both induction and intubation. Main Results: After inducing anesthesia, SBP was significantly higher in Group D-F2 (127 24 mmHg) than Group F2 (90 +/- 20 mmHg) or Group F4 (77 +/- 21 mmHg). The SBP in Groups F2 and F4 reached 160 +/- 31 mmHg and 123 +/- 36 mmHg, respectively, after intubation, but no significant change in SBP was noted in Group D-F2. The percent increase in SBP due to tracheal intubation in Group D-F2 was 3% +/- 4% and was significantly lower than that of Group F2 (70% +/- 34%) or Group F4 (45% +/- 36%). Conclusion: Dexmedetomidine combined with fentanyl during anesthetic induction suppresses the decrease in blood pressure due to anesthetic induction and also blunts the cardiovascular response to tracheal intubation. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kunisawa, Takayuki; Mitamura, Sayuri; Ueno, Megumi; Suzuki, Akihiro; Takahata, Osamu; Iwasaki, Hiroshi] Asahikawa Med Coll, Dept Anesthesiol & Crit Care Med, Asahikawa, Hokkaido 0788510, Japan. [Nagata, Osamu] Tokyo Metropolitan Police Hosp, Dept Anesthesia, Tokyo, Japan. [Nagashima, Michio] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Nagashima, Michio] Harvard Univ, Sch Med, Boston, MA USA. RP Kunisawa, T (reprint author), Asahikawa Med Coll, Dept Anesthesiol & Crit Care Med, Asahikawa, Hokkaido 0788510, Japan. EM taka.kunisawa@nifty.ne.jp OI Nagashima, Michio/0000-0001-7416-5367 NR 19 TC 22 Z9 48 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD MAY PY 2009 VL 21 IS 3 BP 194 EP 199 DI 10.1016/j.jclinane.2008.08.015 PG 6 WC Anesthesiology SC Anesthesiology GA 454MW UT WOS:000266687300008 PM 19464613 ER PT J AU Gorji, R Wang, JP Eller, JL Holsapple, J AF Gorji, Reza Wang, Jingping Eller, Jorge L. Holsapple, James TI Deep hypothermic circulatory arrest for treatment of renal carcinoma SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Editorial Material DE Deep hypothermic circulatory arrest, Complications; Neurosurgical anesthesia; Renal cell carcinoma ID GAMMA-KNIFE RADIOSURGERY; PROFOUND HYPOTHERMIA; BRAIN METASTASES; CELL CARCINOMA; EXTRACORPOREAL CIRCULATION; ANEURYSM; SURGERY AB The case of a 67-year-old woman with multiple medical problems who presented for resection of a metastatic renal cell carcinoma involving the posterior fossa, is presented. Anesthetic management of the patient, who suffered metastasis to the brain, and who required deep hypothermic circulatory arrest, is discussed. (C) 2009 Elsevier Inc. All rights reserved. C1 [Gorji, Reza] Upstate Med Univ, Dept Anesthesiol, Syracuse, NY 13210 USA. [Wang, Jingping] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02115 USA. [Wang, Jingping] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Eller, Jorge L.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97239 USA. [Holsapple, James] Upstate Med Univ, Dept Neurosurg, Syracuse, NY 13210 USA. RP Gorji, R (reprint author), Upstate Med Univ, Dept Anesthesiol, Syracuse, NY 13210 USA. EM gorjir@upstate.edu OI Holsapple, James/0000-0003-0419-4474 NR 14 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 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD MAY PY 2009 VL 21 IS 3 BP 217 EP 219 DI 10.1016/j.jclinane.2008.06.041 PG 3 WC Anesthesiology SC Anesthesiology GA 454MW UT WOS:000266687300013 PM 19464618 ER PT J AU Nanni, S Benvenuti, V Grasselli, A Priolo, C Aiello, A Mattiussi, S Colussi, C Lirangi, V Illi, B D'Eletto, M Cianciulli, AM Gallucci, M De Carli, P Sentinelli, S Mottolese, M Carlini, P Strigari, L Finn, S Mueller, E Arcangeli, G Gaetano, C Capogrossi, MC Donnorso, RP Bacchetti, S Sacchi, A Pontecorvi, A Loda, M Farsetti, A AF Nanni, Simona Benvenuti, Valentina Grasselli, Annalisa Priolo, Carmen Aiello, Aurora Mattiussi, Stefania Colussi, Claudia Lirangi, Vittoria Illi, Barbara D'Eletto, Manuela Cianciulli, Anna Maria Gallucci, Michele De Carli, Piero Sentinelli, Steno Mottolese, Marcella Carlini, Paolo Strigari, Lidia Finn, Stephen Mueller, Elke Arcangeli, Giorgio Gaetano, Carlo Capogrossi, Maurizio C. Donnorso, Raffaele Perrone Bacchetti, Silvia Sacchi, Ada Pontecorvi, Alfredo Loda, Massimo Farsetti, Antonella TI Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; HYPOXIA-INDUCIBLE FACTORS; HUMAN BREAST-CANCER; TELOMERASE ACTIVITY; RESPONSE ELEMENT; GENE-EXPRESSION; CELLS; THERAPY; ALPHA; OVEREXPRESSION AB The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor beta (ER beta). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ER beta/eNOS, ER beta/HIF-1 alpha, or ER beta/HIF-2 alpha combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ER beta and nuclear eNOS plus HIF-2 alpha being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ER beta, and HIF-2 alpha expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases. C1 [Farsetti, Antonella] Regina Elena Canc Inst Expt Res Ctr CRS, Dept Expt Oncol, Mol Oncogenesis Lab, I-00158 Rome, Italy. [Nanni, Simona; Benvenuti, Valentina; Grasselli, Annalisa; Priolo, Carmen; Pontecorvi, Alfredo] Univ Cattolica Sacro Cuore, Dept Endocrinol, I-00168 Rome, Italy. [Nanni, Simona; Aiello, Aurora; Farsetti, Antonella] Natl Res Council CNR, Inst Neurobiol & Mol Med, Rome, Italy. [Priolo, Carmen; Finn, Stephen; Mueller, Elke; Loda, Massimo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Priolo, Carmen; Finn, Stephen; Mueller, Elke; Loda, Massimo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mattiussi, Stefania; Gaetano, Carlo; Capogrossi, Maurizio C.] Ist Dermopat Immacolata IDI, Lab Patol Vasc, Rome, Italy. [Colussi, Claudia; Illi, Barbara] Ctr Cardiol Monzino, Milan, Italy. [Cianciulli, Anna Maria] Regina Elena Inst Canc Res, Dept Clin Pathol, Rome, Italy. [Gallucci, Michele; De Carli, Piero] Regina Elena Inst Canc Res, Dept Urol, Rome, Italy. [Sentinelli, Steno; Mottolese, Marcella; Donnorso, Raffaele Perrone] Regina Elena Inst Canc Res, Dept Pathol, Rome, Italy. [Carlini, Paolo] Regina Elena Inst Canc Res, Dept Med Oncol, Rome, Italy. [Strigari, Lidia] Regina Elena Inst Canc Res, Lab Med Phys & Expert Syst, Rome, Italy. [Arcangeli, Giorgio] Regina Elena Inst Canc Res, Dept Radiotherapy, Rome, Italy. [Pontecorvi, Alfredo; Farsetti, Antonella] Regina Elena Inst Canc Res, Rome Oncogenom Ctr, Rome, Italy. RP Farsetti, A (reprint author), Regina Elena Canc Inst Expt Res Ctr CRS, Dept Expt Oncol, Mol Oncogenesis Lab, Via Messi dOro 156, I-00158 Rome, Italy. EM afarsetti@gmail.com RI Strigari, Lidia/J-3541-2012; Strigari, Lidia/B-9352-2017; Gallucci, Michele/K-9600-2016 OI Strigari, Lidia/0000-0003-4293-2298; Gallucci, Michele/0000-0002-3637-6531 FU Associazione Iraliana Ricerca sin Cancro and Ministero del Lavoro, della Salute a delle Politiche Sociali; Ministero dell'Istruzione, dell'Universita e della Ricerc; NIH [SPS0CA90381, 5R01CA131945] FX We thank F. Graham and S. Soddu for critical reading of the manuscript, D. Del Bufalo for reagents and helpful suggestions, and all members of the Division of Radiotherapy, Regina Elena Cancer Institute for constructive discussions. This work was supported by research grants from Associazione Iraliana Ricerca sin Cancro and Ministero del Lavoro, della Salute a delle Politiche Sociali (to A. Farsetti); Ministero dell'Istruzione, dell'Universita e della Ricerca; grants from NIH (Specialized Programs of Research Excellence SPS0CA90381, 5R01CA131945) and the Prostate Cancer Foundation (to M. Loda). NR 51 TC 67 Z9 68 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2009 VL 119 IS 5 BP 1093 EP 1108 DI 10.1172/JCI35079 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 442LT UT WOS:000265843400012 PM 19363294 ER PT J AU Hassett, MJ Griggs, JJ AF Hassett, Michael J. Griggs, Jennifer J. TI Disparities in Breast Cancer Adjuvant Chemotherapy: Moving Beyond Yes or No SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BODY-MASS INDEX; SOCIOECONOMIC-STATUS; RACIAL DISPARITIES; AFRICAN-AMERICAN; DOSE-INTENSITY; SURVIVAL; QUALITY; CARE; RACE; CARCINOMA C1 [Hassett, Michael J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Griggs, Jennifer J.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Hassett, MJ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 26 TC 16 Z9 16 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2009 VL 27 IS 13 BP 2120 EP 2121 DI 10.1200/JCO.2008.21.1532 PG 2 WC Oncology SC Oncology GA 447MK UT WOS:000266195000004 PM 19307493 ER PT J AU Miksad, RA Gonen, M Lynch, TJ Roberts, TG AF Miksad, Rebecca A. Goenen, Mithat Lynch, Thomas J. Roberts, Thomas G., Jr. TI Interpreting Trial Results in Light of Conflicting Evidence: A Bayesian Analysis of Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; B CALGB PROTOCOL-9633; RESECTED STAGE-I; BREAST-CANCER; MEDICAL STATISTICS; CONSORT STATEMENT; DECISION-MAKING; P-VALUES; TIME; DESIGN AB Purpose When successive randomized trials contradict prior evidence, clinicians may be unsure how to evaluate them: Does accumulating evidence warrant changing practice? An increasingly popular solution, Bayesian statistics quantitatively evaluate new results in context. This study provides a clinically relevant example of Bayesian methods. Methods Three recent non-small-cell lung cancer adjuvant chemotherapy trials were evaluated in light of prior conflicting data. Results were used from International Adjuvant Lung Trial (IALT), JBR. 10, and Adjuvant Navelbine International Trialist Association (ANITA). Prior evidence was sequentially updated to calculate the probability of each survival benefit level (overall and by stage) and variance. Sensitivity analysis was performed using expert opinion and uninformed estimates of survival benefit prior probability. Results The probability of a 4% survival benefit increased from 33% before IALT to 64% after IALT. After sequential updating with JBR. 10 and ANITA, this probability was 82% (hazard ratio = 0.84; 95% CI, 0.77 to 0.91). IALT produced the largest decrease in variance (61%) and decreased the chance of survival decrement to 0%. Sensitivity analysis did not support a survival benefit after IALT. However, sequential updating substantiated a 4% survival benefit and, for stage II and III, more than 90% probability of a 6% benefit and 50% probability of a 12% benefit. Conclusion When evaluated in context with prior data, IALT did not support a 4% survival benefit. However, sequential updating with JBR. 10 and ANITA did. A model for future assessments, this study demonstrates the unique ability of Bayesian analysis to evaluate results that contradict prior evidence. C1 [Miksad, Rebecca A.] Harvard Univ, Beth Israel Deaconess Hosp, Dept Med, Div Hematol & Oncol,Med Sch, Boston, MA 02215 USA. Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Miksad, RA (reprint author), Harvard Univ, Beth Israel Deaconess Hosp, Dept Med, Div Hematol & Oncol,Med Sch, 330 Brookline Ave,Shapiro 9, Boston, MA 02215 USA. EM rmiksad@bidmc.harvard.edu RI Miksad, Rebecca/B-8066-2009; Gonen, Mithat/E-4826-2012; OI Miksad, Rebecca/0000-0003-3194-5122 FU National Cancer Institute [R25T CA 92203]; PhRMA Foundation FX Supported in part by National Cancer Institute Grant No. R25T CA 92203 (R. A. M. and T. G. R.). T. G. R. was also supported in part by an unrestricted Health Outcomes Starter grant from the PhRMA Foundation. NR 90 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2009 VL 27 IS 13 BP 2245 EP 2252 DI 10.1200/JCO.2008.16.2586 PG 8 WC Oncology SC Oncology GA 447MK UT WOS:000266195000022 PM 19307513 ER PT J AU Kane, JM Fleischhacker, WW Hansen, L Perlis, R Pikalov, A Assuncao-Talbott, S AF Kane, John M. Fleischhacker, Wolfgang W. Hansen, Lars Perlis, Roy Pikalov, Andrei, III Assuncao-Talbott, Sheila TI Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID NEUROLEPTIC-INDUCED AKATHISIA; PLACEBO-CONTROLLED TRIAL; TREATMENT-RESISTANT SCHIZOPHRENIA; ACUTE BIPOLAR MANIA; RANDOMIZED CONTROLLED-TRIAL; DRUG-INDUCED AKATHISIA; SUICIDE-PREVENTION TRIAL; BLIND OLANZAPINE TRIAL; SCHIZOAFFECTIVE DISORDER; ACUTE EXACERBATION AB Objectives: To provide a brief description of the pathophysiology of akathisia, the challenges of diagnosing and treating this condition, and potential associated clinical issues. Also, to provide a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs). Data Sources: English-language literature with no date restrictions cited in PubMed was searched for the keywords akathisia, placebo, neuroleptic or haloperidol, and the generic names of SGAs (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole). Study Selection: Limits were set to search clinical trials, meta-analyses, or randomized controlled trials reviewing data from adult schizophrenia or bipolar disorder clinical trials. Studies including SGA comparisons with placebo and with FGAs, and also between SGAs themselves, were selected. Studies that specifically assessed akathisia (either subjectively or objectively or both) were included. Studies reporting generalized results pertaining to extrapyramidal symptoms (EPS) were excluded. Data Extraction: The incidence of akathisia. EPS rating scores, and required medications for the management of movement disorders were reviewed. Data Synthesis: Seventy-seven trials were included in the comparative review. Akathisia was observed with the use of all the SGAs. The akathisia incidence reported in bipolar disorder trials was generally higher compared with schizophrenia trials. The incidence reported for FGAs was consistently higher than that reported for SGAs, regardless of the patient population studied. Conclusions: Akathisia remains a concern with the use of SGAs. More accurate and standardized evaluations are required for a better understanding of the nature and incidence of akathisia. J Clin Psychiatry 2009:70(5):627-643 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Kane, John M.] Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY 11004 USA. [Fleischhacker, Wolfgang W.] Med Univ, Innsbruck, Austria. [Hansen, Lars] Univ Southampton, Royal S Hants Hosp, Southampton, Hants, England. [Perlis, Roy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pikalov, Andrei, III] Otsuka Amer Pharmaceut Inc, Rockville, MD USA. [Assuncao-Talbott, Sheila] Bristol Myers Squibb Co, Plainsboro, NJ USA. RP Kane, JM (reprint author), Zucker Hillside Hosp, Dept Psychiat, 75-59 263rd St,Kaufmann Bldg,Suite 103, Glen Oaks, NY 11004 USA. EM psychiatry@lij.edu FU Janssen Cilag; Servier; Bristol-Myers Squibb/Otsuka; Otsuka America Pharmaceuticals, Inc FX Dr. Kane is a consultant to Bristol-Myers Squibb, Otsuka, Eli Lilly, Pfizer, Janssen, Vanda, and Wyeth; and serves oil the advisory boards of AstraZeneca. Bristol-Myers Squibb. and Janssen. Dr. Fleischhacker is a consultant to Janssen, Servier, AstraZeneca, and Bristol-Myers Squibb/Otsuka; receives grant/research support from Janssen Cilag, Servier, and Bristol-Myers Squibb/Otsuka; receives honoraria from Pfizer, AstraZeneca,Janssen Cilag, Bristol-Myers Squibb/Otsuka, and Eli Lilly; and serves oil the advisory boards of Wyeth, Bristol-Myers Squibb/Otsuka, Janssen Cilag, Eli Lilly. and Pfizer. Dr. Perlis is a consultant for, receives honoraria from, and serves run the advisory boards of Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Pfizer, Proteus, and GlaxoSmithKline. Dr. Pikalov is employed by and receives financial and material support from Otsuka America Pharmaceuticals, Inc. Dr. Assuncao-Talbot receives financial and material support its an employee and stock shareholder of Bristol-Myers Squibb. Dr. Hansen reports no financial or other relationship relevant to the subject of this article. NR 163 TC 68 Z9 71 U1 5 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2009 VL 70 IS 5 BP 627 EP 643 PG 17 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 450TO UT WOS:000266424000003 PM 19389331 ER PT J AU Biederman, J Petty, CR Monuteaux, MC Evans, M Parcell, T Faraone, SV Wozniak, J AF Biederman, Joseph Petty, Carter R. Monuteaux, Michael C. Evans, Margaret Parcell, Tiffany Faraone, Stephen V. Wozniak, Janet TI The Child Behavior Checklist-Pediatric Bipolar Disorder Profile Predicts a Subsequent Diagnosis of Bipolar Disorder and Associated Impairments in ADHD Youth Growing Up: A Longitudinal Analysis SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID ATTENTION-DEFICIT HYPERACTIVITY; COMMUNITY MENTAL-HEALTH; PREPUBERTAL CHILDREN; CONDUCT DISORDER; JUVENILE MANIA; MAJOR DEPRESSION; ONSET MANIA; CBCL; ADOLESCENTS; COMORBIDITY AB Objective: To examine the predictive utility of the Child Behavior Checklist-Pediatric Bipolar Disorder (CBCL-PBD) profile to help identify children at risk for bipolar disorder. Method: Subjects were ascertained from 2 identically designed longitudinal case-control family studies of subjects (males and females aged 6-18 years) with DSM-III-R attention-deficit/hyperactivity disorder (ADHD). Based on data from the baseline assessment, ADHD subjects without a lifetime diagnosis of bipolar disorder were stratified by the presence (CBCL-PBD positive. N = 28) or absence (CBCL-PBD negative, N = 176) of a CBCL-PBD score >= 210 (total of attention, aggression, and anxious/depressed subscales). Subjects were comprehensively assessed at follow-up with structured psychiatric interviews. Data were collected from April 1988 to February 2003. Results: Over a mean follow-up period of 7.4 years, a positive CBCL-PBD score predicted subsequent diagnoses of bipolar disorder, major depressive disorder, and conduct disorder, as well as impaired psychosocial functioning and higher risk for psychiatric hospitalization. Conclusions: This work suggests that a positive CBCL-PBD score based on elevations on the attention problems, aggressive behavior, and anxious/depressed subscales predicts subsequent pediatric bipolar disorder and associated syndrome-congruent impairments. if confirmed in other studies, the CBCL-PBD score has the potential to help identify children at high risk to develop bipolar disorder. J Clin Psychiatry 2009:70(5):732-740 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Yawkey Ctr, Boston, MA 02114 USA. [Biederman, Joseph; Monuteaux, Michael C.; Wozniak, Janet] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Biederman, Joseph; Monuteaux, Michael C.; Wozniak, Janet] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Yawkey Ctr, Suite 6A,Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Mental Health [R01HD036317, R03MH079954] FX This project was supported by National Institute of Mental Health grants R01HD036317 and R03MH079954. NR 63 TC 64 Z9 65 U1 2 U2 9 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2009 VL 70 IS 5 BP 732 EP 740 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 450TO UT WOS:000266424000014 PM 19389330 ER PT J AU Ford, JD Elhai, JD Ruggiero, KJ Frueh, BC AF Ford, Julian D. Elhai, Jon D. Ruggiero, Kenneth J. Frueh, B. Christopher TI Refining Posttraumatic Stress Disorder Diagnosis: Evaluation of Symptom Criteria With the National Survey of Adolescents SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID COMORBIDITY SURVEY REPLICATION; SCREENING INSTRUMENT; PRIMARY-CARE; PTSD; VALIDATION; CHILDHOOD; CHILDREN; MODEL; ABUSE; RISK AB Objective: To compare the prevalence estimates, comorbidity rates, and structural validity of a revised symptom criteria set for the diagnosis of posttraumatic stress disorder (PTSD) with those of the DSM-IV criteria in a representative community sample of adolescents. Method: Cross-sectional data from the National Survey of Adolescents, a 1995 household probability sample of 4,023 adolescents aged 12-17 year:, were examined. DSM-IV PTSD symptoms were assessed with a modification of the National Women's Study PTSD module. Three- and 4-factor DSM-IV models were compared to a 2-factor PTSD model that deleted symptoms potentially overlapping with depression or other anxiety disorders. Comorbidity was assessed using DSM-IV criteria for major depressive episodes and substance use disorders. Results: PTSD prevalence varied across models (ie, 5.2%-8.8%, lifetime; 3.2%-5.7%, past 6 months). When the 2-factor model was used with a proportionate symptom threshold, lifetime PTSD prevalence wits comparable to that with the 3-factor DSM-IV model, and major depressive episode comorbidity was reduced by 9%-14%. Comorbidity with substance use disorders was comparable across models. Structural validity, tested with confirmatory factor analyses, showed that the 2-factor model and a 4-factor DSM-IV model were superior to the DSM-IV 3-factor model. Conclusions: Compared to the DSM-IV 3-factor PTSD model, a 2-factor model that removed depression and anxiety symptoms and used a proportionate symptom threshold may produce comparable lifetime PTSD prevalence estimates, reduced PTSD-depression comorbidity, and Superior structural validity (comparable to a 4-factor PTSD model) when applied to community samples of adolescents. Further research on PTSD structure and diagnosis with adolescents is warranted. J Clin Psychiatry 2009:70(5):748-755 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Ford, Julian D.] Univ Connecticut, Ctr Hlth, Dept Psychiat, Sch Med, Farmington, CT 06032 USA. [Elhai, Jon D.] Univ S Dakota, Dept Psychol, Disaster Mental Hlth Inst, Vermillion, SD 57069 USA. [Ruggiero, Kenneth J.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. [Frueh, B. Christopher] Baylor Coll Med, Menninger Clin, Houston, TX 77030 USA. [Frueh, B. Christopher] Baylor Coll Med, Dept Psychiat, Houston, TX 77030 USA. [Frueh, B. Christopher] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. RP Ford, JD (reprint author), Univ Connecticut, Ctr Hlth, Dept Psychiat, Sch Med, 263 Farmington Ave, Farmington, CT 06032 USA. EM ford@psychiatry.uchc.edu FU Department of Justice Office of Juvenile Justice and Delinquency Programs [CT-52525-JS2] FX Work on this article was partially supported by a grant from the Department of Justice Office of Juvenile Justice and Delinquency Programs CT-52525-JS2 (Dr Ford, principal investigator). NR 38 TC 37 Z9 37 U1 2 U2 6 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2009 VL 70 IS 5 BP 748 EP 755 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 450TO UT WOS:000266424000016 PM 19389336 ER PT J AU Kan, IP Alexander, MP Verfaellie, M AF Kan, Irene P. Alexander, Michael P. Verfaellie, Mieke TI Contribution of Prior Semantic Knowledge to New Episodic Learning in Amnesia SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID MEMORY RETRIEVAL; TEMPORAL-LOBE; SYSTEMS; DEMENTIA; CONSOLIDATION; CONFABULATION; INSIGHTS; SCHEMAS; MODEL AB We evaluated whether prior semantic knowledge would enhance episodic learning in amnesia. Subjects studied prices that are either congruent or incongruent with prior price knowledge for grocery and household items and then performed a forced-choice recognition test for the studied prices. Consistent with a previous report, healthy controls' performance was enhanced by price knowledge congruency; however, only a subset of amnesic patients experienced the same benefit. Whereas patients with relatively intact semantic systems, as measured by an anatomical measure (i.e., lesion involvement of anterior and lateral temporal lobes), experienced a significant congruency benefit, patients with compromised semantic systems did not experience a congruency benefit. Our findings suggest that when prior knowledge structures are intact, they can support acquisition of new episodic information by providing frameworks into which such information can be incorporated. C1 [Kan, Irene P.] Villanova Univ, Dept Psychol, Villanova, PA 19085 USA. [Kan, Irene P.; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02215 USA. [Kan, Irene P.; Verfaellie, Mieke] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA USA. [Alexander, Michael P.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Cambridge, MA 02138 USA. RP Kan, IP (reprint author), Villanova Univ, Dept Psychol, 800 Lancaster Ave, Villanova, PA 19085 USA. EM irene.kan@villanova.edu FU NIH [MH 57681, MH71783, HD 046442]; Office of Research and Development; Medical Research Service; Department of Veterans Affairs FX This research was supported by the NIH grants MH 57681 and MH71783 and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs (awarded to M. V.) and the NIH grant HD 046442 (awarded to M. P. A.). We thank Elizabeth Martin, Karen Fossum, and Sarah Davis for their assistance in data collection and Erin Sakai for her assistance in preparation of this manuscript. NR 36 TC 16 Z9 16 U1 3 U2 8 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD MAY PY 2009 VL 21 IS 5 BP 938 EP 944 DI 10.1162/jocn.2009.21066 PG 7 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 436KM UT WOS:000265413000008 PM 18702596 ER PT J AU Kubert, HL Stepp, CE Zeitels, SM Gooey, JE Walsh, MJ Prakash, SR Hillman, RE Heaton, JT AF Kubert, Heather L. Stepp, Cara E. Zeitels, Steven M. Gooey, John E. Walsh, Michael J. Prakash, S. R. Hillman, Robert E. Heaton, James T. TI Electromyographic control of a hands-free electrolarynx using neck strap muscles SO JOURNAL OF COMMUNICATION DISORDERS LA English DT Article ID TOTAL LARYNGECTOMY; REHABILITATION; COMMUNICATION; INTONATION; SPEECH AB Three individuals with total laryngectomy were studied for their ability to control a hands-free electrolarynx (EL) using neck surface electromyography (EMG) for on/off and pitch modulation. The laryngectomy surgery of participants was modified to preserve neckstrap musculature for EMG-based EL control (EMG-EL), with muscles on one side maintaining natural innervation and those on the other side receiving a transferred recurrent laryngeal nerve (RLN). EMG from each side of the neck controlled the EMG-EL across a day of unstructured practice followed by a day of formal training, including EMG biofeedback. Using either control source, participants spoke intelligibly and fluently with the EMG-EL before formal training. This good initial performance did not consistently improve across testing for either control source in terms of voice timing, speech intelligibility, fluency, and intonation of interrogative versus declarative sentences. Neck strap muscles have activation patterns capable of simple alaryngeal voice control without requiting RLN transfer. Learning outcomes: The reader will better understand (1) functionality of the hands-free electrolarynx (2) modification of laryngectomy surgery to preserve neck strap musculature and (3) performance of hands-free electrolarynx with different control sources. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kubert, Heather L.; Stepp, Cara E.; Prakash, S. R.; Hillman, Robert E.; Heaton, James T.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Kubert, Heather L.; Hillman, Robert E.; Heaton, James T.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Stepp, Cara E.; Zeitels, Steven M.; Prakash, S. R.; Hillman, Robert E.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Zeitels, Steven M.; Hillman, Robert E.; Heaton, James T.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Gooey, John E.] VA Hlth Ctr Boston, Boston, MA USA. [Gooey, John E.; Walsh, Michael J.] Boston Univ, Med Ctr Hosp, Dept Otolaryngol Head & Neck Surg, Boston, MA 02215 USA. RP Heaton, JT (reprint author), MGH Voice Ctr, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM hkubert@hotmail.com; cstepp@mit.edu; zeitels.steven@mgh.harvard.edu; john.Gooey@med.va.gov; Mike.Walsh@bmc.org; srp@mit.edu; hillman.robert@mgh.harvard.edu; James.Heaton@mgh.harvard.edu FU NIDCD NIH HHS [R01 DC006449, R01 DC006449-03, R01 DC006449-06, R01 DC006449-01, R01 DC006449-04, R01-DC006449, R01 DC006449-05, R01 DC006449-02] NR 21 TC 5 Z9 5 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0021-9924 J9 J COMMUN DISORD JI J. Commun. Disord. PD MAY-JUN PY 2009 VL 42 IS 3 BP 211 EP 225 DI 10.1016/j.jcomdis.2008.12.002 PG 15 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 434UX UT WOS:000265300700004 PM 19233382 ER PT J AU Yoon, LS Catalano, OA Fritz, S Ferrone, CR Hahn, PF Sahani, DV AF Yoon, Luke S. Catalano, Onofrio A. Fritz, Stefan Ferrone, Cristina R. Hahn, Peter F. Sahani, Dushyant V. TI Another Dimension in Magnetic Resonance Cholangiopancreatography: Comparison of 2-and 3-Dimensional Magnetic Resonance Cholangiopancreatography for the Evaluation of Intraductal Papillary Mucinous Neoplasm of the Pancreas SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE magnetic resonance cholangiopancreatography; intraductal papillary mucinous neoplasm of the pancreas ID NATURAL-HISTORY; DUCT; TUMOR; MANAGEMENT; SEQUENCE; MRCP; CT AB Purpose: The purpose of this study was to compare 2-dimensional (2D) and 3D magnetic resonance cholangiopancreatography (MRCP) for image quality and diagnostic performance in the evaluation of pathologically verified intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Materials and Methods: In this institutional review board-approved retrospective review, 21 patients (14 women and 7 men; mean age, 69 years; range, 43-93 years) who underwent 2D and 3D MRCPs oil a 1.5-T system for pathologically confirmed IPMN were studied. Two-dimensional MRCP protocol included multiplanar thin- and thick-slab single-shot fast spin-echo imaging, coronal single-shot fast spin-echo, and transverse T2-weighted fast spin-echo imaging. Three-dimensional MRCP was performed using a fast-recovery fast spin-echo sequence with single-volume acquisition and maximum intensity projection reconstructions. Using a 5-point scale, 2 readers independently evaluated MRCPs for (1) image quality, (2) visualization of the pancreatic duct (PD), and (3) Visualization of the cystic lesions. Intraductal papillary mucinous neoplasm's morphological features (septa, mural nodules, and duct communication) were also graded similarly to predict benignity or malignancy. Surgical and pathological data served as reference standard. A pancreatic surgeon reviewed the 21 MRCPs to determine the usefulness of 3D MRCP compared with that of 2D MRCP for Surgical planning. Results: Of the 21 IPMNs, 11 were side-branch IPMNs and 10 were main-duct-lesions IPMNs with side-branch involvement. A statistically significant improvement in image quality and Visualization of the PD and cystic lesion was demonstrated with 3D MRCP in comparison with that demonstrated with 2D MRCP (P <= 0.002). The morphological details of IPMN were also identified, with higher confidence with 3D MRCP in comparison with that using 2D MRCP Two-dimensional and 3D MRCPs performed similarly for predicting benign and malignant lesions, with sensitivity ranging from 50.0% to 66.7% and specificity ranging from 86.7% to 93.3%. The pancreatic surgeon preferred 3D to 2D MRCP for surgical evaluation and planning in 14 of 21 cases. Conclusion: Compared with 2D MRCP, 3D MRCP provides better image quality, offers superior evaluation of the PD and morphological details of IPMN, and is preferred for surgical planning. C1 [Yoon, Luke S.; Catalano, Onofrio A.; Hahn, Peter F.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. [Fritz, Stefan; Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Yoon, LS (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM lyoon@partners.org NR 14 TC 14 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAY-JUN PY 2009 VL 33 IS 3 BP 363 EP 368 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 453XU UT WOS:000266647000008 PM 19478628 ER PT J AU Manolis, EN Filippou, DK Tsoumakas, C Diomidous, M Cunningham, MJ Katostaras, T Weber, AL Eavey, RD AF Manolis, Evangelos N. Filippou, Dimitrios K. Tsoumakas, Constantinos Diomidous, Marianna Cunningham, Michael J. Katostaras, Theophanis Weber, Alfred L. Eavey, Roland D. TI Radiologic Evaluation of the Ear Anatomy in Pediatric Cholesteatoma SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article DE Cholesteatoma; acquired; congenital; computed tomography; middle ear ID MIDDLE-EAR; COMPUTED-TOMOGRAPHY; CHILDREN; DIAGNOSIS; CT; COMPLICATIONS; SURGERY; SCAN; MRI AB The aim of the study was to describe computed tomography (CT) findings in middle ear cholesteatoma in pediatric patients. A cohort of 32 children with cholesteatoma (3-14 years old) entered the study. Froth them, 30 presented acquired cholesteatoma (AC), and 2 presented congenital cholesteatoma. All of the children were investigated using CT before surgery of the middle ear and mastoid. Computed tomography was performed with 1- or 2-mm axial and coronal sections of both temporal bones. Nineteen children with AC (63.3%) revealed a diffuse soft-tissue density isodense with muscle, whereas in 6 of them, the mass mimicked inflammation. The remaining revealed localized soft-tissue mass with partially lobulated contour. In AC, ossicular erosion was detected in 23 cases (76.7%), abnormal pneumatization in 19 cases (63.3%), and erosion-blunting of spur and enlargement of middle ear or mastoid in 8 cases (26.7%). The 2 congenital cholesteatomas revealed soft-tissue mass with polypoid densities, while a semicircular canal fistula was detected in one of them. High-resolution CT facilitates early diagnosis and appropriate treatment of pediatric cholesteatoma by assessing the anatomic abnormalities and the extent of disease, which are crucial in middle ear and mastoid surgery. C1 [Manolis, Evangelos N.; Cunningham, Michael J.; Eavey, Roland D.] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Manolis, Evangelos N.] Univ Athens, Sch Hlth Sci, Dept Anat & Histol, Nursing Fac, Athens 11527, Greece. [Weber, Alfred L.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Manolis, EN (reprint author), Univ Athens, Sch Hlth Sci, Dept Anat & Histol, Nursing Fac, 123 Papadiamantopoulou St, Athens 11527, Greece. EM ENManolis@yahoo.gr NR 26 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD MAY PY 2009 VL 20 IS 3 BP 807 EP 810 DI 10.1097/SCS.0b013e318184346e PG 4 WC Surgery SC Surgery GA 448XN UT WOS:000266295400022 PM 19390457 ER PT J AU Graham, DY Lu, H Yamaoka, Y AF Graham, David Y. Lu, Hong Yamaoka, Yoshio TI African, Asian or Indian enigma, the East Asian Helicobacter pylori: facts or medical myths SO JOURNAL OF DIGESTIVE DISEASES LA English DT Article DE African enigma; Asian enigma; gastric cancer; gastritis; Helicobacter pylori; Indian enigma; peptic ulcer ID GASTRIC-CANCER; PEPTIC-ULCER; BIOLOGICAL-ACTIVITY; IRON-DEFICIENCY; UNITED-STATES; CAGA; INFECTION; POLYMORPHISMS; GENES; RISK AB Helicobacter pylori is etiologically related to peptic ulcer disease and gastric adenocarcinomas. Reports of geographical enigmas (African, Asian, Indian and Costa Rican enigmas) are based on perceptions that clinical presentations in a population or region are not as the authors expected. We discuss the background for these enigmas and examine the evidence whether they are real or are medical myths. The African enigma was challenged almost as soon as it was proposed and recent analyses of endoscopic data have confirmed it is a myth, as H. pylori-related diseases occur in Africa at the expected frequencies. The Asian and Indian enigmas relate to gastric cancer and peptic ulcers, respectively, and when one takes the patterns of gastritis in the different regions, these enigmas disappear. The pattern of gastritis underlies and predicts the clinical outcome and the predominant pattern of gastritis has been observed to change much more rapidly than can be accounted for by changes in host genetics. There is also no evidence that these changes relate to changes in the predominant H. pylori strain. The factors that link most closely to preventing an atrophic corpus are environmental, with food preservation and diet currently assuming the most prominent roles. This focus on diseases (cancer vs duodenal ulcers) instead of the underlying patterns of gastritis has fostered, and possibly helped to perpetuate, these mythical enigmas. We suggest that a better strategy would be to focus on the pathogenesis of underlying histopathologic differences which could also lead to the identification of specific chemoprevention strategies. C1 [Graham, David Y.; Yamaoka, Yoshio] Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Houston, TX 77030 USA. [Graham, David Y.; Yamaoka, Yoshio] Baylor Coll Med, Houston, TX 77030 USA. [Lu, Hong] Shanghai Jiao Tong Univ, Dept Gastroenterol, Renji Hosp, Sch Med,Shanghai Inst Digest Dis, Shanghai 200030, Peoples R China. RP Graham, DY (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Med, RM 3A-320 3D,2002 Holcombe Blvd, Houston, TX 77030 USA. EM dgraham@bcm.tmc.edu FU Meretek; NIH [DK62813]; National Natural Science Foundation of China [30670940] FX In the last 2 years Dr Graham has received small amounts of grant support and/or free drugs or urea breath tests from Meretek, BioHit for completely investigator-controlled research. Dr Yamaoka is supported in part by a grant from the NIH DK62813. Dr Lu is supported in part by a grant from the National Natural Science Foundation of China (30670940). NR 58 TC 35 Z9 38 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-2972 J9 J DIG DIS JI J. Dig. Dis. PD MAY PY 2009 VL 10 IS 2 BP 77 EP 84 DI 10.1111/j.1751-2980.2009.00368.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 436IN UT WOS:000265407100001 PM 19426388 ER PT J AU Rempell, JS Harris, NS Brown, DFM Nadel, ES AF Rempell, Joshua S. Harris, N. Stuart Brown, David F. M. Nadel, Eric S. TI LEFT EYE PTOSIS SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material ID INTERNAL CAROTID-ARTERY; BLUNT CEREBROVASCULAR INJURY; CERVICAL-SPINE MANIPULATION; HORNERS-SYNDROME; HELICAL CT; DISSECTION; DIAGNOSIS; THERAPY; NECK; PAIN C1 [Rempell, Joshua S.; Nadel, Eric S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Rempell, Joshua S.; Harris, N. Stuart; Brown, David F. M.; Nadel, Eric S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Nadel, ES (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 23 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 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD MAY PY 2009 VL 36 IS 4 BP 395 EP 399 PG 5 WC Emergency Medicine SC Emergency Medicine GA 441JL UT WOS:000265765000014 PM 19345048 ER PT J AU Schuberth, JM Cobb, MD Talarico, RH AF Schuberth, John M. Cobb, Matthew D. Talarico, Ross H. TI Minimally Invasive Arthroscopic-Assisted Reduction with Percutaneous Fixation in the Management of Intra-Articular Calcaneal Fractures: A Review of 24 Cases SO JOURNAL OF FOOT & ANKLE SURGERY LA English DT Article DE arthroscopy; Boehler's angle; comminution; complication; critical angle; joint depression; Sanders classification ID INTERNAL-FIXATION; SUBTALAR JOINT; CONTACT CHARACTERISTICS; COMPUTED-TOMOGRAPHY; OPERATIVE TREATMENT; COMPLICATIONS; CLASSIFICATION; OSTEOSYNTHESIS; VIABILITY AB A retrospective analysis of 24 cases of minimally invasive, open reduction, and internal fixation of intra-articular calcaneal fractures is presented. Collected data included articular step-off, medial wall displacement, and Boehler's angle, in addition to other descriptive characteristics of the fracture and case series. The operative technique is described in detail including the optimal screw constructs. Arthroscopic assistance was used in 10 of the cases. The articular step-off of the posterior facet, medial wall displacement, and Boehler's angle all displayed statistically significant change between the preoperative and postoperative periods (P < .0001). These results were consistent with the goal of restoration of articular congruity, calcaneal morphology, and calcaneal height. There were no soft tissue complications. The mean overall follow-up duration was 2.8 years (range 1 to 10 years). Of the 18 patients who were followed for more than I year (range 1.0 to 10 years), none went on to subtalar fusion. The results of this study suggest that a minimally invasive approach can improve radiographic parameters consistent with the ultimate goals of operative reduction of calcaneal fractures, and can be used to achieve satisfactory results with minimal risk of wound complication. Level of Clinical Evidence: 4 (The Journal of Foot & Ankle Surgery 48(3):315-322, 2009) C1 [Schuberth, John M.] Kaiser Fdn Hosp, Dept Orthopaed Surg, San Francisco, CA 94118 USA. [Cobb, Matthew D.] Kaiser Fdn Hosp, Dept Podiatr Surg, Walnut Creek, CA USA. [Talarico, Ross H.] Univ Calif San Francisco, Dept Orthoped Surg, San Francisco, CA 94143 USA. [Talarico, Ross H.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Talarico, Ross H.] Univ Calif San Francisco, Podiatr Surg Sect, San Francisco, CA 94143 USA. RP Schuberth, JM (reprint author), Kaiser Fdn Hosp, Dept Orthopaed Surg, 450 6th Ave, San Francisco, CA 94118 USA. EM Jmfoot@aol.com NR 38 TC 38 Z9 44 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1067-2516 J9 J FOOT ANKLE SURG JI J. Foot Ankle Surg. PD MAY-JUN PY 2009 VL 48 IS 3 BP 315 EP 322 DI 10.1053/j.jfas.2009.01.002 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 441TG UT WOS:000265792800005 PM 19423031 ER PT J AU Agopian, VG Chen, DC Avansino, JR Stelzner, M AF Agopian, Vatche G. Chen, David C. Avansino, Jeffrey R. Stelzner, Matthias TI Intestinal Stem Cell Organoid Transplantation Generates Neomucosa in Dogs SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Intestinal stem cell transplantation; Tissue-engineered intestine; Bioscaffolds; Polyglycolic acid ID ENGINEERED SMALL-INTESTINE; BILE-ACID MALABSORPTION; SMALL-BOWEL RESECTION; MANAGEMENT; SCAFFOLDS; MODEL; REGENERATION; ENGRAFTMENT; EPITHELIUM; REPAIR AB Intestinal stem cell organoid transplantation generates functional intestinal neomucosa and has been used therapeutically to improve nutrient absorption and cure bile acid malabsorption in rats. We hypothesized that intestinal organoids can be harvested and transplanted to generate intestinal neomucosa in a large animal model. In group 1, 2-month old beagles (n = 6) underwent autotransplantation of intestinal organoids prepared from a segment of their own ileum. In group 2, intestinal organoids were harvested from fetuses and allotransplanted into 10-month old mother animals (n = 4). Tissues were harvested after 4 weeks and analyzed by hematoxylin and eosin histology and fluorescent microscopy. Large numbers of viable organoids were harvested in both groups. In group 1, no neomucosal growth was identified in any of the engraftment sites after autotransplantation of juvenile organoids. In group 2, neomucosal growth with large areas of crypts and villi was identified in 11 of 12 polyglycolic acid scaffolds after allotransplantation of fetal organoids. The neomucosa resembled normal canine mucosa in structure and composition. Intestinal stem cell organoid transplantation can be used to generate neomucosa in dogs. This is the first report of successful generation of intestinal neomucosa using intestinal stem cell organoid transplantation in a large animal model. C1 [Agopian, Vatche G.; Chen, David C.; Stelzner, Matthias] Univ Calif Los Angeles, Dept Surg, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90095 USA. [Avansino, Jeffrey R.] Univ Washington, Dept Surg, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Agopian, VG (reprint author), Univ Calif Los Angeles, Dept Surg, VA Greater Los Angeles Hlth Care Syst, 10833 Conte Ave, Los Angeles, CA 90095 USA. EM vagopian@mednet.ucla.edu FU Clowes Career Development Award, American College of Surgeons FX Grant support from the Clowes Career Development Award, American College of Surgeons is acknowledged. NR 31 TC 17 Z9 17 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD MAY PY 2009 VL 13 IS 5 BP 971 EP 982 DI 10.1007/s11605-009-0806-x PG 12 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 431VO UT WOS:000265092500023 PM 19165549 ER PT J AU Eckman, MH Greenberg, SM Rosand, J AF Eckman, Mark H. Greenberg, Steven M. Rosand, Jonathan TI Should We Test for CYP2C9 Before Initiating Anticoagulant Therapy in Patients with Atrial Fibrillation? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE anticoagulant therapy; warfarin; genetic testing; pharmacogenetics; decision analysis; atrial fibrillation; stroke ID CLINICAL CLASSIFICATION SCHEMES; RANDOMIZED CONTROLLED-TRIALS; QUALITY-OF-LIFE; INTRACEREBRAL HEMORRHAGE; RISK-FACTORS; BLEEDING COMPLICATIONS; ANTITHROMBOTIC THERAPY; WARFARIN THERAPY; ORAL ANTICOAGULANT; DECISION-ANALYSIS AB Genetic variants of the warfarin sensitivity gene CYP2C9 have been associated with increased bleeding risk during warfarin initiation. Studies also suggest that such patients remain at risk throughout treatment. Would testing patients with non-valvular atrial fibrillation (AF) for CYP2C9 before initiating warfarin improve outcomes? Markov state transition decision model. Ambulatory or inpatient settings necessitating new initiation of anticoagulation. The base case was a 69-year-old man with newly diagnosed non-valvular AF. Interventions included: (1) warfarin, (2) aspirin, or (3) no antithrombotic therapy without genetic testing; and genetic testing followed by (4) aspirin or (5) no antithrombotic therapy in those with culprit CYP2C9 alleles. Quality-adjusted life years (QALYs). In the base case, testing and treating patients with CYP2C9*2 and/or CYP2C9*3 with aspirin rather than warfarin was best (8.97 QALYs). However, warfarin without genetic testing was a close second (8.96 QALYs), a difference of roughly 5 days. Sensitivity analyses demonstrated that genetic testing followed by aspirin was best for patients at lower risk of embolic events. Warfarin without testing was preferred if the rate of embolic events was greater than 5% per year, or the risk of major bleeding while receiving warfarin was lower. For patients at average risk for ischemic stroke due to AF and at average risk for major hemorrhage, treatment based on genetic testing offers no benefit compared to warfarin initiation without testing. The gain from testing may be larger in patients at lower risk of embolic events or at greater risk of bleeding. C1 [Eckman, Mark H.] Univ Cincinnati, Med Ctr, Div Gen Internal Med, Cincinnati, OH 45267 USA. [Eckman, Mark H.] Univ Cincinnati, Med Ctr, Ctr Clin Effectiveness, Cincinnati, OH 45267 USA. [Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Res Grp, Boston, MA 02114 USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Eckman, MH (reprint author), Univ Cincinnati, Med Ctr, Div Gen Internal Med, POB 670535, Cincinnati, OH 45267 USA. EM mark.eckman@uc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK075599]; National Heart, Lung, and Blood Institute [K30 HL078581-01]; Foundation for Informed Medical Decision Making.; National Institutes of Neurological Disorders and Stroke [R01 NS059727]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke FX Jonathan Rosand: National Institutes of Neurological Disorders and Stroke (R01 NS059727), and the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke. NR 63 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2009 VL 24 IS 5 BP 543 EP 549 DI 10.1007/s11606-009-0927-7 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 434XE UT WOS:000265306700001 PM 19255811 ER PT J AU Sherbourne, CD Asch, SM Shugarman, LR Goebel, JR Lanto, AB Rubenstein, LV Wen, L Zubkoff, L Lorenz, KA AF Sherbourne, Cathy D. Asch, Steven M. Shugarman, Lisa R. Goebel, Joy R. Lanto, Andy B. Rubenstein, Lisa V. Wen, Li Zubkoff, Lisa Lorenz, Karl A. TI Early Identification of Co-Occurring Pain, Depression and Anxiety SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE targeted screening for pain and distress; depression; anxiety ID PRIMARY-CARE; SYMPTOMS; ILLNESS; HEALTH; COMORBIDITY; IMPAIRMENT; PREVALENCE; DISORDERS; SEVERITY; SCREENER AB Depression and anxiety frequently co-occur with pain and may affect treatment outcomes. Early identification of these co-occurring psychiatric conditions during routine pain screening may be critical for optimal treatment. To determine aspects of pain related to psychological distress, and, among distressed patients, to determine whether pain factors are related to provider identification of distress. Cross-sectional interview of primary care patients and their providers participating in a Veteran's Administration HELP-Vets study. A total of 528 predominately male Veterans We measured self-reported pain, including a 0-10 numeric rating scale and interference items from the Brief Pain Inventory. To evaluate distress, brief indicators of depression, anxiety and PTSD were combined. A substantial number of patients had psychological distress (41%), which was even higher (62%) among patients with moderate-severe current pain. Only 29% of those with distress reported talking to their provider about emotional problems during their visit. In multivariate analyses, other pain factors related to distress included interference with enjoyment of life and relationships with others, pain in multiple locations and joint pains. Prior diagnoses of depression and anxiety were also related to current distress. Only prior diagnosis and patient reported headaches and sleep interference because of pain were related to provider identification of distress. VA patients with moderate-severe pain are at high risk for psychological distress, which often goes unrecognized. Providers need to be more vigilant to mental health problems in patients experiencing high pain levels. Targeted screening for co-occurring conditions is warranted. C1 [Sherbourne, Cathy D.; Asch, Steven M.; Shugarman, Lisa R.; Rubenstein, Lisa V.; Lorenz, Karl A.] RAND Corp, Santa Monica, CA 90407 USA. [Asch, Steven M.; Lanto, Andy B.; Rubenstein, Lisa V.; Zubkoff, Lisa; Lorenz, Karl A.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Asch, Steven M.; Rubenstein, Lisa V.; Lorenz, Karl A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goebel, Joy R.] Calif State Univ Long Beach, Dept Nursing, Sch Nursing, Long Beach, CA 90840 USA. [Wen, Li] Vet Adm Long Beach Healthcare Syst, Long Beach, CA USA. RP Sherbourne, CD (reprint author), RAND Corp, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM Cathy_Sherbourne@rand.org FU VA HSR D [03-150] FX Funded by the VA HSR& D 11R # 03-150. NR 24 TC 19 Z9 26 U1 4 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2009 VL 24 IS 5 BP 620 EP 625 DI 10.1007/s11606-009-0956-2 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 434XE UT WOS:000265306700012 PM 19308333 ER PT J AU Keyhani, S Federman, A AF Keyhani, Salomeh Federman, Alex TI Fact or Fiction: The Need for Independent Pharmaceutical Policy Research SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID PRIVATE-SECTOR; ROFECOXIB; INNOVATION; EZETIMIBE; DOCUMENTS; NAPROXEN; TRIAL; COSTS; PRICE; VA C1 [Keyhani, Salomeh] Mt Sinai Sch Med, Dept Hlth Policy, New York, NY 10029 USA. [Keyhani, Salomeh] James J Peters Vet Adm Med Ctr, Bronx, NY USA. [Keyhani, Salomeh; Federman, Alex] Mt Sinai Sch Med, Div Gen Internal Med, New York, NY 10029 USA. RP Keyhani, S (reprint author), Mt Sinai Sch Med, Dept Hlth Policy, Box 1077,1 Gustave L Levy Pl, New York, NY 10029 USA. EM salomeh.keyhani@mountsinai.org NR 27 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 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2009 VL 24 IS 5 BP 692 EP 694 DI 10.1007/s11606-009-0964-2 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 434XE UT WOS:000265306700023 PM 19343457 ER PT J AU Lindenhovius, ALC van de Luijtgaarden, K Ring, D Jupiter, J AF Lindenhovius, Anneluuk L. C. van de Luijtgaarden, Koen Ring, David Jupiter, Jesse TI Open Elbow Contracture Release: Postoperative Management With and Without Continuous Passive Motion SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Continuous passive motion; contracture release; elbow stiffness ID POSTTRAUMATIC CONTRACTURE; OPERATIVE RELEASE; ANTERIOR RELEASE; LATERAL APPROACH; STIFF ELBOW; ARTHROLYSIS; HEAD AB Purpose Surgical contracture release can restore motion to stiff elbows. Some authors suggest that use of continuous passive motion (CPM) in postoperative management can increase ultimate mobility. This study tests the null hypothesis that there is no difference in the arc of flexion and extension between patients who used CPM and those who did not use CPM after open elbow contracture release. Methods Sixteen patients who had an arc of flexion and extension of less than 80 degrees and used CPM after open contracture release were matched based on age, gender, diagnosis, preoperative arc of flexion and extension, and radiographic appearance (joint congruity, heterotopic bone, and arthritis) to 16 control patients who did not use CPM. Stiffness was of posttraumatic origin in 24 patients, related to primary osteoarthrosis in 4 patients, and related to heterotopic ossification after central nervous system injury or burns in 4 patients. The preoperative arc of flexion and extension averaged 38 degrees in the CPM cohort and 42 degrees in the no-CPM cohort. Results Subsequent surgeries included procedures to address residual stiffness in 1 patient in the CPM cohort and in 3 patients in the no-CPM cohort. At an average 6 months of follow-up, there was no difference in improvement in the arc of flexion and extension (58 degrees vs 61 degrees) between the CPM and no-CPM cohorts. At the final evaluation, the improvement in arc of flexion and extension (59 degrees in both cohorts) and the final arc of flexion and extension (96 degrees vs 101 degrees) were comparable between cohorts. Conclusions These matched retrospective data do not demonstrate a benefit of CPM in the postoperative management of elbow contracture release. (J Hand Surg 2009;34A:858-865. (C) 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) Type of study/level of evidence Therapeutic III. C1 [Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org FU AD Foundation; Wright Medical; Joint Active Systems; Smith and Nephew; Small Bone Innovations; Biomet; Acumed; Tomier FX Unrestricted research grants were received from AD Foundation, Wright Medical, Joint Active Systems, Smith and Nephew, Small Bone Innovations, Biomet, Acumed, and Tomier. NR 22 TC 16 Z9 17 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAY-JUN PY 2009 VL 34A IS 5 BP 858 EP 865 DI 10.1016/j.jhsa.2009.01.003 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 443FO UT WOS:000265895800008 PM 19362791 ER PT J AU Jawa, A Jupiter, J AF Jawa, Andrew Jupiter, Jesse TI Fracture-Associated Nerve Dysfunction SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article ID SUPRACONDYLAR HUMERUS FRACTURES; CARPAL-TUNNEL-SYNDROME; DISTAL RADIUS; PALSY; INJURIES; EXPERIENCE; CHILDREN; SHAFT; ULNAR C1 [Jawa, Andrew] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Boston, MA 02114 USA. RP Jawa, A (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM ajawa@partners.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAY-JUN PY 2009 VL 34A IS 5 BP 924 EP 927 DI 10.1016/j.jhsa.2008.11.029 PG 4 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 443FO UT WOS:000265895800020 PM 19233570 ER PT J AU Eisenman, DP Glik, D Maranon, R Gonzales, L Asch, S AF Eisenman, David P. Glik, Deborah Maranon, Richard Gonzales, Lupe Asch, Steven TI Developing a Disaster Preparedness Campaign Targeting Low-Income Latino Immigrants: Focus Group Results for Project PREP SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Latino health; immigrant health; disaster preparedness; formative research ID ETHNICITY; DISSEMINATION; PERCEPTIONS; INFORMATION AB Low-income immigrant Latinos are particularly vulnerable to disasters because they are both ill-prepared and disproportionately affected. Disaster preparedness programs that are culturally appropriate must be developed and tested. To develop such a program, we conducted 12 focus groups with low-income immigrant Latinos to understand their perceptions and understanding of disaster preparedness, and facilitators and obstacles to it. Participants were concerned about remaining calm during an earthquake. Obstacles to storage of disaster supplies in a kit and developing a family communication plan were mentioned frequently. Misunderstandings were voiced about the proper quantity of water to store and about communication plans. Several focus groups spontaneously suggested small group discussions (platicas) as a way to learn about disaster preparedness. They wanted specific help with building their family communication plans. They rated promotoras de salud highly as potential teachers. Results Will guide the development of a disaster preparedness program tailored to the needs of low-income Latino immigrants. C1 [Eisenman, David P.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Glik, Deborah; Maranon, Richard] Univ Calif Los Angeles, Sch Publ Hlth Community Hlth Sci, Los Angeles, CA 90095 USA. [Asch, Steven] W Los Angeles Vet Adm, Dept Med, Los Angeles, CA USA. RP Eisenman, DP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Plaza, Los Angeles, CA 90095 USA. EM deisenman@mednet.ucla.edu NR 37 TC 20 Z9 20 U1 1 U2 7 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD MAY PY 2009 VL 20 IS 2 BP 330 EP 345 PG 16 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 443CF UT WOS:000265887100004 PM 19395833 ER PT J AU Tallaj, JA Franco, V Rayburn, BK Pamboukian, SV Benza, RL Kirklin, JK McGiffin, DC Smallfield, M Bourge, RC AF Tallaj, Jose A. Franco, Veronica Rayburn, Barry K. Pamboukian, Salpy V. Benza, Raymond L. Kirklin, James K. McGiffin, David C. Smallfield, Melissa Bourge, Robert C. TI Safety and Efficacy of Ibutilide in Heart Transplant Recipients SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID ORTHOTOPIC CARDIAC TRANSPLANTATION; ATRIAL-FLUTTER; ARRHYTHMIAS; PREVALENCE AB In this report we describe our experience with ibutilide, a relatively new Class III anti-arrhythmic agent, in 8 heart transplant patients with supraventricular tachycardia in various settings (3 patients with rejection, 2 after endomyocardial biopsy). Ibutilide treatment was successful in all patients, with the arrhythmia recurring early in I patient. There were no complications. J Heart Lung Transplant 2009;28:505-7. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation. C1 [Tallaj, Jose A.; Franco, Veronica; Rayburn, Barry K.; Pamboukian, Salpy V.; Benza, Raymond L.; Kirklin, James K.; McGiffin, David C.; Smallfield, Melissa; Bourge, Robert C.] Univ Alabama, Div Cardiovasc Dis, Sect Heart Failure Transplantat & Pulm Vasc Dis, Birmingham, AL 35294 USA. [Tallaj, Jose A.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Tallaj, JA (reprint author), Univ Alabama, Div Cardiovasc Dis, Sect Heart Failure Transplantat & Pulm Vasc Dis, THT 338,703 19th St S, Birmingham, AL 35294 USA. EM jtallaj@uab.edu RI Franco, Veronica/E-3080-2011 NR 13 TC 0 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 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD MAY PY 2009 VL 28 IS 5 BP 505 EP 507 DI 10.1016/j.healun.2009.02.013 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 447DI UT WOS:000266171400015 PM 19416781 ER PT J AU Lieu, C Janssen, WJ Saint, S Dhaliwal, G AF Lieu, Christopher Janssen, William J. Saint, Sanjay Dhaliwal, Gurpreet TI The Tip of the Iceberg SO JOURNAL OF HOSPITAL MEDICINE LA English DT Editorial Material ID A STREPTOCOCCAL INFECTIONS; TOXIC-SHOCK-SYNDROME; SPECTRUM C1 [Lieu, Christopher; Janssen, William J.; Dhaliwal, Gurpreet] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. [Janssen, William J.] Natl Jewish Med & Res Ctr, Dept Med, Denver, CO USA. [Saint, Sanjay] Ann Arbor Vet Affairs Hlth Serv, Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Saint, Sanjay] Ann Arbor Vet Affairs Med Ctr, Patient Safety Enhancement Program, Ann Arbor, MI USA. [Saint, Sanjay] Univ Michigan Hlth Syst, Dept Internal Med, Ann Arbor, MI USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Lieu, C (reprint author), Univ Texas MD Anderson Canc Ctr, Div Canc Med, 1515 Holcombe Blvd,Unit 10, Houston, TX 77098 USA. EM chlieu@mdanderson.org NR 13 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD MAY-JUN PY 2009 VL 4 IS 5 BP 317 EP 320 DI 10.1002/jhm.471 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 459NI UT WOS:000267109200009 PM 19504498 ER PT J AU Carpenter, AC Yang-Iott, KS Chao, LH Nuskey, B Whitlow, S Alt, FW Bassing, CH AF Carpenter, Andrea C. Yang-Iott, Katherine S. Chao, Linda H. Nuskey, Beth Whitlow, Scott Alt, Frederick W. Bassing, Craig H. TI Assembled DJ beta Complexes Influence TCR beta Chain Selection and Peripheral V beta Repertoire SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; RECOMBINATION SIGNAL SEQUENCE; MAJOR HISTOCOMPATIBILITY COMPLEX; CHROMOSOMAL V(D)J RECOMBINATION; CODING-END SEQUENCE; ALLELIC EXCLUSION; IMMATURE THYMOCYTES; GERMLINE TRANSCRIPTION; POSITIVE SELECTION; GENE SEGMENTS AB TCR beta chain repertoire of peripheral alpha beta T cells is generated through the stepwise assembly and subsequent selection of TCR beta V region exons during thymocyte development. To evaluate the influence of a two-step recombination process on V beta rearrangement and selection, we generated mice with a preassembled D beta 1J beta 1.1 complex on the J beta 1(omega) allele, an endogenous TCRP allele that lacks the D beta 2-J beta 2 cluster, creating the J beta 1(DJ beta) allele. As compared with J beta 1(omega/omega) mice, both J beta 1(DJ beta/omega) and J beta 1(DJ beta/DJ beta) mice exhibited grossly normal thymocyte development and TCR beta allelic exclusion. In addition, V beta rearrangements on J beta 1(DJ beta) and J beta 1(omega) alleles were similarly regulated by TCR beta-mediated feedback regulation. However, in-frame V beta DJ beta rearrangements were present at a higher level on the J beta 1(DJ beta) alleles of J beta 1(DJ beta/omega) alpha beta T cell hybridomas, as compared with on the J beta 1(omega) alleles. This bias was most likely due to both an increased frequency of VP-to-DJ beta rearrangements on J beta 1(DJ beta) alleles and a preferential selection of cells with in-frame V beta DJ beta exons assembled on J beta 1(DJ beta) alleles during the development of J beta 1(DJ beta/omega) alpha beta T cells. Consistent with the differential selection of in-frame V beta DJ beta rearrangements on J beta 1(DJ beta) alleles, the V beta repertoire of alpha beta T cells was significantly altered during alpha beta TCR selection in J beta 1(DJ beta/omega) and J beta 1(DJ beta/DJ beta) mice, as compared with in J beta 1(omega/omega) mice. Our data indicate that the diversity of DJ beta complexes assembled during thymocyte development influences TCR beta chain selection and peripheral VP repertoire. The Journal of Immunology, 2009, 182: 5586-5595. C1 [Carpenter, Andrea C.; Bassing, Craig H.] Univ Penn, Immunol Grad Grp, Sch Med, Philadelphia, PA 19104 USA. [Carpenter, Andrea C.; Yang-Iott, Katherine S.; Chao, Linda H.; Nuskey, Beth; Bassing, Craig H.] Univ Penn, Childrens Hosp Philadelphia, Abramson Family Canc Res Inst, Dept Pathol & Lab Med,Sch Med,Ctr Childhood Canc, Philadelphia, PA 19104 USA. [Whitlow, Scott; Alt, Frederick W.] Harvard Univ, Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst,Sch Med, Boston, MA 02115 USA. [Whitlow, Scott; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Bassing, CH (reprint author), Childrens Hosp Philadelphia, Abramson Res Ctr 807A, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bassing@email.chop.edu FU Howard Hughes Medical Institute; NIAID NIH HHS [R01 AI020047, T32 AI055428, R01 AI020047-28, AI20047] NR 65 TC 9 Z9 9 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2009 VL 182 IS 9 BP 5586 EP 5595 DI 10.4049/jimmunol.0803270 PG 10 WC Immunology SC Immunology GA 563HQ UT WOS:000275119200053 PM 19380806 ER PT J AU Meeran, SM Akhtar, S Katiyar, SK AF Meeran, Syed M. Akhtar, Suhail Katiyar, Santosh K. TI Inhibition of UVB-Induced Skin Tumor Development by Drinking Green Tea Polyphenols Is Mediated Through DNA Repair and Subsequent Inhibition of Inflammation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; IFN-GAMMA PRODUCTION; ULTRAVIOLET-RADIATION; INTERLEUKIN-12-DEFICIENT MICE; PYRIMIDINE DIMERS; COX-2 EXPRESSION; T-CELLS; CANCER; PHOTOCARCINOGENESIS; REGRESSION AB Consumption of green tea polyphenols (GTPs) in drinking water prevents photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Using IL-12p40 knockout (KO) mice and their wild-type counterparts and an established photocarcinogenesis protocol, we found that although administration of GTPs (0.2%, w/v) in drinking water significantly reduced UVB-induced tumor development in wild-type mice, this treatment had a nonsignificant effect in IL-12-KO mice. GTPs resulted in reduction in the levels of markers of inflammation (cyclooxygenase-2, prostaglandin E(2), proliferating cell nuclear antigen, and cyclin D1) and proinflammatory cytokines (tumor necrosis factor-alpha, IL-6, and IL-1 beta) in chronically UVB-exposed skin and skin tumors of wild-type mice but less effective in IL-12p40-KO mice. UVB-induced DNA damage (cyclobutane pyrimidine dimers) was resolved rapidly in GTPs-treated wild-type mice than untreated wild-type mice and this resolution followed the same time course as the GTPs-induced reduction in the levels of inflammatory responses. This effect of GTPs was less pronounced in IL-12-KO mice. The above results were confirmed by treatment of IL-12-KO mice with murine recombinant IL-12 and treatment of wild-type mice with neutralizing anti-IL-12 antibody. To our knowledge, it is previously unreported that prevention of photocarcinogenesis by GTPs is mediated through IL-12-dependent DNA repair and a subsequent reduction in skin inflammation. C1 [Meeran, Syed M.; Akhtar, Suhail; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Katiyar, SK (reprint author), Univ Alabama, Dept Dermatol, 1670 Univ Blvd,Volker Hall 557,POB 202, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU National Center for Complementary and Alternative Medicine/NIH [1 RO1 AT002536]; Veterans Administration Merit Review Award FX This work was supported by grants from the National Center for Complementary and Alternative Medicine/NIH (1 RO1 AT002536, SKK) and the Veterans Administration Merit Review Award (SKK). NR 45 TC 61 Z9 62 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2009 VL 129 IS 5 BP 1258 EP 1270 DI 10.1038/jid.2008.354 PG 13 WC Dermatology SC Dermatology GA 447US UT WOS:000266218000026 PM 19020550 ER PT J AU Hall, C Flores, MV Chien, A Davidson, A Crosier, K Crosier, P AF Hall, Chris Flores, Maria Vega Chien, Annie Davidson, Alan Crosier, Kathryn Crosier, Phil TI Transgenic zebrafish reporter lines reveal conserved Toll-like receptor signaling potential in embryonic myeloid leukocytes and adult immune cell lineages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE MyD88; TLR; immunity; live imaging; neutrophils; macrophages ID DOMAIN-CONTAINING ADAPTERS; HEMATOPOIETIC STEM-CELLS; IN-VIVO; INNATE IMMUNITY; BONE-MARROW; GRANULOMA-FORMATION; CARDIAC MYOCYTES; GENE-EXPRESSION; DANIO-RERIO; TNF-ALPHA AB The immune response of a host to an invading pathogen is dependent on the capacity of its immune cell compartment to recognize highly conserved pathogen components using an ancient class of pattern recognition receptors known as Toll-like receptors (TLRs). Initiation of TLR-mediated signaling results in the induction of proinflammatory cytokines that help govern the scale and duration of any ensuing response. Specificity for TLR signaling is, in part, a result of the differential recruitment of intracellular adaptor molecules. Of these, MyD88 is required for the majority of TLR signaling. Zebrafish have been shown to possess TLRs and adaptor molecules throughout early development, including MyD88, strongly suggesting conservation of this ancient defense mechanism. However, information about which embryonic cells/tissues possess this conserved signaling potential is lacking. To help define which embryonic cells, in particular, those of the innate immune system, have the potential for MyD88-dependent, TLR-mediated signaling, we generated transgenic reporter lines using regulatory elements of the myd88 gene to drive the fluorescent reporters enhanced GFP and Discosoma red fluorescent protein 2 within live zebrafish. These lines possess fluorescently marked cells/tissues consistent with endogenous myd88 expression, including a subset of myeloid leukocytes. These innate immune cells were confirmed to express other TLR adaptors including Mal, trif, and Sarm. Live wound-healing and infection assays validated the potential of these myd88-expressing leukocytes to participate in immune responses. These lines will provide a valuable resource for further resolving the contribution of MyD88 to early vertebrate immunity. J. Leukoc. Biol. 85: 751-765; 2009. C1 [Hall, Chris; Flores, Maria Vega; Chien, Annie; Crosier, Kathryn; Crosier, Phil] Univ Auckland, Sch Med Sci, Dept Mol Med & Pathol, Auckland 1142, New Zealand. [Davidson, Alan] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Crosier, P (reprint author), Univ Auckland, Sch Med Sci, Dept Mol Med & Pathol, Private Bag 92019, Auckland 1142, New Zealand. EM ps.crosier@auckland.ac.nz FU New Economy Research Fund, Foundation for Research Science and Technology, New Zealand FX Funding for this work was provided by a grant awarded to P. C. from the New Economy Research Fund, Foundation for Research Science and Technology, New Zealand. This work would not have been possible without the expert management of our zebrafish facility by Alhad Mahagaonkar. We also thank Koichi Kawakami for generously supplying the Tol2/transposase expression vectors and Nick Trede, John Kanki, and Phil Ingham and Stephen Renshaw for supplying the Tg(lck: GFP), Tg(rag2:GFP), and Tg(mpx:GFP) reporter lines, respectively. We thank the Biomedical Imaging Research Unit, School of Medical Sciences, The University of Auckland, for their expert assistance in fluorescence and confocal microscopy, Lisa Pullin for excellent technical assistance, and Stephen Edgar for FACS analysis support. NR 79 TC 38 Z9 39 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY 1 PY 2009 VL 85 IS 5 BP 751 EP 765 DI 10.1189/jlb.0708405 PG 15 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 453TM UT WOS:000266635800003 PM 19218482 ER PT J AU Fujimi, S Lapchak, PH Zang, Y MacConmara, MP Maung, AA Delisle, AJ Mannick, JA Lederer, JA AF Fujimi, Satoshi Lapchak, Peter H. Zang, Yan MacConmara, Malcolm P. Maung, Adrian A. Delisle, Adam J. Mannick, John A. Lederer, James A. TI Murine dendritic cell antigen-presenting cell function is not altered by burn injury SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Toll-like receptors; costimulatory molecules; Th1; Th2; CD4 T cells ID T-HELPER-CELL; INNATE IMMUNE RECOGNITION; TYROSINE KINASE-3 LIGAND; IN-VIVO; TRAUMA PATIENTS; THERMAL-INJURY; RESPONSES; RECEPTOR; MICE; INFECTION AB Severe injury disrupts normal immune regulation causing a transient hyperinflammatory reaction and suppressed adaptive immune function. This report addresses the potential contribution of dendritic cells (DC) to changes in adaptive immune function after injury by specifically measuring injury-induced changes in splenic DC numbers and subsets, cell-surface markers, TLR responses, and APC function. Using a mouse burn injury model, we found that injury did not markedly alter the relative percentage of lymphoid, myeloid, or plasmacytoid DC in the spleens of burn-injured mice. Moreover, we did not observe a significant reduction in cell-surface expression of several major costimulatory molecules, CD40, CD80, CD86, programmed death 1 ligand, ICOS ligand, and B7-H3, on DC. Instead, we observed increased cell-surface expression of CD86 at 1 day after injury with no significant changes in costimulatory molecule expression at 7 days after injury, suggesting that burn injury causes an early activation of DC. In addition, injury did not suppress DC reactivity to TLR2, TLR4, or TLR9 agonists. Most important, DC prepared from injured mice were able to present peptide antigen to naive OTII TCR transgenic CD4+ T cells as efficiently and effectively as DC from sham-injured mice. We also found that CD4 T cells stimulated with antigen presented by DC from sham or burn mice showed similar levels of IL-2, IFN-gamma, IL-10, and IL-13 production. Taken together, these findings support the conclusion that DC do not acquire a suppressive phenotype following severe injury in mice. J. Leukoc. Biol. 85: 862-870; 2009. C1 [Fujimi, Satoshi; Zang, Yan; MacConmara, Malcolm P.; Maung, Adrian A.; Delisle, Adam J.; Mannick, John A.; Lederer, James A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg Immunol, Boston, MA 02115 USA. [Lapchak, Peter H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med Rheumatol, Boston, MA 02115 USA. [Maung, Adrian A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Lederer, JA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg Immunol, 75 Francis St, Boston, MA 02115 USA. EM jlederer@rics.bwh.harvard.edu OI Lapchak, Peter/0000-0001-8597-088X FU NIH [GM35633, GM57664]; Julian and Eunice Cohen and Brook Family Funds FX This research work was supported by grant funding from NIH ( GM35633 and GM57664) and by the Julian and Eunice Cohen and Brook Family Funds for Surgical Research. The authors thank the Department of Traumatology, Osaka University, Japan, for generously providing outstanding trainees to support our research efforts. NR 52 TC 9 Z9 9 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY 1 PY 2009 VL 85 IS 5 BP 862 EP 870 DI 10.1189/jlb.0408257 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 453TM UT WOS:000266635800014 PM 19228816 ER PT J AU Pott, GB Chan, ED Dinarello, CA Shapiro, L AF Pott, Gregory B. Chan, Edward D. Dinarello, Charles A. Shapiro, Leland TI alpha-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE inflammation; dilution; serine protease inhibitor; interleukin ID MONONUCLEAR-CELLS; GENE-EXPRESSION; HUMAN MONOCYTES; IN-VITRO; RHEUMATOID-ARTHRITIS; FLOW-CYTOMETRY; TNF-ALPHA; DEFICIENCY; ALPHA(1)-ANTITRYPSIN; INTERLEUKIN-18 AB Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. alpha-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-alpha, IL-1 beta, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-alpha, IL-1 beta, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-alpha, and IL-1 beta significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis. J. Leukoc. Biol. 85: 886-895; 2009. C1 [Pott, Gregory B.; Chan, Edward D.; Dinarello, Charles A.; Shapiro, Leland] Univ Colorado, Denver, CO 80202 USA. [Pott, Gregory B.; Chan, Edward D.; Shapiro, Leland] Denver Vet Affairs Med Ctr, Denver, CO USA. [Chan, Edward D.] Natl Jewish Med & Res Ctr, Denver, CO USA. RP Shapiro, L (reprint author), Denver Vet Affairs Med Ctr, 12700 E 19th Ave,Box B168, Aurora, CO 80045 USA. EM leland.shapiro@uchsc.edu FU National Institutes of Health [A115614]; Campbell Foundation FX This work is supported by National Institutes of Health grant A115614 ( to C. A. D.) and the Campbell Foundation ( to L. S.). The authors thank Dr. Kristin Morris and Scott Beard for reviewing the manuscript and the AAT-deficient patients for participating in these investigations. NR 53 TC 76 Z9 81 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY 1 PY 2009 VL 85 IS 5 BP 886 EP 895 DI 10.1189/jlb.0208145 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 453TM UT WOS:000266635800017 PM 19197072 ER PT J AU Cho, H Ryu, S Ackerman, JL Song, YQ AF Cho, H. Ryu, S. Ackerman, J. L. Song, Y. -Q. TI Visualization of inhomogeneous local magnetic field gradient due to susceptibility contrast SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Internal magnetic field; Background gradient; Porous media ID STIMULATED-ECHO METHOD; POROUS-MEDIA; DIFFUSION MEASUREMENTS; NMR; RELAXATION; GEOMETRY; ROCKS; BONE; HE-3 AB We visualized inhomogeneous local magnetic field (internal magnetic field) gradients arising from susceptibility contrast between an array of cylindrical glass tubes (solid matrix) and surrounding water (pore fluids) in a uniform applied magnetic field. MRI was performed to determine the spatially resolved decay rates due to diffusion in the internal magnetic field which were proportional to the strength of local gradient. We also spatially resolved the interference pattern of the cross-terms between the internal and the applied field gradient in order to extract the orientation of the internal field gradient. These experimental results were found to be consistent with the theoretical calculations. This work demonstrates a simple yet representative case for visualizing the strength and orientation of the local susceptibility induced magnetic field gradients in porous media. (C) 2009 Elsevier Inc. All rights reserved. C1 [Cho, H.; Ryu, S.; Song, Y. -Q.] Schlumberger Doll Res Ctr, Cambridge, MA 02139 USA. [Cho, H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ackerman, J. L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Song, YQ (reprint author), Schlumberger Doll Res Ctr, 1 Hampshire St, Cambridge, MA 02139 USA. EM ysong@slb.com RI Cho, HyungJoon/F-1423-2010; Ackerman, Jerome/E-2646-2015 OI Ackerman, Jerome/0000-0001-5176-7496 FU National Institutes of Health [EB003869] FX We thank Dr. Lukasz Zielinski and Dr. Phillip Zhe Sun for stimulating discussions. We also thank Dr. George Dai for his technical support and Dr. Khushali Kotedia for proof reading the manuscript. This work is supported in part by the National Institutes of Health (EB003869). NR 31 TC 15 Z9 15 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 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAY PY 2009 VL 198 IS 1 BP 88 EP 93 DI 10.1016/j.jmr.2009.01.024 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 433UU UT WOS:000265232100011 PM 19231262 ER PT J AU Engelbrektson, A Korzenik, JR Pittler, A Sanders, ME Klaenhammer, TR Leyer, G Kitts, CL AF Engelbrektson, Anna Korzenik, Joshua R. Pittler, Arlyn Sanders, Mary E. Klaenhammer, Todd R. Leyer, Gregory Kitts, Christopher L. TI Probiotics to minimize the disruption of faecal microbiota in healthy subjects undergoing antibiotic therapy SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID GRADIENT GEL-ELECTROPHORESIS; 16S RIBOSOMAL-RNA; FRAGMENT-LENGTH-POLYMORPHISM; HUMAN INTESTINE; HUMAN FECES; TEMPORAL STABILITY; DIVERSITY; BACTERIA; COMMUNITIES; MICROFLORA AB A novel combination of culturing and DNA-based terminal restriction fragment length polymorphism (TRFLP) analysis was used to investigate the effect of probiotics on antibiotic-induced gut microbiota alterations to determine if a probiotic preparation containing bifidobacteria and lactobacilli, taken during and after antibiotic therapy, can minimize antibiotic disturbance of faecal microbiota. Healthy subjects administered amoxicillin/clavulanate were randomized and concomitantly received a placebo or probiotic mixture. The primary end point was similarity of faecal microbiota as determined by culturing and TRFLP from subjects taking, probiotics compared to those taking a placebo measured by comparing data from baseline to post-treatment for each subject. TRFLP analysis revealed a high subject to subject variation in the baseline faecal microbiota. The most common antibiotic-induced disturbance was a relative increase in Clostridium, Eubacterium, Bacteroides and Enterobacteraceae. The mean similarity to the baseline increased over time in both treatment groups, although the probiotic group was less disturbed according to both TRFLP and culture data. The culture method revealed that post-antibiotic faecal microbiota in probiotic-consuming subjects were more similar to the baseline microbiota than the control group (P=0.046). Changes in Enterobactereaceae (P=0.006) and Bifidobacterium (P=0.030) counts were significantly different between the groups. Analysis of TRFLP data reinforced the trend between groups but was not statistically significant (P=0.066). This study indicates this mixture of probiotics promotes a more rapid return to pre-antibiotic baseline faecal bacterial microbiota. C1 [Kitts, Christopher L.] Calif Polytech State Univ San Luis Obispo, Environm Biotechnol Inst, San Luis Obispo, CA 93407 USA. [Engelbrektson, Anna] Joint Genome Inst, Dept Energy, Walnut Creek, CA USA. [Korzenik, Joshua R.] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Pittler, Arlyn] Washington Univ, Sch Med, Div Gastroenterol, St Louis, MO 63110 USA. [Sanders, Mary E.] Dairy & Food Culture Technol, Centennial, CO USA. [Klaenhammer, Todd R.] N Carolina State Univ, Raleigh, NC 27695 USA. [Leyer, Gregory] Cultures Div R&D, Madison, WI USA. RP Kitts, CL (reprint author), Calif Polytech State Univ San Luis Obispo, Environm Biotechnol Inst, San Luis Obispo, CA 93407 USA. EM ckitts@calpoly.edu RI Engelbrektson, Anna/K-5563-2012; Engelbrektson, Anna/F-1687-2013 FU Danisco USA, Inc.; North Carolina Dairy Foundation FX This study was funded by Danisco USA, Inc., and the North Carolina Dairy Foundation. The authors thank Rosemary Sanozky-Dawes (North Carolina State University) for her technical contributions to the microbiological aspects of this study. NR 20 TC 38 Z9 41 U1 4 U2 13 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD MAY PY 2009 VL 58 IS 5 BP 663 EP 670 DI 10.1099/jmm.0.47615-0 PG 8 WC Microbiology SC Microbiology GA 444ZH UT WOS:000266018900018 PM 19369530 ER PT J AU Pino, MS Mino-Kenudson, M Wildemore, BM Ganguly, A Batten, J Sperduti, I Iafrate, AJ Chung, DC AF Pino, Maria Simona Mino-Kenudson, Mari Wildemore, Bernadette Mandes Ganguly, Aniruddha Batten, Julie Sperduti, Isabella Iafrate, Anthony John Chung, Daniel C. TI Deficient DNA Mismatch Repair Is Common in Lynch Syndrome-Associated Colorectal Adenomas SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID NONPOLYPOSIS COLON-CANCER; MICROSATELLITE INSTABILITY; HYPERPLASTIC POLYPS; GENETIC ALTERATIONS; GERMLINE MUTATION; HMLH1; EXPRESSION; HOMOLOG; PREVALENCE; PROTEIN AB Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen subjects with a germline MMR gene mutation who had 44 adenomas removed during surveillance colonoscopy were identified. MSI testing and IHC for MLH1, MSH2, and MSH6 were performed. MSI was detected in 23 adenomas. There was a significant association between MSI and high-grade dysplasia (P = 0.006) and distal location (P = 0.0008). Loss of MMR protein by IHC was detected in 31 adenomas. A significant association was observed between loss of staining by IHC and high-grade dysplasia (P = 0.04). Among the 40 adenomas in which both MSI tests and IHC were performed, the presence of a germline mutation correlated with an abnormal MSI result in 58% of cases, an abnormal IHC result in 70% of cases, and either an abnormal MSI or IHC result in 73% of cases. The combination of MSI and IHC testing in colorectal adenomas is a sensitive screen for the detection of Lynch syndrome and may be particularly useful when Lynch syndrome is suspected and adenomatous polyps are the only tissues available for analysis. (J Mol Diagn 2009, 11:238-247; DOI: 10.2353.jmoldx.2009.080142) C1 [Pino, Maria Simona; Chung, Daniel C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Mino-Kenudson, Mari; Wildemore, Bernadette Mandes; Ganguly, Aniruddha; Batten, Julie; Iafrate, Anthony John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Pino, Maria Simona] Regina Elena Inst Canc Res, Dept Med Oncol, Rome, Italy. [Sperduti, Isabella] Regina Elena Inst Canc Res, Dept Biostat, Rome, Italy. RP Chung, DC (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 50 Blossom St, Boston, MA 02114 USA. EM aiafrate@partners.org; dchung@partners.org RI Sperduti, Isabella /K-8902-2016 OI Sperduti, Isabella /0000-0001-5115-3099 FU Kate J. and Dorothy L. Clapp Fund; NIH [CA92594] FX Supported in part by the Kate J. and Dorothy L. Clapp Fund. D.C.C. is supported in part by NIH CA92594. NR 49 TC 41 Z9 44 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAY PY 2009 VL 11 IS 3 BP 238 EP 247 DI 10.2353/jmoldx.2009.080142 PG 10 WC Pathology SC Pathology GA 438XK UT WOS:000265589300010 PM 19324997 ER PT J AU Lu, A Hiltunen, M Romano, DM Soininen, H Hyman, BT Bertram, L Tanzi, RE AF Lu, Alice Hiltunen, Mikko Romano, Donna M. Soininen, Hilkka Hyman, Bradley T. Bertram, Lars Tanzi, Rudolph E. TI Effects of Ubiquilin 1 on the Unfolded Protein Response SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE UBQLN1; Ubiquilin 1; UPR; Unfolded protein response; CHOP; C/EBP homologous protein; PDI; Protein disulfide isomerase; BiP/GRP78; AD; Alzheimer's disease ID FAMILIAL ALZHEIMERS-DISEASE; DISULFIDE-ISOMERASE; ENDOPLASMIC-RETICULUM; NEUROTROPHIC FACTOR; MISSENSE MUTATIONS; UP-REGULATION; GENE; STRESS; ASSOCIATION; DEGRADATION AB Previous studies have implicated the unfolded protein response (UPR) in the pathogenesis of Alzheimer's disease (AD). We previously reported that DNA variants in the ubiquilin 1 (UBQLN1) gene increase the risk for AD. Since UBQLN1 has been shown to play a role in the UPR, we assessed the effects of overexpression and downregulation of UBQLN1 splice variants during tunicamycin-induced ER stress. In addition to previously described transcript variants, TV1 and TV2, we identified two novel transcript variants of UBQLN1 in brain: TV3 (lacking exons 2-4) and TV4 (lacking exon 4). Overexpression of TV1-3, but not TV4 significantly decreased the mRNA induction of UPR-inducible genes, C/EBP homologous protein (CHOP), BiP/GRP78, and protein disulfide isomerase (PDI) during the UPR. Stable overexpression of TV1-3, but not TV4, also significantly decreased the induction of CHOP protein and increased cell viability during the UPR. In contrast, downregulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. These findings suggest that overexpression UBQLN1 transcript variants TV1-3, but not TV4, exert a protective effect during the UPR by attenuating CHOP induction and potentially increasing cell viability. C1 [Hiltunen, Mikko; Soininen, Hilkka] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland. [Lu, Alice; Hiltunen, Mikko; Romano, Donna M.; Bertram, Lars; Tanzi, Rudolph E.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Lu, Alice; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Hiltunen, Mikko; Soininen, Hilkka] Kuopio Univ Hosp, Dept Neurol, Kuopio 70211, Finland. [Hyman, Bradley T.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Alzheimers Res Unit, Charlestown, MA 02129 USA. RP Hiltunen, M (reprint author), Univ Kuopio, Dept Neurol, POB 1627, FIN-70211 Kuopio, Finland. EM mhiltune@messi.uku.fi; tanzi@helix.mgh.harvard.edu RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X FU Extendicare Foundation, EVO [5772708]; Kuopio University Hospital, Finland; Finnish Academy FX This work was supported by the Extendicare Foundation, EVO grant 5772708 from Kuopio University Hospital, Finland, and the Finnish Academy (Mikko Hiltunen). We thank Petra Makinen for her excellent technical help. NR 29 TC 14 Z9 15 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD MAY PY 2009 VL 38 IS 1 BP 19 EP 30 DI 10.1007/s12031-008-9155-6 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 434AL UT WOS:000265247500004 PM 18953672 ER PT J AU Curry, WT Barker, FG AF Curry, William T., Jr. Barker, Fred G., II TI Racial, ethnic and socioeconomic disparities in the treatment of brain tumors SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Race; Ethnicity; Socioeconomic status; Health care disparities; Health care quality ID CANCER CLINICAL-TRIALS; PATIENT NAVIGATOR PROGRAM; SURGEONS-ONCOLOGY-GROUP; CENTRAL-NERVOUS-SYSTEM; AGE-BASED DISPARITIES; UNITED-STATES; HEALTH-CARE; PROVIDER CASELOAD; MALIGNANT GLIOMA; GLIOBLASTOMA-MULTIFORME AB Disparities in American health care based on socially-defined patient characteristics such as race, ethnicity, and socioeconomic position are well-documented. We review differences and disparities in incidence, pathobiology, processes and outcomes of care, and survival based on social factors for brain tumors of all histologies. In the US, black patients have lower incidences of most brain tumor types and lower-income patients have lower incidences of low grade glioma, meningioma and acoustic neuroma; ascertainment bias may contribute to these findings. Pathogenetic differences between malignant gliomas in patients of different races have been demonstrated, but their clinical significance is unclear. Patients in disadvantaged groups are less often treated by high-volume providers. Mortality and morbidity of initial treatment are higher for brain tumor patients in disadvantaged groups, and they present with markers of more severe disease. Long term survival differences between malignant glioma patients of different races have not yet been shown. Clinical trial enrollment appears to be lower among brain tumor patients from disadvantaged groups. We propose future research both to better define disparities and to alleviate them. C1 [Curry, William T., Jr.; Barker, Fred G., II] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Neurosurg,Pappas Ctr Neurooncol, Boston, MA 02114 USA. RP Curry, WT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Neurosurg,Pappas Ctr Neurooncol, Yawkey 9E,Fruit St, Boston, MA 02114 USA. EM wcurry@partners.org; barker@helix.mgh.harvard.edu NR 127 TC 29 Z9 29 U1 4 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAY PY 2009 VL 93 IS 1 BP 25 EP 39 DI 10.1007/s11060-009-9840-5 PG 15 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 443WN UT WOS:000265941600002 PM 19430880 ER PT J AU Plotkin, SR Halpin, C Blakeley, JO Slattery, WH Welling, DB Chang, SM Loeffler, JS Harris, GJ Sorensen, AG McKenna, MJ Barker, FG AF Plotkin, Scott R. Halpin, Chris Blakeley, Jaishri O. Slattery, William H., III Welling, D. Bradley Chang, Susan M. Loeffler, Jay S. Harris, Gordon J. Sorensen, A. Gregory McKenna, Michael J. Barker, Fred G., II TI Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Vestibular schwannoma; Acoustic neuroma; Neurofibromatosis type 2; Trial design; Phase II trial ID QUALITY-OF-LIFE; ACOUSTIC NEUROMA SURGERY; PROGRESSION-FREE SURVIVAL; POSITRON-EMISSION-TOMOGRAPHY; GAMMA-KNIFE RADIOSURGERY; CLINICAL-TRIAL DESIGN; HIGH-GRADE GLIOMAS; CELL LUNG-CANCER; HEARING-LOSS; STEREOTACTIC RADIOSURGERY AB Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on post-contrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents. C1 [Barker, Fred G., II] Massachusetts Gen Hosp, Neurosurg Serv, Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Halpin, Chris] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Blakeley, Jaishri O.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21205 USA. [Slattery, William H., III] House Ear Res Inst, Dept Otolaryngol, Los Angeles, CA USA. [Welling, D. Bradley] Ohio State Univ, Dept Otolaryngol, Columbus, OH 43210 USA. [Chang, Susan M.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Harris, Gordon J.; Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [McKenna, Michael J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, Pappas Ctr Neurooncol, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM barker@helix.mgh.harvard.edu FU NCI NIH HHS [P30 CA006973] NR 155 TC 24 Z9 25 U1 3 U2 4 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 MAY PY 2009 VL 93 IS 1 SI SI BP 61 EP 77 DI 10.1007/s11060-009-9867-7 PG 17 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 443WN UT WOS:000265941600005 PM 19430883 ER PT J AU Vogelbaum, MA Asher, AL Kondziolka, D Boulis, NM Selden, NR Hoh, BL Barker, FG AF Vogelbaum, Michael A. Asher, Anthony L. Kondziolka, Douglas Boulis, Nicholas M. Selden, Nathan R. Hoh, Brian L. Barker, Fred G., II TI Modern treatment of cerebral metastases: Integrated Medical Learning(SM) at CNS 2007 SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Cerebral metastases; Stereotactic radiosurgery; Whole brain radiotherapy; Medical education ID WHOLE-BRAIN RADIOTHERAPY; THERAPY-ONCOLOGY-GROUP; STEREOTACTIC RADIOSURGERY BOOST; RECURSIVE PARTITIONING ANALYSIS; QUALITY-OF-LIFE; PHASE-III TRIAL; RADIATION-THERAPY; NEUROCOGNITIVE FUNCTION; SINGLE METASTASES; RANDOMIZED-TRIAL AB Introduction Cerebral metastases are a common problem and pose complex treatment decisions, with reference to local control of treated lesions, prevention of new brain metastases, and toxicity of available treatments. At the 2007 Congress of Neurological Surgeons (CNS) Annual Meeting, a novel active learning process, called Integrated Medical Learning(SM), was used to better understand contemporary practice patterns and to monitor the success of education about these critical treatment decisions. Methods CNS members received an electronically distributed premeeting survey and educational materials about single and multiple cerebral metastasis treatment; practice patterns were elicited. At the Annual Meeting, 496 surgeons were polled using handheld devices before and after surgical and radiation oncology expert presentations. Surgeons who had answered premeeting surveys received a second, postmeeting questionnaire. Results In the premeeting questionnaire (N = 214), higher current volume of practice, Tumor Section membership, and academic practice predicted more correct answers (P < 0.05 for all). Fifty five percent favored routine whole brain radiotherapy (WBRT) after metastasis resection. Thirty four percent "most often" used radiosurgery to the resection bed; these respondents cited "cognitive changes" in justifying WBRT omission. At the meeting, expert presentations were followed by audience shifts toward adjuvant WBRT after resection (P = 0.01) or radiosurgery (P < 0.001)-topics for which class I evidence was discussed. There was no shift in preference for surgery or radiosurgery (P = 0.24) or multiple metastasis treatment (P = 0.8)-topics for which clear class I evidence was not presented. Postmeeting questionnaires showed retained knowledge among meeting attendees. Conclusions Using IML, we were able to study baseline knowledge and practice patterns for an important neuro-oncological treatment decision. Evidence suggested expert presentations were effective in changing audience opinion when relevant class I evidence was presented, and that knowledge was retained postmeeting. C1 [Barker, Fred G., II] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Vogelbaum, Michael A.] Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA. [Vogelbaum, Michael A.] Cleveland Clin Fdn, Dept Neurosurg, Cleveland, OH 44195 USA. [Asher, Anthony L.] Carolina Neurosurg & Spine Associates, Brain Tumor Program, Charlotte, NC USA. [Kondziolka, Douglas] Univ Pittsburgh, Sch Med, Med Ctr, Dept Neurol Surg, Pittsburgh, PA USA. [Kondziolka, Douglas] Univ Pittsburgh, Sch Med, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA USA. [Boulis, Nicholas M.] Emory Univ, Dept Neurol Surg, Atlanta, GA 30322 USA. [Selden, Nathan R.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Div Pediat Neurosurg, Portland, OR 97201 USA. [Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. [Barker, Fred G., II] Harvard Univ, Sch Med, Dept Surg Neurosurg, Boston, MA USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Yawkey 9E,Fruit St, Boston, MA 02114 USA. EM barker@helix.mgh.harvard.edu OI Selden, Nathan/0000-0001-6108-9721 NR 74 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAY PY 2009 VL 93 IS 1 SI SI BP 89 EP 105 DI 10.1007/s11060-009-9833-4 PG 17 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 443WN UT WOS:000265941600007 PM 19430885 ER PT J AU Aghi, MK Batchelor, TT Louis, DN Barker, FG Curry, WT AF Aghi, Manish K. Batchelor, Tracy T. Louis, David N. Barker, Fred G., II Curry, William T., Jr. TI Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Infection; Chromosome 10q; Helper T cells ID ANAPLASTIC ASTROCYTOMA; MALIGNANT GLIOMA; TUMOR SPECIMENS; BRAIN-TUMORS; T-CELLS; PTEN; CYTOKINE; SURVIVAL; HETEROZYGOSITY; MULTIFORME AB Introduction Chromosome 10q allelic loss commonly occurs in glioblastoma. Disruption of PTEN, one of three known 10q tumor suppressor genes, affects the immune system by increasing tumor expression of immunosuppressive protein B7-H1 and by increasing tumor release of Th2-inducing cytokines. While the former might impair antitumor cellular immunity, a consideration for immunotherapy, the latter could cause 10q-maintaining tumor patients to experience comparatively higher rates of bacterial infections, a source of morbidity and mortality in glioblastoma patients. Methods We retrospectively reviewed 58 glioblastoma patients whose tumors were designated "normal-10q" (n = 16) or "LOH-10q" (n = 42) using loss of heterozygosity (LOH) assays of microsatellite markers in constitutional/tumor DNA pairs. Records were reviewed for symptomatic, microbiologically or radiographically confirmed infections in the first 2 years after diagnosis. Results Infection occurred more frequently in "normal-10q" than "LOH-10q" patients (56% vs. 14% of patients experiencing infection; P = 0.001). "Normal-10q" patients more commonly developed all four infection types studied (urinary tract = 38% vs. 13%, craniotomy wound = 19% vs. 0%, pneumonia = 19% vs. 5%, sepsis = 6% vs. 3%). "Normal-10q" and "LOH-10q" patients had similar survival, ages, chemotherapy treatment rates, and frequency of patients on dexamethasone 1 month after radiation therapy (P = 0.4-0.98), making these factors unlikely to explain the observed difference in infection rates. Conclusion While tumor mutations may inhibit antitumor immunity, the effects of these mutations on systemic immunity remain undetermined. We found higher infection rates after glioblastoma diagnosis in patients whose tumors maintained chromosome 10q than in patients whose tumors had allelic 10q loss. Differing effects of this genetic alteration on antitumor and systemic immunity may warrant further investigation, potentially providing insight into mechanisms of antitumor immunity and host defenses against local and systemic infections. C1 [Aghi, Manish K.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Batchelor, Tracy T.; Barker, Fred G., II; Curry, William T., Jr.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Louis, David N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurooncol Lab, Boston, MA USA. [Barker, Fred G., II; Curry, William T., Jr.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Aghi, MK (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave Room M779, San Francisco, CA 94143 USA. EM AghiM@neurosurg.ucsf.edu NR 28 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAY PY 2009 VL 93 IS 1 BP 115 EP 120 DI 10.1007/s11060-009-9826-3 PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 443WN UT WOS:000265941600009 PM 19430887 ER PT J AU Wang, Q Tang, XN Swanson, RA Yenari, MA AF Wang, Q. Tang, X. N. Swanson, R. A. Yenari, M. A. TI Pyruvate protects experimental stroke: the involvement of anti-inflammatory mechanisms via inhibition of NF-kappa B and MMP9 SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 3rd International-Society-of-Neurochemistry-Special-Neurochemistry Conference/8th International Meeting on Brain Energy Metabolism CY JUN 27-JUL 01, 2008 CL Beijing, PEOPLES R CHINA SP Int Soc Neurochem C1 [Wang, Q.; Tang, X. N.; Swanson, R. A.; Yenari, M. A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Wang, Q.; Tang, X. N.; Swanson, R. A.; Yenari, M. A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Wang, Q.; Tang, X. N.] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. [Wang, Q.] Univ Wollongong, Fac Hlth & Behav Sci, Neurobiol Res Ctr, Wollongong, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2009 VL 109 BP 278 EP 279 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 430UF UT WOS:000265013900079 ER PT J AU Tang, KS Suh, SW Alano, CC Swanson, RA Anderson, CM AF Tang, K. S. Suh, S. W. Alano, C. C. Swanson, R. A. Anderson, C. M. TI Astrocyte poly (ADP-ribose) polymerase-1 activation causes glutamate excitotoxicity in neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 3rd International-Society-of-Neurochemistry-Special-Neurochemistry Conference/8th International Meeting on Brain Energy Metabolism CY JUN 27-JUL 01, 2008 CL Beijing, PEOPLES R CHINA SP Int Soc Neurochem C1 [Tang, K. S.; Anderson, C. M.] Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada. [Tang, K. S.; Anderson, C. M.] St Boniface Gen Hosp, Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB R2H 2A6, Canada. [Suh, S. W.; Alano, C. C.; Swanson, R. A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Suh, S. W.; Alano, C. C.; Swanson, R. A.] San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RI Anderson, Chris/J-7081-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2009 VL 109 BP 286 EP 286 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 430UF UT WOS:000265013900104 ER PT J AU McFarland, NR Lee, JS Hyman, BT McLean, PJ AF McFarland, Nikolaus R. Lee, Jeng-Shin Hyman, Bradley T. McLean, Pamela J. TI Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adeno-associated virus; gene therapy; Parkinson disease; striatum; substantia nigra; transduction ID ADENOASSOCIATED VIRUS AAV; CENTRAL-NERVOUS-SYSTEM; DOPAMINERGIC NEURON LOSS; VIRAL VECTOR SEROTYPE-1; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; GENE-TRANSFER; SUBSTANTIA-NIGRA; MOUSE-BRAIN; EXPRESSION AB Enhanced delivery and expression of genes in specific neuronal systems is critical for the development of genetic models of neurodegenerative disease and potential gene therapy. Recent discovery of new recombinant adeno-associated viral (rAAV) capsid serotypes has resulted in improved transduction efficiency, but expression levels, spread of transgene, and potential toxicity can differ depending on brain region and among species. We compared the transduction efficiency of titer-matched rAAV 2/1, 2/5, and 2/8 to the commonly used rAAV2/2 in the rat nigrostriatal system via expression of the reporter transgene, enhanced green fluorescent protein. Newer rAAV serotypes 2/1, 2/5, and 2/8 demonstrated marked increase in transduction and spread of enhanced green fluorescent protein expression in dopaminergic nigrostriatal neurons and projections to the striatum and globus pallidus compared to rAAV2/2 at 2 weeks post-injection. The number of nigral cells transduced was greatest for rAAV2/1, but for serotypes 2/5 and 2/8 was still two- to threefold higher than that for 2/2. Enhanced transduction did not cause an increase in glial cell response or toxicity. New rAAV serotypes thus promise improved gene delivery to nigrostriatal system with the potential for better models and therapeutics for Parkinson disease and other neurodegenerative disorders. C1 [McFarland, Nikolaus R.; Hyman, Bradley T.; McLean, Pamela J.] Harvard Univ, Sch Med, Charlestown, MA USA. [McFarland, Nikolaus R.; Hyman, Bradley T.; McLean, Pamela J.] Massachusetts Gen Hosp, Dept Neurol, MIND, Charlestown, MA USA. [Lee, Jeng-Shin] Harvard Univ, Sch Med, Dept Genet, Harvard Gene Therapy Initiat, Boston, MA USA. [Lee, Jeng-Shin] Harvard Univ, Sch Med, Dana Farber Harvard Canc Inst, Boston, MA USA. RP McFarland, NR (reprint author), Bldg 114,16th St 2400, Charlestown, MA 02129 USA. EM nmcfarland@partners.org OI McFarland, Nikolaus/0000-0002-8699-8857 FU NIH [NS038372A-08]; American Parkinson Disease Association (APDA) FX This work was supported by NIH NS038372A-08. NRM is supported by the American Parkinson Disease Association (APDA). NR 31 TC 39 Z9 39 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2009 VL 109 IS 3 BP 838 EP 845 DI 10.1111/j.1471-4159.2009.06010.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 430UD UT WOS:000265013700014 PM 19250335 ER PT J AU Hsieh, CL Koike, M Spusta, SC Niemi, EC Yenari, M Nakamura, MC Seaman, WE AF Hsieh, Christine L. Koike, Maya Spusta, Steve C. Niemi, Erene C. Yenari, Midori Nakamura, Mary C. Seaman, William E. TI A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptotic neurons; microglia; phagocytosis ID CENTRAL-NERVOUS-SYSTEM; MYELOID CELLS; IN-VIVO; FRACTALKINE RECEPTOR; PATTERN-RECOGNITION; DENDRITIC CELLS; IMMUNE-SYSTEM; CUTTING EDGE; DAP12; MACROPHAGES AB Following neuronal injury, microglia initiate repair by phagocytosing dead neurons without eliciting inflammation. Prior evidence indicates triggering receptor expressed by myeloid cells-2 (TREM2) promotes phagocytosis and retards inflammation. However, evidence that microglia and neurons directly interact through TREM2 to orchestrate microglial function is lacking. We here demonstrate that TREM2 interacts with endogenous ligands on neurons. Staining with TREM2-Fc identified TREM2 ligands (TREM2-L) on Neuro2A cells and on cultured cortical and dopamine neurons. Apoptosis greatly increased the expression of TREM2-L. Furthermore, apoptotic neurons stimulated TREM2 signaling, and an anti-TREM2 mAb blocked stimulation. To examine the interaction between TREM2 and TREM2-L in phagocytosis, we studied BV2 microglial cells and their engulfment of apoptotic Neuro2A. One of our anti-TREM2 mAb, but not others, reduced engulfment, suggesting the presence of a functional site on TREM2 interacting with neurons. Further, Chinese hamster ovary cells transfected with TREM2 conferred phagocytic activity of neuronal cells demonstrating that TREM2 is both required and sufficient for competent uptake of apoptotic neuronal cells. Finally, while TREM2-L are expressed on neurons, TREM2 is not; in the brain, it is found on microglia. TREM2 and TREM2-L form a receptor-ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Seaman, WE (reprint author), Vet Affairs Med Ctr, 111R,4150 Clement St, San Francisco, CA 94121 USA. EM bseaman@medicine.ucsf.edu FU Department of Defense [W81XWH-05-2-0094, PT075679]; NIH NINDS [R01 NS40516]; Veterans Administration; NIH NINDS NRSA [5F32NS060338] FX The authors acknowledge and thank Dr Damiana Alvarez for her contributions during the initial phases of this project. The authors also thank Dr Eric Huang and Dr Jiasheng Zhang (UC San Francisco) for their guidance in isolating ventral midbrain neurons, and we thank Dr Daniel Cua and Dr Barbara Shaikh (Schering-Plough, Palo Alto, CA, USA) and Dr Monica Carson (UC Riverside) for their guidance regarding microglial isolation. We also appreciate the help of Ben Harmeling and Dr Ken Scalapino, who operate the flow cytometry core facility at the San Francisco VA Medical Center. This work was funded by the Department of Defense (W81XWH-05-2-0094 and PT075679 to WES), by the NIH NINDS (R01 NS40516 to MY), and by the Veterans Administration. CLH is supported by an NIH NINDS NRSA (5F32NS060338). NR 42 TC 111 Z9 112 U1 0 U2 21 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2009 VL 109 IS 4 BP 1144 EP 1156 DI 10.1111/j.1471-4159.2009.06042.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 433EK UT WOS:000265186900018 PM 19302484 ER PT J AU Wang, CSM Burke, JR Steffens, DC Hulette, CM Breitner, JCS Plassman, BL AF Wang, C. Sheei-Meei Burke, J. R. Steffens, D. C. Hulette, C. M. Breitner, J. C. S. Plassman, B. L. TI Twin pairs discordant for neuropathologically confirmed Lewy body dementia SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID ALZHEIMERS-DISEASE; FRONTOTEMPORAL DEMENTIA; PATHOLOGICAL DIAGNOSIS; PARKINSONS-DISEASE; RISK-FACTOR; BODIES DLB; WORK GROUP; REGISTRY; CONCORDANCE; CONSORTIUM AB Aim: Little is known about the concordance rate in twins for dementia with Lewy bodies (DLB). The rate of agreement between clinical and pathological diagnoses for DLB is typically low, necessitating confirmation of the diagnosis neuropathologically. Methods: Participants were 17 twin pairs enrolled in the Duke Twins Study of Memory in Aging in which at least one member of the pair had an autopsy confirmed diagnosis of DLB, Alzheimer's disease (AD) with Lewy bodies or frontotemporal dementia with Lewy bodies. The characteristics of those with dementia were assessed and rates of concordance for pathological confirmed dementia were examined. Results: Four monozygotic twin pairs had a proband with neuropathologically confirmed pure DLB; all remained discordant for dementia for periods up to 16 years or more. Five of 13 pairs in which the proband had AD plus DLB were concordant for dementia but only one pair was concordant for AD plus DLB, while the co-twins in the other four pairs had other types of dementia. Conclusions: The present study indicates that even among twins, a diagnosis of DLB in one twin does not predict the same diagnosis in the other twin. Neuropathological discordance in type of dementia among monozygotic pairs hints at environmental or epigenetic factors playing a role in Lewy body pathology. C1 [Steffens, D. C.; Plassman, B. L.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27701 USA. [Wang, C. Sheei-Meei] Tainan Hosp, Dept Hlth, Dept Psychiat, Tainan, Taiwan. [Burke, J. R.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Hulette, C. M.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Burke, J. R.; Hulette, C. M.] Duke Univ, Med Ctr, Joseph & Kathleen Bryan Alzheimers Dis Res Ctr, Durham, NC USA. [Breitner, J. C. S.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Breitner, J. C. S.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Plassman, BL (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, 905 Main St,Box 41,Ste 25-D, Durham, NC 27701 USA. EM brenda.plassman@duke.edu RI Burke, James/E-4245-2016 OI Burke, James/0000-0002-3408-7787 FU NIH [AG-08549, AG-05128, AG-02837]; American Health Assistance Foundation [95112] FX NIH AG-08549 (JCSB, BLP), American Health Assistance Foundation # 95112 (JCSB) and NIH AG-05128 and AG-02837 (CMH). NR 25 TC 11 Z9 11 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAY PY 2009 VL 80 IS 5 BP 562 EP 565 DI 10.1136/jnnp.2008.151654 PG 4 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 433ZN UT WOS:000265244900022 PM 19372291 ER PT J AU McFarland, NR Fan, ZY Xu, K Schwarzschild, MA Feany, MB Hyman, BT McLean, PJ AF McFarland, Nikolaus R. Fan, Zhanyun Xu, Kui Schwarzschild, Michael A. Feany, Mel B. Hyman, Bradley T. McLean, Pamela J. TI alpha-Synuclein S129 Phosphorylation Mutants Do Not Alter Nigrostriatal Toxicity in a Rat Model of Parkinson Disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Adeno-associated virus; Dopamine; Lewy bodies; Striatum; Substantia nigra; Tyrosine hydroxylase ID COUPLED RECEPTOR KINASE-5; DOPAMINERGIC NEURON LOSS; VIRAL VECTOR SEROTYPE-1; CENTRAL-NERVOUS-SYSTEM; LEWY BODY DISEASE; IN-VITRO; LOCUS TRIPLICATION; OXIDATIVE STRESS; DROSOPHILA MODEL; FIBRIL FORMATION AB Lewy bodies are found in Parkinson disease and related disorders and are extensively phosphorylated at Ser-129 (S129), but whether S129 phosphorylation mediates alpha-synuclein aggregation and neurotoxicity has been controversial. We used recombinant adeno-associated virus to overexpress alpha-synuclein in the rat nigrostriatal system. Rats were injected with recombinant adeno-associated virus 2/8 expressing either human wild-type (wt) or mutant alpha-synuclein with S129 replaced by alanine (S129A) or aspartate (S129D). Contralateral substantia nigra injections containing empty vector served as controls. Both wt and S129 mutants resulted in significant dopaminergic cell loss in the recipients by 6 weeks, but there were only small decreases in nigrostriatal terminal density and tyrosine hydroxylase expression. There were no significant differences in dopaminergic cell loss, nigrostriatal terminal density, or tyrosine hydroxylase expression among the wt and S129 mutants. Furthermore, we did not observe any differences in alpha-synuclein aggregate formation or distribution among wt and either S129 mutant. These findings contrast with those from previous studies and suggest that injections of both S129 phosphorylation mutants result in dopaminergic neurotoxicity similar to wt injections. Further study is needed to clarify the effects of these S129 Mutants and alpha-synuclein phosphorylation in mammalian systems. C1 [McFarland, Nikolaus R.; Fan, Zhanyun; Xu, Kui; Schwarzschild, Michael A.; Hyman, Bradley T.; McLean, Pamela J.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [McFarland, Nikolaus R.; Fan, Zhanyun; Xu, Kui; Schwarzschild, Michael A.; Hyman, Bradley T.; McLean, Pamela J.] Harvard Univ, Sch Med, Charlestown, MA USA. [Feany, Mel B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Feany, Mel B.] Harvard Univ, Sch Med, Boston, MA USA. RP McFarland, NR (reprint author), Bldg 114,16th St 2400, Charlestown, MA 02129 USA. EM mmcfarland@partners.org OI McFarland, Nikolaus/0000-0002-8699-8857 FU NIH [NS038372A-08]; DOD [W81XWH-04-1-0881]; American Parkinson Disease Association; Koch Jr. Fellowship FX This study was supported by NIH NS038372A-08 (Bradley Hyman) and DOD W81XWH-04-1-0881 (Michael Schwarzschild). Nikolaus McFarland is supported by an American Parkinson Disease Association and the Koch Jr. Fellowship. NR 52 TC 62 Z9 62 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 BP 515 EP 524 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600007 PM 19525899 ER PT J AU Auluck, P Su, J Lindquist, S AF Auluck, Pavan Su, Julie Lindquist, Susan TI The Relationship Between Mitochondria, Oxidative Stress, and alpha-Synuclein Toxicity in Parkinson Disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 11-14, 2009 CL San Antonio, TX SP Amer Assoc Neuropathol C1 [Auluck, Pavan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Su, Julie; Lindquist, Susan] Whitehead Inst Biomed Res, Cambridge, MA USA. RI Auluck, Pavan/A-1160-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 MA 20 BP 557 EP 557 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600031 ER PT J AU Snuderl, M Eichler, A Ligon, K Vu, Q Silver, M Betensky, R Ligon, A Wen, P Louis, D Iafrate, A AF Snuderl, Matija Eichler, April Ligon, Keith Vu, Quynh Silver, Michael Betensky, Rebecca Ligon, Azra Wen, Patrick Louis, David Iafrate, A. TI Polysomy For Chromosomes 1 And 19 Predicts Earlier Recurrence In Anaplastic Oligodendrogliomas With Concurrent 1p/19q Loss SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 11-14, 2009 CL San Antonio, TX SP Amer Assoc Neuropathol C1 [Snuderl, Matija; Vu, Quynh; Louis, David; Iafrate, A.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Eichler, April] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ligon, Keith; Ligon, Azra] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Silver, Michael] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Betensky, Rebecca] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. [Wen, Patrick] Neurooncol Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 MA 43 BP 562 EP 563 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600054 ER PT J AU Yip, S Miao, JY Cahill, D Iafrate, A Aldape, K Nutt, C Louis, D AF Yip, Stephen Miao, Jiangyong Cahill, Daniel Iafrate, A. Aldape, Kenneth Nutt, Catherine Louis, David TI MSH6 Somatic Mutations in Mediating Temozolomide Resistance in Recurrent Glioblastomas SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 11-14, 2009 CL San Antonio, TX SP Amer Assoc Neuropathol C1 [Yip, Stephen; Miao, Jiangyong; Cahill, Daniel; Iafrate, A.; Nutt, Catherine; Louis, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Aldape, Kenneth] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 MA 40 BP 562 EP 562 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600051 ER PT J AU Teich, A Hedley-Whyte, E Goldman, J AF Teich, Andrew Hedley-Whyte, E. Goldman, James TI "Pontinization" of the Medulla: Two Clinical Case Studies SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 11-14, 2009 CL San Antonio, TX SP Amer Assoc Neuropathol C1 [Teich, Andrew; Goldman, James] Columbia Univ, Div Neuropathol, New York, NY 10027 USA. [Hedley-Whyte, E.] Massachusetts Gen Hosp, Dept Neuropathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 MA 99 BP 577 EP 577 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600109 ER PT J AU Kim, Y Yip, S Quant, E Mobapatra, G Louis, D AF Kim, Yeowon Yip, Stephen Quant, Eudocia Mobapatra, Gayatry Louis, David TI Mismatch Repair Defects in Human Glioblastomas Post-Alkylator Treatment SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 11-14, 2009 CL San Antonio, TX SP Amer Assoc Neuropathol C1 [Quant, Eudocia] Massachusetts Gen Hosp, Mol Pathol Unit, Brain Tumor Ctr, Boston, MA 02114 USA. [Louis, David] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2009 VL 68 IS 5 MA 115 BP 581 EP 582 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 441GZ UT WOS:000265758600125 ER PT J AU Wig, GS Buckner, RL Schacter, DL AF Wig, Gagan S. Buckner, Randy L. Schacter, Daniel L. TI Repetition Priming Influences Distinct Brain Systems: Evidence From Task-Evoked Data and Resting-State Correlations SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID INFERIOR PREFRONTAL CORTEX; EVENT-RELATED FMRI; TRANSCRANIAL MAGNETIC STIMULATION; RESONANCE-IMAGING EVIDENCE; LATERAL OCCIPITAL COMPLEX; IMPLICIT MEMORY; TEMPORAL CORTEX; FUNCTIONAL MRI; RECOGNITION MEMORY; INFEROTEMPORAL CORTEX AB Wig GS, Buckner RL, Schacter DL. Repetition priming influences distinct brain systems: evidence from task-evoked data and resting-state correlations. J Neurophysiol 101: 2632-2648, 2009. First published February 18, 2009; doi:10.1152/jn.91213.2008. Behavioral dissociations suggest that a single experience can separately influence multiple processing components. Here we used a repetition priming functional magnetic resonance imaging paradigm that directly contrasted the effects of stimulus and decision changes to identify the underlying brain systems. Direct repetition of stimulus features caused marked reductions in posterior regions of the inferior temporal lobe that were insensitive to whether the decision was held constant or changed between study and test. By contrast, prefrontal cortex showed repetition effects that were sensitive to the exact stimulus-to-decision mapping. Analysis of resting-state functional connectivity revealed that the dissociated repetition effects are embedded within distinct brain systems. Regions that were sensitive to changes in the stimulus correlated with perceptual cortices, whereas the decision changes attenuated activity in regions correlated with middle-temporal regions and a frontoparietal control system. These results thus explain the long-known dissociation between perceptual and conceptual components of priming by revealing how a single experience can separately influence distinct, concurrently active brain systems. C1 [Wig, Gagan S.; Buckner, Randy L.; Schacter, Daniel L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Wig, Gagan S.; Buckner, Randy L.; Schacter, Daniel L.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Wig, GS (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. EM gwig@wjh.harvard.edu OI Schacter, Daniel/0000-0002-2460-6061 FU Canadian Institute; Howard Hughes Medical Institute; National Institute of Mental Health [MH-060941] FX This work was supported by an Institute for Aging Postdoctoral Fellowship from the Canadian Institute for Health Research to G. S. Wig, the Howard Hughes Medical Institute, and a National Institute of Mental Health Grant MH-060941 to D. L. Schacter. NR 101 TC 41 Z9 42 U1 4 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAY PY 2009 VL 101 IS 5 BP 2632 EP 2648 DI 10.1152/jn.91213.2008 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 436FM UT WOS:000265398100041 PM 19225167 ER PT J AU Yehuda, R Harvey, PD Golier, JA Newmark, RE Bowie, CR Wohltmann, JJ Grossman, RA Schmeidler, J Hazlett, EA Buchsbaum, MS AF Yehuda, Rachel Harvey, Philip D. Golier, Julia A. Newmark, Randall E. Bowie, Christopher R. Wohltmann, Janelle J. Grossman, Robert A. Schmeidler, James Hazlett, Erin A. Buchsbaum, Monte S. TI Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID MEDIAL PREFRONTAL CORTEX; CORTICOLIMBIC BLOOD-FLOW; MIXED LATERAL PREFERENCE; CHILDHOOD SEXUAL-ABUSE; SCRIPT-DRIVEN IMAGERY; HIPPOCAMPAL-FORMATION; MEMORY PERFORMANCE; ALZHEIMERS-DISEASE; PERSONALITY-DISORDER; BASOLATERAL AMYGDALA AB The authors aimed to examine central glucocorticoids effects by measuring relative glucose metabolic rate (rGMR) in the hippocampus, amygdala, and anterior cingulate cortex (ACC) and the relationship between amygdala and ACC activity. The participants were male combat veterans with and without PTSD, 52 to 81 years old. The authors utilized randomized, double-blind, placebo-controlled examinations of the rGMR response to 17.5 mg hydrocortisone (HCORT) using 2-Deoxy-2-[(18)F] fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) neuroimaging. Group differences in hemispheric laterality of rGMR were observed following placebo administration, reflecting lower rGMR in the right hippocampus and ventral amygdala, and higher rGMR in the left ventral amygdala in the PTSD+ group compared to the PTSD+ group. HCORT reduced these group differences in laterality. The net effect of HCORT was to restore a normal inverse association between the ACC and amygdala in the PTSD+ group, but disrupt this neural network in the PTSD- group. The magnitude of improvement in working memory correlated with greater hemispheric laterality in the dorsal amygdala following HCORT in both groups. The restorative effects of HCORT on metabolism and working memory provide a rationale for examining the therapeutic benefits of glucocorticoid manipulation in aging PTSD patients. C1 [Yehuda, Rachel; Golier, Julia A.; Bowie, Christopher R.; Wohltmann, Janelle J.; Grossman, Robert A.; Schmeidler, James] Mt Sinai Sch Med, Dept Psychiat, Traumat Stress Studies Program, New York, NY USA. [Yehuda, Rachel; Golier, Julia A.; Bowie, Christopher R.; Wohltmann, Janelle J.] James J Peters Bronx Vet Affairs Med Ctr, PTSD Program, Bronx, NY USA. [Harvey, Philip D.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Newmark, Randall E.; Hazlett, Erin A.; Buchsbaum, Monte S.] Mt Sinai Sch Med, Dept Psychiat, PET Lab, New York, NY USA. RP Yehuda, R (reprint author), Bronx VA OOMH, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Rachel.Yehuda@va.gov FU National Institute of Health [5 M01 RR00071] FX This work was supported by a VA Merit Review Grant (RY) and, in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institute of Health. The authors wish to thank Karina Stavitsky for expert and professional coordination of this research project, Dr. Linda Bierer for database construction, Yuliya Torosjan for scanner operation, Dr. King-Wai Chu for program development and support, and Drs. Lisa Tischler and Alicia Hirsch for conducting diagnostic evaluations. Dr. Yehuda had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 69 TC 18 Z9 21 U1 2 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD MAY PY 2009 VL 21 IS 2 BP 132 EP 143 PG 12 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 472SL UT WOS:000268152300004 PM 19622684 ER PT J AU Erickson, JI Duffy, ME Ditomassi, M Jones, D AF Erickson, Jeanette Ives Duffy, Mary E. Ditomassi, Marianne Jones, Dorothy TI Psychometric Evaluation of the Revised Professional Practice Environment (RPPE) Scale SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article ID INTENSIVE-CARE UNITS; NURSING WORK INDEX; CROSS-VALIDATION; QUESTIONNAIRE; HOSPITALS; SERVICES; ISSUES AB Objective: The purpose was to examine the psychometric properties of the Revised Professional Practice Environment (RPPE) scale. Background: Despite renewed focus on studying health professionals' practice environments, there are still few reliable and valid instruments available to assist nurse administrators in decision making. Methods: A psychometric evaluation using a random-sample cross-validation procedure (calibration sample [CS], n = 775; validation sample [VS], n = 775) was undertaken. Results: Cronbach alpha internal consistency reliability of the total score (r = 0.93 [CS] and 0.92 [VS]), resulting subscale scores (r range: 0.80-0.87 [CS], 0.81-0.88 [VS]), and principal components analyses with Varimax rotation and Kaiser normalization (8 components, 59.2% variance [CS], 59.7% [VS]) produced almost identical results in both samples. Conclusions: The multidimensional RPPE is a psychometrically sound measure of 8 components of the professional practice environment in the acute care setting and sufficiently reliable and valid for use as independent subscales in healthcare research. C1 [Erickson, Jeanette Ives; Duffy, Mary E.; Ditomassi, Marianne; Jones, Dorothy] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Duffy, ME (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM mduffy4@partners.org NR 24 TC 23 Z9 23 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD MAY PY 2009 VL 39 IS 5 BP 236 EP 243 PG 8 WC Nursing SC Nursing GA 445NA UT WOS:000266056300007 PM 19423989 ER PT J AU Ruggiero, SL Dodson, TB Assael, LA Landesberg, R Marx, RE Mehrotra, B AF Ruggiero, Salvatore L. Dodson, Thomas B. Assael, Leon A. Landesberg, Regina Marx, Robert E. Mehrotra, Bhoomi TI American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws-2009 Update SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID MULTIPLE-MYELOMA PATIENTS; PLACEBO-CONTROLLED TRIAL; BONE-MINERAL DENSITY; LONG-TERM EFFICACY; ZOLEDRONIC ACID; RISK-FACTORS; BREAST-CANCER; SKELETAL COMPLICATIONS; PREVENTIVE MEASURES; JAW OSTEONECROSIS AB Bisphosphonate-related osteonecrosis of the jaw (BRONJ) adversely affects the quality of life, producing significant morbidity in afflicted patients. Strategies for the treatment of patients with, or at risk of, BRONJ were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper on Bisphsphonate-Related Osteonecrosis of the jaws (Position Paper) and approved by the Board of Trustees in September 2006.(1) The Position Paper was developed by a Task Force appointed by the Board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing BRONJ has expanded, necessitating modifications and refinements to the original Position Paper. The Task Force was reconvened in August 2008 to review the 2006 recommendations, appraise the current published data, and revise the Position Paper and recommendations, where indicated. This update contains revisions to the diagnosis and staging and management strategies and highlights the status of basic science research. AAOMS considers it vitally important that this information be disseminated to other dental and medical specialties. C1 [Ruggiero, Salvatore L.] Long Isl Jewish Med Ctr, Div Oral & Maxillofacial Surg, Stony Brook Sch Dent Med, New Hyde Pk, NY 11042 USA. [Ruggiero, Salvatore L.] New York Ctr Orthognath & Maxillofacial Surg, Lake Success, NY USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Assael, Leon A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Landesberg, Regina] Columbia Univ, Sch Dent & Oral Surg, Div Oral Maxillofacial Surg, New York, NY USA. [Marx, Robert E.] Univ Miami, Sch Med, Div Oral & Maxillofacial Surg, Miami, FL USA. [Mehrotra, Bhoomi] Long Isl Jewish Med Ctr, Div Med Oncol, New Hyde Pk, NY 11042 USA. [Mehrotra, Bhoomi] Albert Einstein Coll Med, New Hyde Pk, NY USA. RP Ruggiero, SL (reprint author), Long Isl Jewish Med Ctr, Div Oral & Maxillofacial Surg, Stony Brook Sch Dent Med, New Hyde Pk, NY 11042 USA. EM drruggiero@nycoms.com RI de la Flor, Maria/B-9212-2015 NR 62 TC 482 Z9 509 U1 4 U2 32 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 MAY PY 2009 VL 67 IS 5 SU 1 BP 2 EP 12 DI 10.1016/j.joms.2009.01.009 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 439VH UT WOS:000265655000002 PM 19371809 ER PT J AU Dodson, TB AF Dodson, Thomas B. TI Intravenous Bisphosphonate Therapy and Bisphosphonate-Related Osteonecrosis of the Jaws SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID MULTIPLE-MYELOMA PATIENTS; ZOLEDRONIC ACID; RISK-FACTORS; POSTMENOPAUSAL OSTEOPOROSIS; CANCER-CHEMOTHERAPY; PREVENTIVE MEASURES; FREQUENCY; IMPLEMENTATION; ASSOCIATION; EXPERIENCE AB The purposes of this report are to 1) summarize the epidemiologic evidence supporting an association between intravenous bisphosphonate (BP) exposure and BP-related osteonecrosis of the jaws (BRONJ), 2) identify measurable risk factors associated with BRONJ, and 3) assess the risk of BRONJ for patients receiving intravenous BPs to manage osteoporosis. The results of this review suggest a compelling, circumstantial association between intravenous BP exposure and BRONJ. The factors consistently associated with an increased risk of BRONJ included intravenous BP exposure in the setting of malignancy and dentoalveolar procedures. Finally, intravenous BP therapy for osteoporosis does not measurably increase the risk of BRONJ among postmenopausal women. (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:44-52, 2009, Suppl 1 C1 [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, 55 Fruit St,Warren 1201, Boston, MA 02114 USA. EM tbdodson@partners.org NR 31 TC 30 Z9 31 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAY PY 2009 VL 67 IS 5 BP 44 EP 52 DI 10.1016/j.joms.2008.12.004 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 439VH UT WOS:000265655000007 PM 19371814 ER PT J AU Susarla, SM August, M Dewsnup, N Faquin, WC Kaban, LB Dodson, TB AF Susarla, Srinivas M. August, Meredith Dewsnup, Nathan Faquin, William C. Kaban, Leonard B. Dodson, Thomas B. TI CD34 Staining Density Predicts Giant Cell Tumor Clinical Behavior SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; JAWS; GRANULOMA; LESIONS AB Purpose: To evaluate the staining density of CD34, a glycoprotein expressed in hematopoetic precursor and capillary endothelial cells, as a molecular marker for predicting clinical behavior of giant cell tumors. Materials and Methods: This was a retrospective study of patients with giant cell lesions of the jaws treated over a 15-year period. The primary predictor variable was mean CD34 staining density. The outcome measure was giant cell tumor clinical behavior (aggressive vs nonaggressive). Bivariate analyses were computed to evaluate the association between the predictors and outcome. A receiver-operator characteristic (ROC) curve was used to establish the threshold for a positive diagnostic test. A logistic regression model was used to evaluate the association between the clinical behavior and a positive test. A value of P <= .05 was statistically significant. Results: The study sample consisted of 32 subjects with a mean age of 24.4 +/- 19.8 years (range 2-83), including 23 females (71.8%), treated for giant cell lesions during the study period. The sample included 26 aggressive lesions and 6 nonaggressive lesions, with mean CD34 staining densities of 5.1 +/- 3.3% and 2.2 +/- 0.7%, respectively (P = .02). Using a CD34 staining level of equal to or more than 2.5% as indicative of a positive test, the sensitivity, specificity, positive and negative predictive values were 0.77, 0.83, 0.95 and 0.45, respectively. CD34 levels of more than 2.5% were significantly associated with aggressive lesions whereas CD 34 levels of less than 2.5% were associated with nonaggressive lesions (odds ratio: 16.7, P = .04). Conclusions: CD34 staining density levels of more than 2.5% were associated with aggressive giant cell lesions. (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:951-956, 2009 C1 [Susarla, Srinivas M.; Kaban, Leonard B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [August, Meredith; Dewsnup, Nathan; Kaban, Leonard B.; Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Ctr Appl Clin Invest, Boston, MA 02114 USA. RP Susarla, SM (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren 1201, Boston, MA 02114 USA. EM smsusarla@gmail.com OI Susarla, Srinivas/0000-0003-0155-8260 FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; Oral and Maxillofacial Surgery Foundation Fellowship in Clinical Investigation FX This study was supported by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund (S.M.S., N.D.) and the Oral and Maxillofacial Surgery Foundation Fellowship in Clinical Investigation (S.M.S.). NR 15 TC 8 Z9 8 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAY PY 2009 VL 67 IS 5 BP 951 EP 956 DI 10.1016/j.joms.2008.12.045 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 439VE UT WOS:000265654700005 PM 19375002 ER PT J AU Kaban, LB Seldin, EB Kikinis, R Yeshwant, K Padwa, BL Troulis, MJ AF Kaban, Leonard B. Seldin, Edward B. Kikinis, Ron Yeshwant, Krishna Padwa, Bonnie L. Troulis, Maria J. TI Clinical Application of Curvilinear Distraction Osteogenesis for Correction of Mandibular Deformities SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article AB Purpose: To report the use of a semiburied curvilinear distraction device, with a 3-dimensional (3D) Computed tomography treatment planning system, for correction of mandibular deformities. Materials and Methods: This was a retrospective evaluation of 13 consecutive patients, with syndromic and nonsyndromic micrognathia, who underwent correction by curvilinear distraction osteogenesis. A 3D computed tomography scan was obtained for each patient and imported into a 3D treatment planning system (Slicer/Osteoplan). Surgical guides were constructed to localize the osteotomy and to drill holes to secure the distractor's proximal and distal footplates to the mandible. Postoperatively, patients were followed by clinical examination and plain radiographs to ensure the desired vector of movement. At end distraction, when possible, a 3D computed tomography scan was obtained to document the final mandibular position. Results: Of the 13 patients, 8 were females and 5 were males, with a mean age of 11.9 years (range 15 months to 39 years). All 13 underwent bilateral mandibular Curvilinear distraction. Of the 13 patients, 8 were 16 years old or younger and 5 were younger than 6 years of age. The diagnoses included Treacher Collins syndrome (n = 3), Nager syndrome (n = 3), craniofacial microsomia (n = 2), post-traumatic ankylosis (n = 1), and micrognathia (syndromic, n = 3; nonsyndromic, n = 1). The correct distractor placement, vector of movement, and final mandibular position were achieved in 10 of 13 patients. In the other 3 patients, the desired jaw position was achieved by "molding" the regenerate. Conclusions: The use of a semiburied Curvilinear distraction device, with 3D treatment planning, is a potentially powerful tool to correct complex mandibular deformities. (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:996-1008, 2009 C1 [Kaban, Leonard B.] Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Kikinis, Ron] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Kikinis, Ron; Yeshwant, Krishna] Harvard Surg Planning Lab, Boston, MA USA. [Padwa, Bonnie L.] Harvard Univ, Childrens Hosp, Sch Dent Med, Boston, MA 02115 USA. RP Kaban, LB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, Warren 1201, Boston, MA 02114 USA. EM LKaban@Partners.org FU AO-ASIF Foundation (Berne, Switzerland); Synthes CMF (West Chester, PA); Massachusetts General Hospital Center for Innovation and Minimally Invasive Therapy in Medicine; Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; National Institutes of Health [P41RR13218] FX This work was supported by grants from the AO-ASIF Foundation (Berne, Switzerland), Synthes CMF (West Chester, PA), the Massachusetts General Hospital Center for Innovation and Minimally Invasive Therapy in Medicine, the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund, and National Institutes of Health grant P41RR13218 (R. Kikinis, principal investigator). NR 14 TC 28 Z9 30 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAY PY 2009 VL 67 IS 5 BP 996 EP 1008 DI 10.1016/j.joms.2009.01.010 PG 13 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 439VE UT WOS:000265654700012 PM 19375009 ER PT J AU Hosseini, A Gill, TJ Li, GA AF Hosseini, Ali Gill, Thomas J. Li, Guoan TI In vivo anterior cruciate ligament elongation in response to axial tibial loads SO JOURNAL OF ORTHOPAEDIC SCIENCE LA English DT Article ID SITU FORCES; KNEE FLEXION; ANTEROMEDIAL BAND; JOINT KINEMATICS; RECONSTRUCTION; STRAIN; BUNDLES; ACL; WEIGHTBEARING; TRANSLATION AB The knowledge of in vivo anterior cruciate ligament (ACL) deformation is fundamental for understanding ACL injury mechanisms and for improving surgical reconstruction of the injured ACL. This study investigated the relative elongation of the ACL when the knee is subject to no load (< 10 N) and then to full body weight (axial tibial load) at various flexion angles using a combined dual fluoroscopic and magnetic resonance imaging (MRI) technique. Nine healthy subjects were scanned with MRI and imaged when one knee was subject to no load and then to full body weight using a dual fluoroscopic system (0A degrees-45A degrees flexion angles). The ACL was analyzed using three models: a single central bundle; an anteromedial and posterolateral (double functional) bundle; and multiple (eight) surface fiber bundles. The anteromedial bundle had a peak relative elongation of 4.4% +/- 3.4% at 30A degrees and that of the posterolateral bundle was 5.9% +/- 3.4% at 15A degrees. The ACL surface fiber bundles at the posterior portion of the ACL were shorter in length than those at the anterior portion. However, the peak relative elongation of one posterolateral fiber bundle reached more than 13% whereas one anteromedial fiber bundle reached a peak relative elongation of only about 3% at 30A degrees of flexion by increasing the axial tibial load from no load to full body weight. The data quantitatively demonstrated that under external loading the ACL experiences nonhomogeneous elongation, with the posterior fiber bundles stretching more than the anterior fiber bundles. C1 [Hosseini, Ali; Gill, Thomas J.; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02114 USA. [Hosseini, Ali] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. FU NIH [R21AR051078] FX This research was supported by NIH grant R21AR051078. The technical assistance of Ramprasad Papannagari, Jeff Bingham, Dr. Samuel Van de Velde, Dr. Louis E. DeFrate, Dr. Kyung Wook Nha, and Angela Moynihan is greatly appreciated. NR 30 TC 22 Z9 22 U1 1 U2 3 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0949-2658 J9 J ORTHOP SCI JI J. Orthop. Sci. PD MAY PY 2009 VL 14 IS 3 BP 298 EP 306 DI 10.1007/s00776-009-1325-z PG 9 WC Orthopedics SC Orthopedics GA 458MV UT WOS:000267029000010 PM 19499297 ER PT J AU Driscoll, DF Ling, PR Andersson, C Bistrian, BR AF Driscoll, David F. Ling, Pei-Ra Andersson, Charlotte Bistrian, Bruce R. TI Hepatic Indicators of Oxidative Stress and Tissue Damage Accompanied by Systemic Inflammation in Rats Following a 24-Hour Infusion of an Unstable Lipid Emulsion Admixture SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article; Proceedings Paper CT 28th Congress of the European-Society-of-Parenteral-and-Enteral-Nutrition CY OCT, 2006 CL Istanbul, TURKEY SP European Soc Parenteral & Enteral Nutr DE large-diameter fat globules; stability; oxidative stress; hepatic injury; systemic inflammatory response ID CHAIN TRIGLYCERIDE EMULSIONS; TOTAL NUTRIENT ADMIXTURES; RETICULOENDOTHELIAL SYSTEM; LONG-CHAIN; INJECTABLE EMULSIONS; PATHOLOGICAL CONSEQUENCES; PARENTERAL-NUTRITION; STABILITY; HUMANS; GLASS AB Background: Use of lipid emulsions is parenteral nutrition therapy is an important source of daily energy in substitution of potentially harmful glucose calories when given in excess in the intensive care unit. When added to parenteral nutrition (PN) admixtures as a total nutrient admixture (TNA), the stability and safety of the emulsion may be compromised. Development of a rat model of a stable vs unstable lipid infusion would enable a study of the potential risk. Design: Prospective, randomized, controlled study. Methods: Surgical placement of a jugular venous catheter for the administration of TNAs was performed. Two groups were studied: a stable or s-TNA (n = 16) and an unstable or u-TNA (n = 17) as a 24-hour continuous infusion. Stability of TNAs was determined immediately before and after infusion using a laser-based method approved by the United States Pharmacopeia. Results: Blood levels of aspartate aminotransferase, glutathione-S-transferase, and C-reactive protein were significantly elevated in u-TNA vs s-TNA (P < .05). Also, liver tissue concentrations of malondialdehyde were significantly higher in the u-TNA group (P < .05), and triglyceride tissue levels were also higher in u-TNA and approached statistical significance (P = .077). Conclusions: Unstable lipid infusions over 24 hours produce evidence of hepatic accumulation of fat associated with oxidative stress, liver injury, and a low-level systemic inflammatory response. (JPEN J Parenter Enteral Nutr. 2009; 33; 327-335) C1 [Driscoll, David F.] Harvard Univ, Sch Med, BIDMC, Boston, MA 02215 USA. RP Driscoll, DF (reprint author), Harvard Univ, Sch Med, BIDMC, Baker Bldg,Suite 605, Boston, MA 02215 USA. EM ddriscol@bidmc.harvard.edu NR 27 TC 12 Z9 12 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD MAY-JUN PY 2009 VL 33 IS 3 BP 327 EP 335 DI 10.1177/0148607108327155 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 437RL UT WOS:000265504500005 PM 19221047 ER PT J AU Nagao, K Noel, LP Noel, ME Walton, DS AF Nagao, Karina Noel, Leon-Paul Noel, Marie-Eve Walton, David S. TI The Spontaneous Resolution of Primary Congenital Glaucoma SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Article CT 17th Annual Meeting of the American-Glaucoma-Society CY MAR 01-04, 2007 CL San Francisco, CA SP Amer Glaucoma Soc ID IRIDOCORNEAL ANGLE AB Purpose: To describe the ocular findings in a series of children with spontaneous resolution of primary congenital glaucoma (PCG). Methods: The medical records of 356 patients with PCG were reviewed. Nine patients with spontaneous resolution of PCG were studied. Fourteen of 18 eyes possessed evidence of early glaucoma, were found to have normal intraocular pressures, and were clinically classified as having spontaneous resolution of PCG. None of the eyes with spontaneous resolution received surgery or any glaucoma medication. Results: Spontaneous resolution of PCG in all nine patients was recognized after 4 months of age. At the time of diagnosis, large corneas were observed in all affected eyes and Haab's striae in 10 of 14 eyes. Intraocular pressures were normal in 14 eyes. In all 14 eyes, the anterior chambers were deep, the lenses were clear, and the angles were abnormal with the typical appearance of PCG. The eyes with spontaneous resolution of PCG possessed angle abnormalities that were less severe compared to three fellow eyes that required glaucoma treatments. Conclusion: The occurrence of spontaneous resolution of PCG in these patients is supported by objective clinical evidence. The explanation for this spontaneous resolution is unknown. Its mechanism could be related to continued postnatal development of the angle structures in eyes possessing milder angle abnormalities. The anterior segment findings in patients with spontaneous resolution of PCG are similar to those of patients with treated PCG, the intraocular pressures are normal, the optic nerve damage is stable, and the filtration angles possess mild or moderate abnormalities. C1 [Nagao, Karina] COE RIO, Rio De Janeiro, Brazil. [Noel, Leon-Paul; Noel, Marie-Eve] SUNY Upstate Med Univ, Dept Ophthalmol, Syracuse, NY USA. [Noel, Leon-Paul; Noel, Marie-Eve] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY USA. [Walton, David S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Walton, DS (reprint author), 2 Longfellow Pl,Suite 201, Boston, MA 02114 USA. NR 15 TC 8 Z9 9 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD MAY-JUN PY 2009 VL 46 IS 3 BP 139 EP 143 DI 10.9999/01913913-20090505-04 PG 5 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 444BR UT WOS:000265955500003 PM 19496494 ER PT J AU Spencer, TJ AF Spencer, Thomas J. TI Issues in the Management of Patients with Complex ADHD Symptoms SO JOURNAL OF PEDIATRICS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY DISORDER; SUBSTANCE USE DISORDERS; OPPOSITIONAL DEFIANT DISORDER; PLACEBO-CONTROLLED TRIAL; BIPOLAR DISORDER; CONDUCT DISORDER; MAJOR DEPRESSION; ANTIPSYCHOTIC MEDICATIONS; METHYLPHENIDATE TREATMENT AB Children and adolescents with attention deficit hyperactivity disorder (ADHD) have high levels of psychiatric comorbidity. The most common types of comorbidities include disruptive behavior, anxiety, and substance use disorders, as well as major depression. When comorbidities are present, impairments in school and family functioning tend to be more severe and persistent than in children who have ADHD alone. Comorbidities to ADHD are likely to go unrecognized in primary pediatric settings because clinicians may not routinely collect behavioral information, and parents are often reluctant to discuss their children's emotional problems with physicians. Although ADHD with a comorbid component is associated with poorer outcomes, many such patients can be treated successfully. Developing improved methods for the identification and appropriate treatment of comorbid conditions in children with ADHD must be a high clinical priority, because intervention can have a significant positive impact on patients' functioning and long-term outcomes. (J Pediatr 2009;154:S4-S12) C1 [Spencer, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Spencer, Thomas J.] Massachusetts Gen Hosp, Pediat Psychopharmacol Dept, Boston, MA 02114 USA. RP Spencer, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit Street,Warren 705, Boston, MA 02114 USA. EM tspencer@partners.org NR 75 TC 1 Z9 1 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2009 VL 154 IS 5 SU S BP S4 EP S12 DI 10.1016/j.jpeds.2009.01.016 PG 9 WC Pediatrics SC Pediatrics GA 437QF UT WOS:000265501300002 ER PT J AU Menkens, AJ Amelio, RC AF Menkens, Anne J. Amelio, Robert C. TI Leaders and Organizations in Transition SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material C1 [Menkens, Anne J.] Univ N Carolina, Sch Publ Hlth, N Carolina Inst Publ Hlth, Div Execut Educ, Chapel Hill, NC 27599 USA. [Amelio, Robert C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Menkens, AJ (reprint author), Univ N Carolina, Sch Publ Hlth, N Carolina Inst Publ Hlth, Div Execut Educ, CB 8165, Chapel Hill, NC 27599 USA. NR 3 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD MAY-JUN PY 2009 VL 15 IS 3 BP 274 EP 277 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 434GE UT WOS:000265262400014 PM 19363408 ER PT J AU Sloan, PA Berman, ME Zeigler-Hill, V Bullock, JS AF Sloan, Paul A. Berman, Mitchell E. Zeigler-Hill, Virgil Bullock, Joshua S. TI GROUP INFLUENCES ON SELF-AGGRESSION: CONFORMITY AND DISSENTER EFFECTS SO JOURNAL OF SOCIAL AND CLINICAL PSYCHOLOGY LA English DT Article ID IDENTITY MISCLASSIFICATION; SOCIAL-INFLUENCE; DRINKING NORMS; GROUP PRESSURE; ALCOHOL-USE; BEHAVIOR; MUTILATION; CONTAGION; SUICIDE; DETERMINANTS AB Evidence that intentional self-aggressive behaviors are influenced by social groups comes almost exclusively from nonexperimental retrospective studies which fail to address underlying causal processes. Recently, we conducted a study in which experimentally manipulated group norms were found to directly influence self-aggressive behavior (Sloan, Berman, Zeigler-Hill, Greer, & Mae, 2006). The present study was designed to gain a better understanding of the process by which social groups influence self-aggression. More specifically, we examined the effects of dissenters on the adoption of a self-aggressive group norm. Participants (N = 164) were assigned to one of the following conditions: a unanimous self-aggressive group, a nonunanimous group with a single dissenter in either the first or last position who did not engage in self-aggressive behavior, and a group with no systematic agreement concerning self-aggression. Self-aggression was operationally defined as the use of an extreme shock that was self-administered by the participant within the context of an attention task. Results demonstrated that the adoption of a self-aggressive group norm was significantly weakened by the presence of a dissenter. This effect was moderated by gender such that the presence of a dissenter had a greater impact on the self-aggressive behavior of women than it did for men. Clinical and theoretical implications of these findings are discussed. C1 [Sloan, Paul A.] Michael E DeBakey Vet Affairs Med Ctr, Mental Hlth Care Line 116 CMHP, Houston, TX 77030 USA. [Sloan, Paul A.] Baylor Coll Med, Houston, TX 77030 USA. [Berman, Mitchell E.; Zeigler-Hill, Virgil; Bullock, Joshua S.] Univ So Mississippi, Hattiesburg, MS 39406 USA. RP Sloan, PA (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Mental Hlth Care Line 116 CMHP, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM paul.sloan@va.gov NR 64 TC 3 Z9 3 U1 1 U2 5 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0736-7236 J9 J SOC CLIN PSYCHOL JI J. Soc. Clin. Psychol. PD MAY PY 2009 VL 28 IS 5 BP 535 EP 553 PG 19 WC Psychology, Clinical; Psychology, Social SC Psychology GA 453KX UT WOS:000266610400001 ER PT J AU Lee, MLT Whitmore, GA Laden, F Hart, JE Garshick, E AF Lee, Mei-Ling Ting Whitmore, G. A. Laden, Francine Hart, Jaime E. Garshick, Eric TI A case-control study relating railroad worker mortality to diesel exhaust exposure using a threshold regression model SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article CT Conference on Degradation, Damage, Fatigue and Accelerated Life Models in Reliability Testing CY MAY 22-24, 2006 CL Angers, FRANCE DE Biostatistics; Cardiovascular disease; Death; Disease progression; Environmetrics; Epidemiology; Exposure risk; First hitting time; Health status; Healthy worker effect; Kaplan-Meier plot; Latent process; Lung cancer; Occupational health; Stochastic process; Survival analysis; Wiener process; Work environment ID LUNG-CANCER; TIME MODELS; DISEASE; DRIVERS; DENMARK AB A case-control study of lung cancer mortality in U.S. railroad workers in jobs with and without diesel exhaust exposure is reanalyzed using a new threshold regression methodology. The Study included 1256 workers who died of lung cancer and 2385 controls who died primarily of circulatory system diseases. Diesel exhaust exposure was assessed using railroad job history from the US Railroad Retirement Board and an industrial hygiene survey. Smoking habits were available from next-of-kin and potential asbestos exposure was assessed by job history review. The new analysis reassesses lung cancer mortality and examines circulatory system disease mortality. jobs with regular exposure to diesel exhaust had a survival pattern characterized by an initial delay in mortality, followed by a rapid deterioration of health prior to death. The pattern is seen in subjects dying of lung cancer, circulatory system diseases, and other causes. The unique pattern is illustrated using a new type of Kaplan-Meier survival plot in which the time scale represents a measure of disease progression rather than calendar time. The disease progression scale accounts for a healthy-worker effect when describing the effects of cumulative exposures on mortality. (C) 2008 Elsevier B.V. All rights reserved. C1 [Lee, Mei-Ling Ting] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. [Whitmore, G. A.] McGill Univ, Desautels Fac Management, Montreal, PQ, Canada. [Garshick, Eric] VA Boston Healthcare Syst, Med Serv, Pulm & Crit Care Med Sect, Boston, MA USA. [Laden, Francine; Hart, Jaime E.; Garshick, Eric] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. [Laden, Francine; Hart, Jaime E.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Epidemiol & Risk Program, Boston, MA 02115 USA. [Laden, Francine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Lee, MLT (reprint author), Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. EM meilinglee@cph.osu.edu FU NCI NIH HHS [R01 CA079725, R01 CA079725-03]; NIOSH CDC HHS [R01 OH008649] NR 21 TC 11 Z9 12 U1 4 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD MAY 1 PY 2009 VL 139 IS 5 BP 1633 EP 1642 DI 10.1016/j.jspi.2008.05.023 PG 10 WC Statistics & Probability SC Mathematics GA 418JD UT WOS:000264143600006 PM 19221608 ER PT J AU Antonacci, AC Lam, S Lavarias, V Homel, P Eavey, RA AF Antonacci, Anthony C. Lam, Steven Lavarias, Valentina Homel, Peter Eavey, Roland A. TI A Report Card System Using Error Profile Analysis and Concurrent Morbidity and Mortality Review: Surgical Outcome Analysis, Part II SO JOURNAL OF SURGICAL RESEARCH LA English DT Review DE error analysis; gross mortality; morbidity; report cards; surgical outcome ID QUALITY AB Background. An effective report card system for adverse outcome error analysis following surgery is lacking. We hypothesized that a memorialized database could be used in conjunction with error analysis and management evaluation at Morbidity & Mortality conference to generate individualized report cards for Attending Surgeon and System performance. Study Design. Prospectively collected data from September 2000 through April 2005 were reported following Morbidity & Mortality review on 1618 adverse outcomes, including :219 deaths, following 29,237 operative procedures, in a complete loop to approximately 60 individual surgeons and responsible system personnel. Results. A 40% reduction of gross mortality (P<0.001) and 430% reduction of age-adjusted mortality were achieved over 4 years at the Academic Center. Quality issues were identified at a rate three times greater than required by New York State regulations and increased from a baseline 4.96% to 32.7% (odds ratio 1.94; P<0.03) irk cases associated with mortality. A detailed review demonstrated a significant increase (P<0.001) in system errors and physician-related diagnostic and judgment errors associated with mortality highlighted those practices and processes involved, and contrasted the results between academic (43% mortality improvement) and community (no improvement) hospitals. Conclusions. The findings suggest that structured concurrent data collection combined with non-punitive error-based case review and individualized report cards can be used to provide detailed feedback on surgical performance to individual surgeons and possibly improve clinical outcomes. (C) 2009 Elsevier Inc. All rights reserved. C1 [Antonacci, Anthony C.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Antonacci, Anthony C.] Christ Hosp, Jersey City, NJ USA. [Antonacci, Anthony C.; Lam, Steven; Lavarias, Valentina] Lenox Hill Hosp, New York, NY 10021 USA. [Antonacci, Anthony C.; Homel, Peter] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Eavey, Roland A.] Harvard Univ, Sch Med, Dept Otol & Laryngol,Pediat Otolaryngol Serv, Massachusetts Eye & Ear Infirm,Dept Otolaryngol, Boston, MA 02115 USA. RP Antonacci, AC (reprint author), Cornell Univ, Weill Med Coll, Dept Surg, 55 North St, Greenwich, CT 06830 USA. EM aantonacci@gmail.com NR 10 TC 15 Z9 15 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD MAY 1 PY 2009 VL 153 IS 1 BP 95 EP 104 DI 10.1016/j.jss.2008.02.051 PG 10 WC Surgery SC Surgery GA 434FC UT WOS:000265259600013 PM 18511079 ER PT J AU Saunders, GH Lewis, MS Forsline, A AF Saunders, Gabrielle H. Lewis, M. Samantha Forsline, Anna TI Expectations, Prefitting Counseling, and Hearing Aid Outcome SO JOURNAL OF THE AMERICAN ACADEMY OF AUDIOLOGY LA English DT Article; Proceedings Paper CT International Hearing Aid Research Conference CY 2008 CL Lake Tahoe, CA DE Counseling; expectations; hearing aids; outcome ID AUDIOLOGICAL REHABILITATION; AMPLIFICATION; BENEFIT; ADULTS; ATTITUDES; HANDICAP; SCALE; USERS AB Background: Data suggest that having high expectations about hearing aids results in better overall outcome. However, some have postulated that excessively high expectations will result in disappointment and thus poor outcome. It has been suggested that counseling patients with unrealistic expectations about hearing aids prior to fitting may be beneficial. Data, however, are mixed as to the effectiveness of such counseling, in terms of both changes in expectations and final outcome. Purpose: The primary purpose of this study was to determine whether supplementing prefitting counseling with demonstration of real-world listening can (1) alter expectations of new hearing aid users and (2) increase satisfaction over verbal-only counseling. Secondary goals of the study were to examine (1) the relationship between prefitting expectations and postfitting outcome, and (2) the effect of hearing aid fine-tuning on hearing aid outcome. Research Design: Sixty new hearing aid users were fitted binaurally with Beltone Oria behind-the-ear digital hearing aids. Forty participants received prefitting counseling and demonstration of listening situations with the Beltone AVE (TM) (Audio Verification Environment) system; 20 received prefitting counseling without a demonstration of listening situations. Hearing aid expectations were measured at initial contact and following prefitting counseling. Reported hearing aid outcome was measured after eight to ten weeks of hearing aid use. Study Sample: Sixty new hearing aid users aged between 55 and 81 years with symmetrical sensorineural hearing loss. Intervention: Participants were randomly assigned to one of three experimental groups, between which the prefitting counseling and follow-up differed: Group 1 received prefitting counseling in combination with demonstration of listening situations. Additionally, if the participant had complaints about sound quality at the follow-up visit, the hearing aids were fine-tuned using the Beltone AVE system. Group 2 received prefitting counseling in combination with demonstration of listening situations with the Beltone AVE system, but no fine-tuning was provided at follow-up. Group 3 received prefitting hearing aid counseling that did not include demonstration of listening, and the hearing aids were not fine-tuned at the follow-up appointment. Results: The results showed that prefitting hearing aid counseling had small but significant effects on expectations. The two forms of counseling did not differ in their effectiveness at changing expectations; however, anecdotally, we learned from many participants that that they enjoyed listening to the auditory demonstrations and that they found them to be an interesting listening exercise. The data also show that positive expectations result in more positive outcome and that hearing aid fine-tuning is beneficial to the user. Conclusions: We conclude that prefitting counseling can be advantageous to hearing aid outcome and recommend the addition of prefitting counseling to address expectations associated with quality of life and self-image. The data emphasize the need to address unrealistic expectations prior to fitting hearing aids cautiously, so as not to decrease expectations to the extent of discouraging and demotivating the patient. Data also show that positive expectations regarding the impact hearing aids will have on psychosocial well-being are important for successful hearing aid outcome. C1 [Saunders, Gabrielle H.] Portland VA Med Ctr, NCRAR, Portland, OR 97207 USA. [Saunders, Gabrielle H.; Lewis, M. Samantha] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Forsline, Anna] Portland VA Med Ctr, Audiol & Speech Pathol Serv, Portland, OR 97207 USA. RP Saunders, GH (reprint author), Portland VA Med Ctr, NCRAR, 3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. EM Gabrielle.Saunders@va.gov NR 46 TC 20 Z9 22 U1 8 U2 26 PU AMER ACAD AUDIOLOGY PI RESTON PA 11730 PLAZA DR, STE 300, RESTON, VA 20190 USA SN 1050-0545 J9 J AM ACAD AUDIOL JI J. Am. Acad. Audiol. PD MAY PY 2009 VL 20 IS 5 BP 320 EP 334 DI 10.3766/jaaa.20.5.6 PG 15 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 462DE UT WOS:000267325400006 PM 19585963 ER PT J AU Wagner, KD Redden, L Kowatch, RA Wilens, TE Segal, S Chang, K Wozniak, P Vigna, NV Abi-Saab, W Saltarelli, M AF Wagner, Karen Dineen Redden, Laura Kowatch, Robert A. Wilens, Timothy E. Segal, Scott Chang, Kiki Wozniak, Patricia Vigna, Namita V. Abi-Saab, Walid Saltarelli, Mario TI A Double-Blind, Randomized, Placebo-Controlled Trial of Divalproex Extended-Release in the Treatment of Bipolar Disorder in Children and Adolescents SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar disorder; divalproex ER; treatment ID VALPROATE-ASSOCIATED COAGULOPATHIES; WASH-U-KSADS; RATING-SCALE; MOOD STABILIZERS; ACUTE MANIA; LITHIUM; SODIUM; COMBINATION; RELIABILITY; VALIDITY AB Objective: To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. Method: In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 mu g/mL. Sixty-six patients enrolled in the extension study. Results: In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n=74]; placebo -7.9 [n= 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. Conclusions: The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(5):519-532. C1 [Redden, Laura; Vigna, Namita V.; Abi-Saab, Walid; Saltarelli, Mario] Abbott Labs, Abbott Pk, IL 60064 USA. [Kowatch, Robert A.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45221 USA. [Wilens, Timothy E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chang, Kiki] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Wagner, KD (reprint author), Dept Psychiat & Behav Sci, 301 Univ Blvd, Galveston, TX 77555 USA. EM kwagner@utmb.edu FU Abbott Laboratories FX This study was supported by a grant from Abbott Laboratories. NR 52 TC 52 Z9 52 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAY PY 2009 VL 48 IS 5 BP 519 EP 532 DI 10.1097/CHI.0b013e31819c55ec PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 437BO UT WOS:000265461000009 PM 19325497 ER PT J AU Magro, CM Yaniv, S Mihm, MC AF Magro, Cynthia M. Yaniv, Shimrat Mihm, Martin C. TI The superficial atypical Spitz tumor and malignant melanoma of superficial spreading type arising in association with the superficial atypical Spitz tumor: A distinct form of dysplastic Spitzoid nevomelanocytic proliferation SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; MELANOCYTIC LESIONS; DIFFERENTIAL-DIAGNOSIS; CELL NEVUS; MUTATIONS; BRAF; VARIANTS; FEATURES; SPINDLE; RAS AB Spitzoid lesions are diagnostically problematic because of it deceptive morphology and indeterminate behavior. The most problematic are atypical Spitz tumors whereby distinction from melanoma may be difficult. We have recognized it melanocytic lesion with a reproducible histomorphology, demonstrating characteristic demographic features, namely a predilection to involve younger female patients and common occurrence on the thigh. We have designated this lesion as the superficial atypical Spitz tumor and have encountered 27 cases. We believe that these lesions overlap histomorphologically with higher-grade dysplastic nevi and de novo intraepidermal epitheloid melanocytic dysplasia. We identified 19 additional cases that appear to represent transition into malignant melanoma of superficial spreading type arising in a background of the superficial atypical Spitz tumor. A limitation is that complete medical histories were not obtained for all patients. In conclusion, there exists a distinct subset of Spitz tumors that we designate as the superficial atypical Spitz tumor in which there is inherent dysplasia including lesions that evolve into melanoma of superficial spreading type. (J Am Acad Dermatol 2009-160:8.14-23.) C1 [Magro, Cynthia M.] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, Div Dermatopathol, New York, NY 10021 USA. [Yaniv, Shimrat] Albert Einstein Coll Med, New York, NY USA. [Mihm, Martin C.] Massachusetts Gen Hosp, Dept Dermatopathol, Boston, MA 02114 USA. [Mihm, Martin C.] Harvard Univ, Sch Med, Boston, MA USA. RP Magro, CM (reprint author), Weill Cornell Med Coll, Dept Dermatopathol, 1300 York Ave,F-309, New York, NY 10021 USA. EM cym2003@med.cornell.edu NR 22 TC 15 Z9 15 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 MAY PY 2009 VL 60 IS 5 BP 814 EP 823 DI 10.1016/j.jaad.2008.10.040 PG 10 WC Dermatology SC Dermatology GA 438AW UT WOS:000265529300012 PM 19389523 ER PT J AU Lorenz, KA Sherbourne, CD Shugarman, LR Rubenstein, LV Wen, L Cohen, A Goebel, JR Hagenmeier, E Simon, B Lanto, A Asch, SM AF Lorenz, Karl A. Sherbourne, Cathy D. Shugarman, Lisa R. Rubenstein, Lisa V. Wen, Li Cohen, Angela Goebel, Joy R. Hagenmeier, Emily Simon, Barbara Lanto, Andy Asch, Steven M. TI How Reliable is Pain as the Fifth Vital Sign? SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article ID CANCER PAIN; ACCURACY; MODERATE; QUALITY; MILD; CARE; CUTPOINTS; COMMUNITY; SEVERITY; VALIDITY AB Background: Although many health care organizations require routine pain screening (eg, "5th vital sign") with the 0 to 10 numeric rating scale (NRS), its accuracy has been questioned; here we evaluated its accuracy and potential causes for error. Methods: We randomly surveyed veterans and reviewed their charts after outpatient encounters at 2 hospitals and 6 affiliated community sites. Using correlation and receiver operating characteristic analysis, we compared the routinely measured "5th vital sign" (nurse-recorded NRS) with a research-administered NRS (research-recorded NRS) and the Brief Pain Inventory (BPI). Results: During 528 encounters, nurse-recorded NRS and research-recorded NRS correlated moderately (r = 0.627), as did nurse-recorded NRS and BPI severity scales (r = 0.613 for pain during the last 24 hours and r = 0.588 for pain during the past week). Correlation with BPI interference was lower (r = 0.409). However, the research-recorded NRS correlated substantially with the BPI severity during the past 24 hours (r = 0.870) and BPI severity during the last week (r = 0.840). Receiver operating characteristic analysis showed similar results. Of the 98% of cases where a numeric score was recorded, 51% of patients reported their pain was rated qualitatively, rather than with a 0 to 10 scale, a practice associated with pain underestimation (chi(2) = 64.04, P < .001). Conclusion: Though moderately accurate, the outpatient "5th vital sign" is less accurate than under ideal circumstances. Personalizing assessment is a common clinical practice but may affect the performance of research tools such as the NRS adopted for routine use. (J Am Board Fam Med 2009;22:291-8.) C1 [Lorenz, Karl A.; Rubenstein, Lisa V.; Cohen, Angela; Hagenmeier, Emily; Simon, Barbara; Lanto, Andy; Asch, Steven M.] Vet Adm Greater Angeles Healthcare Syst, Los Angeles, CA 90064 USA. [Lorenz, Karl A.; Sherbourne, Cathy D.; Shugarman, Lisa R.; Rubenstein, Lisa V.; Asch, Steven M.] RAND Corp, Santa Monica, CA USA. [Lorenz, Karl A.; Rubenstein, Lisa V.; Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goebel, Joy R.] Calif State Univ Long Beach, Dept Nursing, Long Beach, CA 90840 USA. RP Lorenz, KA (reprint author), Vet Adm Greater Angeles Healthcare Syst, 11301 Wilshire Blvd,Code 111-G, Los Angeles, CA 90064 USA. EM karl.lorenz@med.va.gov OI Cohen, Angela B./0000-0002-0620-1909 FU Veterans Administration Health Services Research and Development IIR [03-150] FX Veterans Administration Health Services Research and Development IIR 03-150. NR 23 TC 42 Z9 45 U1 1 U2 10 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD MAY-JUN PY 2009 VL 22 IS 3 BP 291 EP 298 DI 10.3122/jabfm.2009.03.080162 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 443VR UT WOS:000265939400010 PM 19429735 ER PT J AU Olson, JA Budd, GT Carey, LA Harris, LA Esserman, LJ Fleming, GF Marcom, PK Leight, GS Giuntoli, T Commean, P Bae, K Luo, JQ Ellis, MJ AF Olson, John A., Jr. Budd, G. Thomas Carey, Lisa A. Harris, Lyndsay A. Esserman, Laura J. Fleming, Gini F. Marcom, Paul K. Leight, George S., Jr. Giuntoli, Therese Commean, Paul Bae, Kyongtae Luo, Jingqin Ellis, Matthew J. TI Improved Surgical Outcomes for Breast Cancer Patients Receiving Neoadjuvant Aromatase Inhibitor Therapy: Results from a Multicenter Phase II Trial SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article; Proceedings Paper CT 120th Annual Meeting of the Southern-Surgical-Association CY DEC, 2008 CL Palm Beach, FL SP SE Surg Assoc ID DOUBLE-BLIND; PREOPERATIVE TREATMENT; POSTMENOPAUSAL WOMEN; ADJUVANT TREATMENT; ENDOCRINE THERAPY; CHEMOTHERAPY; TAMOXIFEN; ANASTROZOLE; ARIMIDEX; MAMMOGRAPHY AB BACKGROUND: Neoadjuvant aromatase Inhibitor therapy has been reported to improve Surgical Outcomes for postmenopausal women with clinical stage II or III hormone receptor-positive breast cancer. A multicenter phase II clinical trial was conducted to investigate the value of this approach for US surgical practice. STUDY DESIGN: One hundred fifteen postmenopausal women with >2 cm, estrogen receptor (ER) or progesterone receptor (PgR)-positive breast cancer were enrolled in a trial of 16 to 24 weeks of letrozole 2.5 mg daily before operation. RESULTS: One hundred six patients were eligible for primary analysis, 96 underwent operations, 7 received chemotherapy after progressive disease, and 3 did not undergo an operation. Baseline Surgical status was marginal for breast-conserving surgery (BCS) in 48 (450/8), 47 were definitely ineligible for BCS (44%), and 11 were Inoperable by standard mastectomy (10%). Overall Response Evaluation Criteria In Solid Tumors clinical response rate in the breast was 62%, with 12% experiencing progressive disease. Fifty percent underwent BCS, including 30 of 46 (65%) patients who were initially marginal for BCS and 15 of 39 (38%) patients who were Initially ineligible for BCS. All 11 inoperable patients successfully underwent operations, including 3 (27%) who had BCS. Nineteen percent of patients undergoing mastecromy had a pathologic T1 tumor, Suggesting that some highly responsive tumors were overtreated surgically. CONCLUSIONS: Neoadjuvant aromatase inhibitor improves operability and facilitates BCS, but there was considerable variability in responsiveness. Better techniques to predict response, determine residual tumor burden before operation, and greater willingness to attempt BCS in responsive patients Could additionally improve the rate of successful BCS. (J Am Coll Surg 2009;208:906-916. 9 2009 by the American College Of Surgeons) C1 [Giuntoli, Therese; Ellis, Matthew J.] Washington Univ, Siteman Canc Ctr, Sch Med, Dept Med,Div Oncol, St Louis, MO 63110 USA. [Olson, John A., Jr.; Leight, George S., Jr.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Dept Surg, Durham, NC 27710 USA. [Marcom, Paul K.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Dept Med, Durham, NC 27710 USA. [Harris, Lyndsay A.] Dana Farber Canc Ctr, Boston, MA USA. [Budd, G. Thomas] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Carey, Lisa A.] Univ N Carolina, Lineberger Canc Ctr, Durham, NC USA. [Esserman, Laura J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Esserman, Laura J.] Helen Dillcr Family Comprehens Canc Ctr, San Francisco, CA USA. [Fleming, Gini F.] Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. [Commean, Paul; Bae, Kyongtae] Washington Univ, Mallinckrodt Inst Radiol, Sch Med, St Louis, MO 63110 USA. [Luo, Jingqin] Washington Univ, Dept Biostat, Sch Med, St Louis, MO 63110 USA. RP Ellis, MJ (reprint author), Washington Univ, Siteman Canc Ctr, Sch Med, Dept Med,Div Oncol, Campus Box 8056,660 S Euclid Ave, St Louis, MO 63110 USA. EM mellis@dom.wustl.edu FU NCI NIH HHS [3P50 CA68438-07S2, P50 CA068438, R01 CA095614]; NIGMS NIH HHS [U19 GM061388] NR 20 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD MAY PY 2009 VL 208 IS 5 BP 906 EP 914 DI 10.1016/j.jamcollsurg.2009.01.035 PG 9 WC Surgery SC Surgery GA 441WP UT WOS:000265801500050 PM 19476859 ER PT J AU Bloom, HG Ahmed, I Alessi, CA Ancoli-Israel, S Buysse, DJ Kryger, MH Phillips, BA Thorpy, MJ Vitiello, MV Zee, PC AF Bloom, Harrison G. Ahmed, Imran Alessi, Cathy A. Ancoli-Israel, Sonia Buysse, Daniel J. Kryger, Meir H. Phillips, Barbara A. Thorpy, Michael J. Vitiello, Michael V. Zee, Phyllis C. TI Evidence-Based Recommendations for the Assessment and Management of Sleep Disorders in Older Persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review ID RESTLESS-LEGS-SYNDROME; NURSING-HOME RESIDENTS; POSITIVE AIRWAY PRESSURE; EXCESSIVE DAYTIME SLEEPINESS; BRIGHT-LIGHT THERAPY; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; PERIODIC LIMB MOVEMENTS; COMMUNITY-DWELLING ADULTS; CHEYNE-STOKES RESPIRATION AB Sleep-related disorders are most prevalent in the older adult population. A high prevalence of medical and psychosocial comorbidities and the frequent use of multiple medications, rather than aging per se, are major reasons for this. A major concern, often underappreciated and underaddressed by clinicians, is the strong bidirectional relationship between sleep disorders and serious medical problems in older adults. Hypertension, depression, cardiovascular disease, and cerebrovascular disease are examples of diseases that are more likely to develop in individuals with sleep disorders. Conversely, individuals with any of these diseases are at a higher risk of developing sleep disorders. The goals of this article are to help guide clinicians in their general understanding of sleep problems in older persons, examine specific sleep disorders that occur in older persons, and suggest evidence- and expert-based recommendations for the assessment and treatment of sleep disorders in older persons. No such recommendations are available to help clinicians in their daily patient care practices. The four sections in the beginning of the article are titled, Background and Significance, General Review of Sleep, Recommendations Development, and General Approach to Detecting Sleep Disorders in an Ambulatory Setting. These are followed by overviews of specific sleep disorders: Insomnia, Sleep Apnea, Restless Legs Syndrome, Circadian Rhythm Sleep Disorders, Parasomnias, Hypersomnias, and Sleep Disorders in Long-Term Care Settings. Evidence- and expert-based recommendations, developed by a group of sleep and clinical experts, are presented after each sleep disorder. C1 [Bloom, Harrison G.] Int Longev Ctr USA, New York, NY 10028 USA. [Bloom, Harrison G.] Mt Sinai Sch Med, Brookdale Dept Geriatr & Adult Dev, New York, NY USA. [Ahmed, Imran; Vitiello, Michael V.] Albert Einstein Coll Med, New York, NY USA. [Alessi, Cathy A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Alessi, Cathy A.] Vet Affairs Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Buysse, Daniel J.] Univ Pittsburgh, Sch Med, Neurosci Clin & Translat Ctr, Pittsburgh, PA USA. [Kryger, Meir H.] Gaylord Hosp, Gaylord Sleep Ctr, Wallingford, CT USA. [Kryger, Meir H.] Univ Connecticut, Sch Med, Dept Med, Farmington, CT USA. [Phillips, Barbara A.] Natl Sleep Fdn, Washington, DC USA. [Phillips, Barbara A.] Univ Kentucky, Coll Med, Lexington, KY USA. [Thorpy, Michael J.] Montefiore Med Ctr, Ctr Sleep Wake Disorders, Bronx, NY 10467 USA. [Vitiello, Michael V.] Univ Washington, Seattle, WA 98195 USA. [Zee, Phyllis C.] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. RP Bloom, HG (reprint author), Int Longev Ctr USA, 60 E 86th St, New York, NY 10028 USA. EM HarrisonB@ilcusa.org OI Vitiello, Michael/0000-0002-9776-0473 FU NIA NIH HHS [R01 AG008415, R01 AG008415-17] NR 293 TC 130 Z9 135 U1 6 U2 39 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2009 VL 57 IS 5 BP 761 EP 789 DI 10.1111/j.1532-5415.2009.02220.x PG 29 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 440OP UT WOS:000265709900001 PM 19484833 ER PT J AU Marson, DC Martin, RC Wadley, V Griffith, HR Snyder, S Goode, PS Kinney, FC Nicholas, AP Steele, T Anderson, B Zamrini, E Raman, R Bartolucci, A Harrell, LE AF Marson, Daniel C. Martin, Roy C. Wadley, Virginia Griffith, H. Randall Snyder, Scott Goode, Patricia S. Kinney, F. Cleveland Nicholas, Anthony P. Steele, Terri Anderson, Britt Zamrini, Edward Raman, Rema Bartolucci, Alfred Harrell, Lindy E. TI Clinical Interview Assessment of Financial Capacity in Older Adults with Mild Cognitive Impairment and Alzheimer's Disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE financial capacity; competency; clinical assessment; mild cognitive impairment; Alzheimer's disease ID DECISION-MAKING CAPACITY; PROTOTYPE-INSTRUMENT; ELDERLY PERSONS; COMPETENCE; ABILITIES; DEMENTIA; CONSENT; CONSISTENCY; JUDGMENTS AB To investigate financial capacity in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) using a clinician interview approach. Cross-sectional. Tertiary care medical center. Healthy older adults (n=75) and patients with amnestic MCI (n=58), mild AD (n=97), and moderate AD (n=31). The investigators and five study physicians developed a conceptually based, semistructured clinical interview for evaluating seven core financial domains and overall financial capacity (Semi-Structured Clinical Interview for Financial Capacity; SCIFC). For each participant, a physician made capacity judgments (capable, marginally capable, or incapable) for each financial domain and for overall capacity. Study physicians made more than 11,000 capacity judgments across the study sample (N=261). Very good interrater agreement was obtained for the SCIFC judgments. Increasing proportions of marginal and incapable judgment ratings were associated with increasing disease severity across the four study groups. For overall financial capacity, 95% of physician judgments for older controls were rated as capable, compared with 82% for patients with MCI, 26% for patients with mild AD, and 4% for patients with moderate AD. Physicians and other clinicians can reliably evaluate financial capacity in cognitively impaired older adults using a relatively brief, semistructured clinical interview. Patients with MCI have mild impairment in financial capacity, those with mild AD have emerging global impairment, and those with moderate AD have advanced global impairment. Patients with MCI and their families should proactively engage in financial and legal planning, given these patients' risk of developing AD and accelerated loss of financial abilities. C1 [Marson, Daniel C.; Martin, Roy C.; Wadley, Virginia; Griffith, H. Randall; Kinney, F. Cleveland; Nicholas, Anthony P.; Bartolucci, Alfred; Harrell, Lindy E.] Univ Alabama, Dept Neurol, Alzheimers Dis Res Ctr, Birmingham, AL 35294 USA. [Wadley, Virginia; Goode, Patricia S.] Univ Alabama, Div Gerontol Geriatr & Palliat Care, Dept Med, Birmingham, AL 35294 USA. [Snyder, Scott] Univ Alabama, Dept Educ, Birmingham, AL 35294 USA. [Kinney, F. Cleveland] Univ Alabama, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Bartolucci, Alfred] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Goode, Patricia S.; Harrell, Lindy E.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Anderson, Britt] Univ Waterloo, Dept Psychol, Ctr Theoret Neurosci, Waterloo, ON N2L 3G1, Canada. [Zamrini, Edward] Univ Utah Hlth Sci, Dept Neurol, Salt Lake City, UT USA. [Raman, Rema] Univ Calif San Diego, Dept Family Med & Neurosci, San Diego, CA 92103 USA. RP Marson, DC (reprint author), Univ Alabama, Dept Neurol, Alzheimers Dis Res Ctr, SC 650, Birmingham, AL 35294 USA. EM dmarson@uab.edu FU National Institute of Mental Health [MH55247]; National Institute on Aging [AG024525, AG021927, P50AG16582] FX Sponsor's Role: The funding source had no role in the design or conduct of the study, data management or analysis, or manuscript preparation. NR 35 TC 34 Z9 34 U1 4 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2009 VL 57 IS 5 BP 806 EP 814 DI 10.1111/j.1532-5415.2009.02202.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 440OP UT WOS:000265709900004 PM 19453308 ER PT J AU Lesselroth, BJ Felder, RS Adams, SM Cauthers, PD Dorr, DA Wong, GJ Douglas, DM AF Lesselroth, Blake J. Felder, Robert S. Adams, Shawn M. Cauthers, Phillip D. Dorr, David A. Wong, Gordon J. Douglas, David M. TI Design and Implementation of a Medication Reconciliation Kiosk: the Automated Patient History Intake Device (APHID) SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ERRORS AB Errors associated with medication documentation account for a substantial fraction of preventable medical errors. Hence, the Joint Commission has called for the adoption of reconciliation strategies at all United States healthcare institutions. Although studies suggest that reconciliation tools can reduce errors, it remains unclear how best to implement systems and processes that are reliable and sensitive to clinical workflow. The authors designed a primary care process that Supported reconciliation without compromising clinic efficiency. This manuscript describes the design and implementation of Automated Patient History Intake Device (APHID): ambulatory check-in kiosks that allow patients to review the names, dosage, frequency, and Pictures of their medications before their appointment. Medication lists are retrieved from the electronic health record and patient updates are captured and reviewed by providers during the clinic session. Results from the roll-in phase indicate the device is easy for patients to use and integrates well with clinic workflow. J Am Med Inform Assoc. 2009;16:300-304. DOI 10.1197/jamia.M2642. C1 [Lesselroth, Blake J.] Portland VA Med Ctr, Dept Hosp Specialty Med, Portland, OR 97239 USA. [Lesselroth, Blake J.; Felder, Robert S.; Adams, Shawn M.; Cauthers, Phillip D.; Dorr, David A.; Wong, Gordon J.] Portland VA Med Ctr, Portland Patient Safety Ctr Inquiry, Portland, OR 97239 USA. [Lesselroth, Blake J.; Felder, Robert S.; Cauthers, Phillip D.; Wong, Gordon J.; Douglas, David M.] Portland VA Med Ctr, Technol & Informat Management Sect, Portland, OR 97239 USA. [Lesselroth, Blake J.; Dorr, David A.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. RP Lesselroth, BJ (reprint author), Portland VA Med Ctr, Dept Hosp Specialty Med, Mail Code P3 MED,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM Blake.Lesselroth@va.gov NR 9 TC 22 Z9 22 U1 0 U2 4 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY-JUN PY 2009 VL 16 IS 3 BP 300 EP 304 DI 10.1197/jamia.M2642 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 447DU UT WOS:000266172600009 PM 19261949 ER PT J AU Dux, KE Sage, RA Gocke, SP AF Dux, Katherine E. Sage, Ronald A. Gocke, Sean P. TI Pedal Presentation of Metastatic Invasive Squamous Cell Carcinoma of the Bladder SO JOURNAL OF THE AMERICAN PODIATRIC MEDICAL ASSOCIATION LA English DT Article ID FOOT; TUMORS; BONES; TOE AB Squamous cell carcinoma is a malignant tumor of the squamous epithelium and can occur in many different organs. We present a case of a 61-year-old veteran with metastatic squamous cell carcinoma of the bladder with distal metastasis to the middle phalanx of the fourth toe, which is a rare occurrence in the literature. (J Am Podiatr Med Assoc 99(3): 251-253, 2009) C1 [Dux, Katherine E.; Gocke, Sean P.] Loyola Univ, Med Ctr, Dept Orthopaed Surg & Rehabil, Maywood, IL 60153 USA. [Sage, Ronald A.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Dept Orthoped Surg & Rehabil, Hines, IL 60141 USA. RP Dux, KE (reprint author), Loyola Univ, Med Ctr, Dept Orthopaed Surg & Rehabil, 2160 S 1st Ave, Maywood, IL 60153 USA. EM kduxdpm@gmail.com NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER PODIATRIC MED ASSOC PI BETHESDA PA 9312 OLD GEORGETOWN ROAD, BETHESDA, MD 20814-1621 USA SN 8750-7315 J9 J AM PODIAT MED ASSN JI J. Am. Podiatr. Med. Assoc. PD MAY-JUN PY 2009 VL 99 IS 3 BP 251 EP 253 PG 3 WC Orthopedics SC Orthopedics GA 447UJ UT WOS:000266217000012 PM 19448178 ER PT J AU Moller, CC Flesche, J Reiser, J AF Moeller, Clemens C. Flesche, Jan Reiser, Jochen TI Sensitizing the Slit Diaphragm with TRPC6 Ion Channels SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; NEPHRIN; KIDNEY; ACTIN; FYN AB Physiologic permeability of the glomerular capillary depends on the normal structure of podocyte foot processes forming a functioning slit diaphragm in between. Mutations in several podocyte genes as well as specific molecular pathways have been identified as the cause for progressive kidney failure with urinary protein loss. Podocyte injury is a hallmark of glomerular disease, which is generally displayed by the rearrangement of the podocyte slit diaphragm and the actin cytoskeleton. Recent studies demonstrate a unique role for the Ca(2+)-permeable ion channel protein TRPC6 as a regulator of glomerular ultrafiltration. In both genetic and acquired forms of proteinuric kidney disease, dysregulation of podocyte TRPC6 plays a pathogenic role. This article illustrates how recent findings add to emerging concepts in podocyte biology, particularly mechanosensation and signaling at the slit diaphragm. C1 [Reiser, Jochen] Univ Miami, Div Nephrol & Hypertens, Leonard Miller Sch Med, Miami, FL 33136 USA. [Moeller, Clemens C.; Flesche, Jan; Reiser, Jochen] Harvard Univ, Sch Med, Boston, MA USA. [Moeller, Clemens C.; Flesche, Jan; Reiser, Jochen] Massachusetts Gen Hosp, Dept Med, Program Glomerular Dis, Boston, MA 02114 USA. [Moeller, Clemens C.; Flesche, Jan; Reiser, Jochen] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP Reiser, J (reprint author), Univ Miami, Div Nephrol & Hypertens, Leonard Miller Sch Med, 1120 NW 14th St,Suite 1182 CRB C-211, Miami, FL 33136 USA. EM jreiser@med.miami.edu FU National Institutes of Health [DK73495] FX J.R. is supported by a research project grants from the National Institutes of Health (DK73495). The authors thank Jim Stanis for help with the illustration (Figure 1). NR 16 TC 27 Z9 33 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAY PY 2009 VL 20 IS 5 BP 950 EP 953 DI 10.1681/ASN.2008030329 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 444DE UT WOS:000265959800008 PM 18784209 ER PT J AU Madero, M Wassel, CL Peralta, CA Najjar, SS Sutton-Tyrrell, K Fried, L Canada, R Newman, A Shlipak, MG Sarnak, MJ AF Madero, Magdalena Wassel, Christina L. Peralta, Carmen A. Najjar, Samer S. Sutton-Tyrrell, Kim Fried, Linda Canada, Robert Newman, Anne Shlipak, Michael G. Sarnak, Mark J. CA Health ABC Study TI Cystatin C Associates with Arterial Stiffness in Older Adults SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week CY NOV 14-19, 2006 CL San Diego, CA SP Amer Soc Nephrol ID PULSE-WAVE VELOCITY; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; CARDIOVASCULAR EVENTS; RISK-FACTOR; CREATININE CLEARANCE; AORTIC STIFFNESS; MORTALITY; PRESSURE AB Large arteries commonly become stiff in kidney failure, but few studies have investigated arterial stiffness in earlier stages of kidney disease. We evaluated the association between kidney function and aortic pulse wave velocity (aPWV) and its potential modification by race, diabetes, or coronary heart disease in older adults. We measured aPWV in 2468 participants in the Health Aging and Body Composition (Health ABC) study; mean age was 73.7 yr, 40% were black, and 24% had diabetes. After categorizing kidney function into three groups on the basis of cystatin C level, multivariable analysis revealed that the medium and high cystatin C groups associated with a 5.3% (95% confidence interval 0.8 to 10.0%) and 8.0% (95% confidence interval 2.2 to 14.1%) higher aPWV than the low cystatin C group; however, chronic kidney disease, as defined by estimated GFR <60 ml/min per 1.73 m(2), did not significantly associate with aPWV. We did not identify interactions between cystatin C and race, diabetes, or coronary heart disease. In conclusion, stiffness of large arteries, a major risk factor for cardiovascular disease, may partially mediate the association between cystatin C and cardiovascular risk in older adults. C1 [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Dept Med, Boston, MA 02111 USA. [Madero, Magdalena] Inst Nacl Cardiol Ignacio Chavez Mexico City, Dept Nephrol, Mexico City, DF, Mexico. [Wassel, Christina L.; Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Wassel, Christina L.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Wassel, Christina L.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Najjar, Samer S.] NIA, NIH, Bethesda, MD 20892 USA. [Sutton-Tyrrell, Kim; Newman, Anne] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Fried, Linda] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Canada, Robert] Univ Tennessee, Hlth Sci Ctr, Memphis, TN 38163 USA. RP Sarnak, MJ (reprint author), Tufts Med Ctr, Div Nephrol, Dept Med, Box 391,800 Washington St, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIDDK NIH HHS [K24 DK078204] NR 34 TC 34 Z9 37 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAY PY 2009 VL 20 IS 5 BP 1086 EP 1093 DI 10.1681/ASN.2008030318 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 444DE UT WOS:000265959800022 PM 19357259 ER PT J AU Ashton-Chess, J Dugast, E Colvin, RB Giral, M Foucher, Y Moreau, A Renaudin, K Braud, C Devys, A Brouard, S Soulillou, JP AF Ashton-Chess, Joanna Dugast, Emilie Colvin, Robert B. Giral, Magali Foucher, Yohann Moreau, Anne Renaudin, Karine Braud, Christophe Devys, Anne Brouard, Sophie Soulillou, Jean-Paul TI Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat ID RENAL-ALLOGRAFT REJECTION; ANTIBODY-MEDIATED REJECTION; GENE-EXPRESSION; MESSENGER-RNA; GRANZYME-B; QUANTITATIVE DETECTION; NONINVASIVE DIAGNOSIS; TRANSCRIPTION FACTOR; TOLERANCE; FOXP3 AB Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3+ cells seem to be an inherent component of acute rejection (AR) in human recipients of renal transplants. The balance between regulatory cells and effector/cytotoxic cells may determine graft outcome; this balance has not been described for chronic allograft injury. We investigated the expression of key regulatory, effector, and cytotoxic transcripts (i.e., FOXP3, T-bet, and granzyme B, respectively) in the grafts and peripheral blood of long-term-surviving renal transplant patients. We found that, whereas neither intragraft nor peripheral blood FOXP3 or T-bet mRNA could distinguish between rejection and nonrejection status, granzyme B (GrzB) mRNA could: It was significantly increased in the graft and significantly decreased in the peripheral blood of patients with chronic antibody-mediated rejection (CAMR). Quantifying peripheral blood GrzB mRNA demonstrated potential to aid in the noninvasive diagnosis of CAMR. In summary, these data affirm GrzB as a marker not only for AR but also for CAMR. In addition, we identified several previously unreported clinical or demographic factors influencing regulatory/effector/cytotoxic profiles in the peripheral blood, highlighting the necessity to consider confounding variables when considering the use of potential biomarkers, such as FOXP3, for diagnosis or prognosis in kidney transplantation. C1 [Brouard, Sophie] CHU Nantes, Hotel Dieu, INSERM, ITERT,U643, F-44093 Nantes 1, France. [Ashton-Chess, Joanna; Dugast, Emilie; Giral, Magali; Foucher, Yohann; Braud, Christophe; Brouard, Sophie; Soulillou, Jean-Paul] CHU Nantes, Inst Transplantat & Rech Transplantat, F-44035 Nantes, France. [Ashton-Chess, Joanna; Dugast, Emilie; Giral, Magali; Foucher, Yohann; Braud, Christophe; Brouard, Sophie; Soulillou, Jean-Paul] Univ Nantes, Fac Med, Nantes, France. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Colvin, Robert B.] Harvard Univ, Sch Med, Boston, MA USA. [Moreau, Anne; Renaudin, Karine] CHU Nantes, Serv Anat Pathol, F-44035 Nantes 01, France. [Devys, Anne] Etab Francais Sang, Nantes, France. RP Brouard, S (reprint author), CHU Nantes, Hotel Dieu, INSERM, ITERT,U643, 30 Bd Jean Monnet, F-44093 Nantes 1, France. EM sophie.brouard@university-nantes.fr; paul.soulillou@university-nantes.fr RI Foucher, Yohann/G-2714-2013; brouard, sophie/Q-1285-2016 OI Foucher, Yohann/0000-0003-0330-7457; NR 34 TC 43 Z9 43 U1 2 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAY PY 2009 VL 20 IS 5 BP 1113 EP 1122 DI 10.1681/ASN.2008050450 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 444DE UT WOS:000265959800025 PM 19357258 ER PT J AU Lee, PS Sampath, K Karumanchi, SA Tamez, H Bhan, I Isakova, T Gutierrez, OM Wolf, M Chang, YC Stossel, TP Thadhani, R AF Lee, Po-Shun Sampath, Kartik Karumanchi, S. Ananth Tamez, Hector Bhan, Ishir Isakova, Tamara Gutierrez, Orlando M. Wolf, Myles Chang, Yuchiao Stossel, Thomas P. Thadhani, Ravi TI Plasma Gelsolin and Circulating Actin Correlate with Hemodialysis Mortality SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; UBIQUITIN-PROTEASOME PATHWAY; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; LYSOPHOSPHATIDIC ACID; DIABETES-MELLITUS; DIALYSIS PATIENTS; SCAVENGER SYSTEM; RENAL-FAILURE; VITAMIN-D AB Plasma gelsolin (pGSN) binds actin and bioactive mediators to localize inflammation. Low pGSN correlates with adverse outcomes in acute injury, whereas administration of recombinant pGSN reduces mortality in experimental sepsis. We found that mean pGSN levels of 150 patients randomly selected from 10,044 starting chronic hemodialysis were 140 +/- 42 mg/L, 30 to 50% lower than levels reported for healthy individuals. In a larger sample, we performed a case-control analysis to evaluate the relationship of pGSN and circulating actin with mortality; pGSN levels were significantly lower in 114 patients who died within 1 yr of dialysis initiation than in 109 survivors (117 +/- 38 mg/L versus 147 +/- 42 mg/L, P < 0.001). pGSN levels had a graded, inverse relationship with 1-yr mortality, such that patients with pGSN < 130 mg/L experienced a > 3-fold risk for mortality compared with those with pGSN >= 150 mg/L. The 69% of patients with detectable circulating actin had lower pGSN levels than those without (127 +/- 45 mg/L versus 141 +/- 36 mg/L, P = 0.026). Compared with patients who had elevated pGSN and no detectable actin, those with low pGSN levels and detectable actin had markedly increased mortality (odds ratio 9.8, 95% confidence interval 2.9 to 33.5). Worsening renal function correlated with pGSN decline in 53 subjects with CKD not on dialysis. In summary, low pGSN and detectable circulating actin identify chronic hemodialysis patients at highest risk for 1-yr mortality. C1 [Sampath, Kartik; Tamez, Hector; Bhan, Ishir; Isakova, Tamara; Gutierrez, Orlando M.; Wolf, Myles; Chang, Yuchiao; Thadhani, Ravi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Po-Shun; Stossel, Thomas P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02114 USA. [Karumanchi, S. Ananth] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. [Karumanchi, S. Ananth] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bullfinch 127,55 Fruit St, Boston, MA 02114 USA. EM rthadhani@partners.org FU American Heart Association Scientist Development Grant; Howard Hughes Medical Institute; American Cancer Society Clinical Research Professorship; National Institutes of Health [DK71674, HL093954] FX This work is supported by an American Heart Association Scientist Development Grant (P.S.L.), the Howard Hughes Medical Institute (S.A.K.), an American Cancer Society Clinical Research Professorship (T.P.S.), and grants (DK71674 and HL093954) from the National Institutes of Health (R.T.). We also thank Sze-Man Tsang for her technical support. NR 65 TC 54 Z9 61 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAY PY 2009 VL 20 IS 5 BP 1140 EP 1148 DI 10.1681/ASN.2008091008 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 444DE UT WOS:000265959800028 PM 19389844 ER PT J AU Burstein, HJ AF Burstein, Harold J. TI Do Clinical Trials Belong in Clinical Guidelines? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Burstein, Harold J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Burstein, Harold J.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Burstein, HJ (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD MAY PY 2009 VL 7 IS 5 BP 489 EP 489 PG 1 WC Oncology SC Oncology GA 499ZG UT WOS:000270265000001 PM 19460277 ER PT J AU Temel, JS Greer, JA Goldberg, S Vogel, PD Sullivan, M Pirl, WF Lynch, TJ Christiani, DC Smith, MR AF Temel, Jennifer S. Greer, Joseph A. Goldberg, Sarah Vogel, Paula Downes Sullivan, Michael Pirl, William F. Lynch, Thomas J. Christiani, David C. Smith, Matthew R. TI A Structured Exercise Program for Patients with Advanced Non-small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small cell lung cancer; Exercise; Supportive care ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; HIGH-DOSE CHEMOTHERAPY; PHYSICAL-ACTIVITY; BREAST-CANCER; PULMONARY REHABILITATION; MEGESTROL-ACETATE; FUNCTIONAL ASSESSMENT; AEROBIC EXERCISE; OUTPATIENT REHABILITATION AB Introduction: Exercise improves functional outcome and symptoms for certain cancer populations, but the feasibility, efficacy, and safety of structured exercise in patients with lung cancer is unknown. In this Study, we examined the feasibility of a hospital-based exercise program for patients with advanced non-small cell lung cancer. Methods: This study included patients with newly diagnosed advanced stage non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0-1. A physical therapist facilitated twice-weekly sessions of aerobic exercise and weight training over an 8-week period. The primary end point was feasibility of the intervention, defined as adherence to the exercise program. Secondary endpoints included functional capacity, measured by the 6-minute walk test and Muscle strength, as well as quality Of life, lung cancer symptoms and fatigue, measured by the Functional Assessment of Cancer Therapy-lung and Functional Assessment of Cancer Therapy-fatigue scales. Results: Between October 2004 and August 2007, 25 patients enrolled in the study. All participants received anticancer therapy during the Study period. Twenty patients (80%) underwent the baseline physical therapy evaluation. Eleven patients (44%) completed all 16 sessions. An additional 6 patients attended at least 6 sessions (range, 6-15), and 2 patients only attended one session. Study completers experienced a significant reduction in lung cancer symptoms and no deterioration in their 6-minute walk test or muscle strength. Conclusions: Although the majority of participants attempted the exercise program, less than half were able to complete the intervention. Those who completed the program experienced an improvement in their lung cancer symptoms. Community-based or briefer exercise interventions may be more feasible in this population. C1 [Temel, Jennifer S.; Greer, Joseph A.; Goldberg, Sarah; Vogel, Paula Downes; Sullivan, Michael; Pirl, William F.; Lynch, Thomas J.; Christiani, David C.; Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Yawkey 7B,55 Fruit St, Boston, MA 02114 USA. EM jtemel@partners.org FU Mary Ellen and Dick Denning Foundation; NIH K24 Mid-career Investigator Award [5K24CA121990]; [5RO3CA110779] FX Supported by 5RO3CA110779 and the Mary Ellen and Dick Denning Foundation, and NIH K24 Mid-career Investigator Award (5K24CA121990) (to M. R. S.). NR 75 TC 56 Z9 57 U1 2 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAY PY 2009 VL 4 IS 5 BP 595 EP 601 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 438LU UT WOS:000265557700007 PM 19276834 ER PT J AU Morrow, DA Brickman, CM Murphy, SA Baran, K Krakover, R Dauerman, H Kumar, S Slomowitz, N Grip, L McCabe, CH Salzman, AL AF Morrow, David A. Brickman, Chaim M. Murphy, Sabina A. Baran, Kenneth Krakover, Ricardo Dauerman, Harold Kumar, Sujatha Slomowitz, Natanya Grip, Laura McCabe, Carolyn H. Salzman, Andrew L. TI A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Clinical trials; Myocardial infarction; Reperfusion injury; Poly(ADP-ribose) polymerase ID ADP-RIBOSE SYNTHETASE; REPERFUSION INJURY; ACTIVATION; HEART; PEROXYNITRITE; CONTRACTILE; DISRUPTION; DEPLETION; MUSCLE AB Background Reperfusion injury is a significant complication of the management of ST-elevation MI (STEMI). INO-1001 is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), a mediator of oxidant-induced myocyte dysfunction during reperfusion. Methods & results We assessed the safety and pharmacokinetics of INO-1001 in a randomized, placebo-controlled, single-blind, dose-escalating trial in 40 patients with STEMI undergoing primary percutaneous coronary intervention within 24 h of onset. INO-1001 was well-tolerated. A trend toward more frequent transaminitis was observed with 800 mg. Plasma from INO1001-treated patients reduced in vitro PARP activity > 90% at all doses. Serial C-reactive protein and IL-6 levels showed a trend toward blunting of inflammation with INO-1001. The apparent median terminal half-life (t(1/2)) of INO-1001 was 7.5 (25th, 75th: 5.9, 10.2) h. Conclusions The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury. C1 [Morrow, David A.; Murphy, Sabina A.; Grip, Laura; McCabe, Carolyn H.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Brickman, Chaim M.; Kumar, Sujatha; Slomowitz, Natanya; Salzman, Andrew L.] Inotek Pharmaceut, Beverly, MA USA. [Baran, Kenneth] St Paul Heart Clin, St Paul, MN USA. [Krakover, Ricardo] Assaf Harofeh Med Ctr, Tel Aviv, Israel. [Dauerman, Harold] Univ Vermont, Coll Med, Burlington, VT USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org FU NHLBI NIH HHS [R44 HL074684-01] NR 15 TC 39 Z9 42 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD MAY PY 2009 VL 27 IS 4 BP 359 EP 364 DI 10.1007/s11239-008-0230-1 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 444VV UT WOS:000266009400001 PM 18535785 ER PT J AU Saylor, PJ Smith, MR AF Saylor, Philip J. Smith, Matthew R. TI Metabolic Complications of Androgen Deprivation Therapy for Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; gonadotropin-releasing hormone agonists; cardiovascular diseases; diabetes mellitus; obesity ID CORONARY-HEART-DISEASE; HORMONE AGONIST TREATMENT; BONE-MINERAL DENSITY; LEAN BODY-MASS; CARDIOVASCULAR MORTALITY; SUPPRESSION THERAPY; INSULIN SENSITIVITY; ARTERIAL STIFFNESS; BLOOD CHOLESTEROL; RISK FACTOR AB Purpose: Androgen deprivation therapy has a variety of well recognized adverse effects including vasomotor flushing, loss of libido, fatigue, gynecomastia, anemia and osteoporosis. This review focuses on the more recently described metabolic complications of androgen deprivation therapy including obesity, insulin resistance and lipid alterations as well as the association of androgen deprivation therapy with diabetes and cardiovascular disease. Materials and Methods: We reviewed the medical literature using the PubMed (R) search terms prostate cancer, androgen deprivation therapy, gonadotropin-releasing hormone agonists, obesity, insulin resistance, lipids, diabetes, cardiovascular disease and myocardial infarction. We provide a focused review and our perspective on the relevant literature. Results: Androgen deprivation therapy decreases lean mass and increases fat mass. It also decreases insulin sensitivity while increasing low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides. Consistent with these adverse metabolic effects, androgen deprivation therapy may be associated with a greater incidence of diabetes and cardiovascular disease. Some of these androgen deprivation therapy related metabolic changes (obesity, insulin resistance and increased triglycerides) overlap with features of the metabolic syndrome. However, in contrast to the metabolic syndrome, androgen deprivation therapy increases subcutaneous fat and high density lipoprotein cholesterol. Conclusions: Androgen deprivation therapy increases obesity, decreases insulin sensitivity and adversely alters lipid profiles. It may be associated with a greater incidence of diabetes and cardiovascular disease. The benefits of androgen deprivation therapy should be weighed against these and other potential harms. Little is known about the optimal strategy to mitigate the adverse metabolic effects of androgen deprivation therapy. Thus, we recommend an emphasis on existing strategies for screening and treatment that have been documented to reduce the risk of diabetes and cardiovascular disease in the general population. C1 [Saylor, Philip J.; Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Dept Oncol, Boston, MA 02114 USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Med Oncol, 55 Fruit St,POB 2-221, Boston, MA 02114 USA. EM psaylor@partners.org FU National Institutes of Health [5K24CA12199002]; Prostate Cancer Foundation; Armstrong Foundation FX Supported by a National Institutes of Health K24 Midcareer Investigator Award (5K24CA12199002), and grants from the Prostate Cancer Foundation and Lance Armstrong Foundation. NR 57 TC 118 Z9 121 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2009 VL 181 IS 5 BP 1998 EP 2006 DI 10.1016/j.juro.2009.01.047 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 431PJ UT WOS:000265074800008 PM 19286225 ER PT J AU Twiss, C Kilpatrick, L Craske, M Buffington, CAT Ornitz, E Rodriguez, LV Mayer, EA Naliboff, BD AF Twiss, Christian Kilpatrick, Lisa Craske, Michelle Buffington, C. A. Tony Ornitz, Edward Rodriguez, Larissa V. Mayer, Emeran A. Naliboff, Bruce D. TI Increased Startle Responses in Interstitial Cystitis: Evidence for Central Hyperresponsiveness to Visceral Related Threat SO JOURNAL OF UROLOGY LA English DT Article DE cystitis; interstitial; sensory gating; startle reaction; reflex ID ANXIETY DISORDERS; PELVIC PAIN; FEAR; AMYGDALA; HYPERSENSITIVITY; INDEX; IBS AB Purpose: Hypersensitivity to visceral stimuli in interstitial cystitis/painful bladder syndrome may result from enhanced responsiveness of affective circuits (including the amygdala complex) and associated central pain amplification. Potentiation of the eyeblink startle reflex under threat is mediated by output from the amygdala complex and, therefore, represents a noninvasive marker to study group differences in responsiveness in this brain circuit. Materials and Methods: Acoustic startle responses were examined in female patients with interstitial cystitis/painful bladder syndrome (13) and healthy controls (16) during context threat (application of muscle stimulation electrodes to the lower abdomen overlying the bladder), and cued conditions for safety (no stimulation possible), anticipation and imminent threat of aversive abdominal stimulation over the bladder. Results: Patients showed significantly greater startle responses during nonimminent threat conditions (baseline, safe and anticipation periods) while both groups showed similar robust startle potentiation during the imminent threat condition. Higher rates of anxiety and depression symptoms in the patient group did not account for the group differences in startle reflex magnitude. Conclusions: Compared to controls, female patients with interstitial cystitis/painful bladder syndrome showed increased activation of a defensive emotional circuit in the context of a threat of abdominal pain. This pattern is similar to that previously reported in patients with anxiety disorders as well as those with irritable bowel syndrome. Since these circuits have an important role in central pain amplification related to affective and cognitive processes, these results support the hypothesis that the observed abnormality may be involved in the enhanced perception of bladder signals associated with interstitial cystitis/painful bladder syndrome. C1 [Kilpatrick, Lisa; Craske, Michelle; Buffington, C. A. Tony; Ornitz, Edward; Mayer, Emeran A.; Naliboff, Bruce D.] Univ Calif Los Angeles, Ctr Neurobiol Stress, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Kilpatrick, Lisa; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Physiol, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Ornitz, Edward; Mayer, Emeran A.; Naliboff, Bruce D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Twiss, Christian; Rodriguez, Larissa V.] Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Brain Res Inst, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Craske, Michelle] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90073 USA. [Naliboff, Bruce D.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Buffington, C. A. Tony] Ohio State Univ, Dept Vet Clin Sci, Coll Vet Med, Columbus, OH 43210 USA. RP Naliboff, BD (reprint author), Univ Calif Los Angeles, Ctr Neurobiol Stress, David Geffen Sch Med, CURE Bld 115,Room 223,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM naliboff@ucla.edu RI Buffington, Tony/B-7135-2009; Kilpatrick, Lisa/E-6995-2015 FU NCCIH NIH HHS [R24 AT002681, R24 AT002681-04, R24AT002681]; NIDDK NIH HHS [P50 DK064539, P50 DK064539-06, P50 DK64539]; NINR NIH HHS [NR007768, R01 NR007768, R01 NR007768-03] NR 27 TC 22 Z9 22 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2009 VL 181 IS 5 BP 2127 EP 2133 DI 10.1016/j.juro.2009.01.025 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 431PJ UT WOS:000265074800056 PM 19286199 ER PT J AU Zawacki, WJ Walker, G DeVasher, E Halpern, EF Waltman, AC Wicky, ST Ryan, DP Kalva, SP AF Zawacki, Walter J. Walker, Gregory DeVasher, Emily Halpern, Elkan F. Waltman, Arthur C. Wicky, Stephan T. Ryan, David P. Kalva, Sanjeeva P. TI Wound Dehiscence or Failure to Heal following Venous Access Port Placement in Patients Receiving Bevacizumab Therapy SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID INTERVENTIONAL RADIOLOGISTS AB PURPOSE: To determine the incidence of wound dehiscence or failure to heal after port placement in patients receiving bevacizumab therapy. A hypothesis was tested that the mean interval between bevacizumab administration and port placement was shorter in patients who had dehiscence than in those who did not. MATERIALS AND METHODS: Medical records of all patients who had venous access ports placed from July 2006 through December 2007 were retrospectively reviewed. A total of 195 ports were placed in 189 patients (106 men) who were treated with bevacizumab within 120 days of port placement. The incidence of wound dehiscence and the significance of dose timing relative to port placement in these patients were calculated. RESULTS: Six of 195 ports (3.1%) were associated with wound dehiscence requiring port removal. The mean interval between bevacizumab dosing and port placement in patients without dehiscence (n = 189) was 16.9 days. The mean interval in patients with dehiscence (n = 6) was 10.8 days. A two-tailed Wilcoxon test was performed, which yielded a P value of .0150. A statistically significant difference in the mean interval between bevacizumab dosing and port placement exists between patients with dehiscence and those without. CONCLUSIONS: Wound dehiscence after port placement was related to timing of bevacizumab therapy. Patients receiving bevacizumab within 10 days of port placement had a higher incidence of wound dehiscence. C1 [Zawacki, Walter J.; Walker, Gregory; DeVasher, Emily; Halpern, Elkan F.; Waltman, Arthur C.; Wicky, Stephan T.; Ryan, David P.; Kalva, Sanjeeva P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Zawacki, WJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 290, Boston, MA 02114 USA. EM wzawacki@partners.org NR 9 TC 18 Z9 18 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 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAY PY 2009 VL 20 IS 5 BP 624 EP 627 DI 10.1016/j.jvir.2009.01.022 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 440LD UT WOS:000265700900009 PM 19328717 ER PT J AU Salazar, GM Faintuch, S Gladstone, SR Lang, EV AF Salazar, Gloria M. Faintuch, Salomao Gladstone, Steve R. Lang, Elvira V. TI In Vitro Analysis of Downstream Particulates with Mechanical Thrombectomy Devices: Comparison of 20-kHz Sonothrombolytic and Rotating Dispersion Wire Systems SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID DEEP VENOUS THROMBOSIS; CATHETER-DIRECTED THROMBOLYSIS; RHEOLYTIC THROMBECTOMY; DISTAL EMBOLIZATION; PROTECTION; ANGIOPLASTY; OCCLUSIONS; EMBOLISM; SAFETY; ARTERY AB PURPOSE: To assess the potential of macroembolization, the authors compared the downstream particulate profile generated with use of two thrombectomy devices, a 20-kHz ultrasound-based sonothrombolytic (ST) device and a rotating dispersion wire (RDW). MATERIALS AND METHODS: An arterial flow model was pressurized to 100 mm Hg and perfused with 1,000 mL/min normal saline. Tubing containing 7-mm x 30-cm bovine thrombus proximal to a 75% stenosis was inserted distal to a nonstenosed bypass. The effluent was passed successively through 1,000-, 500-, and 200-mu m filters and a particle analyzer. The ST device and RDW were activated for 10 and 15 minutes, respectively, in randomized sequences of experimental sets with and without the use of 10-mg tissue-type plasminogen activator (tPA). Results are expressed as means and standard deviations of fraction of lysed clot in each category. RESULTS: The ST device produced significantly fewer particulates larger than 1,000 mu m (1.3% +/- 1.4) than did the RDW (16.8% +/- 8.4, P < .001) and significantly more particulates smaller than 10 mu m (90.7% +/- 7.6) than did the RDW (73.9% +/- 9.5; P <.001) at comparable thrombolytic efficacy (P =.982) and without significant effect from tPA (P =.988). There were no significant differences between particles measuring 500-1,000 mu m (ST device: 0.3% +/- 0.3, RDW: 0.4% +/- 0.3; P =.653) and those measuring 10-199 mu m (ST device: 7.5% +/- 7.5, RDW: 8.6% +/- 3.8; P =.624). The amount of particles on the 200-mu m filter after RDW activation (0.4% 0.3) exceeded those trapped after use of the ST device (0.1% +/- 0.1, P =.007) but contributed relatively little overall. CONCLUSIONS: In this in vitro model, the use of the ST device resulted in fewer large particulates than did the use of the RDW, with more clots being reduced to less than 10 mu m. C1 [Salazar, Gloria M.; Faintuch, Salomao; Lang, Elvira V.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Gladstone, Steve R.; Lang, Elvira V.] OmniSon Med Technol, Williamstown, MA USA. RP Salazar, GM (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 290A, Boston, MA 02114 USA. EM gmsalazar@partners.org NR 20 TC 3 Z9 3 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 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAY PY 2009 VL 20 IS 5 BP 634 EP 639 DI 10.1016/j.jvir.2008.12.416 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 440LD UT WOS:000265700900011 PM 19324573 ER PT J AU Siddiqi, NH Devlin, PM AF Siddiqi, Nasir H. Devlin, Phillip M. TI Radiation Lobectomy-A Minimally Invasive Treatment Model for Liver Cancer: Case Report SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; MICROSPHERES; THERAPY AB Chemotherapy-resistant colon carcinoma metastases to a patient's right hepatic lobe progressed after right lobar radioembolization with yttrium-90. The metastasis-free left lobe had adequate volume as a future liver remnant. Repeat right lobar radioembolization with supratherapeutic activity of (90)y caused shrinking of the tumors and the right lobe with no adverse outcome. With an adequate tumor-free future liver remnant, one hepatic lobe bearing a large tumor burden may be administered supratherapeutic activity of (90)Y, risking lobar ablation for greater probability of tumor eradication. This is analogous to hepatic lobectomy. This case is presented as a proof of principle. C1 [Siddiqi, Nasir H.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Div Vasc & Intervent Radiol, St Louis, MO 63110 USA. [Devlin, Phillip M.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Div Brachytherapy,Dept Radiat Oncol, Boston, MA USA. RP Siddiqi, NH (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Div Vasc & Intervent Radiol, 510 S Kingshighway Blvd, St Louis, MO 63110 USA. EM siddiqin@mir.wustl.edu NR 15 TC 15 Z9 15 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 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAY PY 2009 VL 20 IS 5 BP 664 EP 669 DI 10.1016/j.jvir.2009.01.023 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 440LD UT WOS:000265700900017 PM 19328722 ER PT J AU Visser, JJ Williams, M Kievit, J Bosch, JL AF Visser, Jacob J. Williams, Martine Kievit, Jur Bosch, Johanna L. CA 4-A Study Grp TI Prediction of 30-day mortality after endovascular repair or open surgery in patients with ruptured abdominal aortic aneurysms SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID RISK-SCORING METHODS; FEASIBILITY; VALIDATION; SYSTEMS; TRIALS; TOOL AB Objective: To validate the Glasgow Aneurysm Score (GAS) in patients with ruptured abdominal aortic aneurysms (AAAs) treated with endovascular repair or open surgery and to update the GAS so that it predicts 30-day mortality for patients with ruptured AAA treated with endovascular repair or open surgery. Methods: In a multicenter prospective observational study, 233 consecutive patients with ruptured AAAs were evaluated; 32 patients did not survive to repair and statistical analysis was performed using collected data on 201 patients. All patients who were treated with endovascular repair (n = 58) or open surgery (n = 143) were included. The GAS was calculated for each patient. The area under the receiver operating characteristics curve (AUC) was used to indicate discriminative ability. We tested for interactions between risk factors and the procedure performed. The GAS was updated to predict 30-day mortality after endovascular repair or open surgery in patients with ruptured AAAs using logistic regression analysis. Results: Thirty-day mortality was 15/58 (26%) for patients treated with endovascular repair and 57/143 (40%) for patients treated with open surgery (P = .06). The AUC for GAS was 0.69. No relevant interactions were found. The updated prediction rule (AUC = 0.70) clan be calculated with the following formula: + 7 for open surgery + age in years + 17 for shock + 7 for myocardial disease + 10 for cerebrovascular disease + 14 for renal insufficiency. Conclusion: We showed limited discriminative ability of the GAS and therefore updated the GAS by adding the type of procedure performed. This updated prediction rule predicts 30-day mortality for patients with ruptured AAAs treated with endovascular repair or open surgery. (J Vase Surg 2009;49:1093-9.) C1 [Visser, Jacob J.; Bosch, Johanna L.] Erasmus MC, Dept Epidemiol & Biostat, Rotterdam, Netherlands. [Visser, Jacob J.; Bosch, Johanna L.] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Williams, Martine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Cambridge, MA 02138 USA. [Williams, Martine] Univ Med Ctr, Dept Surg, Nijmegen, Netherlands. [Kievit, Jur] Catharina Hosp, Dept Surg, Eindhoven, Netherlands. RP Visser, JJ (reprint author), Care of van Sambeek MRHM, Catharina Hosp, Dept Surg Vasc Surg, Michelangelolaan 2, NL-5623 EJ Eindhoven, Netherlands. EM marc.v.sambeek@cze.nl FU Erasmus MC Health Care Efficiency; "Lijf en Leven" Foundation FX The study was funded by Erasmus MC Health Care Efficiency grant and an Unrestricted educational grant from the "Lijf en Leven" Foundation. NR 27 TC 30 Z9 33 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAY PY 2009 VL 49 IS 5 BP 1093 EP 1099 DI 10.1016/j.jvs.2008.12.027 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 441BQ UT WOS:000265744700001 PM 19394540 ER PT J AU Chang, CK Chuter, TAM Niemann, CU Shlipak, MG Cohen, MJ Reilly, LM Hiramoto, JS AF Chang, Catherine K. Chuter, Timothy A. M. Niemann, Claus U. Shlipak, Michael G. Cohen, Mitchell J. Reilly, Linda M. Hiramoto, Jade S. TI Systemic inflammation, coagulopathy, and acute renal insufficiency following endovascular thoracoabdominal aortic aneurysm repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; ZENITH STENT GRAFT; CYSTATIN-C; BIOLOGICAL RESPONSES; SURGERY; INJURY; REINTERVENTION; CREATININE; BIOMARKERS; FAILURE AB Objective: To characterize the inflammatory and coagulopathic response after endovascular thoracoabdominal aortic aneurysm (TAAA) repair and to evaluate the effect of the response on postoperative renal function. Methods. From July 2005 to June 2008, 42 patients underwent elective endovascular repair of a TAAA using custom designed multi-branched stent-grafts at a single academic institution. Four patients were excluded from the analysis. White blood cell count (WBC), platelet count, prothrombin time (PT), and creatinine were measured in all patients. In the last nine patients, interleukin-6 (IEL-6), protein C, Factor V, cl-dimers, cystatin C, and neutrophil gelatinase-associated lipocatin (NGAL) levels were also measured. Change in lab values were expressed as a percentage of baseline values. Results. The 30-day mortality rate was 5% (2/38). All patients (n = 38) had a higher WBC (mean +/- SD: 139 +/- 80%, P < .0001), lower platelet count (56 +/- 15%, P < .0001), and higher PT (median: 17%, Interquartile range (IQR) 12%-22%, P < .0001) after stent-graft insertion. Twelve of 38 patients (32%) developed postoperative acute renal insufficiency (>50% rise in creatinine). Patients with renal insufficiency had significantly larger changes in WBC (178 +/- 100% vs 121 +/- 64%, P = .04) and platelet count (64 +/- 17% vs 52 +/- 12%, P = .02) compared with those without renal insufficiency. All patients (n = 9) had significant increases in NGAL (182 +/- 115%, P = .008) after stent-graft insertion. Six of nine patients (67%) had increased cystatin C (35 +/- 43%, P = .04) after stent-graft insertion, with a greater rise in those with postoperative renal insufficiency (87 +/- 32% vs 8 +/- 13%, P = .02). IEL-6 levels were markedly increased in all patients (n = 9) after repair (9840 +/- 6160%, P = .008). Protein C (35 +/- 10%, P = .008) and Factor V levels (28 +/- 20%, P = .008) were uniformly decreased, while d-dimers were elevated after repair in all patients (310 +/- 213%, P = .008). Conclusions. Leukocytosis and thrombocytopenia were uniform following endovascular TAAA repair, and the severity of the response correlated with post-operative renal dysfunction. Elevation of a sensitive marker of renal injury (NGAL) suggests that renal injury may occur in all patients after stent-graft insertion. (J Vasc Surg 2009;49:1140-6.) C1 [Chang, Catherine K.; Chuter, Timothy A. M.; Reilly, Linda M.; Hiramoto, Jade S.] Univ Calif San Francisco, Div Vasc Surg, Dept Surg, San Francisco, CA 94143 USA. [Niemann, Claus U.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Niemann, Claus U.] Univ Calif San Francisco, Div Transplantat, Dept Surg, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. RP Hiramoto, JS (reprint author), Univ Calif San Francisco, Div Vasc Surg, Dept Surg, 400 Parnassus Ave,A-581, San Francisco, CA 94143 USA. EM Jade.Hiramoto@ucsfmedctr.org FU National Institutes of Health (NIH)/National Center for Research Resources (NCRR)/OD University of California, Sail Francisco (UCSF)-Clinical and Translational Science Institute (CTSI) [KL2 RR024130]; NIH [K08 GM-085689]; Hellman Award; Research Evaluation and Allocation Committee, San Francisco, CA; Foundation of Anesthesia Research and Education; Foundation for Accelerated Vascular Research, San Francisco; American Heart Association FX This project was Supported by National Institutes of Health (NIH)/National Center for Research Resources (NCRR)/OD University of California, Sail Francisco (UCSF)-Clinical and Translational Science Institute (CTSI) Grant Number KL2 RR024130 (Dr Hiramoto) and NIH K08 GM-085689 (Dr Cohen). Its contents arc the responsibility of the authors and do not necessarily represent the official views of the NIH. This stud), was also supported in part by grants from the Hellman Award, Sail Francisco, CA (Dr Hiramoto); the Research Evaluation and Allocation Committee, San Francisco, CA (Dr Hirarnoto); the Foundation of Anesthesia Research and Education, Rochester, MN (Dr Niemann); the International Anesthesia Research Society, Cleveland, OH (Dr Niemann); the Foundation for Accelerated Vascular Research, San Francisco, CA (Drs Chang and Chuter); and the Established Investigator Award from the American Heart Association (Dr Shlipak). The Clinical-trials.gov number is: NCT00483249. NR 29 TC 33 Z9 36 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAY PY 2009 VL 49 IS 5 BP 1140 EP 1146 DI 10.1016/j.jvs.2008.11.102 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 441BQ UT WOS:000265744700009 PM 19394543 ER PT J AU Kassa, A Finzi, A Pancera, M Courter, JR Smith, AB Sodroski, J AF Kassa, Aemro Finzi, Andres Pancera, Marie Courter, Joel R. Smith, Amos B., III Sodroski, Joseph TI Identification of a Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Variant Resistant to Cold Inactivation SO JOURNAL OF VIROLOGY LA English DT Article ID ENTRY INHIBITOR SENSITIVITY; HUMAN MONOCLONAL-ANTIBODIES; DEPENDENT DNA POLYMERASE; SOLUBLE CD4; HIV-1 GP120; CELL-LINE; NONNEUTRALIZING ANTIBODIES; NEUTRALIZING ANTIBODY; TRANSMEMBRANE PROTEIN; CYTOPLASMIC DOMAIN AB The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein trimer consists of gp120 and gp41 subunits and undergoes a series of conformational changes upon binding to the receptors, CD4 and CCR5/CXCR4, that promote virus entry. Surprisingly, we found that the envelope glycoproteins of some HIV-1 strains are functionally inactivated by prolonged incubation on ice. Serial exposure of HIV-1 to extremes of temperature, followed by expansion of replication-competent viruses, allowed selection of a temperature-resistant virus. The envelope glycoproteins of this virus resisted cold inactivation due to a single passage-associated change, H66N, in the gp120 exterior envelope glycoprotein. Histidine 66 is located within the gp41-interactive inner domain of gp120 and, in other studies, has been shown to decrease the sampling of the CD4-bound conformation by unliganded gp120. Substituting asparagine or other amino acid residues for histidine 66 in cold-sensitive HIV-1 envelope glycoproteins resulted in cold-stable phenotypes. Cold inactivation of the HIV-1 envelope glycoproteins occurred even at high pH, indicating that protonation of histidine 66 is not necessary for this process. Increased exposure of epitopes in the ectodomain of the gp41 transmembrane envelope glycoprotein accompanied cold inactivation, but shedding of gp120 did not. An amino acid change in gp120 (S375W) that promotes the CD4-bound state or treatment with soluble CD4 or a small-molecule CD4 mimic resulted in increased cold sensitivity. These results indicate that the CD4-bound intermediate of the HIV-1 envelope glycoproteins is cold labile; avoiding the CD4-bound state increases temperature stability. C1 [Kassa, Aemro; Finzi, Andres; Pancera, Marie; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Courter, Joel R.; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Kassa, Aemro; Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU NIH [AI24755, AI39420, AI40895, GM56550]; Center for HIV/AIDS Vaccine Immunology [AI67854]; Center for AIDS Research [AI42848]; Bristol-Myers Squibb Foundation; International AIDS Vaccine Initiative FX This work was supported by NIH grants (AI24755, AI39420, AI40895, and GM56550), by a Center for HIV/AIDS Vaccine Immunology grant (AI67854), by a Center for AIDS Research grant (AI42848), by an unrestricted research grant from the Bristol-Myers Squibb Foundation, by a gift from the late William F. McCarty-Cooper, and by funds from the International AIDS Vaccine Initiative. NR 79 TC 23 Z9 23 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY 1 PY 2009 VL 83 IS 9 BP 4476 EP 4488 DI 10.1128/JVI.02110-08 PG 13 WC Virology SC Virology GA 431DN UT WOS:000265041600047 PM 19211747 ER PT J AU Matthews, PC Leslie, AJ Katzourakis, A Crawford, H Payne, R Prendergast, A Power, K Kelleher, AD Klenerman, P Carlson, J Heckerman, D Ndung'u, T Walker, BD Allen, TM Pybus, OG Goulder, PJR AF Matthews, Philippa C. Leslie, Alasdair J. Katzourakis, Aris Crawford, Hayley Payne, Rebecca Prendergast, Andrew Power, Karen Kelleher, Anthony D. Klenerman, Paul Carlson, Jonathan Heckerman, David Ndung'u, Thumbi Walker, Bruce D. Allen, Todd M. Pybus, Oliver G. Goulder, Philip J. R. TI HLA Footprints on Human Immunodeficiency Virus Type 1 Are Associated with Interclade Polymorphisms and Intraclade Phylogenetic Clustering SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; CHRONIC HIV-1 INFECTION; HEPATITIS-C VIRUS; LYMPHOCYTE RESPONSE; SEQUENCE DIVERSITY; DOMINANT INFLUENCE; POPULATION-LEVEL; VACCINE DESIGN; VIRAL LOAD; ESCAPE AB The selection of escape mutations has a major impact on immune control of infections with viruses such as human immunodeficiency virus (HIV). Viral evasion of CD8(+) T-cell responses leaves predictable combinations of escape mutations, termed HLA "footprints." The most clearly defined footprints are those associated with HLA alleles that are linked with successful control of HIV, such as HLA-B*57. Here we investigated the extent to which HLA footprint sites in HIV type 1 (HIV-1) are associated with viral evolution among and within clades. First, we examined the extent to which amino acid differences between HIV-1 clades share identity with sites of HLA-mediated selection pressure and observed a strong association, in particular with respect to sites of HLA-B selection (P < 10(-6)). Similarly, the sites of amino acid variability within a clade were found to overlap with sites of HLA-selected mutation. Second, we studied the impact of HLA selection on interclade phylogeny. Removing the sites of amino acid variability did not significantly affect clade-specific clustering, reflecting the central role of founder effects in establishing distinct clades. However, HLA footprints may underpin founder strains, and we show that amino acid substitutions between clades alter phylogeny, underlining a potentially substantial role for HLA in driving ongoing viral evolution. Finally, we investigated the impact of HLA selection on within-clade phylogeny and demonstrate that even a single HLA allele footprint can result in significant phylogenetic clustering of sequences. In conclusion, these data highlight the fact that HLA can be a strong selection force for both intra- and interclade HIV evolution at a population level. C1 [Matthews, Philippa C.; Leslie, Alasdair J.; Crawford, Hayley; Payne, Rebecca; Prendergast, Andrew; Klenerman, Paul; Goulder, Philip J. R.] Nuffield Dept Med, Dept Paediat, Oxford OX1 3SY, England. [Katzourakis, Aris; Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3SY, England. [Power, Karen; Walker, Bruce D.; Allen, Todd M.; Goulder, Philip J. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA USA. [Carlson, Jonathan; Heckerman, David] Microsoft Res, Redmond, WA USA. [Kelleher, Anthony D.] St Vincents Hosp, Ctr Immunol, Sydney, NSW 2010, Australia. [Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip J. R.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Matthews, PC (reprint author), Nuffield Dept Med, Dept Paediat, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM p.matthews@doctors.org.uk; philip.goulder@paediatrics.ox.ac.uk RI pybus, oliver/B-2640-2012; Allen, Todd/F-5473-2011; OI Katzourakis, Aris/0000-0003-3328-6204; Matthews, Philippa/0000-0002-4036-4269; Pybus, Oliver/0000-0002-8797-2667; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institutes of Health [NO1-A1-15422, 2RO1AI46995-06, R01A1067073]; Wellcome Trust; UK Medical Research Council; Mark and Lisa Schwartz Foundation; AIDS Foundation Scientist FX This work was funded by the National Institutes of Health ( contracts NO1-A1-15422, 2RO1AI46995-06, and R01A1067073), the Wellcome Trust ( A. L. and P. G.), the UK Medical Research Council ( P. M. and A. P.), and the Mark and Lisa Schwartz Foundation. P. G. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist. NR 40 TC 29 Z9 29 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY 1 PY 2009 VL 83 IS 9 BP 4605 EP 4615 DI 10.1128/JVI.02017-08 PG 11 WC Virology SC Virology GA 431DN UT WOS:000265041600059 PM 19244334 ER PT J AU Boudoux, C Leuin, SC Oh, WY Suter, MJ Desiardins, AE Vakoc, BJ Bourna, BE Hartnick, CJ Tearney, GJ AF Boudoux, C. Leuin, S. C. Oh, W. Y. Suter, M. J. Desiardins, A. E. Vakoc, B. J. Bourna, B. E. Hartnick, C. J. Tearney, G. J. TI Preliminary Evaluation of Noninvasive Microscopic Imaging Techniques for the Study of Vocal Fold Development SO JOURNAL OF VOICE LA English DT Article CT 36th Annual Symposium on Care of the Professional Voice CY JUN 01, 2007 CL Philadelphia, PA SP Voice Fdn DE Laryngology; Pediatric vocal fold development; Noninvasive optical imaging; Optical coherence tomography; Reflectance confocal microscopy; Optical coherence microscopy; Porcine vocal fold ID OPTICAL COHERENCE TOMOGRAPHY; ENCODED CONFOCAL MICROSCOPY; IN-VIVO; HIGH-SPEED; LAMINA PROPRIA; HUMAN-SKIN; LASER; MICROFLAP; HISTOLOGY; LESIONS AB Understanding pediatric voice development and laryngeal pathology is predicated on a detailed knowledge of the microanatomy of the layered structure of the vocal fold. Our current knowledge of this microanatomy and its temporal evolution is limited by the lack of pediatric specimen availability. By providing the capability to image pediatric vocal folds in vivo, a noninvasive microscopy technique could greatly expand the existing database of pediatric laryngeal microanatomy and could furthermore make longitudinal Studies possible. A variety of natural-contrast optical imaging technologies, including optical frequency domain imaging (OFDI), full-field optical coherence microscopy (FF-OCM), and spectrally encoded confocal microscopy (SECM) have been recently developed for noninvasive diagnosis in adult patients. In this paper, we demonstrate the potential of these three techniques for laryngeal investigation by obtaining images of excised porcine vocal fold samples. In our study, OFDI allowed visualization of the vocal fold architecture deep within the tissue, from the superficial mucosa to the vocalis muscle. The micron-level resolution of SECM allowed investigation of cells and extracellular matrix fibrils from the superficial mucosa to the intermediate layer of the lamina propria (LP) (350 mu m penetration depth). The large field of view (Lip to 700 Am), penetration depth (up to 500 mu m), and resolution (2 X 2 X 1 mu m [X X Y X Z]) of FF-OCM enabled comprehensive three-dimensional evaluation of the layered structure of the LP. Our results Suggest that these techniques provide important and complementary cellular and structural information, which may be useful for investigating pediatric vocal fold maturation in vivo. C1 [Leuin, S. C.; Hartnick, C. J.] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Boudoux, C.; Oh, W. Y.; Suter, M. J.; Desiardins, A. E.; Vakoc, B. J.; Bourna, B. E.; Tearney, G. J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Boudoux, C.] Ecole Polytech, Dept Engn Phys, Montreal, PQ H3C 3A7, Canada. RP Hartnick, CJ (reprint author), Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu RI Oh, Wang-Yuhl/C-2055-2011; Boudoux, Caroline/A-6399-2012 NR 46 TC 7 Z9 7 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0892-1997 J9 J VOICE JI J. Voice PD MAY PY 2009 VL 23 IS 3 BP 269 EP 276 DI 10.1016/j.jvoice.2007.10.003 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA 448IT UT WOS:000266257000001 PM 18346865 ER PT J AU Wheeler, S Bowen, JD Maynard, C Lowy, E Sun, HL Sales, AE Smith, NL Fihn, SD AF Wheeler, Stephanie Bowen, Jennie D. Maynard, Charles Lowy, Elliot Sun, Haili Sales, Anne E. Smith, Nicholas L. Fihn, Stephan D. TI Women Veterans and Outcomes after Acute Myocardial Infarction SO JOURNAL OF WOMENS HEALTH LA English DT Article ID ACUTE CORONARY SYNDROMES; HEALTH-CARE-SYSTEM; QUALITY-OF-CARE; SEX-DIFFERENCES; HOSPITAL DISCHARGE; ARTERY DISEASE; MEN; MANAGEMENT; MORTALITY; GENDER AB Background: Previous studies have shown that women have decreased survival and receive fewer cardiac procedures after acute myocardial infarction (AMI) compared with men, raising concerns for sexual bias in provision of care. The objective of this study is to describe clinical characteristics, treatment, and survival in women veterans compared with men after admission to VA hospitals for AMI. Methods: This is a retrospective inception cohort study using data drawn from the VA Cardiac Care Follow-up Clinical Study, describing patients admitted for AMI to VA hospitals from October 1, 2003 to March 31, 2005. Subjects were followed for 1 year. Results: There were 236 women and 13,259 men admitted during the study period to VA hospitals with AMI. Women were less likely to have a history of heart failure compared with men (18.2% of women vs. 27.2% of men, p = 0.002) and previous coronary artery bypass grafting (CABG) (11.4% of women vs. 19.6% of men, p=0.002). Diagnostic cardiac catheterization was similar in women and men (36.9% and 34.9%, p = 0.539). Crude in-hospital mortality was 4.2% for women and 7.6% for men (p=0.051). After adjusting for comorbidities and treatment variables, in-hospital mortality was not significantly different for women compared with men (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.60-1.12). Conclusions: Women veterans receive a level of care similar to men veterans for MI treated in VA hospitals. Differences in mortality between women and men were not significant and do not suggest that women fare worse. C1 [Wheeler, Stephanie; Bowen, Jennie D.; Maynard, Charles; Lowy, Elliot; Sun, Haili; Sales, Anne E.; Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, VA NW Hlth Serv Res & Dev Ctr Excellence, Seattle, WA 98108 USA. [Maynard, Charles; Smith, Nicholas L.] VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA. RP Wheeler, S (reprint author), VA Puget Sound Hlth Care Syst, VA NW Hlth Serv Res & Dev Ctr Excellence, S-111-GIMC,1660 S Columbian Way, Seattle, WA 98108 USA. EM stephanie.wheeler@med.va.gov RI Sales, Anne/D-9678-2012; Maynard, Charles/N-3906-2015; OI Maynard, Charles/0000-0002-1644-7814; Sales, Anne/0000-0001-9360-3334 NR 23 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAY PY 2009 VL 18 IS 5 BP 613 EP 618 DI 10.1089/jwh.2008.1073 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 446DP UT WOS:000266100900003 PM 19392640 ER PT J AU Kuy, S AF Kuy, SreyRam TI Women Have Better Outcomes In Cholecystitis SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Kuy, SreyRam] Yale Univ, Sch Med, US Dept Vet Affairs, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06520 USA. [Kuy, SreyRam] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAY PY 2009 VL 18 IS 5 MA 30 BP 753 EP 753 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 446DP UT WOS:000266100900049 ER PT J AU Menefee, DS Gwynn, S Dao, TK Teng, E Graham, DP AF Menefee, Deleene S. Gwynn, Stacy Dao, Tam K. Teng, Ellen Graham, David P. TI Preliminary Examination of Correlates of Deployment Risk and Protective Factors and Mental Health Outcomes among OEF/OIF Women Veterans. SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Menefee, Deleene S.; Gwynn, Stacy; Dao, Tam K.; Teng, Ellen; Graham, David P.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Menefee, Deleene S.; Dao, Tam K.; Teng, Ellen; Graham, David P.] Baylor Coll Med, Menninger Dept Psychiat & Behav Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAY PY 2009 VL 18 IS 5 MA 33 BP 754 EP 754 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 446DP UT WOS:000266100900052 ER PT J AU McCarthy, MW Pelletier, L Morrow, L AF McCarthy, Maureen W. Pelletier, Linda Morrow, Lori TI PREOPERATIVE STOMA MARKING BEGINS THE CARE CONTINUUM SO JOURNAL OF WOUND OSTOMY AND CONTINENCE NURSING LA English DT Meeting Abstract C1 [McCarthy, Maureen W.; Pelletier, Linda; Morrow, Lori] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mmccarthy29@partners.org; LPELLETIER@PARTNERS.ORG; lmorrow@partners.org NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1071-5754 J9 J WOUND OSTOMY CONT JI J. Wound Ostomy Cont. Nurs. PD MAY-JUN PY 2009 VL 36 IS 3 BP S44 EP S44 PG 1 WC Nursing SC Nursing GA 446KH UT WOS:000266120000131 ER PT J AU McCarthy, MW Pelletier, L Morrow, L AF McCarthy, Maureen W. Pelletier, Linda Morrow, Lori TI CREATIVE AND EFFECTIVE FISTULA MANAGEMENT SO JOURNAL OF WOUND OSTOMY AND CONTINENCE NURSING LA English DT Meeting Abstract C1 [McCarthy, Maureen W.; Pelletier, Linda; Morrow, Lori] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mmccarthy29@partners.org; LPELLETIER@PARTNERS.ORG; lmorrow@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1071-5754 J9 J WOUND OSTOMY CONT JI J. Wound Ostomy Cont. Nurs. PD MAY-JUN PY 2009 VL 36 IS 3 BP S18 EP S19 PG 2 WC Nursing SC Nursing GA 446KH UT WOS:000266120000050 ER PT J AU Brunelli, SM Thadhani, R Ikizler, TA Feldman, HI AF Brunelli, Steven M. Thadhani, Ravi Ikizler, T. Alp Feldman, Harold I. TI Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes SO KIDNEY INTERNATIONAL LA English DT Article DE diabetes; dialysis; epidemiology; mortality; survival thiazolidinediones ID IMPROVES GLYCEMIC CONTROL; CHRONIC DIALYSIS PATIENTS; CORONARY-ARTERY-DISEASE; INTIMA-MEDIA THICKNESS; CARDIOVASCULAR-DISEASE; PIOGLITAZONE HYDROCHLORIDE; RANDOMIZED-TRIAL; ROSIGLITAZONE; MELLITUS; THERAPY AB Cardiovascular mortality is especially high among dialysis patients with diabetes, as is morbidity due to protein energy wasting. Given that both of these factors may be decreased by thiazolidinedione treatment, we studied the effect of thiazolidinedione use on survival among chronic dialysis patients in a national cohort of 5290 incident dialysis patients with diabetes. Thiazolidinedione use was assessed according to prescription data, and the analyses were stratified based on insulin use due to observed interaction. In the primary analysis, thiazolidinedione treatment was associated with significantly lower all-cause mortality among insulin-free but not insulin-requiring subjects, with adjusted hazards ratios of 0.53 (0.31-0.89) and 0.82 (0.46-1.47) respectively. Sensitivity analyses found the findings to be robust with respect to confounding by indication, severity of the diabetes, potential reverse causality, and time varying exposure patterns. The mechanism of this decline in all-cause mortality will need to be examined after these studies are confirmed. C1 [Brunelli, Steven M.; Feldman, Harold I.] Univ Penn, Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Brunelli, Steven M.; Feldman, Harold I.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Thadhani, Ravi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit,Dept Med, Boston, MA 02115 USA. [Ikizler, T. Alp] Vanderbilt Univ, Med Ctr, Div Nephrol, Nashville, TN USA. RP Brunelli, SM (reprint author), Harvard Univ, Sch Med, Div Renal, Brigham & Womens Hosp, 75 Francis St,MRB 4, Boston, MA 02115 USA. EM sbrunelli@partners.org FU NIDDK [1K23DK079056]; American Heart Association [0775021N]; National Kidney Foundation Satellite Dialysis Research Fellowship FX We thank Raymond Boston and Russell Localio for their advice regarding competing risks models. This study was supported in part by awards from the NIDDK (1K23DK079056), the American Heart Association (0775021N), and the National Kidney Foundation Satellite Dialysis Research Fellowship) to SMB. SMB had full access to all of the data and takes responsibility for the integrity and accuracy of the data analysis. NR 45 TC 25 Z9 27 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD MAY PY 2009 VL 75 IS 9 BP 961 EP 968 DI 10.1038/ki.2009.4 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 433QM UT WOS:000265220900014 PM 19190679 ER PT J AU Klusmann, JH Godinho, FJ Heitmarm, K Pushpanathan, T Reinhardt, D Orkin, SH Li, Z AF Klusmann, J. H. Godinho, F. J. Heitmarm, K. Pushpanathan, T. Reinhardt, D. Orkin, S. H. Li, Z. TI Developmental stage-specific interplay between GATA1 and IGF signaling during fetal hematopoiesis and leukemogenesis SO KLINISCHE PADIATRIE LA English DT Meeting Abstract C1 [Klusmann, J. H.; Godinho, F. J.; Orkin, S. H.; Li, Z.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, S. H.; Li, Z.] Harvard Univ, Sch Med, Boston, MA USA. [Orkin, S. H.; Li, Z.] Harvard Stem Cell Inst, Boston, MA USA. [Orkin, S. H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Godinho, F. J.; Orkin, S. H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Klusmann, J. H.; Heitmarm, K.; Pushpanathan, T.; Reinhardt, D.] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany. RI Reinhardt, Dirk/D-3939-2011 OI Reinhardt, Dirk/0000-0003-4313-9056 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0300-8630 J9 KLIN PADIATR JI Klinische Padiatr. PD MAY-JUN PY 2009 VL 221 IS 3 MA 29 BP 200 EP 200 PG 1 WC Pediatrics SC Pediatrics GA 446ZL UT WOS:000266161300045 ER PT J AU Pushpanathan, T Klusmann, J Li, Z Bohmer, K Godinho, FJ Koch, ML Orkin, SH Reinhardt, D AF Pushpanathan, T. Klusmann, J. Li, Z. Boehmer, K. Godinho, F. J. Koch, M. L. Orkin, S. H. Reinhardt, D. TI Oncogenic Potential of miR-125b-2 and its Target Genes in Normal and Malignant Hematopoesis SO KLINISCHE PADIATRIE LA English DT Meeting Abstract C1 [Pushpanathan, T.; Klusmann, J.; Boehmer, K.; Koch, M. L.; Reinhardt, D.] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany. [Li, Z.; Orkin, S. H.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Li, Z.; Orkin, S. H.] Harvard Stem Cell Inst, Cambridge, MA USA. [Orkin, S. H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Godinho, F. J.; Orkin, S. H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Li, Z.; Godinho, F. J.; Orkin, S. H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RI Reinhardt, Dirk/D-3939-2011 OI Reinhardt, Dirk/0000-0003-4313-9056 NR 0 TC 1 Z9 1 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0300-8630 J9 KLIN PADIATR JI Klinische Padiatr. PD MAY-JUN PY 2009 VL 221 IS 3 MA 51 BP 205 EP 205 PG 1 WC Pediatrics SC Pediatrics GA 446ZL UT WOS:000266161300066 ER PT J AU Swan, EEL Peppi, M Chen, ZQ Green, KM Evans, JE McKenna, MJ Mescher, MJ Kujawa, SG Sewell, WF AF Swan, Erin E. Leary Peppi, Marcello Chen, Zhiqiang Green, Karin M. Evans, James E. McKenna, Michael J. Mescher, Mark J. Kujawa, Sharon G. Sewell, William F. TI Proteomics Analysis of Perilymph and Cerebrospinal Fluid in Mouse SO LARYNGOSCOPE LA English DT Article DE Intracochlear; drug delivery; biofouling; inner ear; protein ID PROTEIN; ELECTROPHORESIS; PEPTIDES; SEARCH AB Objectives: Proteins in perilymph may alter the delivery profile of implantable intracochlear drug delivery systems through biofouling. Knowledge of protein composition will help anticipate interactions with delivered agents. Study Design: Analysis of mouse perilymph. Methods: Protein composition of perilymph and cerebrospinal fluid (CSF) was analyzed using a capillary liquid chromatography-mass spectrometry-based iTRAQ quantitative proteomics approach. We searched against a mouse subset of the Uniprot FASTA protein database. We sampled perilymph from the apex of the mouse cochlea to minimize CSF contamination. Results: More than 50 explicit protein isoforms were identified with very high confidence. iTRAQ reporter ions allowed determination of relative molar amounts of proteins between perilymph and CSF. Protein in perilymph was almost three times more concentrated than in CSF. More than one-third of the proteins in perilymph comprised protease inhibitors, with serpins being the predominant group. Apolipoproteins constituted 16%. Fifteen percent of the proteins were enzymes. Albumin was the most abundant single protein (14%). Proteins with relatively high perilymph/CSF ratios included broad-spectrum protease inhibitors and apolipoproteins. Discussion: Some proteins found in perilymph, such as albumin and HMW kininogen, have been implicated in biofouling through adsorption to device materials. The relatively large quantities of apolipoprotein and albumin may serve as a reservoir for acidic and lipophillic drugs. Alpha-2-glycoprotein can bind basic drugs. Conclusions: Perilymph is similar in protein composition to CSF, though amounts are 2.8 times higher. Protease inhibitors comprise the largest category of proteins. C1 [Peppi, Marcello; Chen, Zhiqiang; Kujawa, Sharon G.; Sewell, William F.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Swan, Erin E. Leary; McKenna, Michael J.] Charles Stark Draper Lab Inc, Cambridge, MA 02139 USA. [Swan, Erin E. Leary] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Peppi, Marcello; Chen, Zhiqiang; McKenna, Michael J.; Kujawa, Sharon G.; Sewell, William F.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sewell, William F.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Kujawa, Sharon G.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Green, Karin M.; Evans, James E.] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. EM wfs@epl.meei.harvard.edu FU National Institutes of Health (NIH) [5 R01 DC 006848-02] FX This work was supported by Grant Number 5 R01 DC 006848-02 from the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the U.S. government. NR 23 TC 14 Z9 16 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD MAY PY 2009 VL 119 IS 5 BP 953 EP 958 DI 10.1002/lary.20209 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 442UL UT WOS:000265866000019 PM 19358201 ER PT J AU Nadkarni, SK Bouma, BE de Boer, J Tearney, GJ AF Nadkarni, Seemantini K. Bouma, Brett E. de Boer, Johannes Tearney, Guillermo J. TI Evaluation of collagen in atherosclerotic plaques: the use of two coherent laser-based imaging methods SO LASERS IN MEDICAL SCIENCE LA English DT Review DE Lasers; Atherosclerosis; Collagen; Smooth muscle cells; Optical coherence tomography; Laser speckle imaging ID INTRAVASCULAR ULTRASOUND; RAMAN-SPECTROSCOPY; CORONARY ATHEROSCLEROSIS; BIOLOGICAL TISSUE; TOMOGRAPHY; BIREFRINGENCE; CHOLESTEROL; COMPONENTS; THICKNESS; ARTERIES AB Acute coronary events such as myocardial infarction are frequently caused by the rupture of unstable atherosclerotic plaque. Collagen plays a key role in determining plaque stability. Methods to measure plaque collagen content are invaluable in detecting unstable atherosclerotic plaques. Recently, novel coherent laser-based imaging techniques, such as polarization-sensitive optical coherence tomography (PSOCT) and laser speckle imaging (LSI) have been investigated, and they provide a wealth of information related to collagen content and plaque stability. Additionally, given their potential for intravascular use, these technologies will be invaluable for improving our understanding of the natural history of plaque development and rupture and, hence, enable the detection of unstable plaques. In this article we review recent developments in these techniques and potential challenges in translating these methods into intra-arterial use in patients. C1 [Nadkarni, Seemantini K.; Bouma, Brett E.; de Boer, Johannes; Tearney, Guillermo J.] Wellman Ctr Photomed, Boston, MA USA. RP Nadkarni, SK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, BAR 718,40 Blossom St, Boston, MA 02114 USA. EM snadkarni@hms.harvard.edu RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 FU NHLBI NIH HHS [R01 HL076398-04, R01 HL076398] NR 44 TC 23 Z9 25 U1 2 U2 13 PU SPRINGER LONDON LTD PI ARTINGTON PA ASHBOURNE HOUSE, THE GUILDWAY, OLD PORTSMOUTH ROAD, ARTINGTON GU3 1LP, GUILDFORD, ENGLAND SN 0268-8921 J9 LASER MED SCI JI Lasers Med. Sci. PD MAY PY 2009 VL 24 IS 3 BP 439 EP 445 DI 10.1007/s10103-007-0535-x PG 7 WC Engineering, Biomedical; Surgery SC Engineering; Surgery GA 437PL UT WOS:000265499300021 PM 18386093 ER PT J AU Bruns, I Czibere, A Fischer, JC Roels, F Cadeddu, RP Buest, S Bruennert, D Huenerlituerkoglu, AN Stoecklein, NH Singh, R Zerbini, LF Jager, M Kobbe, G Gattermann, N Kronenwett, R Brors, B Haas, R AF Bruns, I. Czibere, A. Fischer, J. C. Roels, F. Cadeddu, R-P Buest, S. Bruennert, D. Huenerlituerkoglu, A. N. Stoecklein, N. H. Singh, R. Zerbini, L. F. Jaeger, M. Kobbe, G. Gattermann, N. Kronenwett, R. Brors, B. Haas, R. TI The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence SO LEUKEMIA LA English DT Article DE CML; BCR-ABL; stem and progenitor cells; gene expression ID PROTEIN-KINASE-C; DOWN-REGULATION; POSITIVE CELLS; IN-VITRO; BCR-ABL; LEUKEMIA; MIGRATION; CXCR4; EXPRESSION; GENES AB We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors. Leukemia (2009) 23, 892-899; doi:10.1038/leu.2008.392; published online 22 January 2009 C1 [Bruns, I.; Czibere, A.; Cadeddu, R-P; Buest, S.; Bruennert, D.; Singh, R.; Kobbe, G.; Gattermann, N.; Kronenwett, R.; Haas, R.] Univ Dusseldorf, Dept Hematol Oncol & Clin Immunol, D-40255 Dusseldorf, Germany. [Fischer, J. C.] Univ Dusseldorf, Inst Transplantat Diagnost & Cell Therapeut, D-40255 Dusseldorf, Germany. [Roels, F.; Brors, B.] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Huenerlituerkoglu, A. N.] Stadtische Kliniken Neuss, Lukaskrankenhaus, Neuss, Germany. [Stoecklein, N. H.] Univ Dusseldorf, Dept Gen & Visceral Surg, D-40255 Dusseldorf, Germany. [Zerbini, L. F.] Harvard Inst Med, BIDMC Genom Ctr, Boston, MA USA. [Jaeger, M.] Univ Dusseldorf, Dept Orthoped Surg, D-40255 Dusseldorf, Germany. RP Bruns, I (reprint author), Univ Dusseldorf, Dept Hematol Oncol & Clin Immunol, Moorenstr 5, D-40255 Dusseldorf, Germany. EM ingmar.bruns@med.uni-duesseldorf.de RI Brors, Benedikt/E-5620-2013; Zerbini, Luiz /B-7720-2015; OI Brors, Benedikt/0000-0001-5940-3101; Brunnert, Daniela/0000-0003-0870-9578; Fischer, Johannes/0000-0002-2079-1845 FU Leukamie Liga e. V. Dusseldorf; Forschungskommission der Medizinischen Fakultat Dusseldorf FX The following sources of financial support to IB and AC are greatly appreciated: Leukamie Liga e. V. Dusseldorf, Forschungskommission der Medizinischen Fakultat Dusseldorf. We thank Anne Koch and Sabrina Pechtel for excellent technical assistance and Dr Bernd Giebel and Dr Frank Neumann for fruitful discussions. NR 45 TC 44 Z9 44 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2009 VL 23 IS 5 BP 892 EP 899 DI 10.1038/leu.2008.392 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 444UO UT WOS:000266006100010 PM 19158832 ER PT J AU Tefferi, A Levine, RL Lim, KH Abdel-Wahab, O Lasho, TL Patel, J Finke, CM Mullally, A Li, CY Pardanani, A Gilliland, DG AF Tefferi, A. Levine, R. L. Lim, K-H Abdel-Wahab, O. Lasho, T. L. Patel, J. Finke, C. M. Mullally, A. Li, C-Y Pardanani, A. Gilliland, D. G. TI Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates SO LEUKEMIA LA English DT Article DE KIT; PDGFRA; JAK2; MPL; myeloproliferative; eosinophilia ID TYROSINE KINASE MUTATION; KIT MUTATION; MYELOPROLIFERATIVE-DISORDERS; BONE-MARROW; MYELOFIBROSIS; JAK2(V617F); FUSION; CELLS; CLASSIFICATION; INVOLVEMENT AB TET2 (TET oncogene family member 2) is a candidate tumor suppressor gene located at chromosome 4q24, and was recently reported to be mutated in similar to 14% of patients with JAK2V617F-positive myeloproliferative neoplasms. We used high-throughput DNA sequence analysis to screen for TET2 mutations in bone marrow-derived DNA from 48 patients with systemic mastocytosis (SM), including 42 who met the 2008 WHO (World Health Organization) diagnostic criteria for SM and 6 with FIP1L1-PDGFRA. Twelve (29%) SM, but no FIP1L1-PDGFRA patients, had TET2 mutations. A total of 17 mutations (13 frameshift, 2 nonsense and 2 missense) were documented in 2 (15%) of 13 indolent SM patients, 2 (40%) of 5 aggressive SM, and 8 (35%) of 23 SM associated with a clonal non-mast cell-lineage hematopoietic disease (P = 0.52). KITD816V was detected by PCR sequencing in 50 or 20% of patients with or without TET2 mutation (P = 0.05), respectively. Multivariable analysis showed a significant association between the presence of TET2 mutation and monocytosis (P = 0.0003) or female sex (P = 0.05). The association with monocytosis was also observed in non-indolent SM (n = 29), in which the presence of mutant TET2 did not affect survival (P = 0.98). We conclude that TET2 mutations are frequent in SM, segregate with KITD816V and influence phenotype without necessarily altering prognosis. Leukemia (2009) 23, 900-904; doi:10.1038/leu.2009.37; published online 5 March 2009 C1 [Tefferi, A.; Lim, K-H; Lasho, T. L.; Finke, C. M.; Li, C-Y; Pardanani, A.] Mayo Clin, Div Hematol, Dept Med, Rochester, MN 55905 USA. [Tefferi, A.; Lim, K-H; Lasho, T. L.; Finke, C. M.; Li, C-Y; Pardanani, A.] Mayo Clin, Div Hematopathol, Dept Lab Med, Rochester, MN 55905 USA. [Levine, R. L.; Abdel-Wahab, O.; Patel, J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Levine, R. L.; Abdel-Wahab, O.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Lim, K-H] Mackay Mem Hosp, Div Hematol Oncol, Taipei, Taiwan. [Lim, K-H] Mackay Med Nursing & Management Coll, Taipei, Taiwan. [Mullally, A.; Gilliland, D. G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Div Hematol,Dept Med, Boston, MA 02115 USA. [Gilliland, D. G.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Tefferi, A (reprint author), Mayo Clin, Div Hematol, Dept Med, 200 1st St SW, Rochester, MN 55905 USA. EM tefferi.ayalew@mayo.edu OI Abdel-Wahab, Omar/0000-0002-3907-6171 FU Myeloproliferative Disorders Foundation, Chicago, IL, USA FX Adriana Heguay and Igor Dolgalev from the Memorial Sloan-Kettering Cancer Center, New York, NY, USA are acknowledged for their assistance with sequence analysis. The current study was supported in part by grants from the Myeloproliferative Disorders Foundation, Chicago, IL, USA. NR 24 TC 140 Z9 147 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2009 VL 23 IS 5 BP 900 EP 904 DI 10.1038/leu.2009.37 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 444UO UT WOS:000266006100011 PM 19262599 ER PT J AU Tefferi, A Pardanani, A Lim, KH Abdel-Wahab, O Lasho, TL Patel, J Gangat, N Finke, CM Schwager, S Mullally, A Li, CY Hanson, CA Mesa, R Bernard, O Delhommeau, F Vainchenker, W Gilliland, DG Levine, RL AF Tefferi, A. Pardanani, A. Lim, K-H Abdel-Wahab, O. Lasho, T. L. Patel, J. Gangat, N. Finke, C. M. Schwager, S. Mullally, A. Li, C-Y Hanson, C. A. Mesa, R. Bernard, O. Delhommeau, F. Vainchenker, W. Gilliland, D. G. Levine, R. L. TI TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis SO LEUKEMIA LA English DT Article DE JAK2; MPL; myeloproliferative; polycythemia; thrombocythemia; myelofibrosis ID TYROSINE KINASE MUTATION; JAK2 EXON-12 MUTATIONS; ACUTE MYELOID-LEUKEMIA; MYELOPROLIFERATIVE-DISORDERS; V617F MUTATION; ACTIVATING MUTATION; ALLELE BURDEN; KIT MUTATION; JAK2V617F; METAPLASIA AB High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA from 239 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Thirty-two mutations (19 frameshift, 10 nonsense, 3 missense; mostly involving exons 4 and 12) were identified for an overall mutational frequency of similar to 13%. Specific diagnoses included polycythemia vera (PV; n = 89), essential thrombocythemia (ET; n = 57), primary myelofibrosis (PMF; n = 60), post-PV MF (n = 14), post-ET MF (n 7) and blast phase PV/ET/MF (n = 12); the corresponding mutational frequencies were similar to 16, 5, 17, 14, 14 and 17% (P = 0.50). Mutant TET2 was detected in similar to 17 and similar to 7% of JAK2V617F-positive and-negative cases, respectively (P = 0.04). However, this apparent clustering of the two mutations was accounted for by an independent association between mutant TET2 and advanced age; mutational frequency was similar to 23% in patients >= 60 years old versus similar to 4% in younger patients (P<0.0001). The presence of mutant TET2 did not affect survival, leukemic transformation or thrombosis in either PV or PMF; a correlation with hemoglobin <10 g per 100 ml in PMF was noted (P = 0.05). We conclude that TET2 mutations occur in both JAK2V617F-positive and-negative MPN, are more prevalent in older patients, display similar frequencies across MPN subcategories and disease stages, and hold limited prognostic relevance. Leukemia (2009) 23, 905-911; doi: 10.1038/leu.2009.47;published online 5 March 2009 C1 [Tefferi, A.; Pardanani, A.; Lim, K-H; Lasho, T. L.; Gangat, N.; Finke, C. M.; Schwager, S.; Li, C-Y; Hanson, C. A.; Mesa, R.] Mayo Clin, Dept Med, Div Hematol, Rochester, MN 55905 USA. [Tefferi, A.; Pardanani, A.; Lim, K-H; Lasho, T. L.; Gangat, N.; Finke, C. M.; Schwager, S.; Li, C-Y; Hanson, C. A.; Mesa, R.] Mayo Clin, Div Hematopathol, Dept Lab Med, Rochester, MN 55905 USA. [Lim, K-H] Mackay Mem Hosp, Div Hematol Oncol, Taipei, Taiwan. [Lim, K-H] Mackay Med Nursing & Management Coll, Div Hematol Oncol, Taipei, Taiwan. [Abdel-Wahab, O.; Patel, J.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, O.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Mullally, A.; Gilliland, D. G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Div Hematol,Dept Med, Boston, MA 02115 USA. [Bernard, O.] Hop Necker Enfants Malad, INSERM, E0210, Paris, France. [Bernard, O.] Hop Cochin, Hematol Lab, APHP, F-75674 Paris, France. [Bernard, O.] Univ Paris 05, Paris, France. [Delhommeau, F.; Vainchenker, W.] Inst Gustave Roussy, INSERM, U790, F-94805 Villejuif, France. [Gilliland, D. G.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Tefferi, A (reprint author), Mayo Clin, Dept Med, Div Hematol, Rochester, MN 55905 USA. EM tefferi.ayalew@mayo.edu; leviner@mskcc.org RI Bernard, Olivier/E-5721-2016; OI Abdel-Wahab, Omar/0000-0002-3907-6171 FU Myeloproliferative Disorders Foundation, Chicago, IL, USA; Howard Hughes Medical Institute; Doris Duke Charitable Foundation FX Adriana Heguy and Igor Dolgalev from Memorial Sloan-Kettering Cancer Center, New York, NY, USA are acknowledged for their assistance with sequence analysis. This study was supported in part by grants from the Myeloproliferative Disorders Foundation, Chicago, IL, USA. DGG is an investigator of the Howard Hughes Medical Institute and is a Doris Duke Charitable Foundation NR 36 TC 246 Z9 261 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2009 VL 23 IS 5 BP 905 EP 911 DI 10.1038/leu.2009.47 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 444UO UT WOS:000266006100012 PM 19262601 ER PT J AU Raje, N Hideshima, T Mukherjee, S Raab, M Vallet, S Chhetri, S Cirstea, D Pozzi, S Mitsiades, C Rooney, M Kiziltepe, T Podar, K Okawa, Y Ikeda, H Carrasco, R Richardson, PG Chauhan, D Munshi, NC Sharma, S Parikh, H Chabner, B Scadden, D Anderson, KC AF Raje, N. Hideshima, T. Mukherjee, S. Raab, M. Vallet, S. Chhetri, S. Cirstea, D. Pozzi, S. Mitsiades, C. Rooney, M. Kiziltepe, T. Podar, K. Okawa, Y. Ikeda, H. Carrasco, R. Richardson, P. G. Chauhan, D. Munshi, N. C. Sharma, S. Parikh, H. Chabner, B. Scadden, D. Anderson, K. C. TI Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma SO LEUKEMIA LA English DT Article DE cyclin D; cyclin-dependent kinase; multiple myeloma; P276-00; small molecule ID ANTITUMOR-ACTIVITY; D1 OVEREXPRESSION; PATHOGENESIS; BORTEZOMIB; CLASSIFICATION; ABNORMALITIES; DYSREGULATION; THALIDOMIDE; IDENTIFY; ARREST AB Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM. Leukemia (2009) 23, 961-970; doi:10.1038/leu.2008.378; published online 8 January 2009 C1 [Raje, N.; Mukherjee, S.; Vallet, S.; Chabner, B.; Scadden, D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc,Div Hematol Oncol, Boston, MA 02114 USA. [Raje, N.; Hideshima, T.; Raab, M.; Vallet, S.; Chhetri, S.; Cirstea, D.; Pozzi, S.; Mitsiades, C.; Rooney, M.; Kiziltepe, T.; Podar, K.; Okawa, Y.; Ikeda, H.; Carrasco, R.; Richardson, P. G.; Chauhan, D.; Munshi, N. C.; Sharma, S.; Anderson, K. C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies,Jerome Lipper Multiple M, Boston, MA 02114 USA. [Sharma, S.; Parikh, H.] Nicholas Piramal India Ltd, Bombay, Maharashtra, India. RP Raje, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc,Div Hematol Oncol, 55 Fruit St,POB 216, Boston, MA 02114 USA. EM nraje@partners.org RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU Multiple Myeloma Research Foundation Awards; ASCO Career Development Award; Department of Veterans Affairs merit review; Leukemia and Lymphoma Society Scholar in Translational Research Award (NCM); NIH [P50-100707, PO1-78378, RO1-50947] FX This work was supported by Multiple Myeloma Research Foundation Awards (NR, NCM and KCA); ASCO Career Development Award (NR); Department of Veterans Affairs merit review grant and the Leukemia and Lymphoma Society Scholar in Translational Research Award (NCM); NIH grants P50-100707 and PO1-78378 (KCA, NCM) as well as NIH grant RO1-50947 (KCA). NR 37 TC 42 Z9 42 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2009 VL 23 IS 5 BP 961 EP 970 DI 10.1038/leu.2008.378 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 444UO UT WOS:000266006100019 PM 19151776 ER PT J AU Randolph, C Hilsabeck, R Kato, A Kharbanda, P Li, YY Mapelli, D Ravdin, LD Romero-Gomez, M Stracciari, A Weissenborn, K AF Randolph, Christopher Hilsabeck, Robin Kato, Ainobu Kharbanda, Parampreet Li, Yu-Yuan Mapelli, Daniela Ravdin, Lisa D. Romero-Gomez, Manuel Stracciari, Andrea Weissenborn, Karin TI Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines SO LIVER INTERNATIONAL LA English DT Review DE assessment; encephalopathy; hepatic; neuropsychological; outcome; psychometric ID QUALITY-OF-LIFE; PORTAL-SYSTEMIC ENCEPHALOPATHY; CRITICAL FLICKER FREQUENCY; LIVER-TRANSPLANTATION; REPEATABLE BATTERY; NONALCOHOLIC CIRRHOTICS; MAGNETIZATION-TRANSFER; CEREBRAL-DYSFUNCTION; PSYCHOMETRIC TESTS; GLUCOSE-METABOLISM AB Low-grade or minimal hepatic encephalopathy (MHE) is characterised by relatively mild neurocognitive impairments, and occurs in a substantial percentage of patients with liver disease. The presence of MHE is associated with a significant compromise of quality of life, is predictive of the onset of overt hepatic encephalopathy and is associated with a poorer prognosis for outcome. Early identification and treatment of MHE can improve quality of life and may prevent the onset of overt encephalopathy, but to date, there has been little agreement regarding the optimum method for detecting MHE. The International Society on Hepatic Encephalopathy and Nitrogen Metabolism convened a group of experts for the purpose of reviewing available data and making recommendations for a standardised approach for neuropsychological assessment of patients with liver disease who are at risk of MHE. Specific recommendations are presented, along with a proposed methodology for further refining these assessment procedures through prospective research. C1 [Randolph, Christopher] Loyola Univ, Med Ctr, Dept Neurol, Maywood, IL 60153 USA. [Hilsabeck, Robin] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Hilsabeck, Robin] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Kato, Ainobu] Iwate Med Univ, Dept Internal Med, Morioka, Iwate, Japan. [Kharbanda, Parampreet] Postgrad Inst Med Educ & Res, Dept Neurol, Chandigarh 160012, India. [Li, Yu-Yuan] First Municipal Peoples Hosp Guangzhou, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China. [Mapelli, Daniela] Univ Padua, Dept Gen Psychol, Padua, Italy. [Ravdin, Lisa D.] Weill Cornell Med Ctr, Dept Neurol, New York, NY USA. [Romero-Gomez, Manuel] Hosp Univ Valme, UGC Enfermedades Digestivas, Seville, Spain. [Stracciari, Andrea] St Orsola Marcello Malpighi Hosp, Dept Neurol, Bologna, Italy. [Weissenborn, Karin] Hannover Med Sch, Dept Neurol, D-30623 Hannover, Germany. RP Randolph, C (reprint author), 1 E Erie,Suite 355, Chicago, IL 60611 USA. EM crandol@lumc.edu RI Romero Gomez, Manuel/L-8030-2014; IBIS, DIGESTIVAS/O-1913-2015; OI MAPELLI, DANIELA/0000-0003-2168-1426 NR 70 TC 84 Z9 93 U1 3 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1478-3223 J9 LIVER INT JI Liver Int. PD MAY PY 2009 VL 29 IS 5 BP 629 EP 635 DI 10.1111/j.1478-3231.2009.02009.x PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 430UI UT WOS:000265014300003 PM 19302444 ER PT J AU Corey, KE Shah, N Misdraji, J Abu Dayyeh, BK Zheng, H Bhan, AK Chung, RT AF Corey, Kathleen E. Shah, Nirali Misdraji, Joseph Abu Dayyeh, Barham K. Zheng, Hui Bhan, Atul K. Chung, Raymond T. TI The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C SO LIVER INTERNATIONAL LA English DT Article DE ACE inhibitors; angiotensin II receptor blocking agents; cirrhosis; diabetes; hypertension ID CONVERTING ENZYME-INHIBITOR; INSULIN-RESISTANCE; RECEPTOR ANTAGONIST; PORTAL-HYPERTENSION; VIRUS-INFECTION; PROGRESSION; SYSTEM; RATS; PERINDOPRIL; INTERFERON AB Multiple studies implicate the renin-angiotensin system in hepatic fibrogenesis. Few studies have examined the effects of angiotensin blockade on liver fibrosis via human histology. We studied the histological effect of angiotensin II blocking agents in chronic hepatitis C patients. This was a retrospective study of 284 chronic hepatitis C patients from 2001 to 2006 who underwent a liver biopsy. Group I was comprised of 143 hypertensive patients who received angiotensin-blocking agents. Group II was comprised of 91 hypertensive subjects who received hypertensive agents other than angiotensin blockers. Group III was comprised of 50 non-hypertensive subjects. The groups were similar in age, sex, hepatitis C genotype, viral load and disease duration. They varied significantly in total diabetic patients (Group I, 43; Group II, 10; Group III, 1; P=0.0001), consistent with recommended use of angiotensin-converting enzyme inhibitors in hypertensive diabetics. Non-hypertensive patients had significantly less fibrosis than hypertensive patients, regardless of antihypertensive medications (Group I, 3.20; Group II, 3.73; Group III, 2.5; P=0.0002). Group I had significantly less fibrosis than Group II (P=0.02). This finding persisted in a non-diabetic subgroup of Groups I and II (Group I, 3.07; Group II, 3.69; P=0.0129). Patients with hepatitis C and hypertension have increased fibrosis compared with non-hypertensive patients. Hypertensive patients receiving angiotensin-blocking agents had less fibrosis than hypertensive patients who did not receive angiotensin-blocking agents. This suggests an association with hypertension, possibly via the renin-angiotensin system in the fibrosis development and suggests a beneficial role of angiotensin II blockade in hepatitis C virus-related fibrosis. C1 [Corey, Kathleen E.; Abu Dayyeh, Barham K.; Chung, Raymond T.] Harvard Univ, Sch Med, Gastrointestinal Unit, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Corey, Kathleen E.; Shah, Nirali; Abu Dayyeh, Barham K.; Chung, Raymond T.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shah, Nirali] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Misdraji, Joseph; Bhan, Atul K.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zheng, Hui] Harvard Univ, Sch Med, Ctr Biostat, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Chung, RT (reprint author), Harvard Univ, Sch Med, Gastrointestinal Unit, Massachusetts Gen Hosp, Warren 1007C,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU NIH [AI069939-01, DK078722] FX Financial support: NIH AI069939-01 (RTC) and DK078722 (RTC).; Conflicts of interest: No conflicts of interest exist. NR 33 TC 35 Z9 36 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD MAY PY 2009 VL 29 IS 5 BP 748 EP 753 DI 10.1111/j.1478-3231.2009.01973.x PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 430UI UT WOS:000265014300022 PM 19220742 ER PT J AU Long, AA AF Long, Aidan A. TI Monoclonal antibodies and other biologic agents in the treatment of asthma SO MABS LA English DT Review DE cytokine blockers; dendritic cell; monoclonal antibodies; immunomodulators; T(H)2 cells; T(H)1 cells; airway inflammation; IgE; omalizumab ID NECROSIS-FACTOR-ALPHA; ANTI-IGE ANTIBODY; SEVERE PERSISTENT ASTHMA; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; PLACEBO-CONTROLLED TRIAL; HUMAN EPITHELIAL-CELLS; CHURG-STRAUSS-SYNDROME; IL-5 RECEPTOR-ALPHA; AIRWAY HYPERRESPONSIVENESS; T-CELLS AB Asthma represents a syndrome of airway inflammatory diseases with complex pathology. The immunologic pathogenesis is being increasingly revealed and provides opportunity for targeted biological intervention. Current experience with immunomodulators as targeted therapy in asthma is described in this literature review. Targeted therapies have included strategies to activate dendritic cells through the TLR-9 receptors, to interrupt the action of T(H)2 cytokines with cytokine blockers and monoclonal antibodies, to promote development of TO responses, to block IgE mediated pathways and to block TNF alpha. Omalizumab is the only biological therapy that has an approved indication in asthma at this time. An improved understanding of the heterogeneity of asthma should allow for specific targeting of different disease phenotypes specific therapies including immunomodulators. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Long, AA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, 201,55 Fruit St, Boston, MA 02114 USA. EM aalong@mgh.harvard.edu NR 99 TC 13 Z9 14 U1 3 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1942-0862 J9 MABS JI mAbs PD MAY-JUN PY 2009 VL 1 IS 3 BP 237 EP 246 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 521CU UT WOS:000271898000006 PM 20065638 ER PT J AU Noworolski, SM Tien, PC Merriman, R Vigneron, DB Qayyum, A AF Noworolski, Susan M. Tien, Phyllis C. Merriman, Raphael Vigneron, Daniel B. Qayyum, Aliya TI Respiratory motion-corrected proton magnetic resonance spectroscopy of the liver SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Spectroscopy; Liver; Steatosis; Nonalcoholic fatty liver disease; Respiration; Motion correction ID WOMENS INTERAGENCY HIV; CHRONIC HEPATITIS-C; IN-VIVO; NONALCOHOLIC STEATOHEPATITIS; MR SPECTROSCOPY; IMAGING DATA; SIGNAL LOSS; H-1; DISEASE; QUANTIFICATION AB Purpose: To develop a post-processing, respiratory-motion correction algorithm for magnetic resonance spectroscopy (MRS) of the liver and to determine the incidence and impact of respiratory motion in liver MRS. Materials and Methods: One hundred thirty-two subjects (27 healthy, 31 with nonalcoholic fatty liver disease and 74 HIV-infected with or without hepatitis C) were scanned with free breathing MRS at 1.5 T. Two spectral time series were acquired on an 8-ml single voxel using TR/TE=2500 ms/30 ms and (1) water suppression, 128 acquisitions, and (2) no water suppression, 8 acquisitions. Individual spectra were phased and frequency aligned to correct for intrallepatic motion. Next, water peaks more than 50% different from the median water peak area were identified and removed, and remaining spectra averaged to correct for presumed extrallepatic motion. Total CH(2)+CH(3) lipids to unsuppressed water ratios were compared before and after corrections. Results: Intrahepatic-motion correction increased the signal to noise ratio (S/N) in all cases (median=11-fold). Presumed extrahepatic motion was present in 41% (54/132) of the subjects. Its correction altered the lipids/water magnitude (magnitude change: median=2.6%, maximum=290%, and was >5% in 25% of these subjects). The incidence and effect of respiratory motion on lipids/water magnitude were similar among the three groups. Conclusion: Respiratory-motion correction of free breathing liver MRS greatly increased the S/N and, in a significant number of subjects, changed the lipids/water ratios, relevant for monitoring subjects. (C) 2009 Elsevier Inc. All rights reserved. C1 [Noworolski, Susan M.; Vigneron, Daniel B.; Qayyum, Aliya] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94107 USA. [Noworolski, Susan M.; Vigneron, Daniel B.] Univ Calif San Francisco, Grad Grp Bioengn, San Francisco, CA 94107 USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94107 USA. [Tien, Phyllis C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Merriman, Raphael] Calif Pacific Med Ctr, Dept Gastroenterol, San Francisco, CA USA. RP Noworolski, SM (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 185 Berry St,Suite 350, San Francisco, CA 94107 USA. EM sue@radiology.ucsf.edu FU NCRR NIH HHS [M01 RR000071, M01 RR000079, M01 RR000083, M01-RR-00071, M01-RR-00079, M01-RR-00083]; NIAID NIH HHS [K23 AI066943, K23 AI 66943, K23 AI066943-05, U01 AI 34993, U01 AI 31834, U01 AI 34989, U01 AI 34994, U01 AI 35004, U01 AI 42590, U01 AI031834, U01 AI034989, U01 AI034993, U01 AI034994, U01 AI035004, U01 AI042590]; NICHD NIH HHS [P01 HD 40543, P01 HD040543, P01 HD040543-019001, U01 HD 32632, U01 HD032632]; NIDDK NIH HHS [DK 061738-SI, DK 074718-01, R01 DK074718, R01 DK074718-01A1, U01 DK061738, U01 DK061738-03S1] NR 32 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD MAY PY 2009 VL 27 IS 4 BP 570 EP 576 DI 10.1016/j.mri.2008.08.008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 435DL UT WOS:000265323800016 PM 18993007 ER PT J AU Cowley, MJ Cotsapas, CJ Williams, RBH Chan, EKF Pulvers, JN Liu, MY Luo, OJ Nott, DJ Little, PFR AF Cowley, Mark J. Cotsapas, Chris J. Williams, Rohan B. H. Chan, Eva K. F. Pulvers, Jeremy N. Liu, Michael Y. Luo, Oscar J. Nott, David J. Little, Peter F. R. TI Intra- and inter-individual genetic differences in gene expression SO MAMMALIAN GENOME LA English DT Article ID QUANTITATIVE TRAIT LOCI; INBRED MOUSE STRAINS; TRANSCRIPTION FACTOR; NETWORKS; COEXPRESSION; PROFILES; DISEASE; BRAIN; YEAST; SUSCEPTIBILITY AB Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52-79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intraindividual differences. This will create substantial challenges in humans, where multiple tissues are not readily available. C1 [Cowley, Mark J.; Cotsapas, Chris J.; Williams, Rohan B. H.; Chan, Eva K. F.; Pulvers, Jeremy N.; Liu, Michael Y.; Luo, Oscar J.; Little, Peter F. R.] Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia. [Cowley, Mark J.] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. [Cotsapas, Chris J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotsapas, Chris J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Cotsapas, Chris J.] MIT & Harvard, Broad Inst, Cambridge, MA USA. [Williams, Rohan B. H.; Little, Peter F. R.] Univ New S Wales, Clive & Vera Ramaciotti Ctr Gene Funct Anal, Sydney, NSW, Australia. [Williams, Rohan B. H.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Chan, Eva K. F.] Univ Calif Davis, Dept Plant Sci, Davis, CA 95616 USA. [Nott, David J.] Univ New S Wales, Sch Math & Stat, Sydney, NSW, Australia. [Nott, David J.] Dept Stat & Appl Probabil, Singapore, Singapore. [Little, Peter F. R.] Natl Univ Singapore, Singapore 117548, Singapore. RP Little, PFR (reprint author), Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia. EM rohan.williams@anu.edu.au; peter.little@nus.edu.sg RI Forkel, Stephanie/A-4018-2011; Little, Peter. F.R./C-9971-2009; Simon, Simon/D-5128-2012; Cowley, Mark/D-4504-2012; OI Forkel, Stephanie/0000-0003-0493-0283; Cowley, Mark/0000-0002-9519-5714; Cotsapas, Chris/0000-0002-7772-5910 NR 55 TC 14 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD MAY PY 2009 VL 20 IS 5 BP 281 EP 295 DI 10.1007/s00335-009-9181-x PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 454EL UT WOS:000266664800003 PM 19424753 ER PT J AU Kitambi, SS McCulloch, KJ Peterson, RT Malicki, JJ AF Kitambi, Satish S. McCulloch, Kyle J. Peterson, Randall T. Malicki, Jarema J. TI Small molecule screen for compounds that affect vascular development in the zebrafish retina SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Blood; Circulation; Intraocular; Hyaloid; Vasculature; Angiogenesis; Chemical; Disease ID MACULAR DEGENERATION; TRANSGENIC ZEBRAFISH; DRUG DISCOVERY; HYALOID SYSTEM; DANIO-RERIO; CELL-DEATH; GENE; INHIBITORS; IDENTIFICATION; EMBRYOGENESIS AB Blood vessel formation in the vertebrate eye is a precisely regulated process. in the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kitambi, Satish S.; McCulloch, Kyle J.; Malicki, Jarema J.] Harvard Univ, Sch Med, Dept Ophthalmol, MEEI, Boston, MA 02114 USA. [Kitambi, Satish S.] Sodertorns Univ Coll, Sch Life Sci, Sodertorn, Sweden. [Kitambi, Satish S.] Karolinska Inst, Dept Biosci & Nutr, S-10401 Stockholm, Sweden. [Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Malicki, JJ (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, MEEI, 243 Charles St, Boston, MA 02114 USA. EM jarema_malicki@meei.harvard.edu RI malicki, jarema/G-8611-2014 FU National Eye Institute [R01 EY016859] FX We would like to thank Dr. William F. Sewell from the Department of otolaryngology at Harvard Medical School for providing access to an inverted microscope, Dr. Chengtian Zhao for help with designing anti-ACE morpholino, Drs. Agneta Mode, Arindam Majumdar, and Breandan Kennedy for comments on earlier versions of this manuscript, Drs. Jan Ake Gustafsson, Agneta Mode, Lotta Hambraeus, Sodertoms Hogskola, and the Department of Biosciences and Medical Nutrition at Karolinska Institutet for funding and support. Drs. Peter Schulter, Amy Doherty, and David Kokel from Randall Peterson lab as well as Dr. Caroline Shamu of the Institute of Chemistry and Cell Biology at Harvard Medical School provided valuable technical advice during this work. This project was funded in part by a National Eye Institute award R01 EY016859 (to JM). NR 57 TC 52 Z9 58 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD MAY-JUN PY 2009 VL 126 IS 5-6 BP 464 EP 477 DI 10.1016/j.mod.2009.01.002 PG 14 WC Developmental Biology SC Developmental Biology GA 457YU UT WOS:000266975100016 PM 19445054 ER PT J AU Vogeli, C Kang, R Landrum, MB Hasnain-Wynia, R Weissman, JS AF Vogeli, Christine Kang, Raymond Landrum, Mary Beth Hasnain-Wynia, Romana Weissman, Joel S. TI Quality of Care Provided to Individual Patients in US Hospitals Results From an Analysis of National Hospital Quality Alliance Data SO MEDICAL CARE LA English DT Article DE quality indicators; hospitalizations; inpatients ID ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE; PERFORMANCE-MEASURES; MORTALITY-RATES; UNITED-STATES; PNEUMONIA; OUTCOMES; THERAPY; TRIALS; RISK AB Background: There is little national data oil the characteristics of patients who receive high quality inpatient care defined as either the receipt of all appliable processes (all-or-none performance) or the proportion of applicable processes received during thier hospitalization. Objectives: To assess the quality of care provided to patients hospitalized for acute myocardial infarction (AMI), heart failure or pneumonia, to describe variations in quality by patient and hospital characteristics, and the sensitivity of all-or-none performance to the number and type of processes. Design and Subjects: Retrospective analysis of previously unavailable Hospital Quality Alliance patient-level data on 2.3 million individuals receiving care in non-federal US hospitals in 2005. Measures: The proportion of patients who received all applicable care processes, and the mean proportion of applicable processes received by hospitalized patients. C1 [Vogeli, Christine] Massachusetts Gen Hosp, Inst Hlth Policy, Dept Med, Boston, MA 02114 USA. HRET, Amer Hosp Assoc, Chicago, IL USA. [Landrum, Mary Beth] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Kang, Raymond; Hasnain-Wynia, Romana] Northwestern Univ, Feinberg Sch Med, Inst Healthcare Studies, Chicago, IL 60611 USA. [Weissman, Joel S.] Execut Off Hlth & Human Serv, Boston, MA USA. RP Vogeli, C (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM cvogeli@partners.org FU The Commonwealth Fund; Robert Wood Johnson Foundation's Changes in Health Care Financing and Organization (HCFO) Initiative FX Neither funding organization was involved in the design, data acquisition, analysis and interpretation of the data, or preparation of the manuscript. NR 24 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2009 VL 47 IS 5 BP 591 EP 599 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 438NY UT WOS:000265563500013 PM 19365292 ER PT J AU Beddar, S Archambault, L Sahoo, N Poenisch, F Chen, GT Gillin, MT Mohan, R AF Beddar, Sam Archambault, Louis Sahoo, Narayan Poenisch, Falk Chen, George T. Gillin, Michael T. Mohan, Radhe TI Exploration of the potential of liquid scintillators for real-time 3D dosimetry of intensity modulated proton beams SO MEDICAL PHYSICS LA English DT Article DE biomedical optical imaging; CCD image sensors; dosimetry; intensity modulation; liquid scintillation detectors; Monte Carlo methods; proton beams; radiation quenching; radiation therapy ID DETECTORS; VERIFICATION; RADIATION; THERAPY AB In this study, the authors investigated the feasibility of using a 3D liquid scintillator (LS) detector system for the verification and characterization of proton beams in real time for intensity and energy-modulated proton therapy. A plastic tank filled with liquid scintillator was irradiated with pristine proton Bragg peaks. Scintillation light produced during the irradiation was measured with a CCD camera. Acquisition rates of 20 and 10 frames per second (fps) were used to image consecutive frame sequences. These measurements were then compared to ion chamber measurements and Monte Carlo simulations. The light distribution measured from the images acquired at rates of 20 and 10 fps have standard deviations of 1.1% and 0.7%, respectively, in the plateau region of the Bragg curve. Differences were seen between the raw LS signal and the ion chamber due to the quenching effects of the LS and due to the optical properties of the imaging system. The authors showed that this effect can be accounted for and corrected by Monte Carlo simulations. The liquid scintillator detector system has a good potential for performing fast proton beam verification and characterization. C1 [Beddar, Sam; Archambault, Louis; Sahoo, Narayan; Poenisch, Falk; Gillin, Michael T.; Mohan, Radhe] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Unit 94, Houston, TX 77030 USA. [Chen, George T.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Beddar, S (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Unit 94, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM abeddar@mdanderson.org FU National Cancer Institute (NCI) [1R01CA120198-01A2, 2P01CA021239-29A1]; Houston Endowment, Inc.; Award for Scientific Achievement at The University of Texas M. D. Anderson Cancer Center FX This work was supported in part by the National Cancer Institute (NCI) (Grant Nos. 1R01CA120198-01A2 and 2P01CA021239-29A1). One of the authors (L. A.) was supported in part by the Odyssey program and the Houston Endowment, Inc. Award for Scientific Achievement at The University of Texas M. D. Anderson Cancer Center. NR 17 TC 27 Z9 27 U1 1 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2009 VL 36 IS 5 BP 1736 EP 1743 DI 10.1118/1.3117583 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 437ZX UT WOS:000265526800032 PM 19544791 ER PT J AU Nappi, J Yoshida, H AF Naeppi, Janne Yoshida, Hiroyuki TI Virtual tagging for laxative-free CT colonography: Pilot evaluation SO MEDICAL PHYSICS LA English DT Article DE biological organs; computerised tomography; identification technology; medical image processing; statistical analysis; virtual reality ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; COLORECTAL-CANCER; OBSERVER PERFORMANCE; FALSE POSITIVES; AIDED DETECTION; POLYPS; COLONOSCOPY; SEGMENTATION; FEASIBILITY; VALIDATION AB Laxative-free computed tomographic colonography (lfCTC) could significantly improve patient adherence to colorectal screening. However, the interpretation of lfCTC data is complicated by the presence of poorly tagged feces and partial-volume artifacts that imitate colorectal lesions. The authors developed a method for virtual tagging of such artifacts. A probabilistic model of colonic wall was developed, and virtual tagging was performed on artifacts that were identified by the model. The method was evaluated with 46 clinical lfCTC cases that were prepared with dietary fecal tagging only. Visual examples show that the method can label partial-volume artifacts, poorly tagged feces, nonadhering completely untagged feces, and artifacts such as rectal tubes. The effect of virtual tagging was evaluated by comparing the detection accuracy of a fully automated polyp detection scheme without and with the method. With virtual tagging, the per-lesion detection sensitivity was 100% for lesions >= 10 mm (n=4) with 3.8 false positives per patient (per two CT scan volumes) and 90% for lesions >= 6 mm (n=10) with 5.4 false positives per patient on average. The improvement in detection performance by virtual tagging was statistically significant (p=0.03; JAFROC and JAFROC-1). C1 [Naeppi, Janne] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Nappi, J (reprint author), Massachusetts Gen Hosp, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. EM jnappi@partners.org RI Nappi, Janne/B-9424-2008 OI Nappi, Janne/0000-0002-0108-0992 FU U. S. Public Health Service [CA095279]; American Cancer Society [RSG-05-088-01-CCE] FX The author thank Dr. Philippe Lefere and Dr. Stefaan Gryspeerdt (Stedelijk Ziekenhuis, Roeselare, Belgium) and Dr. Michael Zalis (Massachusetts General Hospital and Harvard Medical School, Boston, MA) for providing the CTC cases for this study. This study was supported in part by Grant No. CA095279 from the U. S. Public Health Service and by research scholar Grant No. RSG-05-088-01-CCE from the American Cancer Society. NR 39 TC 13 Z9 13 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2009 VL 36 IS 5 BP 1830 EP 1838 DI 10.1118/1.3113893 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 437ZX UT WOS:000265526800043 PM 19544802 ER PT J AU Daartz, J Bangert, M Bussiere, MR Engelsman, M Kooy, HM AF Daartz, J. Bangert, M. Bussiere, M. R. Engelsman, M. Kooy, H. M. TI Characterization of a mini-multileaf collimator in a proton beamline SO MEDICAL PHYSICS LA English DT Article DE biomedical equipment; collimators; dosimetry; proton beams; radiation therapy ID NEUTRON DOSE-EQUIVALENT; HEAVY-ION RADIOTHERAPY; IRRADIATION SYSTEM; SECONDARY NEUTRON; THERAPY; EXPOSURES; MOTHER; FETUS; BEAMS; FIELD AB A mini-multileaf collimator (MMLC) was mounted as a field shaping collimator in a proton beamline at the Massachusetts General Hospital. The purpose is to evaluate the device's dosimetric and mechanical properties for the use in a proton beamline. For this evaluation, the authors compared MMLC and brass aperture shaped dose distributions with regard to lateral and depth dose properties. The lateral fall off is generally broader with the MMLC, with difference varying with proton range from 0.2 to 1.2 mm. Central axis depth dose curves did not show a difference in peak-to-entrance ratio, peak width, distal fall off, or range. Two-dimensional dose distributions to investigate the conformity of MMLC shaped doses show that the physical leaf width of approximate to 2.5 mm does not have a significant impact. All differences seen in dose distribution shaped by the MMLC versus brass apertures were shown to be clinically insignificant. Measured neutron doses of 0.03-0.13 mSv/Gy for a closed brass beam block (depending on range) are very low compared to the previously published data. Irradiation of the tungsten MMLC, however, produced 1.5-1.8 times more neutrons than brass apertures. Exposure of the staff resulting from activation of the device is below regulatory limits. The measurements established an equivalency between aperture and MMLC shaped dose distributions. C1 [Daartz, J.; Bussiere, M. R.; Engelsman, M.; Kooy, H. M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Daartz, J.; Bangert, M.] German Canc Res Ctr, Dept Med Phys Radiat Oncol, D-69120 Heidelberg, Germany. [Bussiere, M. R.; Engelsman, M.; Kooy, H. M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Daartz, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. EM jdaartz@partners.org NR 21 TC 10 Z9 10 U1 0 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2009 VL 36 IS 5 BP 1886 EP 1894 DI 10.1118/1.3116382 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 437ZX UT WOS:000265526800049 PM 19544808 ER PT J AU Shah, S Kimberly, H Marill, K Noble, VE AF Shah, Sachita Kimberly, Heidi Marill, Keith Noble, Vicki E. TI Ultrasound techniques to measure the optic nerve sheath: Is a specialized probe necessary? SO MEDICAL SCIENCE MONITOR LA English DT Article CT Annual Meeting of the Society-of-Academic-Emergency-Medicine CY MAY 16-19, 2007 CL Chicago, IL SP Soc Acad Emergency Med DE ultrasound; intracranial pressure (ICP); optic nerve sheath ID RAISED INTRACRANIAL-PRESSURE; BRAIN-INJURY; DIAMETER; ULTRASONOGRAPHY; SONOGRAPHY; AGREEMENT AB Background: Ultrasound measurement of the optic nerve sheath diameter (ONSD) had been shown to correlate with intracranial pressure (ICP). This study looked at intra-observer and inter-observer reliability among three emergency physicians (EPs) using three different imaging protocols. Material/Methods: Ocular ultrasound was performed in 20 healthy volunteers. Each physician obtained 3 measurements of the right eye ONSD with both the 10-5 MHz and 13-6 MHz probes using the axial imaging technique (experiment 1). The ONSD was then measured with the 10-5 MHz probe using the axial technique and the intracavitary 8-5 MHz probe using the coronal technique (experiment 2). Results: In experiment 1, larger measurements were obtained with the standard 10-5 MHz probe with an adjusted difference of 0.21 mm (p<0.001). The standard deviation between intra-observer measurements for the 10-5 MHz probe was slightly but not significantly larger with an adjusted difference of 0.039 (p=0.10). In experiment 2, larger measurements were obtained with the standard 10-5 MHz probe with an adjusted difference of 0.91 mm (p<0.001). The standard deviation between intra-observer measurements was greater for the 10-5 MHz probe with an adjusted difference of 0.06 (p=0.03). The inter-observer measurements in experiment 2 had significantly larger variance with the 10-5 MHz probe (p=0.001). Conclusions: These data suggest comparable precision and inter-observer reliability can be achieved. However, larger values when using the 10-5 MHz probe suggest different cut-off thresholds for normal upper limits. The coronal imaging technique demonstrated less inter-rater variance and may be a better technique when such small measurement differences are important. C1 [Shah, Sachita; Kimberly, Heidi; Marill, Keith; Noble, Vicki E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Noble, VE (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM vnoble@partners.org NR 14 TC 10 Z9 10 U1 0 U2 1 PU INT SCIENTIFIC LITERATURE, INC PI ALBERTSON PA 1125 WILLIS AVE, ALBERTSON, NY 11507 USA SN 1234-1010 J9 MED SCI MONITOR JI Med. Sci. Monitor PD MAY PY 2009 VL 15 IS 5 BP MT63 EP MT68 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 452DK UT WOS:000266519800018 PM 19396044 ER PT J AU Regensteiner, JG Bauer, TA Reusch, JEB Quaife, RA Chen, MY Smith, SC Miller, TM Groves, BM Wolfel, EE AF Regensteiner, Judith G. Bauer, Timothy A. Reusch, Jane E. B. Quaife, Robert A. Chen, Marcus Y. Smith, Susan C. Miller, Tyler M. Groves, Bertron M. Wolfel, Eugene E. TI Cardiac Dysfunction during Exercise in Uncomplicated Type 2 Diabetes SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PEAK OXYGEN CONSUMPTION; TYPE 2 DIABETES MELLITUS; PULMONARY CAPILLARY WEDGE PRESSURE; HEMODYNAMIC; MYOCARDIAL PERFUSION ID VENTRICULAR SYSTOLIC FUNCTION; SOCIETY-OF-ECHOCARDIOGRAPHY; CORONARY FLOW RESERVE; DOPPLER-ECHOCARDIOGRAPHY; DIASTOLIC DYSFUNCTION; MYOCARDIAL-PERFUSION; CARDIOMYOPATHY; MELLITUS; DISEASE; NOMENCLATURE AB REGENSTEINER, J. G., T. A. BAUER, J. E. REUSCH. R. A. QUAIFE, M. CHEN, S. C. SMITH, T. M. MILLER, B. M. GROVES, and E. E. WOLFEL. Cardiac Dysfunction during Exercise in Uncomplicated Type 2 Diabetes. Med. Sci. Sports Exerc., Vol. 41, No. 5, pp. 977-984, 2009. Purpose: Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity ((V) over dotO(2peak)). The causes of this impairment are not clearly established, but evidence Suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications. Methods: After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with all indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99 sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients. Results: Resting measures of cardiac hemodynamics were similar in T2DM and control Subjects. Absolute (V) over dotO(2peak) (mL.min(-1)) and peak cardiac output tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P<0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls(11.0 +/- 3.5 x e(-9) vs 17.5 +/- 8.1 x e(-9), respectively, P < 0.05) and inversely related to peak exercise PCWP (R = -0.56, P < 0.05). Conclusions: Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may precede the more greatly impaired cardiac function at rest and with exercise observed in longer established T2DM. C1 [Regensteiner, Judith G.] Univ Colorado, Div Gen Internal Med, Dept Med, Sch Med,Hlth Sci Ctr, Aurora, CO 80045 USA. [Regensteiner, Judith G.; Quaife, Robert A.; Chen, Marcus Y.; Miller, Tyler M.; Groves, Bertron M.; Wolfel, Eugene E.] Univ Colorado, Div Cardiol, Dept Med, Aurora, CO 80045 USA. [Bauer, Timothy A.; Reusch, Jane E. B.] Univ Colorado, Div Endocrinol, Dept Med, Aurora, CO 80045 USA. [Regensteiner, Judith G.; Reusch, Jane E. B.] Ctr Womens Hlth Res, Aurora, CO USA. [Bauer, Timothy A.; Reusch, Jane E. B.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Regensteiner, JG (reprint author), Univ Colorado, Div Gen Internal Med, Dept Med, Sch Med,Hlth Sci Ctr, B180,Acad Off Bldg A01,Rm 8221,12631 E 17th Ave, Aurora, CO 80045 USA. EM judy.regensteiner@uchsc.edu FU NIH [R55 DK53776, M01-RR00051]; VA merit review FX Results of the current study do not constitute endorsement by the ACSM. The authors are very grateful to the 20 participants for their participation. Funding support was provided to Dr. Regensteiner by NIH grant no. R55 DK53776 and by the General Clinical Research Center NIH grant no. M01-RR00051. Dr. Reusch is supported by VA merit review funding. The authors also thank the Medical and Nursing Staff of the Cardiac Catheterization Laboratory and the General Clinical Research Center who gave generously of their time for this study. The authors also thank Vermed, Inc., for their generous donation of ECG electrodes for all of our exercise studies. NR 36 TC 30 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2009 VL 41 IS 5 BP 977 EP 984 DI 10.1249/MSS.0b013e3181942051 PG 8 WC Sport Sciences SC Sport Sciences GA 435DS UT WOS:000265324500002 PM 19346991 ER PT J AU Littman, AJ Forsberg, CW Koepsell, TD AF Littman, Alyson J. Forsberg, Christopher W. Koepsell, Thomas D. TI Physical Activity in a National Sample of Veterans SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE EXERCISE; MODERATE; VIGOROUS; BEHAVIORAL RISK FACTORS SURVEILLANCE SYSTEM; EXERCISE MAINTENANCE ID OF-SPORTS-MEDICINE; CARDIOVASCULAR-DISEASE; DOSE-RESPONSE; PUBLIC-HEALTH; RECOMMENDATION AB LITTMAN, A, J., C, W, FORSBERG, and T, D, KOEPSELL, Physical Activity in a National Sample of Veterans. Med. Sci. Sports Exerc., Vol. 41, No. 5, pp. 1006-1013, 2009. Purpose: To describe and compare the prevalence of physical activity (PA) in relation to veteran status and use of Department of Veterans Affairs (VA) facilities. Methods: Data were obtained from the 2003 Behavioral Risk Factor Surveillance System surveys of US adults. Veteran status, VA health care use, and PA were determined in 245,564 adults. Individuals were classified as inactive, insufficiently active, or meeting recommendations for moderate or strenuous PA. To adjust for confounding, we used model-based direct adjustment and chi-square tests corrected for the survey design. Results: After adjusting for age and gender, the prevalence of inactivity was significantly lower (16.2% vs 20.5%), and meeting PA recommendations was significantly greater (46.0% vs 42.0%) in veterans than in nonveterans (P < 0.0001). Compared with veterans who did not obtain their health care from the VA, VA users were more likely to be inactive (20.8% vs 14.7%) and less likely to be insufficiently active (34.1% vs 38.2%) or meet recommendations (45.1% vs 47.1%; P < 0.0001). Differences in PA levels between veterans and nonveterans and between VA users and nonusers did not change substantially after additional adjustment for education, race/ethnicity, and smoking. Conclusion: Despite the high level of PA required of active duty military personnel, only a minority of veterans met PA recommendations, and the prevalence of inactivity was particularly high in VA users. These findings suggest a large potential to increase PA and improve health in VA users. C1 [Littman, Alyson J.] US Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, VA Puget Sound Hlth Care Syst 152E, Seattle, WA 98101 USA. [Littman, Alyson J.; Koepsell, Thomas D.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Koepsell, Thomas D.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Littman, AJ (reprint author), US Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, VA Puget Sound Hlth Care Syst 152E, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM alyson@u.washington.edu FU Office of Research and Development Cooperative Studies Program, Department of Veterans Affairs FX The authors have no conflicts of interest to report. NR 15 TC 21 Z9 21 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2009 VL 41 IS 5 BP 1006 EP 1013 DI 10.1249/MSS.0b013e3181943826 PG 8 WC Sport Sciences SC Sport Sciences GA 435DS UT WOS:000265324500006 PM 19346987 ER PT J AU Pru, JK AF Pru, James K. TI The risks of androgen treatment in postmenopausal women remain controversial: a need for equitable comparisons SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID SEXUAL DESIRE DISORDER; BREAST-CANCER; TESTOSTERONE PATCH; COMBINED ESTROGEN; MENOPAUSAL WOMEN; RECEPTOR; THERAPY; PROLIFERATION; MICE C1 Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Pru, JK (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAY-JUN PY 2009 VL 16 IS 3 BP 430 EP 431 DI 10.1097/gme.0b013e3181a057cf PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 443JG UT WOS:000265905400004 PM 19265724 ER PT J AU Suffoletto, JA Hess, R AF Suffoletto, Jo-Anne Hess, Rachel TI Tapening versus cold turkey: symptoms versus successful discontinuation of menopausal hormone therapy SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID ESTROGEN PLUS PROGESTIN; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; POSITION STATEMENT; SOCIETY; TRIAL C1 [Suffoletto, Jo-Anne] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Hess, Rachel] Univ Pittsburgh, Dept Med, Ctr Res Hlth Care, Pittsburgh, PA USA. [Hess, Rachel] Univ Pittsburgh, Dept Epidemiol, Ctr Res Hlth Care, Pittsburgh, PA 15261 USA. RP Suffoletto, JA (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. FU NIA NIH HHS [K23 AG024254-05, AG024254, K23 AG024254] NR 12 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAY-JUN PY 2009 VL 16 IS 3 BP 436 EP 437 DI 10.1097/gme.0b013e3181a057db PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 443JG UT WOS:000265905400007 PM 19276996 ER PT J AU Nakano, T Inoue, I Seo, M Takahashi, S Komoda, T Katayama, S AF Nakano, Takanari Inoue, Ikuo Seo, Makoto Takahashi, Seiichiro Komoda, Tsugikazu Katayama, Shigehiro TI Acarbose attenuates postprandial hyperlipidemia: investigation in an intestinal absorptive cell model SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID LIPID-METABOLISM; TRIGLYCERIDE C1 [Nakano, Takanari; Seo, Makoto; Takahashi, Seiichiro; Komoda, Tsugikazu] Saitama Med Univ, Dept Biochem, Fac Med, Saitama 3500495, Japan. [Nakano, Takanari] Univ Calif Los Angeles, CURE, Los Angeles, CA 90073 USA. [Nakano, Takanari] W Los Angeles VA Med Ctr, BBRI, Los Angeles, CA 90073 USA. [Inoue, Ikuo; Katayama, Shigehiro] Saitama Med Univ, Dept Endocrinol & Diabet, Fac Med, Saitama 3500495, Japan. RP Nakano, T (reprint author), Saitama Med Univ, Dept Biochem, Fac Med, Saitama 3500495, Japan. EM nk.takanari@gmail.com NR 7 TC 1 Z9 1 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD MAY PY 2009 VL 58 IS 5 BP 583 EP 585 DI 10.1016/j.metabol.2009.02.003 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 439YL UT WOS:000265663700001 PM 19375578 ER PT J AU Fitch, KV Guggina, LM Keough, HM Looby, SED Hadigan, C Anderson, EJ Hubbard, J Liebau, JG Johnsen, S Wei, J Makimura, H Stanley, TL Lo, J Grinspoon, SK AF Fitch, Kathleen V. Guggina, LaUren M. Keough, Hester M. Looby, Sara E. Dolan Hadigan, Colleen Anderson, Ellen J. Hubbard, Jane Liebau, James G. Johnsen, Stine Wei, Jeffery Makimura, Hideo Stanley, Takara L. Lo, Janet Grinspoon, Steven K. TI Decreased respiratory quotient in relation to resting energy expenditure in HIV-infected and noninfected subjects SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HIGH-FAT DIET; LIPODYSTROPHY SYNDROME; INSULIN SENSITIVITY; METABOLIC SYNDROME; CONTROLLED-TRIAL; BONE-DENSITY; WEIGHT-LOSS; WOMEN AB The purpose of this study was to evaluate the relationship of respiratory quotient (RQ), a surrogate marker of substrate oxidation, as well as body composition and dietary intake to resting energy expenditure (REE) among HIV-infected patients in the current era of highly active antiretroviral therapy and among non-HIV-infected control subjects. Resting energy expenditure is increased in HIV-infected patients; but little is known regarding the potential contribution of altered substrate metabolism, body composition, and dietary intake to increased energy expenditure in this Population. Respiratory quotient, REE, body composition, and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls who were evaluated for metabolic Studies between 1998 and 2005. Respiratory quotient was lower (0.83 +/- 0.00 vs 0.85 +/- 0.01, P = .005), whereas REE adjusted for fat-free mass (FFM) was higher (31.8 +/- 0.3 vs 29.8 +/- 0.3 kcal/[d kg], P <= .0001), in HIV-infected compared with control subjects. In multivariate modeling among HIV-infected patients, including age, sex, and parameters of immune function, FFM (beta = 24.811334, P < .0001), visceral adiposity (beta = .7182746, P = .008), and total body fat (beta = 8.0506839, P = .041) were positively associated with REE. whereas RQ was negatively associated with REE (beta = -528.4808, P = .024). Overall r(2) was equal to 0.705 and P was less than .0001 for the model. In control subjects, by contrast, only visceral adiposity (beta = 1.0612073, P = .004), total body fat (beta = 15.805547, P = .010), and FFM (beta = 22.613005, P < .0001) were significant predictors of REE and there was no relationship with RQ. Overall r(2) was equal to 0.825 and P was less than .0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared with control subjects. (C) 2009 Elsevier Inc. All rights reserved. C1 [Fitch, Kathleen V.; Guggina, LaUren M.; Keough, Hester M.; Looby, Sara E. Dolan; Hadigan, Colleen; Liebau, James G.; Johnsen, Stine; Wei, Jeffery; Makimura, Hideo; Stanley, Takara L.; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Anderson, Ellen J.; Hubbard, Jane] Massachusetts Gen Hosp, Gen Clin Res Ctr, Boston, MA 02114 USA. [Hadigan, Colleen] NIAID, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU National Institutes of Health (NIH) [DKRO1-49302, NIH DK-02844, NIH T32HD-052691, NIH K24 DK064545, NIH MO1-RR01066]; Mary Fisher Clinical AIDS Research and Education Fund FX This work was supported by National Institutes of Health (NIH) DKRO1-49302, NIH DK-02844, NIH T32HD-052691, NIH K24 DK064545, NIH MO1-RR01066, and the Mary Fisher Clinical AIDS Research and Education Fund. We wish to thank the nutrition and nursing staff of the MGH and MIT General Clinical Research Center for their dedicated patient care. NR 40 TC 7 Z9 7 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD MAY PY 2009 VL 58 IS 5 BP 608 EP 615 DI 10.1016/j.metabol.2008.12.005 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 439YL UT WOS:000265663700005 PM 19375582 ER PT J AU Brochmann, EJ Behnam, K Murray, SS AF Brochmann, Elsa J. Behnam, Keyvan Murray, Samuel S. TI Bone morphogenetic protein-2 activity is regulated by secreted phosphoprotein-24 kd, an extracellular pseudoreceptor, the gene for which maps to a region of the human genome important for bone quality SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID VITAMIN-D-RECEPTOR; BAND ULTRASOUND ATTENUATION; X-RAY ABSORPTIOMETRY; QUANTITATIVE ULTRASOUND; POSTMENOPAUSAL WOMEN; MINERAL DENSITY; OSTEOPOROTIC FRACTURES; BINDING PEPTIDE; ELDERLY-WOMEN; II RECEPTOR AB The material properties of bone are the sum of the complex and interrelated anabolic and catabolic processes that modulate formation and turnover. The 2q33-37 region of the human genome contains quantitative trait loci important in determining the broadband ultrasound attenuation (an index of trabecular microarchitecture, bone elasticity, and susceptibility to fracture) of the calcaneus, but no genes of significance to boric metabolism have been identified in this domain. Secreted phosphoprotein-24 kd (SPP24 or SPP2) is a novel and relatively poorly characterized growth hormone-regulated gene that maps to 2q37. The purpose of this review is to summarize the status of research related to spp24 and how it regulates bone morphogenetic protein (BMP) bioactivity in bone. SPP24 codes for an extracellular matrix protein that contains a high-affinity BMP-2-binding transforming growth factor-beta receptor 11 homology I loop similar to those identified in fetuin and the receptor itself. SPP24 is transcribed primarily in the liver and bone. High levels of spp24 (a hydroxyapatite-binding protein) arc found in bone, and small amounts are found in fetuin-mineral complexes. Full-length secretory spp24 inhibits ectopic bone formation, and overexpression of spp24 reduces murine bone mass and density. Spp24 is extremely labile to proteolysis, a process that regulates its bioactivity in vivo. For example, an 18.5-kd degradation product of spp24, designated spp 18,5, is pro-osteogenic. A synthetic cyclized Cys(1)-to-Cys(19) disulfide-bonded peptide (BMP binding peptide) corresponding to the transforming growth factor-beta receptor 11 homology 1 domain of spp24 and spp 18.5 binds BMP-2 and increases the rate and magnitude of BMP-2-mediated ectopic bone formation. Thus, the mechanism of action of spp 18.5 and spp24 may be to regulate the local bioavailability of BNIP cytokines. SPP24 is regulated by growth hormone and 3 major families of transcription factors (nuclear factor of activated T cells, CCAAT/enhancer-binding protein, Cut/Cux/CCAAT displacement protein) that regulate mesenchymal cell proliferation, embryonic patterning, and terminal differentiation. The gene contains at least 2 single nucleotide polymorphisms. Given its mechanism of action and sequence variability, SPP24 may be an interesting candidate for future studies of the genetic regulation of bone mass, particularly during periods of BMP-mediated endochondral bone growth, development, and fracture healing. Published by Elsevier Inc. C1 [Brochmann, Elsa J.; Murray, Samuel S.] Sepulveda Ambulatory Care Clin & Nursing Home, GRECC 11E, VA Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. [Brochmann, Elsa J.; Murray, Samuel S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Behnam, Keyvan] Lanx, Broomfield, CO 80021 USA. RP Murray, SS (reprint author), Sepulveda Ambulatory Care Clin & Nursing Home, GRECC 11E, VA Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. EM samuel.murray@med.va.gov FU Geriatric Research, Education, and Clinical Center of the VA Greater Los Angeles Healthcare System; Office of Research and Development, Department of Veterans Affairs; National Institutes of Health [5R21AR53259] FX Supported in part by the Geriatric Research, Education, and Clinical Center of the VA Greater Los Angeles Healthcare System; the Office of Research and Development, Department of Veterans Affairs; and the National Institutes of Health (5R21AR53259). The authors wish to thank Dr Matthew Beckman for his helpful discussion of the early observations of Sen, Walker, and Einarson. NR 60 TC 15 Z9 16 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 J9 METABOLISM JI Metab.-Clin. Exp. PD MAY PY 2009 VL 58 IS 5 BP 644 EP 650 DI 10.1016/j.metabol.2009.01.001 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 439YL UT WOS:000265663700010 PM 19375587 ER PT J AU Liu, MC Chien, CC Grigoryev, DN Gandolfo, MT Colvin, RB Rabb, H AF Liu, Manchang Chien, Chu-Chun Grigoryev, Dmitry N. Gandolfo, Maria Teresa Colvin, Robert B. Rabb, Hamid TI Effect of T cells on vascular permeability in early ischemic acute kidney injury in mice SO MICROVASCULAR RESEARCH LA English DT Article DE Acute kidney injury; Gene microarray; Intracellular cytokine stain; Ischemia-reperfusion; Vascular permeability ID ACUTE-RENAL-FAILURE; REPERFUSION INJURY; INFLAMMATORY RESPONSES; ENDOTHELIAL INJURY; BARRIER FUNCTION; EVANS BLUE; LYMPHOCYTES; DYSFUNCTION; IDENTIFICATION AB Although previous studies have demonstrated that microvascular dysfunction and inflammation occur in ischemia-reperfusion injury (IRI), the underlying mechanisms are poorly understood. We hypothesized that T cells could mediate renal vascular permeability (RVP) during IRI. We evaluated renal vascular permeability by extravasation of Evans blue dye from the kidney in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice in our mouse model of kidney ischemia-reperfusion injury. In wild type mice, RVP was significantly increased at 3 h, peaked at 6 h and declined by 24 h after ischemia. Immunohistochemistry revealed that CD3(+) T cells trafficked into ischemic kidney at 1 h and peaked at 6 h. Gene microarray analysis demonstrated that endothelial-related genes including TNF-alpha were upregulated in ischemic kidney. The production of TNF-alpha and IFN-gamma protein was increased in CD3 and CD4 T cells from the blood and kidney after ischemia. The rise in RVP after ischemia in wild type mice was attenuated in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice. The attenuation of RVP in CD3 T-cell deficient mice after ischemia was restored by adoptive transfer of T cells from WT mice. Our data demonstrate that T cells directly contribute to the increased RVP after kidney ischemia-reperfusion, potentially through T cell cytokine production. (C) 2009 Elsevier Inc. All rights reserved. C1 [Liu, Manchang; Chien, Chu-Chun; Grigoryev, Dmitry N.; Gandolfo, Maria Teresa; Rabb, Hamid] Johns Hopkins Univ, Sch Med, Div Nephrol, Baltimore, MD 21205 USA. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Liu, MC (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, 720 Rutland Ave, Baltimore, MD 21205 USA. EM manchang@jhmi.edu RI Grigoryev, Dmitry/C-9422-2015 OI Grigoryev, Dmitry/0000-0002-1849-1763 FU NHLBI; National Kidney Foundation FX This work was supported by grants from the NHLBI (ML and HR) & National Kidney Foundation (DG). NR 31 TC 21 Z9 23 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0026-2862 J9 MICROVASC RES JI Microvasc. Res. PD MAY PY 2009 VL 77 IS 3 BP 340 EP 347 DI 10.1016/j.mvr.2009.01.011 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 436QR UT WOS:000265430200014 PM 19323971 ER PT J AU King, R Hayzen, BA Page, RN Googe, PB Zeagler, D Mihm, MC AF King, Roy Hayzen, Brett A. Page, Robert N. Googe, Paul B. Zeagler, Deborah Mihm, Martin C., Jr. TI Recurrent nevus phenomenon: a clinicopathologic study of 357 cases and histologic comparison with melanoma with regression SO MODERN PATHOLOGY LA English DT Article DE recurrent nevus; pseudomelanoma; melanoma; regression ID PIGMENTED NEVI; MELANOCYTIC NEVUS; ELECTRODESICCATION; REMOVAL AB Recurrent nevus phenomenon and regression in melanoma may have overlapping histologic features. The clinical findings and histologic changes in 357 cases of recurrent nevus phenomenon were compared with 34 cases of melanoma with regression. Regression was defined as (1) Early: dense lymphoid infiltrates replacing nests of melanocytes, (2) Intermediate: absence/loss of tumor with replacement by mix of lymphocytes and melanophages and early fibrosis, and (3) Late: tumor absence with extensive fibrosis and telangiectasia, melanophages and epidermal effacement. Four broad histologic patterns of recurrent nevus were identified and classified into type 1: junctional melanocytic hyperplasia with effacement of the retiform epidermis and associated dermal scar, type 2: compound melanocytic proliferation with effacement of the retiform epidermis and associated dermal scar, type 3: junctional melanocytic hyperplasia with retention of the retiform epidermis, and type 4: compound melanocytic hyperplasia with retention of the retiform epidermis and scar. Melanomas with early and intermediate regression were recognizable due to the presence of residual melanoma. Melanomas with late regression had overlapping features of type 1 and 2 recurrent nevi. Type 3 recurrent nevi resembled primary melanoma with scar/fibrosis. Histologically, the vast majority of recurrent nevi are readily identifiable; however, partial biopsies or cases without prior knowledge of the original biopsy may lead to misdiagnosis. This is especially true in recurrent nevus and regression in malignant melanoma, where these two lesions share overlapping histologic features. Correlation with the clinical findings and prior biopsy will avoid these pitfalls. Modern Pathology (2009) 22, 611-617; doi: 10.1038/modpathol.2009.22; published online 6 March 2009 C1 [King, Roy; Hayzen, Brett A.; Page, Robert N.; Googe, Paul B.] Univ Tennessee, Grad Sch Med, Dept Pathol, Knoxville Dermatopathol Lab, Knoxville, TN 37919 USA. [King, Roy; Page, Robert N.; Googe, Paul B.] Vanderbilt Univ Sch Med, Nashville, TN USA. [Zeagler, Deborah] Florida Hosp Waterman, Tavares, FL USA. [Mihm, Martin C., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP King, R (reprint author), Univ Tennessee, Grad Sch Med, Dept Pathol, Knoxville Dermatopathol Lab, 315 Erin Dr, Knoxville, TN 37919 USA. EM rking@labpath.com OI Googe, Paul/0000-0002-9185-3548 NR 13 TC 24 Z9 24 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD MAY PY 2009 VL 22 IS 5 BP 611 EP 617 DI 10.1038/modpathol.2009.22 PG 7 WC Pathology SC Pathology GA 439PT UT WOS:000265640200001 PM 19270643 ER PT J AU Ferry, JA Sohani, AR Longtine, JA Schwartz, RA Harris, NL AF Ferry, Judith A. Sohani, Aliyah R. Longtine, Janina A. Schwartz, Robert A. Harris, Nancy L. TI HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma and HHV8-positive intravascular large B-cell lymphoma SO MODERN PATHOLOGY LA English DT Article DE HHV8; KSHV; HIV; lymphoma; intravascular lymphoma ID PRIMARY-EFFUSION LYMPHOMA; SARCOMA-ASSOCIATED HERPESVIRUS; MULTICENTRIC CASTLEMANS-DISEASE; KAPOSIS-SARCOMA; DNA-SEQUENCES; SOLID LYMPHOMAS; VARIANT; HISTOGENESIS; PATHOGENESIS; EXPRESSION AB Human herpesvirus type 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus, is a human c herpesvirus that underlies the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. We recently encountered two cases of HHV8-positive large B-cell lymphoma with features not previously described. The first patient was a 61-year-old immunocompetent man with an enlarged cervical lymph node containing scattered large, bizarre cells in a reactive background of lymphocytes, plasma cells and scattered regressed follicles resembling those of hyaline-vascular Castleman's disease. The appearance suggested classical Hodgkin's lymphoma, but the large cells were negative for CD15, CD30, CD20 and CD3, and positive for MUM1/IRF4, EMA, HHV8, EBER and dim IgM lambda. The second patient was a 59-year-old HIV-positive man who died after several weeks of fever, night sweats, anemia, thrombocytopenia, hepatosplenomegaly and multiorgan failure. At autopsy an intravascular large B-cell lymphoma that was positive for MUM1/IRF4, HHV8 and IgM lambda, and negative for CD20 and EBER involved multiple organs, including lung, heart, kidney, liver and spleen. On the basis of the histologic features in these two cases, the presence of HHV8 was unexpected. These cases expand the spectrum of lymphoproliferative disorders that can be associated with HHV8. Modern Pathology (2009) 22, 618-626; doi: 10.1038/modpathol.2009.36; published online 13 March 2009 C1 [Ferry, Judith A.; Sohani, Aliyah R.; Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Longtine, Janina A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Schwartz, Robert A.] Manchester Mem Hosp, Dept Pathol, Manchester, CT USA. RP Ferry, JA (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Fruit St, Boston, MA 02114 USA. EM jferry@partners.org NR 31 TC 22 Z9 24 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD MAY PY 2009 VL 22 IS 5 BP 618 EP 626 DI 10.1038/modpathol.2009.36 PG 9 WC Pathology SC Pathology GA 439PT UT WOS:000265640200002 PM 19287457 ER PT J AU Saxena, UH Powell, CMH Fecko, JK Cacioppo, R Chou, HS Cooper, GM Hansen, U AF Saxena, Utsav H. Powell, Christina M. H. Fecko, Jill K. Cacioppo, Roxanne Chou, Hubert S. Cooper, Geoffrey M. Hansen, Ulla TI Phosphorylation by Cyclin C/Cyclin-Dependent Kinase 2 following Mitogenic Stimulation of Murine Fibroblasts Inhibits Transcriptional Activity of LSF during G(1) Progression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID THYMIDYLATE SYNTHASE EXPRESSION; MAMMALIAN-CELL CYCLE; DNA-BINDING PROTEIN; RNA-POLYMERASE-III; RETINOBLASTOMA PROTEIN; FACTOR CP2; FAMILY; COMPLEXES; PROMOTER; GENE AB sTranscription factor LSF is required for progression from quiescence through the cell cycle, regulating thymidylate synthase (Tyms) expression at the G(1)/S boundary. Given the constant level of LSF protein from G(0) through S, we investigated whether LSF is regulated by phosphorylation in G(1). In vitro, LSF is phosphorylated by cyclin E/cyclin-dependent kinase 2 (CDK2), cyclin C/CDK2, and cyclin C/CDK3, predominantly on S309. Phosphorylation of LSF on S309 is maximal 1 to 2 h after mitogenic stimulation of quiescent mouse fibroblasts. This phosphorylation is mediated by cyclin C-dependent kinases, as shown by coimmunoprecipitation of LSF and cyclin C in early G(1) and by abrogation of LSF S309 phosphorylation upon suppression of cyclin C with short interfering RNA. Although mouse fibroblasts lack functional CDK3 (the partner of cyclin C in early G(1) in human cells), CDK2 compensates for this absence. By transient transfection assays, phosphorylation at S309, mediated by cyclin C overexpression, inhibits LSF transactivation. Moreover, overexpression of cyclin C and CDK3 inhibits induction of endogenous Tyms expression at the G(1)/S transition. These results identify LSF as only the second known target (in addition to pRb) of cyclin C/CDK activity during progression from quiescence to early G(1). Unexpectedly, this phosphorylation prevents induction of LSF target genes until late G(1). C1 [Saxena, Utsav H.; Powell, Christina M. H.; Fecko, Jill K.; Cacioppo, Roxanne; Cooper, Geoffrey M.; Hansen, Ulla] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Chou, Hubert S.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Chou, Hubert S.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Hansen, U (reprint author), Boston Univ, Dept Biol, 5 Cummington St, Boston, MA 02215 USA. EM uhansen@bu.edu FU National Cancer Institute [CA-081157, CA-18689] FX This work was supported by Public Health Service grants CA-081157 to U. H. and CA-18689 to G. M. C. from the National Cancer Institute.; We thank Essi Vulli for technical assistance in constructing plasmids; Ed Harlow for facilitating the research in early stages; Shengjun Ren and Barrett Rollins for providing plasmid constructs and encouragement; Phil Hinds, Anindya Dutta, and William Kaelin for generously providing plasmids; and Philipp Kaldis for generously providing Cdk2+/- and Cdk2-/- MEFs. NR 55 TC 15 Z9 15 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY 1 PY 2009 VL 29 IS 9 BP 2335 EP 2345 DI 10.1128/MCB.00687-08 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 432AV UT WOS:000265106800001 PM 19237534 ER PT J AU Vilardaga, JP Bunemann, M Feinstein, TN Lambert, N Nikolaev, VO Engelhardt, S Lohse, MJ Hoffmann, C AF Vilardaga, Jean-Pierre Buenemann, Moritz Feinstein, Timothy N. Lambert, Nevin Nikolaev, Viacheslav O. Engelhardt, Stefan Lohse, Martin J. Hoffmann, Carsten TI Minireview: GPCR and G Proteins: Drug Efficacy and Activation in Live Cells SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID RESONANCE ENERGY-TRANSFER; PARATHYROID-HORMONE RECEPTOR; HETEROTRIMERIC G-PROTEINS; BETA-ADRENERGIC-RECEPTOR; CHRONIC HEART-FAILURE; MU-OPIOID RECEPTORS; COUPLED-RECEPTORS; LIVING CELLS; CONFORMATIONAL STATES; CONSTITUTIVE ACTIVITY AB Many biochemical pathways are driven by G protein-coupled receptors, cell surface proteins that convert the binding of extracellular chemical, sensory, and mechanical stimuli into cellular signals. Their interaction with various ligands triggers receptor activation that typically couples to and activates heterotrimeric G proteins, which in turn control the propagation of secondary messenger molecules (e. g. cAMP) involved in critically important physiological processes (e. g. heart beat). Successful transfer of information from ligand binding events to intracellular signaling cascades involves a dynamic interplay between ligands, receptors, and G proteins. The development of Forster resonance energy transfer and bioluminescence resonance energy transfer-based methods has now permitted the kinetic analysis of initial steps involved in G protein-coupled receptor-mediated signaling in live cells and in systems as diverse as neurotransmitter and hormone signaling. The direct measurement of ligand efficacy at the level of the receptor by Forster resonance energy transfer is also now possible and allows intrinsic efficacies of clinical drugs to be linked with the effect of receptor polymorphisms. (Molecular Endocrinology 23: 590-599, 2009) C1 [Vilardaga, Jean-Pierre; Feinstein, Timothy N.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Vilardaga, Jean-Pierre] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Vilardaga, Jean-Pierre] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Buenemann, Moritz; Nikolaev, Viacheslav O.; Lohse, Martin J.; Hoffmann, Carsten] Univ Wurzburg, Inst Pharmacol & Toxicol, D-97078 Wurzburg, Germany. [Engelhardt, Stefan; Lohse, Martin J.] Univ Wurzburg, Rudolf Virchow Ctr, Deutsch Forsch Gemeinschaft Res Ctr Expt Biomed, D-97078 Wurzburg, Germany. [Lambert, Nevin] Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA 30809 USA. RP Vilardaga, JP (reprint author), Dept Pharmacol & Chem Biol, Thomas E Starzl Biochem Sci Tower,E1357,200 Lothr, Pittsburgh, PA 15261 USA. EM jpv@pitt.edu RI Feinstein, Timothy/G-3110-2011; Lohse, Martin/A-7160-2012; OI Lohse, Martin/0000-0002-0599-3510; Feinstein, Timothy/0000-0002-9801-9708 FU Department of Medicine; Massachusetts General Hospital; Department of Pharmacology and Chemical Biology, University of Pittsburgh FX This work was supported by start up funds from the Department of Medicine, Massachusetts General Hospital, and the Department of Pharmacology and Chemical Biology, University of Pittsburgh (to J.P.V.). NR 72 TC 47 Z9 49 U1 2 U2 10 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2009 VL 23 IS 5 BP 590 EP 599 DI 10.1210/me.2008-0204 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 438YP UT WOS:000265593100002 PM 19196832 ER PT J AU Kimbrel, EA Davis, TN Bradner, JE Kung, AL AF Kimbrel, Erin A. Davis, Tina N. Bradner, James E. Kung, Andrew L. TI In Vivo Pharmacodynamic Imaging of Proteasome Inhibition SO MOLECULAR IMAGING LA English DT Article ID UBIQUITIN-INDEPENDENT SUBSTRATE; ORNITHINE-DECARBOXYLASE; DRUG DEVELOPMENT; CANCER-THERAPY; PATHWAY; SYSTEM; HIF-1; DEGRADATION; COMBINATION; MODULATION AB Inhibiting the proteolytic activity of the 26S proteasome has been shown to have selective apoptotic effects on cancer cells and to be clinically efficacious in certain malignancies. There is an unmet medical need for additional proteasome inhibitors, and their development will be facilitated by surrogate markers of proteasome function. Toward this end, ectopic fusion of the destruction domain from ornithine decarboxylase (ODC) to reporter proteins is often used for assessing proteasome function. For luciferase-based reporters, we hypothesized that the oxygen-dependent destruction domain (ODD) from hypoxia-inducible factor 1 alpha (HIF-1 alpha) may provide improved sensitivity over luciferase-ODC, owing to its extremely rapid turnover by the proteasome (HIF-1a has a half-life of less than 5 minutes). In the current study, we show that ODD-luciferase affords a greater dynamic range and faster kinetics than luciferase-ODC in sensing proteasome inhibition in vitro. Importantly, ODD-luciferase also serves as an effective in vivo marker of proteasome function in xenograft tumor models, with inhibition being detected by noninvasive imaging within 3 hours of bortezomib administration. These data establish ODD-luciferase as a surrogate marker of proteasome function that can be used both in vitro and in vivo for the development of novel proteasome inhibitors. C1 [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Broad Inst Harvard, Cambridge, MA USA. MIT, Cambridge, MA 02139 USA. Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. RP Kung, AL (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM andrew_kung@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X NR 30 TC 21 Z9 21 U1 0 U2 2 PU B C DECKER INC PI HAMILTON PA 50 KING STREET EAST, 2ND FLOOR, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD MAY-JUN PY 2009 VL 8 IS 3 BP 140 EP 147 DI 10.2310/7290.2009.00007 PG 8 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 462ZE UT WOS:000267396800002 PM 19723471 ER PT J AU Chiara, DC Hong, FH Arevalo, E Husain, SS Miller, KW Forman, SA Cohen, JB AF Chiara, David C. Hong, Filbert H. Arevalo, Enrique Husain, S. Shaukat Miller, Keith W. Forman, Stuart A. Cohen, Jonathan B. TI Time-Resolved Photolabeling of the Nicotinic Acetylcholine Receptor by [(3)H]Azietomidate, an Open-State Inhibitor SO MOLECULAR PHARMACOLOGY LA English DT Article ID GAMMA-AMINOBUTYRIC-ACID; GENERAL-ANESTHETICS; BINDING-SITE; ION-CHANNEL; IDENTIFICATION; AGONIST; ETOMIDATE; SUBUNIT; MUTATIONS; PORE AB Azietomidate is a photoreactive analog of the general anesthetic etomidate that acts as a nicotinic acetylcholine receptor (nAChR) noncompetitive antagonist. We used rapid perfusion electrophysiological techniques to characterize the state dependence and kinetics of azietomidate inhibition of Torpedo californica nAChRs and time-resolved photolabeling to identify the nAChR binding sites occupied after exposure to [(3)H]azietomidate and agonist for 50 ms (open state) or at equilibrium (desensitized state). Azietomidate acted primarily as an open channel inhibitor characterized by a bimolecular association rate constant of k(+) = 5 x 10(5) M(-1) s(-1) and a dissociation rate constant of <3 s(-1). Azietomidate at 10 mu M, when perfused with acetylcholine (ACh), inhibited the ACh response by similar to 50% after 50 ms; when preincubated for 10 s, it decreased the peak initial response by similar to 15%. Comparison of the kinetics of recovery of ACh responses after exposure to ACh and azietomidate or to ACh alone indicated that at subsecond times, azietomidate inhibited nAChRs without enhancing the kinetics of agonist-induced desensitization. In nAChRs frozen after 50-ms exposure to agonist and [(3)H] azietomidate, amino acids were photolabeled in the ion channel [position M2-20 (alpha Glu-262, beta Asp-268, delta Gln-276)], in delta M1 (delta Cys-236), and in alpha MA/alpha M4 (alpha Glu-390, alpha Cys-412) that were also photolabeled in nAChRs in the equilibrium desensitized state at approximately half the efficiency. These results identify azietomidate binding sites at the extracellular end of the ion channel, in the delta subunit helix bundle, and in the nAChR cytoplasmic domain that seem similar in structure and accessibility in the open and desensitized states of the nAChR. C1 [Chiara, David C.; Hong, Filbert H.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Arevalo, Enrique; Husain, S. Shaukat; Miller, Keith W.; Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Cohen, JB (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM jonathan_cohen@hms.harvard.edu FU National Institutes of Health National Institute of General Medical Sciences [GM58448]; Howard Hughes Biomedical Research Support Program for Medical Schools FX This research was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM58448] and by an award to Harvard Medical School from the Howard Hughes Biomedical Research Support Program for Medical Schools. NR 40 TC 21 Z9 21 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2009 VL 75 IS 5 BP 1084 EP 1095 DI 10.1124/mol.108.054353 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 436VS UT WOS:000265444800009 PM 19218367 ER PT J AU Tannous, BA Christensen, AP Pike, L Wurdinger, T Perry, KF Saydam, O Jacobs, AH Garcia-Anoveros, J Weissleder, R Sena-Esteves, M Corey, DP Breakefield, XO AF Tannous, Bakhos A. Christensen, Adam P. Pike, Lisa Wurdinger, Thomas Perry, Katherine F. Saydam, Okay Jacobs, Andreas H. Garcia-Anoveros, Jaime Weissleder, Ralph Sena-Esteves, Miguel Corey, David P. Breakefield, Xandra O. TI Mutant Sodium Channel for Tumor Therapy SO MOLECULAR THERAPY LA English DT Article ID SIMPLEX-VIRUS TYPE-1; CANCER GENE-THERAPY; EPSTEIN-BARR-VIRUS; CAENORHABDITIS-ELEGANS; AMPLICON VECTORS; IN-VIVO; IODIDE SYMPORTER; GLIOMA-CELLS; EXPRESSION; BRAIN AB Viral vectors have been used to deliver a wide range of therapeutic genes to tumors. In this study, a novel tumor therapy was achieved by the delivery of a mammalian brain sodium channel, ASIC2a, carrying a mutation that renders it constitutively open. This channel was delivered to tumor cells using a herpes simplex virus-1/Epstein-Barr virus (HSV/EBV) hybrid amplicon vector in which gene expression was controlled by a tetracycline regulatory system (tet-on) with silencer elements. Upon infection and doxycycline induction of mutant channel expression in tumor cells, the open channel led to amiloride-sensitive sodium influx as assessed by patch clamp recording and sodium imaging in culture. Within hours, tumor cells swelled and died. In addition to cells expressing the mutant channel, adjacent, noninfected cells connected by gap junctions also died. Intratumoral injection of HSV/EBV amplicon vector encoding the mutant sodium channel and systemic administration of doxycycline led to regression of subcutaneous tumors in nude mice as assessed by in vivo bioluminescence imaging. The advantage of this direct mode of tumor therapy is that all types of tumor cells become susceptible and death is rapid with no time for the tumor cells to become resistant. C1 [Tannous, Bakhos A.; Pike, Lisa; Wurdinger, Thomas; Perry, Katherine F.; Saydam, Okay; Sena-Esteves, Miguel; Breakefield, Xandra O.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Mol Neurogenet Unit, Boston, MA 02115 USA. [Tannous, Bakhos A.; Wurdinger, Thomas; Weissleder, Ralph; Breakefield, Xandra O.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Ctr Mol Imaging Res, Boston, MA 02115 USA. [Tannous, Bakhos A.; Christensen, Adam P.; Wurdinger, Thomas; Saydam, Okay; Corey, David P.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Christensen, Adam P.; Corey, David P.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Jacobs, Andreas H.] MPI Neurol Res, Lab Gene Therapy & Mol Imaging, Cologne, Germany. [Garcia-Anoveros, Jaime] Northwestern Univ, Dept Anesthesiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Corey, David P.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Tannous, BA (reprint author), Massachusetts Gen Hosp East, Dept Neurol, Mol Neurogenet Unit, Bldg 149,13th St, Boston, MA 02129 USA. EM btannous@hms.harvard.edu OI Corey, David/0000-0003-4497-6016 FU National Cancer Institute [CA69246, CA86355, 1K99CA126839]; NINDS [NS44363]; Brain Tumor Society; Investigator of the Howard Hughes Medical Institute. FX We thank Dr Bujard for providing tetracycline regulatory elements used in the amplicon vector and Dr Fraefel for providing the HSV-TK amplicon plasmid; Dr Rachamimov (Pathologist at MGH) for analyzing the hematoxylin and eosin stained sections. Nicole Lewandrowski, Juliet Fernandez, Ozlem Senol, and Johanna M. Niers for technical help; Dr Yellen for access to the sodium imaging microscope; Suzanne McDavitt for skilled editorial assistance; and Igor Bagayev for assistance with confocal microscopy. This work was supported by grants from the National Cancer Institute (CA69246 and CA86355 to XOB and RW, and 1K99CA126839 to BAT), from NINDS (NS44363 to JG-A) and from the Brain Tumor Society (to B. A. T. and X. O. B.). D. P. C. is an Investigator of the Howard Hughes Medical Institute. NR 50 TC 12 Z9 13 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 IS 5 BP 810 EP 819 DI 10.1038/mt.2009.33 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 439PY UT WOS:000265640700013 PM 19259066 ER PT J AU Anthony, RM Maeder, ML Joung, JK McCray, PB AF Anthony, Reshma M. Maeder, Morgan L. Joung, J. Keith McCray, Paul B., Jr. TI Efficient Site-Specific Breaks and Non-Homologous End-Joining in the Human CFTR Locus by Adenovirus-Mediated Delivery of Zinc Finger Nucleases SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Anthony, Reshma M.; McCray, Paul B., Jr.] Univ Iowa, Carver Coll Med, Dept Pediat, Iowa City, IA USA. [Maeder, Morgan L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Maeder, Morgan L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 MA 109 BP S43 EP S43 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019800110 ER PT J AU Hardcastle, JJ Kurozumi, K Dmitrieva, N Sayers, MP Ahmad, S Waterman, P Weissleder, R Chiocca, EA Kaur, B AF Hardcastle, Jayson J. Kurozumi, Kazuhiko Dmitrieva, Nina Sayers, Martin P. Ahmad, Sarwat Waterman, Peter Weissleder, Ralph Chiocca, E. A. Kaur, Balveen TI Vasculostatin Expression Mediated by Oncolytic HSV Inhibits Tumor Growth and Angiogenesis SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Hardcastle, Jayson J.; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P.; Chiocca, E. A.; Kaur, Balveen] Ohio State Univ, Dardinger Lab Neuro Oncol & Neurosci, Columbus, OH 43210 USA. [Hardcastle, Jayson J.] Ohio State Univ, Integrated Biomed Sci Grad Program, Columbus, OH 43210 USA. [Ahmad, Sarwat] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Hardcastle, Jayson J.; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P.; Ahmad, Sarwat; Chiocca, E. A.; Kaur, Balveen] James Comprehens Canc Ctr, Dept Neurol Surg, Columbus, OH USA. [Hardcastle, Jayson J.; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P.; Ahmad, Sarwat; Chiocca, E. A.; Kaur, Balveen] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Kurozumi, Kazuhiko] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg, Okayama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S303 EP S303 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801364 ER PT J AU Maeder, ML Yeh, JRJ Foley, JE Zou, JH Thibodeau-Beganny, S Cheng, LH Peterson, RT Joung, JK AF Maeder, Morgan L. Yeh, Jing-Ruey J. Foley, Jonathan E. Zou, Jizhong Thibodeau-Beganny, Stacey Cheng, Linzhao Peterson, Randall T. Joung, J. Keith TI Further Improvements and Applications of OPEN (Oligomerized Pool ENgineering): A Rapid, Robust, and Publicly Available Method for Engineering Customized Zinc Finger Nucleases SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Maeder, Morgan L.; Foley, Jonathan E.; Thibodeau-Beganny, Stacey; Joung, J. Keith] Harvard Univ, Sch Med, Mol Pathol Unit, Massachusetts Gen Hosp, Charlestown, MA USA. [Peterson, Randall T.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Charlestown, MA USA. [Zou, Jizhong; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD USA. RI Zou, Jizhong/B-4902-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 MA 415 BP S162 EP S163 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019800414 ER PT J AU Maguire, CA Gianni, D Meijer, DH Breakefield, XO Shaket, LA Sena-Esteves, M AF Maguire, Casey A. Gianni, Davide Meijer, Dimphna H. Breakefield, Xandra O. Shaket, Lev A. Sena-Esteves, Miguel TI Directed Evolution of Adeno-Associated Virus for Glioma Cell Transduction SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Maguire, Casey A.; Gianni, Davide; Breakefield, Xandra O.; Shaket, Lev A.; Sena-Esteves, Miguel] Massachusetts Gen Hosp, Charlestown, MA USA. [Meijer, Dimphna H.] Rudolf Magnus Inst Neurosci, NL-3508 TA Utrecht, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S181 EP S181 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801041 ER PT J AU Nemunaitis, J Geevarghese, SK Geller, DA de Haan, HA Iagaru, A Knoll, A Reid, TR Sze, DY Tanabe, K AF Nemunaitis, J. Geevarghese, S. K. Geller, D. A. de Haan, H. A. Iagaru, A. Knoll, A. Reid, T. R. Sze, D. Y. Tanabe, K. TI Phase II Efficacy Results Using an Oncolytic Herpes Simplex Virus (NV1020) in Patients with Colorectal Cancer Metastatic to Liver (mCRC) SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Nemunaitis, J.] Mary Crowley Canc Res Ctr, Dallas, TX USA. [Geevarghese, S. K.] Vanderbilt Univ, Nashville, TN USA. [Geller, D. A.] Univ Pittsburgh, Pittsburgh, PA USA. [de Haan, H. A.] MediGene Inc, San Diego, CA USA. [Iagaru, A.; Knoll, A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Reid, T. R.] Univ Calif San Diego, San Diego, CA 92103 USA. [Tanabe, K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S304 EP S304 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801365 ER PT J AU Sahin, A Maxfield, S Sanchez, CE Bullain, SA Baratta, B Carter, BS AF Sahin, Ayguen Maxfield, Steven Sanchez, Carlos E. Bullain, Szofi A. Baratta, Beth Carter, Bob S. TI Engineering of "3rd Generation" Chimeric Immune Receptor Expressing T Cells for Improved Adoptive Immunotherapy Against Glioblastoma SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Sahin, Ayguen; Maxfield, Steven; Sanchez, Carlos E.; Bullain, Szofi A.; Baratta, Beth; Carter, Bob S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S217 EP S218 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801144 ER PT J AU Scaria, A MacLachlan, T Lukason, M Pechan, P DuFresne, E Isenberger, L Andrews, L Veres, G Kim, I Hauswirth, W Wadsworth, S AF Scaria, Abraham MacLachlan, Tim Lukason, Michael Pechan, Peter DuFresne, Elizabeth Isenberger, Liz Andrews, Laura Veres, Gabor Kim, Ivana Hauswirth, William Wadsworth, Samuel TI Safety and Efficacy of Intravitreal Anti-VEGF Gene Delivery in Non-Human Primates for the Treatment of Ocular Neovascularization SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Scaria, Abraham; MacLachlan, Tim; Lukason, Michael; Pechan, Peter; DuFresne, Elizabeth; Isenberger, Liz; Andrews, Laura; Wadsworth, Samuel] Genzyme Corp, Framingham, MA 01701 USA. [Veres, Gabor] AGTC, Alachua, FL USA. [Kim, Ivana] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Hauswirth, William] Univ Florida, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S287 EP S288 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801326 ER PT J AU Skog, J Lessard, R Balaj, L Breakefield, XO AF Skog, Johan Lessard, Ryan Balaj, Leonora Breakefield, Xandra O. TI Monitoring of Transgene Expression In Vivo Via Exosomes Shed from Transduced Cells into the Bloodstream SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Skog, Johan; Lessard, Ryan; Balaj, Leonora; Breakefield, Xandra O.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S303 EP S303 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801363 ER PT J AU Tannous, BA Wurdinger, T Badr, C Breakefield, X AF Tannous, Bakhos A. Wurdinger, Thomas Badr, Christian Breakefield, Xandra TI Blood and Urine Assay To Monitor Viral Transduction, Tumor Growth and Stem Cells Survival and Proliferation SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Tannous, Bakhos A.; Wurdinger, Thomas; Badr, Christian; Breakefield, Xandra] Massachusetts Gen Hosp, Mol Neurogenet Unit, Boston, MA 02114 USA. [Tannous, Bakhos A.; Wurdinger, Thomas; Badr, Christian; Breakefield, Xandra] Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 BP S384 EP S385 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019801582 ER PT J AU Ugai, H Wang, MH Le, LP Matthews, DA Yamamoto, M Curiel, DT AF Ugai, Hideyo Wang, Minghui Le, Long P. Matthews, David A. Yamamoto, Masato Curiel, David T. TI In Vitro Trafficking of Fluorescently Labeled Minor Capsid Protein IX and Core Protein V during Adenoviral Infection SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 12th Annual Meeting of the American Society of Gene Therapy CY MAY 27-30, 2009 CL San Diego, CA SP Amer Soc Gene Therapy C1 [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Gene Therapy Ctr, Birmingham, AL USA. [Ugai, Hideyo; Wang, Minghui; Curiel, David T.] Univ Alabama, Div Human Gene Therapy, Dept Med, Birmingham, AL USA. [Le, Long P.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Matthews, David A.] Univ Bristol, Sch Med Sci, Dept Cellular & Mol Med, Bristol BS8 1TD, Avon, England. [Yamamoto, Masato] Univ Minnesota, Dept Surg, Div Basic & Translat Res, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2009 VL 17 SU 1 MA 119 BP S46 EP S47 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 600WO UT WOS:000278019800120 ER PT J AU van Haaften, G Dalgliesh, GL Davies, H Chen, L Bignell, G Greenman, C Edkins, S Hardy, C O'Meara, S Teague, J Butler, A Hinton, J Latimer, C Andrews, J Barthorpe, S Beare, D Buck, G Campbell, PJ Cole, J Forbes, S Jia, MM Jones, D Kok, CY Leroy, C Lin, ML McBride, DJ Maddison, M Maquire, S Mclay, K Menzies, A Mironenko, T Mulderrig, L Mudie, L Pleasance, E Shepherd, R Smith, R Stebbings, L Stephens, P Tang, G Tarpey, PS Turner, R Turrell, K Varian, J West, S Widaa, S Wray, P Collins, VP Ichimura, K Law, S Wong, J Yuen, ST Leung, SY Tonon, G DePinho, RA Tai, YT Anderson, KC Kahnoski, RJ Massie, A Khoo, SK Teh, BT Stratton, MR Futreal, PA AF van Haaften, Gijs Dalgliesh, Gillian L. Davies, Helen Chen, Lina Bignell, Graham Greenman, Chris Edkins, Sarah Hardy, Claire O'Meara, Sarah Teague, Jon Butler, Adam Hinton, Jonathan Latimer, Calli Andrews, Jenny Barthorpe, Syd Beare, Dave Buck, Gemma Campbell, Peter J. Cole, Jennifer Forbes, Simon Jia, Mingming Jones, David Kok, Chai Yin Leroy, Catherine Lin, Meng-Lay McBride, David J. Maddison, Mark Maquire, Simon Mclay, Kirsten Menzies, Andrew Mironenko, Tatiana Mulderrig, Lee Mudie, Laura Pleasance, Erin Shepherd, Rebecca Smith, Raffaella Stebbings, Lucy Stephens, Philip Tang, Gurpreet Tarpey, Patrick S. Turner, Rachel Turrell, Kelly Varian, Jennifer West, Sofie Widaa, Sara Wray, Paul Collins, V. Peter Ichimura, Koichi Law, Simon Wong, John Yuen, Siu Tsan Leung, Suet Yi Tonon, Giovanni DePinho, Ronald A. Tai, Yu-Tzu Anderson, Kenneth C. Kahnoski, Richard J. Massie, Aaron Khoo, Sok Kean Teh, Bin Tean Stratton, Michael R. Futreal, P. Andrew TI Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer SO NATURE GENETICS LA English DT Article ID MYELOMA CELL-LINE; TARGET GENES; METHYLTRANSFERASE; JMJD3; MICE AB Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene. C1 [van Haaften, Gijs; Dalgliesh, Gillian L.; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O'Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J.; Cole, Jennifer; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J.; Maddison, Mark; Maquire, Simon; Mclay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Mulderrig, Lee; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S.; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Stratton, Michael R.; Futreal, P. Andrew] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England. [Collins, V. Peter; Ichimura, Koichi] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Law, Simon; Wong, John] Univ Hong Kong, Queen Mary Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Yuen, Siu Tsan; Leung, Suet Yi] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Tonon, Giovanni; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Innovat Canc Sci,Dept Med Oncol,Ctr A, Boston, MA 02115 USA. [Tonon, Giovanni; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Innovat Canc Sci,Dept Med & Genet,Ctr, Boston, MA 02115 USA. [Tai, Yu-Tzu; Anderson, Kenneth C.] Dana Farber Canc Inst, Lebow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Tai, Yu-Tzu; Anderson, Kenneth C.] Dana Farber Canc Inst, Lipper Myeloma Ctr, Boston, MA 02115 USA. [Kahnoski, Richard J.; Massie, Aaron] Spectrum Hlth Hosp, Dept Urol, Grand Rapids, MI USA. [Khoo, Sok Kean; Teh, Bin Tean] Van Andel Inst, Canc Genet Lab, Grand Rapids, MI USA. [Stratton, Michael R.] Inst Canc Res, Sutton, Surrey, England. RP Stratton, MR (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England. EM mrs@sanger.ac.uk; paf@sanger.ac.uk RI van Haaften, Gijs/G-7832-2012; Tang, Macy/B-9798-2014; Yuen , Siu /K-6311-2014; Leung, Suet Yi/C-4340-2009; Dalgliesh, Gillian/B-7799-2008 OI van Haaften, Gijs/0000-0003-3033-0329; Dalgliesh, Gillian/0000-0001-8526-5064 FU Wellcome Trus; EMBO fellowship; Kay Kendall Leukaemia Fund fellowship; Robert A. and Renee E. Belfer Foundation for Innovative Cancer Science; Leukemia and Lymphoma Society FX Funding was provided by the Wellcome Trust. G. v. H. is supported by an EMBO fellowship and P.J.C. by a Kay Kendall Leukaemia Fund fellowship. R. A. D. is supported by the Robert A. and Renee E. Belfer Foundation for Innovative Cancer Science. G. T. is supported by a fellowship from the Leukemia and Lymphoma Society. GlaxoSmithKline provided support for the SNP 6.0 microarray analyses. UTX antibodies were a kind gift from E. Canaani (Weizmann Institute of Science). NR 15 TC 377 Z9 383 U1 3 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2009 VL 41 IS 5 BP 521 EP 523 DI 10.1038/ng.349 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 438SL UT WOS:000265575600011 PM 19330029 ER PT J AU Dankort, D Curley, DP Cartlidge, RA Nelson, B Karnezis, AN Damsky, WE You, MJ DePinho, RA McMahon, M Bosenberg, M AF Dankort, David Curley, David P. Cartlidge, Robert A. Nelson, Betsy Karnezis, Anthony N. Damsky, William E., Jr. You, Mingjian J. DePinho, Ronald A. McMahon, Martin Bosenberg, Marcus TI Braf(V600E) cooperates with Pten loss to induce metastatic melanoma SO NATURE GENETICS LA English DT Article ID CELL-CYCLE ARREST; MALIGNANT-MELANOMA; BRAF MUTATIONS; B-RAF; MELANOCYTES; SENESCENCE; MOUSE; MICE; INHIBITOR; GENETICS AB Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease. C1 [Dankort, David; Cartlidge, Robert A.; Karnezis, Anthony N.; McMahon, Martin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Canc Res Inst, San Francisco, CA 94143 USA. [Curley, David P.; Nelson, Betsy; Damsky, William E., Jr.; Bosenberg, Marcus] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Dankort, David; Cartlidge, Robert A.; McMahon, Martin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Cell & Mol Pharmacol, San Francisco, CA 94143 USA. [Karnezis, Anthony N.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Pathol, San Francisco, CA 94143 USA. [You, Mingjian J.; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. [You, Mingjian J.; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med, Boston, MA 02115 USA. [You, Mingjian J.; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Genet, Boston, MA 02115 USA. [You, Mingjian J.; DePinho, Ronald A.] Harvard Univ, Sch Med, Boston, MA USA. RP McMahon, M (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Canc Res Inst, San Francisco, CA 94143 USA. EM mcmahon@cc.ucsf.edu; marcus.bosenberg@yale.edu RI McMahon, Martin/L-3303-2013; OI McMahon, Martin/0000-0003-2812-1042; Dankort, David/0000-0002-5862-6829 FU University of California San Francisco Helen Diller Family Comprehensive Cancer Center Mouse Pathology and Pre-Clinical Therapeutics cores; Melanoma Research Foundation; U.C. Discovery Award; US National Institutes of Health [CA 108972, CA 84313, CA 89124, CA 112054] FX We thank the members of the McMahon and Bosenberg laboratories as well as B. Bastian, L. Chin, E. Filenova, B. Hann, M. Herlyn, L. Johnson, G. Merlino, P. P. Pandolfi, V. Hearing, M. Held, G. Kay and D. Matzen for the provision of mouse strains, reagents, advice and support. M. M. thanks A. Ricart and J. Sebolt-Leopold (Pfizer) for provision of PD325901 and acknowledges the support of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center Mouse Pathology and Pre-Clinical Therapeutics cores. R. A. D. is supported as an American Cancer Society Research Professor. This work was supported by grants from the Melanoma Research Foundation, U.C. Discovery Award and from the US National Institutes of Health (CA 108972 to M. M., CA 84313 to R. A. D. and CA 89124 and CA 112054 to M. B., respectively). NR 50 TC 432 Z9 437 U1 3 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2009 VL 41 IS 5 BP 544 EP 552 DI 10.1038/ng.356 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 438SL UT WOS:000265575600015 PM 19282848 ER PT J AU Suzuki, H Forrest, ARR van Nimwegen, E Daub, CO Balwierz, PJ Irvine, KM Lassmann, T Ravasi, T Hasegawa, Y de Hoon, MJL Katayama, S Schroder, K Carninci, P Tomaru, Y Kanamori-Katayama, M Kubosaki, A Akalin, A Ando, Y Arner, E Asada, M Asahara, H Bailey, T Bajic, VB Bauer, D Beckhouse, AG Bertin, N Bjorkegren, J Brombacher, F Bulger, E Chalk, AM Chiba, J Cloonan, N Dawe, A Dostie, J Engstrom, PG Essack, M Faulkner, GJ Fink, JL Fredman, D Fujimori, K Furuno, M Gojobori, T Gough, J Grimmond, SM Gustafsson, M Hashimoto, M Hashimoto, T Hatakeyama, M Heinzel, S Hide, W Hofmann, O Hornquist, M Huminiecki, L Ikeo, K Imamoto, N Inoue, S Inoue, Y Ishihara, R Iwayanagi, T Jacobsen, A Kaur, M Kawaji, H Kerr, MC Kimura, R Kimura, S Kimura, Y Kitano, H Koga, H Kojima, T Kondo, S Konno, T Krogh, A Kruger, A Kumar, A Lenhard, B Lennartsson, A Lindow, M Lizio, M MacPherson, C Maeda, N Maher, CA Maqungo, M Mar, J Matigian, NA Matsuda, H Mattick, JS Meier, S Miyamoto, S Miyamoto-Sato, E Nakabayashi, K Nakachi, Y Nakano, M Nygaard, S Okayama, T Okazaki, Y Okuda-Yabukami, H Orlando, V Otomo, J Pachkov, M Petrovsky, N Plessy, C Quackenbush, J Radovanovic, A Rehli, M Saito, R Sandelin, A Schmeier, S Schonbach, C Schwartz, AS Semple, CA Sera, M Severin, J Shirahige, K Simons, C Laurent, GS Suzuki, M Suzuki, T Sweet, MJ Taft, RJ Takeda, S Takenaka, Y Tan, K Taylor, MS Teasdale, RD Tegner, J Teichmann, S Valen, E Wahlestedt, C Waki, K Waterhouse, A AWells, C Winther, O Wu, L Yamaguchi, K Yanagawa, H Yasuda, J Zavolan, M Hume, DA Arakawa, T Fukuda, S Imamura, K Kai, C Kaiho, A Kawashima, T Kawazu, C Kitazume, Y Kojima, M Miura, H Murakami, K Murata, M Ninomiya, N Nishiyori, H Noma, S Ogawa, C Sano, T Simon, C Tagami, M Takahashi, Y Kawai, J Hayashizaki, Y AF Suzuki, Harukazu Forrest, Alistair R. R. van Nimwegen, Erik Daub, Carsten O. Balwierz, Piotr J. Irvine, Katharine M. Lassmann, Timo Ravasi, Timothy Hasegawa, Yuki de Hoon, Michiel J. L. Katayama, Shintaro Schroder, Kate Carninci, Piero Tomaru, Yasuhiro Kanamori-Katayama, Mutsumi Kubosaki, Atsutaka Akalin, Altuna Ando, Yoshinari Arner, Erik Asada, Maki Asahara, Hiroshi Bailey, Timothy Bajic, Vladimir B. Bauer, Denis Beckhouse, Anthony G. Bertin, Nicolas Bjorkegren, Johan Brombacher, Frank Bulger, Erika Chalk, Alistair M. Chiba, Joe Cloonan, Nicole Dawe, Adam Dostie, Josee Engstrom, Par G. Essack, Magbubah Faulkner, Geoffrey J. Fink, J. Lynn Fredman, David Fujimori, Ko Furuno, Masaaki Gojobori, Takashi Gough, Julian Grimmond, Sean M. Gustafsson, Mika Hashimoto, Megumi Hashimoto, Takehiro Hatakeyama, Mariko Heinzel, Susanne Hide, Winston Hofmann, Oliver Hornquist, Michael Huminiecki, Lukasz Ikeo, Kazuho Imamoto, Naoko Inoue, Satoshi Inoue, Yusuke Ishihara, Ryoko Iwayanagi, Takao Jacobsen, Anders Kaur, Mandeep Kawaji, Hideya Kerr, Markus C. Kimura, Ryuichiro Kimura, Syuhei Kimura, Yasumasa Kitano, Hiroaki Koga, Hisashi Kojima, Toshio Kondo, Shinji Konno, Takeshi Krogh, Anders Kruger, Adele Kumar, Ajit Lenhard, Boris Lennartsson, Andreas Lindow, Morten Lizio, Marina MacPherson, Cameron Maeda, Norihiro Maher, Christopher A. Maqungo, Monique Mar, Jessica Matigian, Nicholas A. Matsuda, Hideo Mattick, John S. Meier, Stuart Miyamoto, Sei Miyamoto-Sato, Etsuko Nakabayashi, Kazuhiko Nakachi, Yutaka Nakano, Mika Nygaard, Sanne Okayama, Toshitsugu Okazaki, Yasushi Okuda-Yabukami, Haruka Orlando, Valerio Otomo, Jun Pachkov, Mikhail Petrovsky, Nikolai Plessy, Charles Quackenbush, John Radovanovic, Aleksandar Rehli, Michael Saito, Rintaro Sandelin, Albin Schmeier, Sebastian Schonbach, Christian Schwartz, Ariel S. Semple, Colin A. Sera, Miho Severin, Jessica Shirahige, Katsuhiko Simons, Cas Laurent, George St. Suzuki, Masanori Suzuki, Takahiro Sweet, Matthew J. Taft, Ryan J. Takeda, Shizu Takenaka, Yoichi Tan, Kai Taylor, Martin S. Teasdale, Rohan D. Tegner, Jesper Teichmann, Sarah Valen, Eivind Wahlestedt, Claes Waki, Kazunori Waterhouse, Andrew AWells, Christine Winther, Ole Wu, Linda Yamaguchi, Kazumi Yanagawa, Hiroshi Yasuda, Jun Zavolan, Mihaela Hume, David A. Arakawa, Takahiro Fukuda, Shiro Imamura, Kengo Kai, Chikatoshi Kaiho, Ai Kawashima, Tsugumi Kawazu, Chika Kitazume, Yayoi Kojima, Miki Miura, Hisashi Murakami, Kayoko Murata, Mitsuyoshi Ninomiya, Noriko Nishiyori, Hiromi Noma, Shohei Ogawa, Chihiro Sano, Takuma Simon, Christophe Tagami, Michihira Takahashi, Yukari Kawai, Jun Hayashizaki, Yoshihide CA FANTOM Consortium Riken Omics Sci Ctr TI The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line SO NATURE GENETICS LA English DT Article ID SERUM RESPONSE FACTOR; MONOCYTE-MACROPHAGE MATURATION; MESSENGER-RNA EXPRESSION; FACTOR-BINDING-SITES; GENE-EXPRESSION; SIGNALING PATHWAYS; STEM-CELLS; GENOME; PHOSPHORYLATION; PROLIFERATION AB Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process. C1 [Hume, David A.] Univ Edinburgh, Roslin Inst, Roslin, Midlothian, Scotland. [Hume, David A.] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin, Midlothian, Scotland. [Suzuki, Harukazu; Forrest, Alistair R. R.; Daub, Carsten O.; Lassmann, Timo; Hasegawa, Yuki; de Hoon, Michiel J. L.; Katayama, Shintaro; Carninci, Piero; Tomaru, Yasuhiro; Kanamori-Katayama, Mutsumi; Kubosaki, Atsutaka; Ando, Yoshinari; Arner, Erik; Bertin, Nicolas; Bulger, Erika; Furuno, Masaaki; Hashimoto, Takehiro; Ishihara, Ryoko; Kawaji, Hideya; Kimura, Yasumasa; Kondo, Shinji; Lennartsson, Andreas; Lizio, Marina; Maeda, Norihiro; Nakano, Mika; Okuda-Yabukami, Haruka; Plessy, Charles; Severin, Jessica; Suzuki, Masanori; Suzuki, Takahiro; Waki, Kazunori; Waterhouse, Andrew; Yamaguchi, Kazumi; Yasuda, Jun] RIKEN, Yokohama Inst, Omics Sci Ctr, Kanagawa, Japan. [Forrest, Alistair R. R.; Beckhouse, Anthony G.; Chalk, Alistair M.; Matigian, Nicholas A.; AWells, Christine] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Nathan, Qld 4111, Australia. [van Nimwegen, Erik; Balwierz, Piotr J.; Pachkov, Mikhail; Zavolan, Mihaela] Univ Basel, Bioctr, CH-4056 Basel, Switzerland. [van Nimwegen, Erik; Balwierz, Piotr J.; Pachkov, Mikhail; Zavolan, Mihaela] Swiss Inst Bioinformat, Basel, Switzerland. [Irvine, Katharine M.; Schroder, Kate; Bailey, Timothy; Bauer, Denis] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. [Ravasi, Timothy; Schwartz, Ariel S.; Tan, Kai] Univ Calif San Diego, Jacobs Sch Engn, Dept Bioengn, La Jolla, CA 92093 USA. [Akalin, Altuna; Engstrom, Par G.; Fredman, David; Lenhard, Boris] Bergen Ctr Computat Sci, Bergen, Norway. [Asada, Maki; Asahara, Hiroshi; Hashimoto, Megumi] Natl Res Inst Child Hlth & Dev, Tokyo, Japan. [Bajic, Vladimir B.; Dawe, Adam; Essack, Magbubah; Hide, Winston; Hofmann, Oliver; Kaur, Mandeep; Kruger, Adele; MacPherson, Cameron; Maqungo, Monique; Meier, Stuart; Radovanovic, Aleksandar; Schmeier, Sebastian; AWells, Christine] Univ Western Cape, S African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. [Bjorkegren, Johan; Tegner, Jesper] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Computat Med Grp,Atherosclerosis Res Unit,Ctr Mol, Stockholm, Sweden. [Brombacher, Frank] Univ Cape Town, Fac Hlth Sci, IIDMM, Observatory, South Africa. [Chiba, Joe; Kimura, Ryuichiro; Nakabayashi, Kazuhiko] Tokyo Univ Sci, Dept Biol Sci & Technol, Tokyo 162, Japan. [Cloonan, Nicole; Faulkner, Geoffrey J.; Grimmond, Sean M.; Mattick, John S.; Simons, Cas; Taft, Ryan J.] Univ Queensland, Inst Mol Biosci, Special Res Ctr Funct & Appl Genom, ARC, St Lucia, Qld, Australia. [Dostie, Josee] McGill Univ, Dept Biochem, Montreal, PQ, Canada. [Fink, J. Lynn; Kerr, Markus C.; Teasdale, Rohan D.] Univ Queensland, Inst Mol Biosci, Ctr Excellence Bioinformat, ARC, St Lucia, Qld, Australia. [Fujimori, Ko] Osaka Univ Pharmaceut Sci, Lab Biodef & Regulat, Osaka 580, Japan. [Gojobori, Takashi; Ikeo, Kazuho; Konno, Takeshi; Miyamoto, Sei; Okayama, Toshitsugu; Sera, Miho] Natl Inst Genet, Res Org Informat & Syst, Ctr Informat Biol, Shizuoka, Japan. [Gojobori, Takashi; Ikeo, Kazuho; Konno, Takeshi; Miyamoto, Sei; Okayama, Toshitsugu; Sera, Miho] Natl Inst Genet, DDBJ, Shizuoka, Japan. [Gough, Julian] Univ Bristol, Dept Comp Sci, Bristol, Avon, England. [Gustafsson, Mika; Hornquist, Michael] Linkoping Univ, Dept Sci & Technol, Norrkoping, Sweden. [Hatakeyama, Mariko; Kojima, Toshio] RIKEN, Yokohama Inst, Genom Sci Ctr, Computat & Expt Syst Biol Grp, Kanagawa, Japan. [Heinzel, Susanne; Petrovsky, Nikolai] Flinders Univ & Med Ctr, Dept Endocrinol & Diabet, Adelaide, SA, Australia. [Hide, Winston; Hofmann, Oliver] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Huminiecki, Lukasz] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Imamoto, Naoko] RIKEN, Wako Inst, Discovery & Res Inst, Cellular Dynam Lab, Saitama, Japan. [Inoue, Satoshi] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Inoue, Satoshi] Univ Tokyo, Fac Med, Tokyo 113, Japan. [Inoue, Yusuke] Gunma Univ, Fac Engn, Dept Biol & Chem Engn, Gunma, Japan. [Iwayanagi, Takao] Hitachi Ltd, Res & Dev Grp, R&D Solut Ctr, Tokyo, Japan. [Jacobsen, Anders; Krogh, Anders; Lindow, Morten; Nygaard, Sanne; Sandelin, Albin; Valen, Eivind; Winther, Ole] Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark. [Jacobsen, Anders; Krogh, Anders; Lindow, Morten; Nygaard, Sanne; Sandelin, Albin; Valen, Eivind; Winther, Ole] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Kimura, Syuhei] Tottori Univ, Fac Engn, Dept Informat & Knowledge Engn, Tottori 680, Japan. [Kitano, Hiroaki] Syst Biol Inst, Shibuya Ku, Tokyo, Japan. [Koga, Hisashi] Kazusa DNA Res Inst, Dept Human Gene Res, Chiba, Japan. [Kumar, Ajit; Laurent, George St.] George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Mar, Jessica; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Matsuda, Hideo; Takenaka, Yoichi] Osaka Univ, Grad Sch Informat Sci & Technol, Dept Bioinformat Engn, Osaka, Japan. [Miyamoto-Sato, Etsuko; Yanagawa, Hiroshi] Keio Univ, Fac Sci & Technol, Dept Biosci & Informat, Yokohama, Kanagawa 223, Japan. [Nakachi, Yutaka; Okazaki, Yasushi] Saitama Med Sch, Res Ctr Genom Med, Div Funct Genom & Syst Med, Saitama, Japan. [Orlando, Valerio] IRCCS Fdn Santa Lucia EBRI, Dulbecco Telethon Inst, Rome, Italy. [Orlando, Valerio] IGB CNR, Naples, Italy. [Otomo, Jun; Takeda, Shizu] Hitachi Ltd, Cent Res Labs, Tokyo, Japan. [Rehli, Michael] Univ Regensburg, Dept Hematol & Oncol, Regensburg, Germany. [Saito, Rintaro] Keio Univ, Fac Environm & Informat Studies, Kanagawa, Japan. [Schonbach, Christian] Nanyang Technol Univ, Div Genom & Genet, Sch Biol Sci, Singapore, Singapore. [Semple, Colin A.] Western Gen Hosp, Human Genet Unit, MRC, Edinburgh EH4 2XU, Midlothian, Scotland. [Shirahige, Katsuhiko] Tokyo Inst Technol, Grad Sch Informat Sci & Engn, Dept Comp Sci, Tokyo 152, Japan. [Sweet, Matthew J.] Univ Queensland, CRC Chron Inflammatory Dis, Sch Mol & Microbial Sci, Inst Mol Biosci, St Lucia, Qld, Australia. [Taylor, Martin S.] EMBL European Bioinformat Inst, Cambridge, England. [Tegner, Jesper] Linkoping Univ, Dept Phys Chem & Biol, Linkoping, Sweden. [Teichmann, Sarah] MRC, Mol Biol Lab, Struct Studies Div, Cambridge CB2 2QH, England. [Wahlestedt, Claes] Scripps Res Inst, Jupiter, FL USA. RP Hume, DA (reprint author), Univ Edinburgh, Roslin Inst, Roslin, Midlothian, Scotland. EM david.hume@roslin.ed.ac.uk; yosihide@gsc.riken.jp RI Bertin, Nicolas/C-3025-2008; Bajic, Vladimir/D-2810-2009; Essack, Magbubah/G-5008-2013; Plessy, Charles/N-5054-2015; de Hoon, Michiel/N-8006-2015; Hayashizaki, Yoshihide/N-6590-2015; Suzuki, Harukazu/N-9553-2015; Semple, Colin/A-5613-2009; Faulkner, Geoffrey/M-3168-2014; Mattick, John/I-7789-2012; Kawai, Jun/A-6451-2016; Okada, Mariko/N-6933-2015; Grimmond, Sean/J-5304-2016; Schmeier, Sebastian/D-4731-2011; Kawaji, Hideya/N-5116-2015; Simons, Cas/A-7905-2011; Hofmann, Oliver/F-1800-2013; Fredman, David/H-3566-2013; Schroder, Kate/C-6132-2008; Lassmann, Timo/A-8271-2008; Kimura, Yasumasa/M-9720-2013; Kerr, Markus/A-9864-2014; Carninci, Piero/K-1568-2014; Sandelin, Albin/G-2881-2011; Krogh, Anders/M-1541-2014; Nygaard, Sanne/M-2569-2014; Imamoto, Naoko/A-7458-2015; Jacobsen, Anders/K-1081-2013; Rehli, Michael/E-9093-2011; Sweet, Matthew/F-2229-2011; Forrest, Alistair/A-6597-2008; Cloonan, Nicole/B-5272-2008; Irvine, Katharine/A-5559-2011; AKALIN, ALTUNA/A-4424-2012; Matigian, Nicholas/A-4935-2009; Wells, Christine/A-5071-2010; Radovanovic, Aleksandar/D-1313-2012; Katayama, Shintaro/F-2958-2010; Schonbach, Christian/B-1998-2009; de Hoon, Michiel/A-6443-2013; Hume, David/C-7695-2013; Dawe, Adam/C-5295-2009; Lennartsson, Andreas/E-7823-2011; Fink, Lynn/C-2031-2008; Teasdale, Rohan/B-2538-2009; Bauer, Denis/C-3903-2009; Ravasi, Timothy/B-8777-2008; Taylor, Martin/C-3825-2009; Arner, Erik/A-1895-2010; Beckhouse, Anthony/A-2601-2010; Taft, Ryan/B-2945-2010; Valen, Eivind/A-8617-2011; Daub, Carsten/A-7436-2010; Hide, Winston Hide/C-7217-2009; OI Petrovsky, Nikolai/0000-0002-1580-5245; Fujimori, Ko/0000-0002-2506-0769; Valen, Eivind/0000-0003-1840-6108; Chalk, Alistair/0000-0002-9630-6236; Lenhard, Boris/0000-0002-1114-1509; Lennartsson, Andreas/0000-0002-3272-2505; Teichmann, Sarah/0000-0002-6294-6366; Bertin, Nicolas/0000-0002-9835-9606; Bajic, Vladimir/0000-0001-5435-4750; Engstrom, Par/0000-0001-5265-2121; van Nimwegen, Erik/0000-0001-6338-1312; Essack, Magbubah/0000-0003-2709-5356; Plessy, Charles/0000-0001-7410-6295; Suzuki, Harukazu/0000-0002-8087-0836; Semple, Colin/0000-0003-1765-4118; Faulkner, Geoffrey/0000-0001-5769-4494; Mattick, John/0000-0002-7680-7527; Grimmond, Sean/0000-0002-8102-7998; Schmeier, Sebastian/0000-0002-3947-8226; Kawaji, Hideya/0000-0002-0575-0308; Simons, Cas/0000-0003-3147-8042; Hofmann, Oliver/0000-0002-7738-1513; Fredman, David/0000-0003-3507-0554; Schroder, Kate/0000-0001-9261-3805; Lassmann, Timo/0000-0002-0138-2691; Carninci, Piero/0000-0001-7202-7243; Sandelin, Albin/0000-0002-7109-7378; Krogh, Anders/0000-0002-5147-6282; Nygaard, Sanne/0000-0002-3002-6047; Imamoto, Naoko/0000-0002-2886-3022; Jacobsen, Anders/0000-0001-6847-4980; Rehli, Michael/0000-0003-3992-932X; Sweet, Matthew/0000-0002-0406-8139; Forrest, Alistair/0000-0003-4543-1675; AKALIN, ALTUNA/0000-0002-0468-0117; Matigian, Nicholas/0000-0001-7735-9415; Wells, Christine/0000-0003-3133-3628; Radovanovic, Aleksandar/0000-0002-8749-7608; Katayama, Shintaro/0000-0001-7581-5157; Schonbach, Christian/0000-0002-0693-7617; Fink, Lynn/0000-0003-2912-6048; Teasdale, Rohan/0000-0001-7455-5269; Taylor, Martin/0000-0001-7656-330X; Arner, Erik/0000-0003-1225-4908; Beckhouse, Anthony/0000-0002-5141-8250; Daub, Carsten/0000-0002-3295-8729; Hide, Winston Hide/0000-0002-8621-3271; Zavolan, Mihaela/0000-0002-8832-2041 FU Ministry of Education, Culture, Sports, Science and Technology, Japan; RIKEN Frontier Research System, Functional RNA research program; Australian National Health and Medical Research Council [ID 428261]; SNF [SNF 3100A0-118318]; Fondazione Telethon FX We thank A. Ambesi, H. Atsui, M. Bansal, V. Belcastro, H. Daub, D. di Bernardo, M. Furuya, A. Hasegawa, K. Hayashida, A. Hirakiyama, F. Hori, K. Koseki, S. Kuhara, N. Miyamoto, S. Miyano, M. Nishikawa, C. Ohinata, M. Persson, S. Saihara, C. Sakaba, H. Sano, E. Shibazaki, T. Takagi, K. Toyoda, Y. Tsujimura and M. Yamamoto for discussion, encouragement and technical assistance. We thank M. Muramatsu, T. Ogawa, Y. Sakaki and A. Wada for support and encouragement. This work was mainly supported by grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y. H.), Research Grant for the RIKEN Genome Exploration Research Project from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Y. H.) and the RIKEN Frontier Research System, Functional RNA research program (Y. H.). A. R. R. F. is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (ID 428261). E. v. N. acknowledges support from SNF grant SNF # 3100A0-118318. NR 49 TC 252 Z9 254 U1 1 U2 40 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2009 VL 41 IS 5 BP 553 EP 562 DI 10.1038/ng.375 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 438SL UT WOS:000265575600016 ER PT J AU Dejean, AS Beisner, DR Ch'en, IL Kerdiles, YM Babour, A Arden, KC Castrillon, DH DePinho, RA Hedrick, SM AF Dejean, Anne S. Beisner, Daniel R. Ch'en, Irene L. Kerdiles, Yann M. Babour, Anna Arden, Karen C. Castrillon, Diego H. DePinho, Ronald A. Hedrick, Stephen M. TI Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells SO NATURE IMMUNOLOGY LA English DT Article ID TRYPTOPHAN CATABOLISM; OXIDATIVE STRESS; MLL GENE; IN-VIVO; SURVIVAL; AUTOIMMUNITY; ACTIVATION; PROTEINS; FAMILY; CTLA-4 AB Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic. Instead, it was caused by the enhanced capacity of Foxo3-deficient dendritic cells to sustain T cell viability by producing more interleukin 6. Stimulation of dendritic cells mediated by the coinhibitory molecule CTLA-4 induced nuclear localization of Foxo3, which in turn inhibited the production of interleukin 6 and tumor necrosis factor. Thus, Foxo3 acts to constrain the production of key inflammatory cytokines by dendritic cells and to control T cell survival. C1 [Dejean, Anne S.; Beisner, Daniel R.; Ch'en, Irene L.; Kerdiles, Yann M.; Babour, Anna; Hedrick, Stephen M.] Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, San Diego, CA 92103 USA. [Dejean, Anne S.; Beisner, Daniel R.; Ch'en, Irene L.; Kerdiles, Yann M.; Babour, Anna; Hedrick, Stephen M.] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92103 USA. [Arden, Karen C.] Univ Calif, San Diego Sch Med, Ludwig Inst Canc Res, La Jolla, CA USA. [Castrillon, Diego H.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Adult Oncol, Ctr Appl Canc Sci,Belfer Inst Innovat Canc Sci, Boston, MA 02115 USA. [Castrillon, Diego H.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med, Ctr Appl Canc Sci,Belfer Inst Innovat Canc Sci, Boston, MA 02115 USA. [Castrillon, Diego H.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Genet, Ctr Appl Canc Sci,Belfer Inst Innovat Canc Sci, Boston, MA 02115 USA. RP Hedrick, SM (reprint author), Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, San Diego, CA 92103 USA. EM shedrick@ucsd.edu RI Dejean, Anne/K-6739-2014 FU American Cancer Society; Robert A. and Renee E. Belfer Institute for Innovative Cancer Research; US National Cancer Institute; Division of Biological Sciences of the University of California, San Diego; Fondation pour la Recherche Medicale FX We thank J. P. Allison (Sloan-Kettering Memorial Hospital) and J. A. Bluestone (University of California at San Diego) for CTLA-4-specific blocking antibodies; A. Brunet (Stanford University) for Foxo3-specific antibody; L. Lefranc, ois (University of Connecticut Health Center) for OVA-expressing vesicular stomatitis virus; L. Mack and E. Zuniga for assistance with virus titers; and M. Niwa for microscope facility use. Supported by the American Cancer Society (R. A. D.), the Robert A. and Renee E. Belfer Institute for Innovative Cancer Research (R. A. D.), the US National Cancer Institute (R. A. D.), the Division of Biological Sciences of the University of California, San Diego (S. M. H.) and the Fondation pour la Recherche Medicale (A. S. D.). NR 45 TC 115 Z9 121 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAY PY 2009 VL 10 IS 5 BP 504 EP 513 DI 10.1038/ni.1729 PG 10 WC Immunology SC Immunology GA 436EC UT WOS:000265394400012 PM 19363483 ER PT J AU Stadtfeld, M Hochedlinger, K AF Stadtfeld, Matthias Hochedlinger, Konrad TI Without a trace? PiggyBac-ing toward pluripotency SO NATURE METHODS LA English DT Editorial Material ID STEM-CELLS; GENERATION AB A transposon-based approach has been added to the growing arsenal of technologies to produce transgene-free and potentially safer induced pluripotent stem cells. C1 [Stadtfeld, Matthias] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Stadtfeld, M (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. EM mstadtfeld@mgh.harvard.edu; khochedlinger@helix.mgh.harvard.edu OI Stadtfeld, Matthias/0000-0002-5852-9906 NR 11 TC 8 Z9 8 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD MAY PY 2009 VL 6 IS 5 BP 329 EP 330 DI 10.1038/nmeth0509-329 PG 2 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 439XS UT WOS:000265661600009 PM 19404251 ER PT J AU DuBois, SG Grier, HE AF DuBois, Steven G. Grier, Holcombe E. TI The role of ifosfamide and etoposide in Ewing sarcoma SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID RECURRENT SARCOMAS; TUMOR; CHEMOTHERAPY; BENEFIT; BONE AB The EICESS-92 trial compared the efficacy of cyclophosphamide and ifosfamide in patients with Ewing sarcoma. Subgroup analysis suggested that patients with large, localized tumors benefited from the addition of etoposide, whereas patients with metastases did not. C1 [DuBois, Steven G.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Grier, Holcombe E.] Harvard Univ, Sch Med, Boston, MA USA. RP Grier, HE (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM holcombe_grier@dfci.harvard.edu NR 7 TC 3 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAY PY 2009 VL 6 IS 5 BP 251 EP 253 DI 10.1038/nrclinonc.2009.25 PG 4 WC Oncology SC Oncology GA 442PT UT WOS:000265853800005 PM 19390548 ER PT J AU Weisbord, SD Palevsky, PM AF Weisbord, Steven D. Palevsky, Paul M. TI ACUTE KIDNEY INJURY Intravenous fluid to prevent contrast-induced AKI SO NATURE REVIEWS NEPHROLOGY LA English DT Editorial Material ID INDUCED NEPHROPATHY; SODIUM-BICARBONATE; CORONARY-ANGIOGRAPHY; N-ACETYLCYSTEINE; TRIAL; INTERVENTION; HYDRATION; CHLORIDE AB Trials that compared sodium bicarbonate and sodium chloride for the prevention of contrast-induced acute kidney injury have yielded highly conflicting results. the authors of a recent meta-analysis endeavored to provide a definitive assessment of the relative efficacy of these two intravenous fluids. C1 [Weisbord, Steven D.] Vet Affairs Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. RP Weisbord, SD (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Renal Sect, 111F-U,Room 7E 120,Univ Dr Div, Pittsburgh, PA 15240 USA. EM weisbordsd@upmc.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 8 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD MAY PY 2009 VL 5 IS 5 BP 256 EP 257 DI 10.1038/nrneph.2009.26 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 442QA UT WOS:000265854500007 PM 19384326 ER PT J AU Lal, A Pan, YF Navarro, F Dykxhoorn, DM Moreau, L Meire, E Bentwich, Z Lieberman, J Chowdhury, D AF Lal, Ashish Pan, Yunfeng Navarro, Francisco Dykxhoorn, Derek M. Moreau, Lisa Meire, Eti Bentwich, Zvi Lieberman, Judy Chowdhury, Dipanjan TI miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID EXPRESSION; MICRORNAS; PROLIFERATION; PROTEIN; RNA AB Terminally differentiated cells have a reduced capacity to repair double-stranded breaks, but the molecular mechanism behind this downregulation is unclear. Here we find that miR-24 is upregulated during postmitotic differentiation of hematopoietic cell lines and regulates the histone variant H2AX, a protein that has a key role in the double-stranded break response. We show that the H2AX 3' untranslated region contains conserved miR-24 binding sites that are indeed regulated by miR-24. During terminal differentiation, both H2AX mRNA and protein levels are substantially reduced by miR-24 upregulation in in vitro differentiated cells; similar diminished levels are found in primary human blood cells. miR-24-mediated suppression of H2AX renders cells hypersensitive to gamma-irradiation and genotoxic drugs, a phenotype that is fully rescued by overexpression of miR-24-insensitive H2AX. Therefore, miR-24 upregulation in postreplicative cells reduces H2AX and makes them vulnerable to DNA damage. C1 [Lal, Ashish; Navarro, Francisco; Dykxhoorn, Derek M.; Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Lal, Ashish; Navarro, Francisco; Dykxhoorn, Derek M.; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pan, Yunfeng; Moreau, Lisa; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pan, Yunfeng; Moreau, Lisa; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Meire, Eti; Bentwich, Zvi] Rosetta Genom, Rehovot, Israel. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu; dipanjan_chowdhury@dfci.harvard.edu RI Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015 FU US National Institutes of Health [AI070302] FX This work was supported in part by the US National Institutes of Health grant AI070302 and a GSK-IDI Alliance grant ( to J.L.) and by a Barr Award ( to D. C.). We thank members of the Lieberman and Chowdhury laboratories for useful discussions. NR 24 TC 165 Z9 171 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2009 VL 16 IS 5 BP 492 EP 498 DI 10.1038/nsmb.1589 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 447VS UT WOS:000266220700015 PM 19377482 ER PT J AU Dhaese, I Vanneste, G Sips, P Buys, ES Brouckaert, P Lefebvre, RA AF Dhaese, Ingeborg Vanneste, Gwen Sips, Patrick Buys, Emmanuel S. Brouckaert, Peter Lefebvre, Romain A. TI Small intestinal motility in soluble guanylate cyclase alpha(1) knockout mice SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article DE Soluble guanylate cyclase; Nitric oxide; Small intestinal motility; In vivo; In vitro; sGC alpha(1) knockout ID NITRIC-OXIDE; SMOOTH-MUSCLE; GASTROINTESTINAL TRANSIT; LONGITUDINAL MUSCLE; INHIBITORY PATHWAYS; DEFICIENT MICE; RAT JEJUNUM; KINASE I; RELAXATION; ENDOTHELIUM AB Nitric oxide (NO) activates soluble guanylate cyclase (sGC) to produce guanosine-3',5'-cyclic-monophosphate (cGMP). The aim of this study was to investigate the nitrergic regulation of jejunal motility in sGC alpha(1) knockout (KO) mice. Functional responses to nitrergic stimuli and cGMP levels in response to nitrergic stimuli were determined in circular muscle strips. Intestinal transit was determined. Nitrergic relaxations induced by electrical field stimulation and exogenous NO were almost abolished in male KO strips, but only minimally reduced and sensitive to ODQ in female KO strips. Basal cGMP levels were decreased in KO strips, but NO still induced an increase in cGMP levels. Transit was not attenuated in male nor female KO mice. In vitro, sGC alpha(1)beta(1) is the most important isoform in nitrergic relaxation of jejunum, but nitrergic relaxation can also occur via sGC alpha(2)beta(1) activation. The latter mechanism is more pronounced in female than in male KO mice. In vivo, no important implications on intestinal motility were observed in male and female KO mice. C1 [Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Sips, Patrick; Buys, Emmanuel S.; Brouckaert, Peter] Univ Ghent, Dept Mol Biol, B-9000 Ghent, Belgium. [Sips, Patrick; Buys, Emmanuel S.; Brouckaert, Peter] VIB, Dept Mol Biomed Res, Ghent, Belgium. [Dhaese, Ingeborg; Vanneste, Gwen; Lefebvre, Romain A.] Univ Ghent, Heymans Inst Pharmacol, B-9000 Ghent, Belgium. RP Lefebvre, RA (reprint author), Pintelaan 185, B-9000 Ghent, Belgium. EM Romain.Lefebvre@UGent.be OI Sips, Patrick/0000-0001-9241-5980 FU Special Investigation Fund of Ghent University [GOA 1251004]; Scientific Research Flanders [0053.02]; Interuniversity Attraction Pole Programme [P5/20] FX The study was financially supported by the Special Investigation Fund of Ghent University (GOA 1251004), the fund for Scientific Research Flanders (G. 0053.02), and by Interuniversity Attraction Pole Programme P5/20. NR 35 TC 6 Z9 7 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAY PY 2009 VL 379 IS 5 BP 473 EP 487 DI 10.1007/s00210-008-0380-x PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 423KI UT WOS:000264494800005 PM 19052725 ER PT J AU Baba, Y Nosho, K Shima, K Irahara, N Kure, S Toyoda, S Kirkner, GJ Goel, A Fuchs, C Ogino, S AF Baba, Yoshifumi Nosho, Katsuhiko Shima, Kaori Irahara, Natsumi Kure, Shoko Toyoda, Saori Kirkner, Gregory J. Goel, Ajay Fuchs, Charles Ogino, Shuji TI Aurora-A Expression Is Independently Associated with Chromosomal Instability in Colorectal Cancer SO NEOPLASIA LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; FATTY-ACID SYNTHASE; MICROSATELLITE INSTABILITY; COLON-CANCER; CENTROSOME AMPLIFICATION; POOR-PROGNOSIS; OVARIAN-CANCER; KINASE-A; CYCLOOXYGENASE-2 EXPRESSION; EPIGENETIC INSTABILITY AB AURKA (the official symbol for Aurora-A, STK15, or BTAK) regulates the function of centrosomes, spindles, and kinetochores for proper mitotic progression. AURKA overexpression is observed in various cancers including colon cancer, and a link between AURKA and chromosomal instability (CIN) has been proposed. However, no study has comprehensively examined AURKA expression in relation to CIN or prognosis using a large number of tumors. Using 517 colorectal cancers in two prospective cohort studies, we detected AURKA overexpression (by immunohistochemistry) in 98 tumors (19%). We assessed other molecular events including loss of heterozygosity (LOH) in 2p, 5q, 17q, and 18q, the CpG island methylation phenotype (CIMP), and microsatellite instability (MSI). Prognostic significance of AURKA was evaluated by Cox regression and Kaplan-Meier method. In both univariate and multivariate logistic regressions, AURKA overexpression was significantly associated with CIN (defined as the presence of LOH in any of the chromosomal segments; multivariate odds ratio, 2.97; 95% confidence interval, 1.40-6.29; P = .0045). In multivariate analysis, AURKA was associated with cyclin D1 expression (P= .010) and inversely with PIK3CA mutation (P= .014), fatty acid synthase expression (P= .028), and family history of colorectal cancer (P = .050), but not with sex, age, body mass index, tumor location, stage, CIMP, MSI, KRAS, BRAF, BMI, LINE-1 hypomethylation, p53, p21, beta-catenin, or cyclooxygenase 2. AURKA was not significantly associated with clinical outcome or survival. In conclusion, AURKA overexpression is independently associated with CIN in colorectal cancer, supporting a potential role of Aurora kinase-A in colorectal carcinogenesis through genomic instability (rather than epigenomic instability). C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Mol Oncol Pathol,Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Mol Oncol Pathol,Dana Farber Canc Inst, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institutes of Health (NIH) [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation; Japan Society for Promotion of Science FX This work was supported by US National Institutes of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003 (to C. S. F.), and K07 CA122826 (to S.O.) and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA). K. N. was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No conflicts of interest exist. NR 72 TC 61 Z9 63 U1 0 U2 3 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAY PY 2009 VL 11 IS 5 BP 418 EP 425 DI 10.1593/neo.09154 PG 8 WC Oncology SC Oncology GA 432AS UT WOS:000265106500001 PM 19412426 ER PT J AU Lee, H Park, JW Kim, SP Lo, EH Lee, SR AF Lee, Hyung Park, Jong-Wook Kim, Sang-Pyo Lo, Eng H. Lee, Seong-Ryong TI Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Doxycycline; Matrix metalloproteinase; Neuroprotection; Global ischemia ID DELAYED NEURONAL DEATH; BLOOD-BRAIN-BARRIER; MATRIX METALLOPROTEINASES; GERBIL HIPPOCAMPUS; PLASMINOGEN ACTIVATORS; FOREBRAIN ISCHEMIA; DAMAGE; INJURY; MODEL; APOPTOSIS AB Doxycycline, a tetracycline antibiotic inhibits matrix metalloproteinase (MMP) and reduces neuronal damage in local brain ischemia. This study was undertaken to assess if doxycycline reduces delayed neuronal damage following transient global cerebral ischemia through MMIP inhibition. C57BL/6 mice were subjected to 20 min global cerebral ischemia. Doxycycline was administered to mice 30 min before and 2 h after ischemia. In TUNEL assay, damaged neurons were also apparent in the CA1 and CA2 areas and doxycycline reduced TUNEL-positive neurons. Gelatin gel and in situ zymography showed upregulation of gelatinase activity after ischemia. Doxycycline significantly inhibited MMP-9 activity in gel zymography and also suppressed in situ gelatinase activity. Laminin degradation was remarkable in CA1 and CA2 areas after ischemia and doxycycline reduced the laminin degradation and neuronal loss. Our data suggest that doxycycline may provide a neuroprotection against global cerebral ischemia since it reduces perineuronal laminin degradation by inhibiting MMP-9 activity. (C) 2008 Elsevier Inc. All rights reserved. C1 [Lee, Seong-Ryong] Keimyung Univ, Sch Med, Dept Pharmacol, Taegu 700712, South Korea. [Lee, Hyung; Kim, Sang-Pyo; Lee, Seong-Ryong] Keimyung Univ, Brain Res Inst, Taegu 700712, South Korea. [Park, Jong-Wook; Lee, Seong-Ryong] Keimyung Univ, Sch Med, Chron Dis Res Ctr, Taegu 700712, South Korea. [Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Radiol, Boston, MA USA. [Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Neurol, Boston, MA USA. RP Lee, SR (reprint author), Keimyung Univ, Sch Med, Dept Pharmacol, 194 Dongsan Dong, Taegu 700712, South Korea. EM srlee@kmu.ac.kr NR 34 TC 43 Z9 44 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAY PY 2009 VL 34 IS 2 BP 189 EP 198 DI 10.1016/j.nbd.2008.12.012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 442VT UT WOS:000265869400001 PM 19200854 ER PT J AU Langbaum, JBS Chen, K Lee, W Reschke, C Bandy, D Fleisher, AS Alexander, GE Foster, NL Weiner, MW Koeppe, RA Jagust, WJ Reiman, EM AF Langbaum, Jessica B. S. Chen, Kewei Lee, Wendy Reschke, Cole Bandy, Dan Fleisher, Adam S. Alexander, Gene E. Foster, Norman L. Weiner, Michael W. Koeppe, Robert A. Jagust, William J. Reiman, Eric M. CA Alzheimer's Dis Neuroimaging Initi TI Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) SO NEUROIMAGE LA English DT Article DE Alzheimer's disease; MCI; MMSE; Positron emission tomography ID MILD COGNITIVE IMPAIRMENT; CEREBRAL GLUCOSE-METABOLISM; POSTERIOR CINGULATE CORTEX; PITTSBURGH COMPOUND-B; FDG-PET; APOLIPOPROTEIN-E; F-18-FDG PET; CLINICAL-DIAGNOSIS; DEMENTIA; MCI AB In mostly small single-center studies, Alzheimer's disease (AD) is associated with characteristic and progressive reductions in fluorodeoxyglucose positron emission tomography (PET) measurements of the regional cerebral metabolic rate for glucose (CMRgl). The AD Neuroimaging Initiative (ADNI) is acquiring FDG PET, volumetric magnetic resonance imaging, and other biomarker measurements in a large longitudinal multi-center study of initially mildly affected probable AD (pAD) patients, amnestic mild cognitive impairment (aMCI) patients, who are at increased AD risk, and cognitively normal controls (NC), and we are responsible for analyzing the PET images using statistical parametric mapping (SPM). Here we compare baseline CMRgl measurements from 74 pAD patients and 142 aMCI patients to those from 82 NC, we correlate CMRgl with categorical and continuous measures of clinical disease severity, and we compare apolipoprotein E (APOE) epsilon 4 carriers to non-carriers in each of these subject groups. In comparison with NC, the pAD and aMCI groups each had significantly lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal and frontal cortex. Similar reductions were observed when categories of disease severity or lower Mini-Mental State Exam (MMSE) scores were correlated with lower CMRgl. However, when analyses were restricted to the pAD patients, lower MMSE scores were significantly correlated with lower left frontal and temporal CMRgl. These findings from a large, multi-site study support previous single-site findings, supports the characteristic pattern of baseline CMRgl reductions in AD and aMCI patients, as well as preferential anterior CMRgl reductions after the onset of AD dementia. (C) 2009 Elsevier Inc. All rights reserved. C1 [Langbaum, Jessica B. S.; Chen, Kewei; Lee, Wendy; Reschke, Cole; Bandy, Dan; Fleisher, Adam S.; Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ 85006 USA. [Langbaum, Jessica B. S.; Chen, Kewei; Lee, Wendy; Reschke, Cole; Bandy, Dan; Fleisher, Adam S.; Reiman, Eric M.] Banner Good Samaritan PET Ctr, Phoenix, AZ USA. [Chen, Kewei] Arizona State Univ, Dept Math, Tempe, AZ 85287 USA. [Chen, Kewei] Univ Arizona, Dept Radiol, Tucson, AZ 85724 USA. [Alexander, Gene E.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Alexander, Gene E.] Univ Arizona, Evelyn F McKnight Brain Inst, Tucson, AZ 85721 USA. [Reiman, Eric M.] Univ Arizona, Dept Psychiat, Tucson, AZ USA. [Foster, Norman L.] Univ Utah, Ctr Alzheimers Care Imaging & Res, Salt Lake City, UT USA. [Foster, Norman L.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Weiner, Michael W.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Koeppe, Robert A.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Jagust, William J.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA USA. [Jagust, William J.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA USA. [Reiman, Eric M.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Fleisher, Adam S.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Langbaum, Jessica B. S.; Chen, Kewei; Lee, Wendy; Reschke, Cole; Bandy, Dan; Fleisher, Adam S.; Alexander, Gene E.; Reiman, Eric M.] Arizona Alzheimers Consortium, Phoenix, AZ USA. RP Reiman, EM (reprint author), Banner Alzheimers Inst, 901 E Willetta St, Phoenix, AZ 85006 USA. EM eric.reiman@bannerhealth.com RI Scharre, Douglas/E-4030-2011; Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU Alzheimer's Disease Neuroimaging Initiative (ADNI); NIH [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering (NIBIB); Pfizer Inc.; Wyeth Research; Bristol-Myers Squibb; Eli Lilly and Company; GlaxoSmithKline; Merck Co. Inc.; AstraZeneca AB; Novartis Pharmaceuticals Corporation; Eisai Global Clinical Development; Elan Corporation plc; Forest Laboratories; Institute for the Study of Aging; U.S. Food and Drug Administration FX Data collection and sharing for this project were funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; Principal Investigator: MichaelWeiner; NIH grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and through generous contributions from the following: Pfizer Inc., Wyeth Research, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co. Inc., `AstraZeneca AB, Novartis Pharmaceuticals Corporation, Alzheimer's Association, Eisai Global Clinical Development, Elan Corporation plc, Forest Laboratories, and the Institute for the Study of Aging, with participation from the U.S. Food and Drug Administration. Industry partnerships are coordinated through the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. NR 56 TC 135 Z9 136 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAY 1 PY 2009 VL 45 IS 4 BP 1107 EP 1116 DI 10.1016/j.neuroimage.2008.12.072 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SL UT WOS:000264378500007 PM 19349228 ER PT J AU Lu, J Dai, G Egi, Y Huang, S Kwon, SJ Lo, EH Kim, YR AF Lu, Jie Dai, Guangping Egi, Yasu Huang, Shuning Kwon, Seon Joo Lo, Eng H. Kim, Young Ro TI Characterization of cerebrovascular responses to hyperoxia and hypercapnia using MRI in rat SO NEUROIMAGE LA English DT Article DE Hyperoxia; Hypercapnia; Rat; BOLD; CBV; CBF; fMRI ID CEREBRAL-BLOOD-FLOW; NORMOBARIC HYPEROXIA; FUNCTIONAL MRI; CARBON-DIOXIDE; INSPIRED OXYGEN; BRAIN; VOLUME; FMRI; ISCHEMIA; BOLD AB Understanding cerebrovascular responses to hyperoxia and hypercapnia is important for investigating exogenous regulation of cerebral hemodynamics. We characterized gas-induced vascular changes in the brains of anesthetized healthy rats using magnetic resonance imaging (MRI) while the rats inhaled 100% O(2) (hyperoxia) and 5% CO(2) (hypercapnia). We used echo planar imaging (EPI), arterial spin labeling (ASL), and intravascular superparamagnetic iron oxide nanoparticles (SPION) to quantify vascular responses as measured by blood oxygenation level dependence (BOLD), cerebral blood flow (CBF), cerebral blood volume (CBV), microvascular volume (MVV), and vessel size index (VSI) in multiple brain regions. Hyperoxia resulted in a statistically significant increase in BOLD-weighted MRI signal and significant decrease in CBF and CBV (P < 0.05). During hypercapnia, we observed significant increases in BOLD signal, CBF, MVV, and CBV (P < 0.05). Despite the regional variability, general trends of vasoconstriction and vasodilation were reflected in VSI changes during O(2) and CO(2) challenges. Interestingly, there was an evident spatial disparity between the O(2) and CO(2) stimuli-induced functional activation maps; that is, cortical and subcortical regions of the brain exhibited notable differences in response to the two gases. Hemodynamic parameters measured in the cortical regions showed greater reactivity to CO(2), whereas these same parameters measured in subcortical regions showed greater responsivity to O(2). Our results demonstrate significant changes of hemodynamic MRI parameters during systemic hypercapnia and hyperoxia in normal cerebral tissue. These gas-dependent changes are spatiotemporally distinctive, suggesting important feasibility for exogenously controlling local cerebral perfusion. (C) 2008 Elsevier Inc. All rights reserved. C1 [Lu, Jie; Egi, Yasu; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Lab Neuroprotect,Dept Neurol, Charlestown, MA 02129 USA. [Lu, Jie; Dai, Guangping; Huang, Shuning; Kwon, Seon Joo; Kim, Young Ro] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA 02129 USA. [Lu, Jie] Capital Med Univ, Dept Radiol, Xuanwu Hosp, Beijing 100053, Peoples R China. RP Kim, YR (reprint author), Harvard Univ, Sch Med, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Massachusetts Gen Hosp, Bldg 149,13th St, Charlestown, MA 02129 USA. EM spmn@nmr.mgh.harvard.edu FU National Institute of Health [RO1-5R01EB002066] FX We thank Nichole Eusemann and Drs. Kwong Ken and A. Gregory Sorensen for their critical and helpful comments. This work was supported in part by grants from National Institute of Health (RO1-5R01EB002066). NR 46 TC 44 Z9 45 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAY 1 PY 2009 VL 45 IS 4 BP 1126 EP 1134 DI 10.1016/j.neuroimage.2008.11.037 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SL UT WOS:000264378500009 PM 19118633 ER PT J AU Alpert, NM Yuan, F AF Alpert, Nathaniel M. Yuan, Fang TI A general method of Bayesian estimation for parametric imaging of the brain SO NEUROIMAGE LA English DT Article ID DYNAMIC PET DATA; POSITRON-EMISSION-TOMOGRAPHY; SPATIAL CONSTRAINT; RIDGE-REGRESSION; KINETIC-ANALYSIS; IMAGES; VARIABILITY; MODEL AB We report a general method of Bayesian estimation that uses prior measurements to improve the signal-to-noise ratio of parametric images computed from dynamic PET scanning. In our method, the ordinary weighted least squares cost function is augmented by a penalty term to yield F K; S min(K){(C-f(K))(T) Omega(-1)(C)(C-f(K)) + S Phi(K, S = 0)(K-(K) over cap)(T)W(K)(-1)(K-(K) over cap) , where C is a PET concentration history and Omega(C) is its variance, f is the model of the concentration history, K = [k(1), k(2),..., k(m)](T) is the parameter vector, (K) over cap is the vector of population means for the model parameters, Omega(K) is its covariance, Phi(K)(K, S = 0) is the conventional weighted sum of squares. S > 0 is chosen to control the balance between the prior and new data. Data from a prior population of subjects are analyzed with standard methods to provide maps of the mean parameter values and their variances. As an example of this approach we used the dynamic image data of 10 normal subjects who had previously been studied with (11)C-raclopride to estimate the prior distribution. The dynamic data were transformed to stereotactic coordinates and analyzed by standard methods. The resulting parametric maps were used to compute the voxel-wise sample statistics. Then the cohort of priors was analyzed as a function of S, using nonlinear least squares estimation and the cost function shown above. As S is increased the standard error in estimating BP in single subjects was substantially reduced allowing measurement in BP in thalamus, cortex, brain stem, etc. Additional studies demonstrate that a range of S values exist for which the bias is not excessive, even when parameter values differ markedly from the sample mean. This method can be used with any kinetic model so long as it is possible to compute a map of a priori mean parameters and their variances. (C) 2009 Elsevier Inc. All rights reserved. C1 [Alpert, Nathaniel M.; Yuan, Fang] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Dept Radiol, Boston, MA 02114 USA. RP Alpert, NM (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Dept Radiol, 50 Fruit St, Boston, MA 02114 USA. EM alpert@pet.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering [5T32EB002102] FX Dr. Yuan was supported by the Postgraduate Program in Radiological Science, 5T32EB002102, a National Institute of Biomedical Imaging and Bioengineering postdoctoral training grant. NR 29 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAY 1 PY 2009 VL 45 IS 4 BP 1183 EP 1189 DI 10.1016/j.neuroimage.2008.12.064 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SL UT WOS:000264378500015 PM 19349233 ER PT J AU Liu, LP Yenari, MA AF Liu, Liping Yenari, Midori A. TI Clinical application of therapeutic hypothermia in stroke SO NEUROLOGICAL RESEARCH LA English DT Article DE Temperature; heart; brain; cooling methods; combination ID TRANSIENT GLOBAL-ISCHEMIA; COMBINED POSTISCHEMIC HYPOTHERMIA; MILD RESUSCITATIVE HYPOTHERMIA; HOSPITAL CARDIAC-ARREST; MODERATE HYPOTHERMIA; COMATOSE SURVIVORS; FEASIBILITY; RATS; NEUROPROTECTION; TEMPERATURE AB Objective: Hypothermia has long been known to be a potent neuroprotectant. In this mini-review, we highlighted clinical experience that hypothermia protects the brain from cerebral injury. We discussed the clinical practice of hypothermia in ischemic stroke. Results: Multiple factors play a significant role in the mechanisms. Clinical application drew first from two clinical trials with comatose patients after cardiac arrest is attractive. The Australian and European study have led to renewed interest in these patients. More and more evidences bring the insight into its effects on cerebral ischemia. The type of cooling technique to be used, the duration of cooling and speed of rewarming appear to be key factors in determining whether hypothermia is effective in preventing or mitigating neurological injury. Although until now, there are no clear therapeutic standards of the parameters in therapeutic hypothermia, it is well accepted that cooling should be initiated as soon as possible. By combining hypothermia with other neuroprotectants, it may be possible to enhance protective effects, reduce side effects and lengthen the maximum time. Conclusion: In addition to its neuroprotective properties, hypothermia may extend the therapeutic window for other neuroprotective treatment. Thus, combination therapies with neuroprotective, anti-inflammatory and thrombolytic agents are likely to be investigated in the clinical setting in the future. [Neurol Res 2009; 31: 331-335] C1 [Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Liu, Liping] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, Beijing 100050, Peoples R China. [Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Yenari, MA (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM yenari@alum.mit.edu FU NINDS NIH HHS [R01 NS040516, R01 NS040516-09] NR 33 TC 17 Z9 19 U1 1 U2 1 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 0161-6412 J9 NEUROL RES JI Neurol. Res. PD MAY PY 2009 VL 31 IS 4 BP 331 EP 335 DI 10.1179/174313209X444099 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 458KV UT WOS:000267020000002 PM 19508813 ER PT J AU Mesholam-Gately, RI Giuliano, AJ Goff, KP Faraone, SV Seidman, LJ AF Mesholam-Gately, Raquelle I. Giuliano, Anthony J. Goff, Kirsten P. Faraone, Stephen V. Seidman, Larry J. TI Neurocognition in First-Episode Schizophrenia: A Meta-Analytic Review SO NEUROPSYCHOLOGY LA English DT Review DE schizophrenia; psychosis; first-episode; neurocognition; meta-analysis ID EXECUTIVE FUNCTIONS; MEMORY IMPAIRMENT; SOCIAL COGNITION; PROCESSING SPEED; WORKING-MEMORY; 1ST EPISODE; FOLLOW-UP; HIGH-RISK; NEUROPSYCHOLOGICAL DEFICITS; DIFFERENTIAL DEFICIT AB Compromised neurocognition is a core feature of schizophrenia. Following Heinrichs and Zakzanis's (1998) seminal meta-analysis of middle-aged and predominantly chronic schizophrenia samples, the aim of this study is to provide a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007. The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20). Findings indicate that impairments are reliably and broadly present by the FE, approach or match the degree of deficit shown in well-established illness, and are maximal in immediate verbal memory and processing speed. Larger IQ impairments in the FE compared to the premorbid period, but comparable to later phases of illness suggests deterioration between premorbid and FE phases followed by deficit stability at the group level. Considerable heterogeneity of effect sizes across studies, however, underscores variability in manifestations of the illness and a need for improved reporting of sample characteristics to support moderator variable analyses. C1 [Mesholam-Gately, Raquelle I.] Harvard Univ, Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr,Dept Psychiat, Commonwealth Res Ctr,Publ Psychiat Div,Sch Med, Jamaica Plain, MA 02130 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, New York, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, New York, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Physiol, New York, NY USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Mesholam-Gately, RI (reprint author), Harvard Univ, Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr,Dept Psychiat, Commonwealth Res Ctr,Publ Psychiat Div,Sch Med, Lemuel Shattuck Hosp Campus,180 Morton St, Jamaica Plain, MA 02130 USA. EM rmeshola@bidmc.harvard.edu OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [MH 43518, MH 63951, MH 65562, P50 MH 080272] NR 146 TC 371 Z9 375 U1 6 U2 37 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD MAY PY 2009 VL 23 IS 3 BP 315 EP 336 DI 10.1037/a0014708 PG 22 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 439XW UT WOS:000265662000005 PM 19413446 ER PT J AU Glazer, G Ponte, PR Stuart-Shor, EM Cooley, ME AF Glazer, Greer Ponte, Pat Reid Stuart-Shor, Eileen M. Cooley, Mary E. TI The power of partnership: Addressing cancer health disparities through an academic-service partnership SO NURSING OUTLOOK LA English DT Article AB Partnerships between universities and healthcare organizations help foster interdisciplinary collaboration and can yield programs to address pressing needs in both sectors. In spite of these benefits, such partnerships remain more the exception than the norm. This article describes a partnership between a comprehensive cancer center and a university-based college of nursing and health sciences that serves a diverse student population. With the support of U-56 funding, the 2 organizations collaborated to develop a new, 87-credit BS-to-PhD in Nursing program and to enhance the university's traditional PhD in nursing program. Both PhD programs prepare nurses for careers in teaching, health policy, and research related to cancer health disparities. In addition to an innovative curriculum, the programs include a mentorship that leverages the research expertise and scholarly resources of both organizations and a community outreach component that gives students experience in planning and implementing educational and risk-reduction programs addressing cancer health disparities. C1 [Glazer, Greer; Ponte, Pat Reid; Stuart-Shor, Eileen M.; Cooley, Mary E.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Glazer, Greer; Ponte, Pat Reid; Stuart-Shor, Eileen M.; Cooley, Mary E.] Dana Farber Canc Ctr, Patient Care Serv, Boston, MA USA. [Glazer, Greer; Stuart-Shor, Eileen M.; Cooley, Mary E.] Dana Farber Canc Ctr, Phyllis F Cantor Ctr Res Nursing, Boston, MA USA. [Ponte, Pat Reid] Brigham & Womens Hosp, Oncol Nursing & Clin Serv, Boston, MA 02115 USA. RP Glazer, G (reprint author), Univ Massachusetts, Boston Coll Nursing & Hlth Sci, 100 Morrissey Blvd, Boston, MA 02125 USA. EM Greer.glazer@umb.edu FU NIH-/NCI [1 U56 CA11863502]; Lynch Foundation; GAANN; US Department of Education [P200A060243] FX The work described in this manuscript was supported in part by NIH-/NCI Grant 1 U56 CA11863502, and by grants from the Lynch Foundation and GAANN, US Department of Education, P200A060243. NR 16 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD MAY-JUN PY 2009 VL 57 IS 3 BP 123 EP 131 DI 10.1016/j.outlook.2008.07.007 PG 9 WC Nursing SC Nursing GA 451FX UT WOS:000266457200003 PM 19447232 ER PT J AU Zhao, R Xiang, N Domann, FE Zhong, WX AF Zhao, Rui Xiang, Nong Domann, Fredrick E. Zhong, Weixiong TI Effects of Selenite and Genistein on G(2)/M Cell Cycle Arrest and Apoptosis in Human Prostate Cancer Cells SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID KINASE INHIBITOR GENISTEIN; CASPASE-MEDIATED APOPTOSIS; METHYLSELENINIC ACID; UNITED-STATES; IN-VITRO; PREVENTION; SELENOMETHIONINE; CHEMOPREVENTION; EXPRESSION; MORTALITY AB Combination of chemopreventive agents with distinct molectilar mechanisms is considered to offer a potential for enhancing cancer prevention efficacy while minimizing toxicity. Here we report two chemopreventive agents, selenite and genistein, that have synergistic effects on apoptosis, cell cycle arrest, and associated signaling pathways in p53-expressing LNCaP and p53-null PC3 prostate cancer cells. We show that selenite induced apoptosis only, whereas genistein induced both apoptosis and G(2)/M cell cycle arrest. Combination of these two agents exhibited enhanced effects, which were slightly greater in LNCaP than PC3 cells. Selenite or genistein alone upregulated protein levels of p53 in LNCaP cells only and p21(waf1) and Bax in both cell lines. Additionally, genistein inhibited AKT phosphorylation. Downregulation of AKT by siRNA caused apoptosis and G2/M cell cycle arrest and masked the effects of genistein. Treatment with insulin-like growth factor I (IGF-I) elevated levels of total and phosphorylated AKT and suppressed the effects of genistein. Neither downregulation of AKT nor IGF-I treatment altered the cellular effects of selenite. Our study demonstrates that selenium and genistein act via different molecular mechanisms and exhibit enhanced anticancer effects, suggesting that a combination of selenium and genistein may offer better efficacy and reduction of toxicity in prostate cancer prevention. C1 [Zhao, Rui; Xiang, Nong; Zhong, Weixiong] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53792 USA. [Domann, Fredrick E.] Univ Iowa, Free Rad & Radiat Biol Grad Program, Iowa City, IA USA. [Zhong, Weixiong] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Madison, WI 53705 USA. RP Zhong, WX (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53792 USA. EM wzhong3@wisc.edu OI Domann, Frederick/0000-0002-0489-2179 FU NCI NIH HHS [CA114281, CA73612,, R01 CA073612-09, R01 CA073612, R01 CA073612-10, R01 CA114281, R01 CA114281-03, R01 CA114281-04, R01 CA115438, R01 CA115438-02, R01 CA115438-03, R29 CA073612, R56 CA073612] NR 52 TC 44 Z9 48 U1 0 U2 4 PU LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS PI PHILADELPHIA PA 325 CHESTNUT STREET, STE 800, PHILADELPHIA, PA 19106 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PD MAY-JUN PY 2009 VL 61 IS 3 BP 397 EP 407 DI 10.1080/01635580802582751 PG 11 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 473WM UT WOS:000268242000014 PM 19373614 ER PT J AU Blackburn, GL Hu, FB Hutter, MM AF Blackburn, George L. Hu, Frank B. Hutter, Matthew M. TI Updated Evidence-based Recommendations for Best Practices in Weight Loss Surgery SO OBESITY LA English DT Article ID EVIDENCE-BASED MEDICINE; BARIATRIC SURGERY; MORBID-OBESITY; MORTALITY C1 [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Ctr Study Nutr Med, Boston, MA 02215 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Blackburn, GL (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Ctr Study Nutr Med, Boston, MA 02215 USA. EM gblackbu@bidmc.harvard.edu NR 25 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 839 EP 841 DI 10.1038/oby.2008.572 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800001 PM 19396062 ER PT J AU Blackburn, GL Hutter, MM Harvey, AM Apovian, CM Boulton, HRW Cummings, S Fallon, JA Greenberg, I Jiser, ME Jones, DB Jones, SB Kaplan, LM Kelly, JJ Kruger, RS Lautz, DB Lenders, CM LoNigro, R Luce, H McNamara, A Mulligan, AT Paasche-Orlow, MK Perna, FM Pratt, JSA Riley, SM Robinson, MK Romanelli, JR Saltzman, E Schumann, R Shikora, SA Snow, RL Sogg, S Sullivan, MA Tarnoff, M Thompson, CC Wee, CC Ridley, N Auerbach, J Hu, FB Kirle, L Buckley, RB Annas, CL AF Blackburn, George L. Hutter, Matthew M. Harvey, Alan M. Apovian, Caroline M. Boulton, Hannah R. W. Cummings, Susan Fallon, John A. Greenberg, Isaac Jiser, Michael E. Jones, Daniel B. Jones, Stephanie B. Kaplan, Lee M. Kelly, John J. Kruger, Rayford S., Jr. Lautz, David B. Lenders, Carine M. LoNigro, Robert Luce, Helen McNamara, Anne Mulligan, Ann T. Paasche-Orlow, Michael K. Perna, Frank M. Pratt, Janey S. A. Riley, Stancel M., Jr. Robinson, Malcolm K. Romanelli, John R. Saltzman, Edward Schumann, Roman Shikora, Scott A. Snow, Roger L. Sogg, Stephanie Sullivan, Mary A. Tarnoff, Michael Thompson, Christopher C. Wee, Christina C. Ridley, Nancy Auerbach, John Hu, Frank B. Kirle, Leslie Buckley, Rita B. Annas, Catherine L. TI Expert Panel on Weight Loss Surgery: Executive Report Update SO OBESITY LA English DT Article ID LAPAROSCOPIC SLEEVE GASTRECTOMY; GASTRIC BYPASS-SURGERY; SERVICES-TASK-FORCE; LONG-TERM MORTALITY; HIGH-RISK PATIENTS; QUALITY-OF-LIFE; BARIATRIC-SURGERY; MORBID-OBESITY; UNITED-STATES; BILIOPANCREATIC DIVERSION AB Rapid shifts in the demographics and techniques of weight loss surgery (WLS) have led to new issues, new data, new concerns, and new challenges. In 2004, this journal published comprehensive evidence-based guidelines on WLS. In this issue, we've updated those guidelines to assure patient safety in this fast-changing field. WLS involves a uniquely vulnerable population in need of specialized resources and ongoing multidisciplinary care. Timely best-practice updates are required to identify new risks, develop strategies to address them, and optimize treatment. Findings in these reports are based on a comprehensive review of the most current literature on WLS; they directly link patient safety to methods for setting evidence-based guidelines developed from peer-reviewed scientific publications. Among other outcomes, these reports show that WLS reduces chronic disease risk factors, improves health, and confers a survival benefit on those who undergo it. The literature also shows that laparoscopy has displaced open surgery as the predominant approach; that government agencies and insurers only reimburse procedures performed at accredited WLS centers; that best practice care requires close collaboration between members of a multidisciplinary team; and that new and existing facilities require wide-ranging changes to accommodate growing numbers of severely obese patients. More than 100 specialists from across the state of Massachusetts and across the many disciplines involved in WLS came together to develop these new standards. We expect them to have far-reaching effects of the development of health care policy and the practice of WLS. C1 [Blackburn, George L.; Jones, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Hutter, Matthew M.; Pratt, Janey S. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Harvey, Alan M.] Mercy Med Ctr Catholic Hlth E, Dept Anesthesiol, Springfield, MA USA. [Apovian, Caroline M.; Lenders, Carine M.] Boston Med Ctr, Dept Med, Boston, MA USA. [Boulton, Hannah R. W.] S Shore Hosp, Dept Nursing, Weymouth, MA USA. [Cummings, Susan] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. [Fallon, John A.] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. [Greenberg, Isaac] Tufts Univ New England Med Ctr, Obes Consult Ctr, Boston, MA USA. [Jiser, Michael E.] Saints Med Ctr, Dept Surg, Lowell, MA USA. [Jones, Stephanie B.] Beth Israel Deaconess Med Ctr, Dept Anesthesiol, Boston, MA 02215 USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kelly, John J.] Univ Massachusetts, Mem Med Ctr, Dept Surg, Worcester, MA 01605 USA. [Kruger, Rayford S., Jr.] Tobey Hosp, Dept Surg, Wareham, MA USA. [Lautz, David B.; Robinson, Malcolm K.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [LoNigro, Robert] Tufts Hlth Plan, Care Management, Boston, MA USA. [Luce, Helen] Consumer Representat, Boston, MA USA. [McNamara, Anne] Beth Israel Deaconess Med Ctr, Dept Nursing & Surg, Boston, MA 02215 USA. [Mulligan, Ann T.] Newton Wellesley Hosp, Dept Nursing, Newton, MA USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Perna, Frank M.] NCI, Hlth Promot Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Riley, Stancel M., Jr.] Massachusetts Board Registrat Med, Patient Care Assessment Div, Boston, MA USA. [Robinson, Malcolm K.] Baystate Med Ctr, Dept Surg, Springfield, MA 01107 USA. [Saltzman, Edward] Tufts Univ New England Med Ctr, Dept Med, Boston, MA USA. [Schumann, Roman] Tufts Univ New England Med Ctr, Dept Anesthesiol, Boston, MA USA. [Shikora, Scott A.; Tarnoff, Michael] Tufts Univ New England Med Ctr, Dept Surg, Boston, MA USA. [Snow, Roger L.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Snow, Roger L.] MassHealth, Boston, MA USA. [Sogg, Stephanie] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. [Sogg, Stephanie] Massachusetts Gen Hosp, MGH Weight Ctr, Boston, MA 02114 USA. [Sullivan, Mary A.] Lahey Clin & Massachusetts Coalit Prevent Med Err, Div Med Specialties, Burlington, MA USA. [Thompson, Christopher C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wee, Christina C.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Ridley, Nancy; Auerbach, John; Hu, Frank B.; Kirle, Leslie; Buckley, Rita B.; Annas, Catherine L.] Commonwealth Massachusetts, Betsy Lehman Ctr Patient Safety & Med Error Reduc, Boston, MA USA. RP Blackburn, GL (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, 330 Brookline Ave, Boston, MA 02215 USA. EM gblackbu@bidmc.harvard.edu OI Paasche-Orlow, Michael/0000-0002-9276-7190; Apovian, Caroline/0000-0002-8029-1922; Jones, Stephanie/0000-0001-8342-0374 NR 80 TC 54 Z9 54 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 842 EP 862 DI 10.1038/oby.2008.578 PG 21 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800002 PM 19396063 ER PT J AU Kelly, JJ Shikora, S Jones, DB Hutter, MH Robinson, MK Romanelli, J Buckley, F Lederman, A Blackburn, GL Lautz, D AF Kelly, John J. Shikora, Scott Jones, Daniel B. Hutter, Matthew H. Robinson, Malcolm K. Romanelli, John Buckley, Frederick Lederman, Andrew Blackburn, George L. Lautz, David TI Best Practice Updates for Surgical Care in Weight Loss Surgery SO OBESITY LA English DT Article ID ROUX-EN-Y; PROSPECTIVE RANDOMIZED-TRIAL; LAPAROSCOPIC GASTRIC BYPASS; VERTICAL BANDED GASTROPLASTY; HIGH-RISK PATIENTS; BARIATRIC-SURGERY; MORBID-OBESITY; SUPER-OBESE; BILIOPANCREATIC DIVERSION; SLEEVE GASTRECTOMY AB To update evidence-based best practice guidelines for surgical care in weight loss surgery (WLS). Systematic search of English-language literature on WLS in MEDLINE, EMBASE, and the Cochrane Library between April 2004 and May 2007. Use of key words to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. Evidence-based best practice recommendations from the most recent literature on surgical methods and technologies, risks and benefits, outcomes, and surgeon qualifications and credentialing. We identified >135 articles; the 65 most relevant were reviewed in detail. Regular updates of evidence-based recommendations for best practices in WLS are required to address rapid changes in surgical techniques and patient demographics. Key factors in patient safety include surgical risk factors, type of procedure, surgeon training, and facility certification. C1 [Kelly, John J.] Univ Massachusetts, Med Ctr, Dept Surg, Worcester, MA 01605 USA. [Shikora, Scott] Tufts Univ New England Med Ctr, Dept Surg, Boston, MA USA. [Jones, Daniel B.; Blackburn, George L.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Hutter, Matthew H.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Robinson, Malcolm K.; Lautz, David] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Romanelli, John] Baystate Med Ctr, Dept Surg, Springfield, MA 01107 USA. [Buckley, Frederick] N Shore Med Ctr, Dept Surg, Salem, MA USA. [Lederman, Andrew] Berkshire Med Ctr, Dept Surg, Pittsfield, MA USA. RP Kelly, JJ (reprint author), Univ Massachusetts, Med Ctr, Dept Surg, Worcester, MA 01605 USA. EM kellyj@ummhc.org FU NIDDK NIH HHS [P30-DK-46200] NR 86 TC 14 Z9 14 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 863 EP 870 DI 10.1038/oby.2008.570 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800003 PM 19396064 ER PT J AU Apovian, CM Cummings, S Anderson, W Borud, L Boyer, K Day, K Hatchigian, E Hodges, B Patti, ME Pettus, M Perna, F Rooks, D Saltzman, E Skoropowski, J Tantillo, MB Thomason, P AF Apovian, Caroline M. Cummings, Sue Anderson, Wendy Borud, Loren Boyer, Kelly Day, Kristina Hatchigian, Edward Hodges, Barbara Patti, Mary E. Pettus, Mark Perna, Frank Rooks, Daniel Saltzman, Edward Skoropowski, June Tantillo, Michael B. Thomason, Phyllis TI Best Practice Updates for Multidisciplinary Care in Weight Loss Surgery SO OBESITY LA English DT Article ID Y GASTRIC BYPASS; QUALITY-OF-LIFE; MORBIDLY OBESE-PATIENTS; LOW-ENERGY DIET; BARIATRIC SURGERY; NUTRITIONAL-STATUS; NONALCOHOLIC STEATOHEPATITIS; BILIOPANCREATIC DIVERSION; PREOPERATIVE ASSESSMENT; CALCIUM-ABSORPTION AB The objective of this study is to update evidence-based best practice guidelines for multidisciplinary care of weight loss surgery (WLS) patients. We performed systematic search of English-language literature on WLS, patient selection, and medical, multidisciplinary, and nutritional care published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. Key words were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. A total of 150 papers were retrieved from the literature search and 112 were reviewed in detail. We made evidence-based best practice recommendations from the most recent literature on multidisciplinary care of WLS patients. New recommendations were developed in the areas of patient selection, medical evaluation, and treatment. Regular updates of evidence-based recommendations for best practices in multidisciplinary care are required to address changes in patient demographics and levels of obesity. Key factors in patient safety include comprehensive preoperative medical evaluation, patient education, appropriate perioperative care, and long-term follow-up. C1 [Apovian, Caroline M.; Anderson, Wendy; Perna, Frank] Boston Univ, Med Ctr, Dept Endocrinol Diabet & Nutr, Boston, MA 02215 USA. [Borud, Loren; Boyer, Kelly; Day, Kristina; Hatchigian, Edward; Rooks, Daniel; Skoropowski, June; Tantillo, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Cummings, Sue] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hodges, Barbara] Brigham & Womens Hosp, Boston, MA 02115 USA. [Patti, Mary E.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Pettus, Mark] Berkshire Med Ctr, Pittsfield, MA USA. [Saltzman, Edward] Tufts Univ New England Med Ctr, Boston, MA USA. [Thomason, Phyllis] Faulkner Hosp, Boston, MA USA. RP Apovian, CM (reprint author), Boston Univ, Med Ctr, Dept Endocrinol Diabet & Nutr, Boston, MA 02215 USA. EM caroline.apovian@bmc.org OI Apovian, Caroline/0000-0002-8029-1922 FU NIDDK NIH HHS [P30-DK-46200, P30 DK046200, P30 DK046200-17] NR 94 TC 26 Z9 26 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 871 EP 879 DI 10.1038/oby.2008.580 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800004 PM 19396065 ER PT J AU Greenberg, I Sogg, S Perna, FM AF Greenberg, Isaac Sogg, Stephanie Perna, Frank M. TI Behavioral and Psychological Care in Weight Loss Surgery: Best Practice Update SO OBESITY LA English DT Article ID QUALITY-OF-LIFE; NIGHT EATING SYNDROME; BARIATRIC SURGERY; GASTRIC BYPASS; PSYCHOSOCIAL PREDICTORS; OBESITY SURGERY; MORBID-OBESITY; MENTAL-HEALTH; CANDIDATES; DISORDERS AB The objective of this study is to update evidence-based best practice guidelines for psychological evaluation and treatment of weight loss surgery (WLS) patients. We performed a systematic search of English-language literature on WLS and mental health, quality of life, and behavior modification published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. Key words were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. Our literature search identified 17 articles of interest; 13 of the most relevant were reviewed in detail. From these, we developed evidence-based best practice recommendations on the psychological assessment and treatment of WLS patients. Regular updates of evidence-based recommendations for best practices in psychological care are required to address the impact of mental health on short- and long-term outcomes after WLS. Key factors in patient safety include comprehensive preoperative evaluation, use of appropriate and reliable evaluation instruments, and the development of short- and long-term treatment plans. C1 [Greenberg, Isaac] Tufts Sch Med, Dept Psychiat, Boston, MA USA. [Sogg, Stephanie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Weight Ctr, Boston, MA USA. [Perna, Frank M.] NCI, Hlth Promot Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Greenberg, I (reprint author), Tufts Sch Med, Dept Psychiat, Boston, MA USA. EM igreenberg@tufts-nemc.org FU NIDDK NIH HHS [P30-DK-46200] NR 40 TC 48 Z9 50 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 880 EP 884 DI 10.1038/oby.2008.571 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800005 PM 19396066 ER PT J AU Wee, CC Pratt, JS Fanelli, R Samour, PQ Trainor, LS Paasche-Orlow, MK AF Wee, Christina C. Pratt, Janey S. Fanelli, Robert Samour, Patricia Q. Trainor, Linda S. Paasche-Orlow, Michael K. TI Best Practice Updates for Informed Consent and Patient Education in Weight Loss Surgery SO OBESITY LA English DT Article ID OPEN GASTRIC BYPASS; BARIATRIC SURGERY; HEALTH LITERACY; OBESITY; RISK; METAANALYSIS; MORTALITY; PROGRAM AB To update evidence-based best practice guidelines for obtaining informed consent from weight loss surgery (WLS) patients, with an emphasis on appropriate content and communications approaches that might enhance patient understanding of the information, we performed a systematic search of English-language literature published between April 2004 and May 2007 in MEDLINE and the Cochrane database. Keywords included WLS and informed consent, comprehension, health literacy, and patient education; and WLS and outcomes, risk, patient safety management, and effectiveness. Recommendations are based on the most current literature and the consensus of the expert panel; they were graded according to systems used in established evidence-based models. We identified over 120 titles, 38 of which were reviewed in detail. Evidence suggests that WLS outcomes, including long-term rates of relapse, vary by procedure. For some weight loss surgeries, long-term outcomes may not be known. Risks also vary by patient and provider characteristics. Informed consent should incorporate realistic projections of the short- and long-term risks, benefits, and consequences of surgery, as well as alternatives to WLS. For consent to be informed, the education process should continue until the patient demonstrates comprehension of all relevant material and concepts. Confirmation of comprehension can protect patients engaged in the process of consent for WLS. Future research should focus on the outcomes and consequences of WLS, and different approaches that facilitate patient understanding of, and decision making about, WLS. C1 [Wee, Christina C.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Wee, Christina C.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Pratt, Janey S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Pratt, Janey S.] Massachusetts Gen Hosp, MGH Weight Ctr, Boston, MA 02114 USA. [Fanelli, Robert] Berkshire Med Ctr, Dept Surg, Pittsfield, MA USA. [Fanelli, Robert] Univ Massachusetts, Sch Med, Dept Surg, Pittsfield, MA USA. [Samour, Patricia Q.] Beth Israel Deaconess Med Ctr, Dept Nutr, Boston, MA 02215 USA. [Trainor, Linda S.] Beth Israel Deaconess Med Ctr, Minimally Invas Surg & Dept Surg, Boston, MA 02215 USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Wee, CC (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. EM cwee@bidmc.harvard.edu OI Paasche-Orlow, Michael/0000-0002-9276-7190 FU NIDDK NIH HHS [P30-DK-46200] NR 43 TC 18 Z9 18 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 885 EP 888 DI 10.1038/oby.2008.567 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800006 PM 19396067 ER PT J AU Schumann, R Jones, SB Cooper, B Kelley, SD Bosch, MV Ortiz, VE Connor, KA Kaufman, MD Harvey, AM Carr, DB AF Schumann, Roman Jones, Stephanie B. Cooper, Bronwyn Kelley, Scott D. Bosch, Mark Vanden Ortiz, Vilma E. Connor, Kathleen A. Kaufman, Michael D. Harvey, Alan M. Carr, Daniel B. TI Update on Best Practice Recommendations for Anesthetic Perioperative Care and Pain Management in Weight Loss Surgery, 2004-2007 SO OBESITY LA English DT Article ID MORBIDLY OBESE-PATIENTS; OBSTRUCTIVE SLEEP-APNEA; LAPAROSCOPIC GASTRIC BYPASS; END-EXPIRATORY PRESSURE; POSITIVE AIRWAY PRESSURE; BARIATRIC SURGERY; NONINVASIVE VENTILATION; ARTERIAL OXYGENATION; GENERAL-ANESTHESIA; PATIENT AB To reevaluate and update evidence-based best practice recommendations published in 2004 for anesthetic perioperative care and pain management in weight loss surgery (WLS), we performed a systematic search of English-language literature on anesthetic perioperative care and pain management in WLS published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. We identified relevant abstracts by using key words, retrieved full text articles, and stratified the resulting evidence according to systems used in established evidence-based models. We updated prior evidence-based best practice recommendations based upon interim literature. In instances of controversial or inadequate scientific evidence, the task force reached consensus recommendations following evaluation of the best available information and expert opinion. The search yielded 1,788 abstracts, with 162 potentially relevant titles; 45 were reviewed in detail. Despite more information on perioperative management of patients with obstructive sleep apnea (OSA), evidence to support preoperative testing and treatment or to guide perioperative monitoring is scarce. New evidence on appropriate intraoperative dosing of muscle relaxants allows for greater precision in their use during WLS. A novel application of alpha-2 agonists for perioperative anesthetic care is emerging. Key elements that may enhance patient safety include integration of the latest evidence on WLS, obesity, and collaborative multidisciplinary care into clinical care. However, large gaps remain in the evidence base. C1 [Schumann, Roman; Carr, Daniel B.] Tufts Univ New England Med Ctr, Dept Anesthesia, Boston, MA USA. [Jones, Stephanie B.] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA. [Cooper, Bronwyn] Univ Massachusetts, Mem Med Ctr, Dept Anesthesiol, Worcester, MA 01605 USA. [Kelley, Scott D.; Harvey, Alan M.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Bosch, Mark Vanden] Berkshire Hlth Syst, Dept Anesthesiol, Pittsfield, MA USA. [Ortiz, Vilma E.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Connor, Kathleen A.] Newton Wellesley Hosp, Dept Anesthesiol, Newton, MA USA. [Kaufman, Michael D.] Lahey Clin Fdn, Dept Anesthesiol, Burlington, MA USA. RP Schumann, R (reprint author), Tufts Univ New England Med Ctr, Dept Anesthesia, Boston, MA USA. EM rschumann@tufts-nemc.org OI Jones, Stephanie/0000-0001-8342-0374 FU NIDDK NIH HHS [P30-DK-46200] NR 52 TC 24 Z9 26 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 889 EP 894 DI 10.1038/oby.2008.569 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800007 PM 19396068 ER PT J AU Pratt, JSA Lenders, CM Dionne, EA Hoppin, AG Hsu, GLK Inge, TH Lawlor, DF Marino, MF Meyers, AF Rosenblum, JL Sanchez, VM AF Pratt, Janey S. A. Lenders, Carine M. Dionne, Emily A. Hoppin, Alison G. Hsu, George L. K. Inge, Thomas H. Lawlor, David F. Marino, Margaret F. Meyers, Alan F. Rosenblum, Jennifer L. Sanchez, Vivian M. TI Best Practice Updates for Pediatric/Adolescent Weight Loss Surgery SO OBESITY LA English DT Article ID GASTRIC-BYPASS-SURGERY; MORBIDLY OBESE ADOLESCENTS; QUALITY-OF-LIFE; LAPAROSCOPIC SLEEVE GASTRECTOMY; BARIATRIC SURGICAL-PATIENT; TYPE-2 DIABETES-MELLITUS; FATTY LIVER-DISEASE; OVERWEIGHT ADOLESCENTS; METABOLIC SYNDROME; EXTREME OBESITY AB The objective of this study is to update evidence-based best practice guidelines for pediatric/adolescent weight loss surgery (WLS). We performed a systematic search of English-language literature on WLS and pediatric, adolescent, gastric bypass, laparoscopic gastric banding, and extreme obesity published between April 2004 and May 2007 in PubMed, MEDLINE, and the Cochrane Library. Keywords were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. In light of evidence on the natural history of obesity and on outcomes of WLS in adolescents, guidelines for surgical treatment of obesity in this age group need to be updated. We recommend modification of selection criteria to include adolescents with BMI >= 35 and specific obesity-related comorbidities for which there is clear evidence of important short-term morbidity (i.e., type 2 diabetes, severe steatohepatitis, pseudotumor cerebri, and moderate-to-severe obstructive sleep apnea). In addition, WLS should be considered for adolescents with extreme obesity (BMI >= 40) and other comorbidities associated with long- term risks. We identified >1,085 papers; 186 of the most relevant were reviewed in detail. Regular updates of evidence-based recommendations for best practices in pediatric/adolescent WLS are required to address advances in technology and the growing evidence base in pediatric WLS. Key considerations in patient safety include carefully designed criteria for patient selection, multidisciplinary evaluation, choice of appropriate procedure, thorough screening and management of comorbidities, optimization of long-term compliance, and age-appropriate fully informed consent. C1 [Pratt, Janey S. A.; Lawlor, David F.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Pratt, Janey S. A.; Dionne, Emily A.; Hoppin, Alison G.; Rosenblum, Jennifer L.] Massachusetts Gen Hosp, MGH Weight Ctr, Boston, MA 02114 USA. [Lenders, Carine M.; Marino, Margaret F.; Meyers, Alan F.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Hsu, George L. K.] Tufts Univ New England Med Ctr, Dept Psychiat, Boston, MA USA. [Inge, Thomas H.] Cincinnati Childrens Hosp, Dept Pediat Surg, Cincinnati, OH USA. [Sanchez, Vivian M.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. RP Pratt, JSA (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM jpratt@partners.org OI Meyers, Alan/0000-0002-1138-0024; Sanchez, Vivian/0000-0001-5565-9687; Lawlor, Debbie A/0000-0002-6793-2262 FU NIDDK NIH HHS [P30 DK040561, P30 DK040561-14, P30 DK046200, P30 DK046200-16, P30-DK-46200, R01 DK056690] NR 89 TC 129 Z9 135 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 901 EP 910 DI 10.1038/oby.2008.577 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800009 PM 19396070 ER PT J AU Shikora, SA Kruger, RS Blackburn, GL Fallon, JA Harvey, AM Johnson, EQ Kaplan, L Mun, EC Riley, S Robinson, MK Sabin, JE Snow, RL LoNigro, R Steingisser, LJ Lautz, DB AF Shikora, Scott A. Kruger, Rayford S., Jr. Blackburn, George L. Fallon, John A. Harvey, Alan M. Johnson, Elvira Q. Kaplan, Lee Mun, Edward C. Riley, Stancel, Jr. Robinson, Malcolm K. Sabin, James E. Snow, Roger L. LoNigro, Robert Steingisser, Lee J. Lautz, David B. CA Policy Access Task Grp TI Best Practices in Policy and Access (Coding and Reimbursement) for Weight Loss Surgery SO OBESITY LA English DT Article ID EVIDENCE-BASED MEDICINE; GASTRIC BYPASS-SURGERY; BARIATRIC SURGERY; MORBID-OBESITY; CHILDHOOD OBESITY; ADOLESCENTS; MORTALITY; TRENDS; PATIENT; SAFETY AB To update evidence-based best practice guidelines for coding and reimbursement and establish policy and access standards for weight loss surgery (WLS). Systematic search of English-language literature on WLS and health-care policy, access, insurance reimbursement, coding, private payers, public policy, and mandated benefits published between April 2004 and May 2007 in MEDLINE, EMBASE, and the Cochrane Library. Use of key words to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. We identified 51 publications in our literature search; the 20 most relevant were examined in detail. These included reviews, cost-benefit analyses, and trend and cost studies from administrative databases. Literature on policy issues surrounding WLS are very sparse and largely focused on economic analyses. Reports on policy initiatives in the public and private arenas are primarily limited to narrative reviews of nonsurgical efforts to fight obesity. A substantial body of work shows that WLS improves or reverses most obesity-related comorbidities. Mounting evidence also indicates that WLS confers a significant survival advantage for those who undergo it. WLS is a viable and cost-effective treatment for an increasingly common disease, and policy decisions are more frequently being linked to incentives for national health-care goals. However, access to WLS often varies by payer and region. Currently, there are no uniform criteria for determining patient appropriateness for surgery. C1 [Shikora, Scott A.] Tufts Med Ctr, Boston, MA USA. [Kruger, Rayford S., Jr.] Tobey Hosp, Wareham, MA USA. [Blackburn, George L.; Mun, Edward C.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fallon, John A.; Steingisser, Lee J.] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. [Harvey, Alan M.; Robinson, Malcolm K.; Lautz, David B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Johnson, Elvira Q.] Massachusetts Dietet Assoc, Reading, MA USA. [Kaplan, Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Riley, Stancel, Jr.] Board Registrat Med, Boston, MA USA. [Sabin, James E.] Harvard Pilgrim Hlth Care, Wellesley, MA USA. [Snow, Roger L.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Snow, Roger L.] MassHealth, Boston, MA USA. [LoNigro, Robert] Tufts Associated Hlth Plan, Watertown, MA USA. RP Shikora, SA (reprint author), Tufts Med Ctr, Boston, MA USA. EM Sshikora@tuftsmedicalcenter.org FU NIDDK NIH HHS [P30-DK-46200] NR 49 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 918 EP 923 DI 10.1038/oby.2008.573 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800011 PM 19396072 ER PT J AU Hutter, MM Jones, DB Riley, SM Snow, RL Cella, RJ Schneider, BE Clancy, KA AF Hutter, Matthew M. Jones, Daniel B. Riley, Stancel M., Jr. Snow, Roger L. Cella, Robert J. Schneider, Benjamin E. Clancy, Kerri A. TI Best Practice Updates for Weight Loss Surgery Data Collection SO OBESITY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; BARIATRIC SURGICAL-PROCEDURES; ADULT CARDIAC-SURGERY; PATIENT-SAFETY; VETERANS-AFFAIRS; GASTRIC BYPASS; MORBID-OBESITY; COST-EFFECTIVENESS; OUTCOMES; MORTALITY AB To update evidence-based best practice guidelines for collection of data on weight loss surgery (WLS). Systematic search of English-language literature in MEDLINE and the Cochrane Library on WLS and data collection, registries, risk adjustment, accreditation, benchmarks, and administrative and outcomes databases published between April 2004 and May 2007. Use of key words to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. During our search, we identified 212 papers; the 63 most relevant were reviewed in detail. Most data collection on WLS has relied on administrative data sets, single-institution studies, and other sources that are not WLS specific. A six-center, nationwide study involving data collection has been started by the longitudinal assessment of bariatric surgery, but results are not yet available. Two WLS-specific, longitudinal, national data collection systems are about to be implemented. Key factors in patient safety include data collection for all weight loss procedures; prospective, risk-adjusted, universal, benchmarked, longitudinal data collection systems; and use of WLS-specific data points that track clinical effectiveness and complications following WLS. Data collection will need to include assessments of novel therapies and specific subgroups (e.g., adolescents, the elderly, and individuals who are at the greatest risk or have the most to gain from WLS). Quality indicators, including metrics on processes of care and determination of outliers, need to be established and monitored to advance patient safety and quality improvement. C1 [Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Jones, Daniel B.; Schneider, Benjamin E.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Riley, Stancel M., Jr.] Massachusetts Board Registrat Med, Boston, MA USA. [Snow, Roger L.] Massachusetts Medicaid, Boston, MA USA. [Cella, Robert J.] Berkshire Med Ctr, Dept Med, Pittsfield, MA USA. [Clancy, Kerri A.] Brigham & Womens Hosp, Dept Nursing, Boston, MA 02115 USA. RP Hutter, MM (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM mhutter@partners.org FU NIDDK NIH HHS [P30-DK-46200] NR 56 TC 8 Z9 8 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 924 EP 928 DI 10.1038/oby.2008.568 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800012 PM 19396073 ER PT J AU Ellsmere, JC Thompson, CC Brugge, WR Chuttani, R Desilets, DJ Rattner, DW Tarnoff, ME Kaplan, LM AF Ellsmere, James C. Thompson, Christopher C. Brugge, William R. Chuttani, Ram Desilets, David J. Rattner, David W. Tarnoff, Michael E. Kaplan, Lee M. TI Endoscopic Interventions for Weight Loss Surgery SO OBESITY LA English DT Article ID Y GASTRIC BYPASS; MORBIDLY OBESE-PATIENTS; BARIATRIC SURGERY; INTRAGASTRIC BALLOON; TRANSORAL GASTROPLASTY; BOTULINUM TOXIN; DOUBLE-BLIND; REDUCTION; ENDOTHERAPY; MANAGEMENT AB In this paper we review the state-of-the-art in endoscopic interventions for obesity treatment and make best practice recommendations for weight loss surgery (WLS). We performed a systematic search of English-language literature published between April 2004 and June 2008 in MEDLINE and the Cochrane Library on WLS and endoscopic interventions, endoscopically placed devices, minimally invasive surgery, image-guided surgery, endoluminal surgery, endoscopic instrumentation, interventional gastroenterology, transluminal surgery, and natural orifice transluminal surgery. We also searched the literature on endoscopic interventions and WLS and patient safety. We identified 36 pertinent articles, all of which were reviewed in detail; assessed the current science in endoscopic interventions for WLS; and made best practice recommendations based on the latest available evidence. Our findings indicate that endoscopic interventions and endoscopically placed devices may provide valuable approaches to the management of WLS complications and the primary management of obesity. Given the rapid changes in endoscopic technologies and techniques, systematic literature review is required to address issues related to the emerging role of endoluminal surgery in the treatment of obesity. These interventions should be a high priority for development and investigation. C1 [Ellsmere, James C.] Beth Israel Deaconess Med Ctr, Dept Surg, Sect Minimally Invas Surg, Boston, MA 02215 USA. [Thompson, Christopher C.] Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA. [Brugge, William R.; Rattner, David W.; Kaplan, Lee M.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA. [Chuttani, Ram] Beth Israel Deaconess Med Ctr, Dept Med, Div Gastroenterol, Boston, MA 02215 USA. [Desilets, David J.] Baystate Med Ctr, Dept Med, Div Gastroenterol, Springfield, MA 01199 USA. [Tarnoff, Michael E.] Tufts Med Ctr, Dept Surg, Div Minimally Invas Surg, Boston, MA USA. RP Ellsmere, JC (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, Sect Minimally Invas Surg, 330 Brookline Ave, Boston, MA 02215 USA. EM jellsmer@bidmc.harvard.edu FU NIDDK NIH HHS [P30-DK-46200] NR 37 TC 14 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2009 VL 17 IS 5 BP 929 EP 933 DI 10.1038/oby.2008.588 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 440OO UT WOS:000265709800013 PM 19396074 ER PT J AU Bautista, LE Casas, JP Herrera, VM Miranda, JJ Perel, P Pichardo, R Gonzalez, A Sanchez, JR Ferreccio, C Aguilera, X Silva, E Orostegui, M Gomez, LF Chirinos, JA Medina-Lezama, J Perez, CM Suarez, E Ortiz, AP Rosero, L Schapochnik, N Ortiz, Z Ferrante, D AF Bautista, L. E. Casas, J. P. Herrera, V. M. Miranda, J. J. Perel, P. Pichardo, R. Gonzalez, A. Sanchez, J. R. Ferreccio, C. Aguilera, X. Silva, E. Orostegui, M. Gomez, L. F. Chirinos, J. A. Medina-Lezama, J. Perez, C. M. Suarez, E. Ortiz, A. P. Rosero, L. Schapochnik, N. Ortiz, Z. Ferrante, D. CA Investigators Latin-American TI The Latin American Consortium of Studies in Obesity (LASO) SO OBESITY REVIEWS LA English DT Review DE Consortium; health surveys; Latin America; obesity; risk factors ID CORONARY-HEART-DISEASE; RISK-FACTORS; METABOLIC SYNDROME; NUTRITION TRANSITION; CARDIOVASCULAR RISK; DEVELOPING-WORLD; PREVALENCE; DETERMINANTS; PREDICTION; EXPERIENCE AB Current, high-quality data are needed to evaluate the health impact of the epidemic of obesity in Latin America. The Latin American Consortium of Studies of Obesity (LASO) has been established, with the objectives of (i) Accurately estimating the prevalence of obesity and its distribution by sociodemographic characteristics; (ii) Identifying ethnic, socioeconomic and behavioural determinants of obesity; (iii) Estimating the association between various anthropometric indicators or obesity and major cardiovascular risk factors and (iv) Quantifying the validity of standard definitions of the various indexes of obesity in Latin American population. To achieve these objectives, LASO makes use of individual data from existing studies. To date, the LASO consortium includes data from 11 studies from eight countries (Argentina, Chile, Colombia, Costa Rica, Dominican Republic, Peru, Puerto Rico and Venezuela), including a total of 32 462 subjects. This article describes the overall organization of LASO, the individual studies involved and the overall strategy for data analysis. LASO will foster the development of collaborative obesity research among Latin American investigators. More important, results from LASO will be instrumental to inform health policies aiming to curtail the epidemic of obesity in the region. C1 [Bautista, L. E.; Herrera, V. M.] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Pichardo, R.; Gonzalez, A.] Inst Dominicano Cardiol, Santo Domingo, Dominican Rep. [Sanchez, J. R.] Inst nacl Salud, Ctr Nacl Alimentac & Nutr, Lima, Peru. [Ferreccio, C.] Pontificia Univ Catolica Chile, Dept Salud Publ, Santiago, Chile. [Aguilera, X.] Ministerio Salud Chile, Santiago, Chile. [Silva, E.] Univ Zulia, Fac Med, Inst Invest & Estudios Enfermedades Cardiovasc, Maracaibo 4011, Venezuela. [Orostegui, M.] Univ Ind Santander, Epidemiol Res Ctr, Cardiovasc Dis Epidemiol Observ, Bucaramanga, Colombia. [Gomez, L. F.] Fdn FES Social, Hlth Div, Bogota, Colombia. [Chirinos, J. A.] Univ Penn, Sch Med, Div Cardiol, Philadelphia, PA 19104 USA. [Medina-Lezama, J.] Santa Maria Catholic Univ, Arequipa, Peru. [Perez, C. M.; Suarez, E.; Ortiz, A. P.] Univ Puerto Rico, Dept Biostat & Epidemiol, Grad Sch Publ Hlth, San Juan, PR 00936 USA. [Rosero, L.] Univ Costa Rica, Ctr Ctr Amer Poblac, San Jose, Costa Rica. [Schapochnik, N.] Ministerio Salud Prov Tierra Fuego, Ushuaia, Argentina. [Ortiz, Z.] Acad Nacl Med Buenos Aires, Inst Invest Epidemiol, Buenos Aires, DF, Argentina. [Ferrante, D.] Ministerio Salud & Ambiente, Buenos Aires, DF, Argentina. [Casas, J. P.; Miranda, J. J.; Perel, P.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Chirinos, J. A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Medina-Lezama, J.] Santa Maria Res Inst, Arequipa, Peru. RP Bautista, LE (reprint author), Univ Wisconsin, Dept Populat Hlth Sci, 610 Walnut St,703 WARF, Madison, WI 53726 USA. EM lebautista@wisc.edu RI Herrera, Victor/C-5602-2008; Miranda, J. Jaime/A-8482-2008; Aguilera, Ximena/D-9861-2014 OI Miranda, J. Jaime/0000-0002-4738-5468; Aguilera, Ximena/0000-0002-8153-6733 FU Ministerio de Salud de la Republica Argentina; Gobierno de la Provincia de Tierra del Fuego; Antartida e Islas del Atlantico Sur, Argentina; Ministerio de Salud, Chile; Secretaria Distrital de Salud de Bogota, Colombia; Secretaria de Salud Municipal de Bucaramanga; Secretaria Departamental de Salud de Santander, Colombia; Wellcome Trust Foundation [072406, GR074833MA]; Sociedad Dominicana de Cardiologia; Brystol Myers Squibb; Warners Lambert (Pfizer); Novartis; Merck Sharp Dohme and Magnachen International; Instituto Nacional de Salud, Lima, Peru; Instituto de Investigacion Santa Maria; Merck Sharp & Dohme Corporation; National Institutes of Health/National Center for Research Resources (NCRR/NIH) [G12RR03051, \P20RR011126]; Fondo Nacional de Ciencia, Tecnologia e Innovacion (FONACIT); Fundacion Venezolana de Hipertension Arterial (FUNDAHIPERTENSION) FX The 'Prueba de Validacion de la Encuesta Nacional de Factores de Riesgo' was funded by the Ministerio de Salud de la Republica Argentina and the Gobierno de la Provincia de Tierra del Fuego, Antartida e Islas del Atlantico Sur, Argentina. The 'Encuesta Nacional de Factores de Riesgo' was funded by the Ministerio de Salud de la Republica Argentina. The 'Encuesta Nacional de Salud 2003' was funded by the Ministerio de Salud, Chile. The 'Estudio CARMEN Santa Fe' was funded by the Secretaria Distrital de Salud de Bogota, Colombia. CARMEN-Bucaramanga was funded by the Secretaria de Salud Municipal de Bucaramanga and the Secretaria Departamental de Salud de Santander, Colombia. The 'Costa Rica: Estudio de Longevidad y Envejecimeinto Saludable (CRELES)' was funded by The Wellcome Trust Foundation, grant number 072406. The 'Estudio de Factores de Riesgo Cardiovascular en la Republica Dominicana (EFRICARD)' was funded by the Sociedad Dominicana de Cardiologia, Brystol Myers Squibb, Warners Lambert (Pfizer), Novartis, Merck Sharp Dohme and Magnachen International. The 'Encuesta Nacional de Indicadores Nutricionales, Bioquimicos, Socioeconomicos y Culturales Relacionados con las Enfermedades Cronico Degenerativas (ENINBSC-ECNT)' was funded by the Instituto Nacional de Salud, Lima, Peru. JJM and the 'PERU MIGRANT study' were supported by a Wellcome Trust Research Training Fellowship (GR074833MA). The study 'Prevalencia de Enfermedades Cardiovasculares y Factores de Riesgo Coronario en Arequipa (PREVENCION)' was partially supported by the Instituto de Investigacion Santa Maria. The study of the 'Prevalence of Metabolic Syndrome and its Individual Components in the adult population of the San Juan Metropolitan Area in Puerto Rico' was funded by an unrestricted grant from Merck Sharp & Dohme Corporation with additional support from the National Institutes of Health/National Center for Research Resources (NCRR/NIH) grant awards G12RR03051 and P20RR011126. The Zulia Coronary Heart Disease Risk Factor Study was funded by the Fondo Nacional de Ciencia, Tecnologia e Innovacion (FONACIT) and the Fundacion Venezolana de Hipertension Arterial (FUNDAHIPERTENSION). NR 44 TC 18 Z9 21 U1 3 U2 11 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1467-7881 J9 OBES REV JI Obes. Rev. PD MAY PY 2009 VL 10 IS 3 BP 364 EP 370 DI 10.1111/j.1467-789X.2009.00591.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 437UB UT WOS:000265511300015 PM 19438980 ER PT J AU Growdon, WB Wolfberg, AJ Goldstein, DP Feltmate, CM Chinchilla, ME Lieberman, ES Berkowitz, RS AF Growdon, Whitfield B. Wolfberg, Adam J. Goldstein, Donald P. Feltmate, Colleen M. Chinchilla, Manuel E. Lieberman, Ellice S. Berkowitz, Ross S. TI Evaluating Methotrexate Treatment in Patients With Low-Risk Postmolar Gestational Trophoblastic Neoplasia SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB The response of low-risk persistent gestational trophoblastic neoplasia (GTN) to methotrexate (MTX) monotherapy is close to 100%. With use of various MTX regimens, 48%-92% of patients go into remission. There is limited data on potential clinical risk factors indicating the need for additional courses of MTX or alternative chemotherapy following an initial course of MTX. This retrospective observational study identified possible clinical factors predictive of the requirement for additional MTX or alternative chemotherapy to obtain a remission in patients with postmolar low-risk GTN who had received MTX initially. Data was analyzed for 1801 women diagnosed with molar pregnancies between 1973 and 2003. Of the 150 women in the final study population, 110 had been diagnosed as complete mole and 40 as partial mole, and all had received MTX as initial therapy for GTN. All women had low-risk disease according to the combined International Federation of Obstetrics and Gynecology (FIGO) stage and the World Health Organization prognostic scores. Remission was defined as achievement and maintenance of undetectable serum beta human chorionic gonadotropin (beta-hCG) levels for 1 year. All 150 patients ultimately achieved remission. Of the 70 women (47%) requiring additional courses of chemotherapy including MTX, 45 (64%) required alternative chemotherapy. Multivariate analysis showed that independent prognostic factors predicting increased risk of requiring additional MTX or alternative chemotherapy were complete mole histology, presence of metastasis, single day MTX infusion and any increase in beta-hCG levels 1 week after MTX therapy. Dilatation and curettage within 1 week after the diagnosis of persistence was not an independent risk factor for additional or alternative chemotherapy. For GTN following complete mole, beta-hCG levels >= 2000 mIU/ml at 1 week post-MTX were associated with an 89% risk of requiring additional MTX chemotherapy and a 64% risk of alternative chemotherapy to achieve remission. These data identify several independent risk factors that predispose women with low-risk GTN to require additional MTX cycles and alternative chemotherapy after initial MTX. C1 [Growdon, Whitfield B.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. Donald P Goldstein MD Tumor Registry, New England Trophoblast Dis Ctr, Boston, MA USA. Harvard Univ, Dana Farber Canc Inst, Ctr Canc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Growdon, WB (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAY PY 2009 VL 64 IS 5 BP 308 EP 309 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 438OY UT WOS:000265566200014 ER PT J AU Christo, K Cord, J Mendes, N Miller, KK Goldstein, MA Klibanski, A Misra, M AF Christo, Karla Cord, Jennalee Mendes, Nara Miller, Karen K. Goldstein, Mark A. Klibanski, Anne Misra, Madhusmita TI Acylated Ghrelin and Leptin in Adolescent Athletes With Amenorrhea, Eumenorrheic Athletes and Controls: A Cross-Sectional Study SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Previous reports suggest that adolescent endurance athletes such as gymnasts and swimmers may be at higher risk of amenorrhea (AA) than other adolescent athletes. Neuroendocrine factors that differentiate athletes with AA from eumenorrheic athletes (EA) have been investigated but are not completely understood. Two neuroendocrine peptides, leptin and ghrelin, appear to be involved in regulation of the hypothalamo-pituitary-gonadal axis. Low leptin levels and high ghrelin levels have been implicated in the occurrence of amenorrhea in adult athletes. The investigators hypothesized that blood levels of leptin and/or ghrelin could predict levels of gonadal steroids in adolescent athletes and identify which will develop ammenorhea. This cross-sectional study compared the levels of leptin, ghrelin, and gonadal steroids among adolescent athletes with AA, EA, and nonathletic controls at a large urban hospital. The study enrolled 58 adolescent girls, 12-18 years old, including 21 AA, 19 EA and 18 nonathletic controls. There was no history of amenorrhea or menarchal delay in the nonathletic controls. Active ghrelin, leptin, estrogen (E(2)), and testosterone were measured in fasting blood. The body mass index (BMI) in AA was significantly lower than among EA and controls at baseline (P = 0.003). Log active ghrelin levels were significantly higher in AA compared to the other two groups (P < 0.0001); the difference was maintained after controlling for BMI Z-scores (P = 0.0007). Leptin levels were lower in AA compared to the other two groups (P < 0.0001), but did not remain significant after controlling for BMI Z-scores. Total testosterone levels were lower among AA compared to the EA and controls (P = 0.002), and the differences remained significant after controlling for BMI Z-scores (P = 0.03. There was a significant trend for lower E(2) scores among AA than the EA (P = 0.07), but the effect was not significant after controlling for BMI Z-scores. Inverse associations of log active ghrelin with testosterone were noted (P = 0.05), whereas there were positive associations of leptin with testosterone (P = 0.05) and log E(2) (P = 0.01). These data show that ghrelin and leptin are independent predictors of levels of gonadal steroids. The investigators conclude from these findings that lower leptin levels and especially higher ghrelin levels may predict which athletes will develop amenorrhea. C1 [Christo, Karla] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp Children, Adolescent Med Unit, Boston, MA USA. Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. RP Christo, K (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RI Mendes Estella, Nara/E-4682-2013 NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAY PY 2009 VL 64 IS 5 BP 313 EP 314 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 438OY UT WOS:000265566200017 ER PT J AU Subak, LL Wing, R West, DS Franklin, F Vittinghoff, E Creasman, JM Richter, HE Myers, D Burgio, KL Gorin, AA Macer, J Kusek, JW Grady, D Investigators, P AF Subak, Leslee L. Wing, Rena West, Delia Smith Franklin, Frank Vittinghoff, Eric Creasman, Jennifer M. Richter, Hotly E. Myers, Deborah Burgio, Kathryn L. Gorin, Amy A. Macer, Judith Kusek, John W. Grady, Deborah Investigators, P. R. I. D. E. TI Weight Loss to Treat Urinary Incontinence in Overweight and Obese Women SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Obesity is a strong risk factor for urinary incontinence. Although marked weight loss after bariatric surgery in morbidly obese women was associated in previous studies with a reduction in urinary incontinence, the overall evidence for a benefit of weight loss in obese women is inconclusive. In this randomized clinical trial, the Program to Reduce Incontinence by Diet and Exercise, the potential benefits of a behavioral weight-reduction intervention were compared with a structured educational program in 338 overweight and obese women with at least 10 urinary incontinence episodes per week. The study subjects were randomized to receive either an intensive 6-month weight-loss program that included diet, exercise, and behavior modification (intervention group, n = 226) or a structured education program consisting of general information about healthy eating, physical activity, and weight loss (control group, n = 112). The mean (+/- SD) age of the study subjects was 53 +/- 11 years. Body-mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. The primary study outcome was the change in the total number of self-reported incontinence episodes of any type (including stress and urge incontinence) recorded in a 7-day voiding diary at 6 months after randomization. At baseline, the mean BMI and the total number of incontinence episodes per week were the same in the intervention and control groups (BMI, 36 6 vs. 36 5, respectively; incontinence episodes, 24 18 vs. 24 16, respectively). At 6 months, the mean weight loss among women in the intervention group was 8.0% (7.8 kg), whereas the mean weight loss among women in the control group was 1.6% (1.5 kg) (P < .001). There was a greater decrease in total number of incontinence episodes per week in the intervention group at 6 months compared with the control group (intervention: 47.4% vs. control: 28.1%, P = 0.01). The frequency of stress incontinence episodes was reduced more in the intervention group (57.6%) than the control group (32.7%, P = 0.02). The frequency of episodes of urge incontinence was also decreased more in the intervention group (42.4% vs. 26.0%), but the difference was not statistically significant (P = 0.14). In comparison with the control group, a higher proportion of women in the intervention group reported a clinically meaningful reduction of at least 70% in the total weekly number of episodes of any type of incontinence (P < 0.001), stress-incontinence (P = 0.009), and urge-incontinence (P = 0.04). The investigators conclude from these findings that weight loss should be considered as a first-line treatment in overweight and obese women with incontinence. C1 [Subak, Leslee L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. Miriam Hosp, Providence, RI 02906 USA. Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. Univ Arkansas Med Sci, Coll Publ Hlth, Little Rock, AR 72205 USA. Univ Alabama, Birmingham, AL USA. Ctr Geriatr Res Educ & Clin, Dept Vet Affairs, Birmingham, AL USA. Univ Connecticut, Storrs, CT USA. NIDDK, Bethesda, MD USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Subak, LL (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAY PY 2009 VL 64 IS 5 BP 317 EP 318 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 438OY UT WOS:000265566200019 ER PT J AU Ruddy, KJ Partridge, AH AF Ruddy, Kathryn J. Partridge, Ann H. TI Breast Cancer in Young Women: Clinical Decision-Making in the Face of Uncertainty The Peppercorn Article Reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 [Ruddy, Kathryn J.; Partridge, Ann H.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ruddy, KJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 6 Z9 6 U1 1 U2 1 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAY PY 2009 VL 23 IS 6 BP 474 EP 477 PG 2 WC Oncology SC Oncology GA V18PP UT WOS:000208017000002 PM 19544686 ER PT J AU Jakobiec, FA Hanna, E Townsend, DJ AF Jakobiec, Frederick A. Hanna, Eissa Townsend, Daniel J. TI Basal Cell Carcinoma of the Eyelid With Exceptional Histomorphologic Expressions SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID MICROCYSTIC ADNEXAL CARCINOMA AB A basal cell carcinoma of the eyelid had unique and potentially confusing histopathologic features. The tumor displayed a carcinoma in situ pattern with replacement of an extensive segment of the tarsal epithelium by neoplastic basaloid cells, a finding to the best of the authors' knowledge that has not been previously documented. Within the infiltrating component of the dermis were classical solid basaloid nests and lobules; they were accompanied, however, by a separate and exceptionally prominent component of duct-like (pseudoglandular) units mimicking a microcystic adnexal carcinoma. C1 [Jakobiec, Frederick A.; Hanna, Eissa; Townsend, Daniel J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol,Dept Ophthamol, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol,Dept Ophthamol, 243 Charles St, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 6 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAY-JUN PY 2009 VL 25 IS 3 BP 232 EP 234 DI 10.1097/IOP.0b013e3181a33887 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 449EP UT WOS:000266313900018 PM 19454940 ER PT J AU Halpin, C Rauch, SD AF Halpin, Chris Rauch, Steven D. TI Hearing aids and cochlear damage: The case against fitting the pure tone audiogram SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Editorial Material AB Here we propose a different approach to hearing aids, an approach that flows logically from the pathophysiology of cochlear disorders. This approach challenges some central tenets of the industry by 1) suggesting that many, if not most, cases would be better served by flat, undistored gain across all frequencies rather than by "fitting" gain to the audiogram; and 2) suggesting that most of the improvements in hearing aid technology are targeted at reducing patient complaints as opposed to increasing measurable word recognition performance. We recommend that it is better to accommodate the damaged cochlea in these cases than to attempt to reverse-engineer the audiometric test results. (C) 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Halpin, Chris] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Halpin, Chris; Rauch, Steven D.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Halpin, C (reprint author), Massachusetts Eye & Ear Infirm, Dept Audiol, 243 Charles St, Boston, MA 02114 USA. EM cfhalpin@meei.harvard.edu NR 8 TC 4 Z9 4 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAY PY 2009 VL 140 IS 5 BP 629 EP 632 DI 10.1016/j.otohns.2008.12.020 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 441ZZ UT WOS:000265810700004 PM 19393401 ER PT J AU Chen, L Malarick, C Seefeld, L Wang, SX Houghton, M Mao, JR AF Chen, Lucy Malarick, Charlene Seefeld, Lindsey Wang, Shuxing Houghton, Mary Mao, Jianren TI Altered quantitative sensory testing outcome in subjects with opioid therapy SO PAIN LA English DT Article DE Opioid-induced hyperalgesia; Opioid therapy; Clinical pain; Quantitative sensory testing ID SHORT-TERM INFUSION; SMALL-DOSE KETAMINE; INDUCED HYPERALGESIA; WITHDRAWAL HYPERALGESIA; MORPHINE-TOLERANCE; PHYSICAL-DEPENDENCE; CHRONIC PAIN; REMIFENTANIL; HUMANS; RATS AB Preclinical studies have suggested that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred as opioid-induced hyperalgesia (OIH). While OIH may have implications in acute and chronic pain management, its clinical features remain unclear. Using an office-based quantitative sensory testing (QST) method, we compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects; those with neither pain nor opioid therapy (group 1), with chronic pain but without opioid therapy (group 2), and with both chronic pain and opioid therapy (group 3). We also examined the possible correlation between QST responses to thermal stimulation and opioid dose, opioid treatment duration, opioid analgesic type, pain duration, or gender in group 3 subjects. As compared with both group 1 (n = 41) and group 2 (n = 41) subjects, group 3 subjects (n = 58) displayed a decreased heat pain threshold and exacerbated temporal summation of the second pain to thermal stimulation. In contrast, there were no differences in cold or warm sensation among three groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of the second pain in group 3 subjects. These results indicate that decreased hear pain threshold and exacerbated temporal summation of the second pain may be characteristic QST changes in subjects with opioid therapy. The data suggest that QST may be a useful tool in the clinical assessment of OIH. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Chen, Lucy; Malarick, Charlene; Seefeld, Lindsey; Wang, Shuxing; Houghton, Mary; Mao, Jianren] Harvard Univ, Sch Med,Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res, Boston, MA 02114 USA. RP Mao, JR (reprint author), Harvard Univ, Sch Med,Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res, Boston, MA 02114 USA. EM jmao@partners.org FU NIH [DA22576] FX This Study is supported by NIH RO1 Grant DA22576 (J.M.). We would like to thank Drs. James Rathmell, Gary Brenner, Milan Stojanovic, Shihab Ahmed, Padma Gulur, and Gary Polykoff and Tina Toland, B.A., M.H.A. of the Massachusetts General Hospital Center for Pain Medicine for their help in the Subject recruitment. NR 39 TC 65 Z9 66 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD MAY PY 2009 VL 143 IS 1-2 BP 65 EP 70 DI 10.1016/j.pain.2009.01.022 PG 6 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 441PH UT WOS:000265780600012 PM 19237249 ER PT J AU Morone, NE Karp, JF Lynch, CS Bost, JE El Khoudary, SR Weiner, DK AF Morone, Natalia E. Karp, Jordan F. Lynch, Cheryl S. Bost, James E. El Khoudary, Samar R. Weiner, Debra K. TI Impact of Chronic Musculoskeletal Pathology on Older Adults: A Study of Differences between Knee OA and Low Back Pain SO PAIN MEDICINE LA English DT Article DE Low Back Pain; Knee Pain; Physical Function; Psychosocial Factors ID PHYSICAL PERFORMANCE BATTERY; LOWER-EXTREMITY FUNCTION; SELF-RATED HEALTH; GAIT SPEED; PSYCHOLOGICAL-FACTORS; BODY-COMPOSITION; EFFICACY; DISABILITY; DEPRESSION; COMMUNITY AB The study aimed to compare the psychological and physical characteristics of older adults with knee osteoarthritis (OA) vs those of adults with chronic low back pain (CLBP) and to identify psychological and physical predictors of function as measured by gait speed. Secondary data analysis. Eighty-eight older adults with advanced knee OA and 200 with CLBP who had participated in separate randomized controlled trials were selected for this study. Inclusion criteria for both trials included age >= 65 and pain of at least moderate intensity that occurred daily or almost every day for at least the previous 3 months. Psychological constructs (catastrophizing, fear avoidance, self-efficacy, depression, affective distress) and physical measures (comorbid medical conditions, pain duration, pain severity, pain related interference, self-rated health) were obtained. Subjects with CLBP had slower gait (0.88 m/s vs 0.96 m/s, P = 0.002) and more comorbid conditions than subjects with knee pain (mean 3.36 vs 1.97, P < 0.001). All the psychological measures were significantly worse in the CLBP group except the Multidimensional Pain Inventory-Affective Distress score. Self-efficacy, pain severity, and medical comorbidity burden were associated with slower gait regardless of the location of the pain. Older adults with chronic pain may have distinct psychological and physical profiles that differentially impact gait speed. These findings suggest that not all pain conditions are the same in their psychological and physical characteristics and may need to be taken into consideration when developing treatment plans. C1 [Morone, Natalia E.; Lynch, Cheryl S.; Bost, James E.; El Khoudary, Samar R.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. [Karp, Jordan F.] Univ Pittsburgh, Dept Psychiat, Div Geriatr Med, Pittsburgh, PA USA. [Karp, Jordan F.; Weiner, Debra K.] Univ Pittsburgh, Dept Anesthesiol, Div Geriatr Med, Pittsburgh, PA USA. [Lynch, Cheryl S.; Weiner, Debra K.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. [El Khoudary, Samar R.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Morone, NE (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM moronene@upmc.edu OI El Khoudary Abushaban, Samar/0000-0003-2913-0821 FU National Center for Complementary and Alternative Medicine [R01AG018299, R21AG24288]; National Institute on Aging, National Institutes of Health; NIH Roadmap Multidisciplinary Clinical Research Career Development Award [1KL2RR024154-03, UL1RR024153, AG 021885-05]; National Center for Research Resources (NCRR) FX This research was supported by research grants (R01AG018299, R21AG24288) from the National Center for Complementary and Alternative Medicine and the National Institute on Aging, National Institutes of Health. During the time of this work, Drs. Morone and Karp were funded by the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (1KL2RR024154-03) from the NIH. This publication was also made possible by Grant Number UL1RR024153 from the National Center for Research Resources (NCRR), a component of the NIH and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Dr. Lynch was supported by grant T32 AG 021885-05 from the NIH. NR 41 TC 18 Z9 18 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD MAY-JUN PY 2009 VL 10 IS 4 BP 693 EP 701 DI 10.1111/j.1526-4637.2009.00565.x PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 454JQ UT WOS:000266678600014 PM 19254337 ER PT J AU Manchikanti, L Derby, R Wolfer, L Singh, V Datta, S Hirsch, JA AF Manchikanti, Laxmaiah Derby, Richard Wolfer, Lee Singh, Vijay Datta, Sukdeb Hirsch, Joshua A. TI Evidence-Based Medicine, Systematic Reviews, and Guidelines in Interventional Pain Management: Part 5. Diagnostic Accuracy Studies SO PAIN PHYSICIAN LA English DT Review DE Evidence-based medicine; diagnostic studies; systematic reviews; randomized trials; interventional pain management; standards for the reporting of diagnostic accuracy studies (STARD) ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; ZYGAPOPHYSIAL JOINT PAIN; RANDOMIZED CONTROLLED-TRIALS; MEDIAL BRANCH BLOCKS; CHRONIC SPINAL PAIN; LOCAL-ANESTHETIC BLOCKS; OPERATING CHARACTERISTIC CURVES; PRESSURE-CONTROLLED DISCOGRAPHY; PERIPHERAL ARTERIAL-DISEASE AB Diagnosis is a critical component of health care. The world of diagnostic tests is highly dynamic. New tests are developed at a fast pace and technology of existing tests is continuously being improved. However, clinicians, policy makers, and patients routinely face a range of questions regarding diagnostic tests. Well designed diagnostic test accuracy studies can help in making these decisions, provided that they transparently and fully report their participants, tests, methods, and results (as facilitated). For example, by the standards for the reporting of diagnostic accuracy studies (STARD) statement. Exaggerated and biased results from poorly designed and reported diagnostic test studies can trigger their premature dissemination and lead physicians into making in a diagnostic test is useful only to the extent that it correct treatment decisions. Thus, distinguishes between conditions or disorders that might otherwise be confused. While almost any test can differentiate healthy persons from severely affected ones, appropriate diagnostic tests should differentiate mild and moderate forms of disease. Shortcomings in a study design and interpretation can affect estimates of diagnostic accuracy. Thus, quality diagnostic studies are essential in medicine in general and interventional pain management in particular. The STARD initiative was developed to improve the accuracy and completeness in the reporting of studies of diagnostic accuracy and provide guidance to assist in reducing the potential for bias in the study and to evaluate a study's generalizability. In the practice of interventional pain management, in addition to diagnostic tests which include laboratory tests, imaging tests, and physical examination, diagnostic interventional techniques are crucial. Interventional techniques as a diagnostic tool in painful conditions is important due to multiple challenging clinical situations, which include the purely subjective nature of pain and underdetermined and uncertain pathophysiology in most painful spinal conditions. Precision diagnostic blocks are used to clarify these challenging clinical situations in order to determine the pathophysiology of clinical pain, the site of nociception, and the pathway of afferent neural signals. Part 5 of evidence-based medicine (EBM) in interventional pain management describes the various aspects of diagnostic accuracy studies. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Derby, Richard; Wolfer, Lee] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Datta, Sukdeb] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 234 TC 47 Z9 47 U1 0 U2 5 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAY-JUN PY 2009 VL 12 IS 3 BP 517 EP 540 PG 24 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 455NF UT WOS:000266766800007 PM 19461821 ER PT J AU Manchikanti, L Derby, R Benyamin, RM Helm, S Hirsch, JA AF Manchikanti, Laxmaiah Derby, Richard Benyamin, Ramsin M. Helm, Standiford Hirsch, Joshua A. TI A Systematic Review of Mechanical Lumbar Disc Decompression with Nucleoplasty SO PAIN PHYSICIAN LA English DT Review DE Intervertebral disc disease; chronic low back pain; disc herniation; disc protrusion; radiculitis; contained disc herniation; mechanical disc decompression; nucleoplasty; coblation technology; nucleotomy ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; EVIDENCE-BASED MEDICINE; FACET JOINT INTERVENTIONS; BLIND CONTROLLED-TRIAL; MANAGING CHRONIC PAIN; MEDIAL BRANCH BLOCKS; EQUIVALENCE TRIAL; SURGERY SYNDROME; FOLLOW-UP AB Background: Lumbar disc prolapse, protrusion, or extrusion account for less than 5% of all low problems but are the most common causes of nerve root pain and surgical interventions., The primary rationale for any form of surgery for disc prolapse is to relieve nerve root irritation or compression due to herniated disc material. The primary modality of treatment continues to be either open or microdiscectomy, but several alternative techniques including nucleoplasty, automated percutaneous discectomy, and laser discectomy have been described. There is a paucity of evidence for all decompression techniques, specifically alternative techniques including nucleoplasty. Study Design: A systematic review of the literature. Objective: To determine the effectiveness of mechanical lumbar disc decompression with nucleoplasty. Methods: A comprehensive evaluation of the literature relating to mechanical lumbar disc decompression with nucleoplasty was performed. The literature was evaluated according to Cochrane review criteria for randomized controlled trials (RCTs), and Agency for Healthcare Research and Quality (AHRQ) criteria was utilized for observational studies. The level of evidence was classified as Level I, II, or III with 3 subcategories in Level II based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). A literature search was conducted using only English language literature through PubMed, EMBASE, the Cochrane library, systematic reviews, and cross-references from reviews and systematic reviews. Outcome Measures: Pain relief was the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, opioid intake, and return to work. Short-term effectiveness was defined as one year or less, whereas, long-term effectiveness was defined as greater than one year. Results: Based on USPSTF criteria the level of evidence for nucleoplasty is Level II-3 in managing predominantly lower extremity pain due to contained disc herniation. Limitations: Paucity of literature, both observational and randomized. Conclusion: This systematic review illustrates Level II-3 evidence for mechanical lumbar percutaneous disc decompression with nucleoplasty in treatment of leg pain. However, there is no evidence available in managing axial low back pain. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Derby, Richard] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Helm, Standiford] Pacific Coast Pain Management Ctr, Laguna Hills, CA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 81 TC 56 Z9 59 U1 0 U2 4 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAY-JUN PY 2009 VL 12 IS 3 BP 561 EP 572 PG 12 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 455NF UT WOS:000266766800009 PM 19461823 ER PT J AU Singh, V Manchikanti, L Benyamin, RM Helm, S Hirsch, JA AF Singh, Vijay Manchikanti, Laxmaiah Benyamin, Ramsin M. Helm, Standiford Hirsch, Joshua A. TI Percutaneous Lumbar Laser Disc Decompression: A Systematic Review of Current Evidence SO PAIN PHYSICIAN LA English DT Review DE Intervertebral disc disease; chronic low back pain; disc herniation; disc protrusion; radiculitis; contained disc herniation; mechanical disc decompression; percutaneous lumbar laser discectomy; laser assisted spinal endoscopy ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; EVIDENCE-BASED MEDICINE; FACET JOINT INTERVENTIONS; BLIND CONTROLLED-TRIAL; MANAGING CHRONIC PAIN; MEDIAL BRANCH BLOCKS; FOLLOW-UP; EQUIVALENCE TRIAL; SURGERY SYNDROME AB Background: Since the descriptions by Mixter and Barr of open surgical treatment for rupture of the intervertebral disc in 1934, open surgical procedures have become a common practice. Disc herniations have been reported as being contained and non-contained. The results of open surgical discectomy for contained disc herniation have been poor. Consequently, several alternative techniques have been developed which are minimally invasive including percutaneous laser disc decompression. Study Design: A systematic review of the literature. Objective: The objective of this systematic review is to evaluate the clinical effectiveness of percutaneous laser discectomy in managing radicular pain secondary to contained disc herniation. Methods: A comprehensive evaluation of the literature relating to mechanical disc decompression was performed. The literature was evaluated according to Cochrane review criteria for randomized controlled trials (RCTs), and Agency for Healthcare Research and Quality (AHRQ) criteria was utilized for observational studies. A literature search was conducted by using only the English language literature through PubMed, EMBASE, the Cochrane library, systematic reviews, and cross references from reviews and systematic reviews. The level of evidence was classified as Level I, II, or III with 3 subcategories in Level II based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). Outcome Measures: Pain relief was the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, opioid intake, and return to work. Short-term effectiveness was defined as one year or less, whereas, long-term effectiveness was defined as greater than one year. Results: Based on USPSTF criteria the indicated level of evidence for percutaneous lumbar laser discectomy (PLLD) is II-2 for short- and long-term relief. Limitations: Even though laser discectomy has been in utilization for a number of years and numerous procedures have been performed there continues to be a paucity of literature of randomized clinical trials. Conclusion: This systematic review illustrates Level II-2 evidence for percutaneous laser disc decompression which is equivalent to automated percutaneous lumbar disc decompression. C1 [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Helm, Standiford] Pacific Coast Pain Management Ctr, Laguna Hills, CA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Singh, V (reprint author), W8090 Millie Hill Estates Dr, Iron Mt, MI 49801 USA. EM vj@wmpnet.net NR 97 TC 60 Z9 67 U1 1 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAY-JUN PY 2009 VL 12 IS 3 BP 573 EP 588 PG 16 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 455NF UT WOS:000266766800010 PM 19461824 ER PT J AU Hirsch, JA Singh, V Falco, FJE Benyamin, RM Manchikanti, L AF Hirsch, Joshua A. Singh, Vijay Falco, Frank J. E. Benyamin, Ramsin M. Manchikanti, Laxmaiah TI Automated Percutaneous Lumbar Discectomy for the Contained Herniated Lumbar Disc: A Systematic Assessment of Evidence SO PAIN PHYSICIAN LA English DT Review DE Intervertebral disc disease; chronic low back pain; mechanical disc decompression; automated percutaneous lumbar discectomy; internal disc disruption; radiculitis ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; EVIDENCE-BASED MEDICINE; FACET JOINT INTERVENTIONS; BLIND CONTROLLED-TRIAL; MEDIAL BRANCH BLOCKS; TERM FOLLOW-UP; SURGERY SYNDROME; EQUIVALENCE TRIAL; CLINICAL-TRIAL AB Background: Lumbar disc prolapse, protrusion, and extrusion account for less than 5% of all low back problems, but are the most common causes of nerve root pain and surgical interventions. The typical rationale for traditional surgery is an effort to provide more rapid relief of pain and disability. It should be noted that the majority of patients will recover with conservative management. The primary rationale for any form of surgery for disc prolapse associated with radicular pain is to relieve nerve root irritation or compression due to herniated disc material. The primary modality of treatment continues to be either open or microdiscectomy, but several alternative techniques including automated percutaneous lumbar discectomy (APLD) have been described. However, there is a paucity of evidence for all decompression techniques, specifically alternative techniques including automated and laser discectomy. Study Design: A systematic review of the literature. Objective: To determine the effectiveness of APLD. Methods: A comprehensive evaluation of the literature relating to automated lumbar disc decompression was performed. The literature was evaluated according to Cochrane review criteria for randomized controlled trials (RCTs), and Agency for Healthcare Research and Quality (AHRQ) criteria was utilized for observational studies. A literature search was conducted of English language literature through PubMed, EMBASE, the Cochrane library, systematic reviews, and cross references from reviews and systematic reviews. The level of evidence was classified as Level I, II, or III with 3 subcategories in Level II based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). Outcome Measures: Pain relief was the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, opioid intake, and return to work. Short-term effectiveness was defined as one-year or less, whereas, long-term effectiveness was defined as greater than one-year. Results: Based on USPSTF criteria, the indicated evidence for APLD is Level II-2 for short- and long-term relief. Limitations: Paucity of RCTs in the literature. Conclusion: This systematic review indicated Level II-2 evidence for APLD. APLD may provide appropriate relief in properly selected patients with contained lumbar disc prolapse. C1 [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Physicians, Newark, DE USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, 55 Blossom St,Gray 289, Boston, MA 02114 USA. EM jahirsch@partners.org NR 143 TC 50 Z9 58 U1 3 U2 9 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAY-JUN PY 2009 VL 12 IS 3 BP 601 EP 620 PG 20 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 455NF UT WOS:000266766800012 PM 19461826 ER PT J AU Fox, SA Heritage, J Stockdale, SE Asch, SM Duan, NH Reise, SP AF Fox, Sarah A. Heritage, John Stockdale, Susan E. Asch, Steven M. Duan, Naihua Reise, Steven P. TI Cancer screening adherence: Does physician-patient communication matter? SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Physician/patient communication; Cancer screening; Patient adherence ID COLORECTAL-CANCER; HEALTH COMMUNICATION; MEDICAL VISITS; UNITED-STATES; SELF-REPORTS; CARE; WOMEN; DISPARITIES; POPULATION; VALIDITY AB Objective: The objective of this study was to examine the separate contributions of patients and physicians to their communication regarding cancer screening. Methods: Research design and subjects: The authors conducted a cross-sectional analysis of survey data collected from 63 community-based primary care physicians and 904 of their female patients in Los Angeles. Results: Patients who perceived their physicians to be enthusiastic (at any level) in their discussions of mammography or fecal occult blood tests (FOBT) were significantly more likely to report a recent test than patients who reported no discussions. Conclusion: Physician discussions of cancer screening are important and effective even when, as in the case of mammography, screening rates are already high, or. as in the case of FOBT. rates have tended to remain low. The value of communication about screening should be taught and promoted to primary care physicians who serve as gatekeepers to screening. Practice implications: Those who train physicians in communication skills should take into account our finding that the communication style of physicians (e.g., enthusiasm for screening) was the only patient or physician variable that both influenced screening adherence and that could be taught. (C) 2009 Published by Elsevier Ireland Ltd. C1 [Fox, Sarah A.; Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Heritage, John] Univ Calif Los Angeles, Dept Sociol, Los Angeles, CA 90095 USA. [Stockdale, Susan E.] Univ Calif Los Angeles, Inst Neuropsychiat, Hlth Serv Res Ctr, Los Angeles, CA 90095 USA. [Duan, Naihua] Columbia Univ, New York State Psychiat Inst, Div Biostat, Dept Psychiat & Biostat, New York, NY 10032 USA. [Reise, Steven P.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Fox, SA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Box 951736,911 Broxton, Los Angeles, CA 90095 USA. EM s.fox@ucla.edu FU National institutes of Health, National Cancer Institute [1 R01 CA61249] FX This work was supported by National institutes of Health, National Cancer Institute, Award No. 1 R01 CA61249 (SAF). The authors would like to acknowledge the extensive editing of the original draft by Jeanette Chung, PhD, American Medical Association, Chicago. NR 33 TC 22 Z9 22 U1 3 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD MAY PY 2009 VL 75 IS 2 BP 178 EP 184 DI 10.1016/j.pec.2008.09.010 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 437FH UT WOS:000265471500007 PM 19250793 ER PT J AU Yan, BP Rosenfield, K Garasic, JM de Moor, M AF Yan, Bryan P. Rosenfield, Kenneth Garasic, Joseph M. de Moor, Michael TI Carotid Artery Stent Migration in a Child with Williams Syndrome SO PEDIATRIC CARDIOLOGY LA English DT Editorial Material DE Williams syndrome; Carotid artery stent ID STENOSES AB We report a case of distal migration of a stent from the brachiocephalic artery to the distal right common carotid artery 7 months after implantation in a 5-year-old child with Williams syndrome. There were no neurological sequelae and the migrated stent remained widely patent 5 years following implantation. C1 [de Moor, Michael] MassGen Hosp Children, Div Pediat Cardiol, Boston, MA 02114 USA. [Yan, Bryan P.; Rosenfield, Kenneth; Garasic, Joseph M.] Massachusetts Gen Hosp, Div Cardiol, Sect Vasc Med, Boston, MA 02114 USA. [Yan, Bryan P.; Rosenfield, Kenneth; Garasic, Joseph M.; de Moor, Michael] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP de Moor, M (reprint author), MassGen Hosp Children, Div Pediat Cardiol, Boston, MA 02114 USA. EM mdemoor@partners.org RI Yan, Bryan/P-5928-2015 NR 3 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0172-0643 J9 PEDIATR CARDIOL JI Pediatr. Cardiol. PD MAY PY 2009 VL 30 IS 4 BP 551 EP 552 DI 10.1007/s00246-009-9400-y PG 2 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 447BW UT WOS:000266167600032 PM 19294459 ER PT J AU Melendez, E Bachur, R AF Melendez, Elliot Bachur, Richard TI Serious Adverse Events During Procedural Sedation With Ketamine SO PEDIATRIC EMERGENCY CARE LA English DT Article DE ketamine; laryngospasm; adverse event; procedural sedation; conscious sedation ID DEPARTMENT SAFETY PROFILE; EMERGENCY-DEPARTMENT; INTRAMUSCULAR KETAMINE; DISSOCIATIVE SEDATION; INTRAVENOUS KETAMINE; PEDIATRIC SEDATION; PAINFUL PROCEDURES; CHILDREN; MIDAZOLAM; CARE AB Objectives: Compare the frequency of respiratory adverse events between patients who received intramuscular (IM) versus intravenous ketamine. Methods: Case control study from 1997 to 2005 at a large urban pediatric emergency department. Adverse events were defined as apnea, hypoxemia (oximetry <93%), hypoventilation, laryngospasm, and other upper airway obstruction. Serious adverse events were defined by the level of intervention and included those cases that required positive pressure ventilation, insertion of oral or nasal airway, or endotracheal intubation. Minor adverse events were respiratory events requiring minimal intervention (stimulation, supplemental 02, airway repositioning). Controls (2: 1) were selected by the next chronological patient in the data set who received ketamine but had no respiratory adverse event. Results: Four thousand two hundred fifty-two patients received ketamine; 102 cases (2.4%) had respiratory adverse events, including 38 patients with severe adverse events (0.9%). Interventions for the cases included supplemental 02 (59/102, 58%), airway repositioning (36/102, 35%), continuous positive airway pressure (7/102, 7%), positive pressure ventilation (33/102, 32%), nasal airway (2/102, 2%), oral airway (1/102, 1%), stimulation (11/102, 11%), and intubation (1/102, 1%). Overall, 33% of all subjects received IM ketamine including 47% of cases and 27% of controls. Intramuscular IM ketamine was associated with increased likelihood of adverse events (odds ratio [OR] 2.1, 95% Cl, 1.3-3). Twenty (69%) of the 29 patients with laryngospasm received IM ketamine (OR, 5.2; 95% CI, 2.3-11.9) and 20 (53%) of the 38 patients who had severe events were administered IM (OR, 2.4; 95% Cl, 1.2-4.9). Use of pre-sedation morphine or combined administration with midazolam and/or atropine was not associated with adverse events. Specific procedures were not associated with increased adverse events. Conclusions: Respiratory adverse events with ketamine are uncommon. Serious events, like laryngospasm, are rare but occur more commonly with IM administration. This increased risk associated with IM administration should be considered in the sedation plan. C1 [Melendez, Elliot] Massachusetts Gen Hosp, Div Pediat Crit Care, Dept Pediat, Boston, MA 02114 USA. [Melendez, Elliot; Bachur, Richard] Childrens Hosp, Dept Med, Div Emergency Med, Boston, MA 02115 USA. RP Melendez, E (reprint author), Massachusetts Gen Hosp, Div Pediat Crit Care, Dept Pediat, 175 Cambridge St,5th Floor, Boston, MA 02114 USA. EM elliot.melendez@childrens.harvard.edu OI Bachur, Richard/0000-0001-8831-014X NR 17 TC 33 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD MAY PY 2009 VL 25 IS 5 BP 325 EP 328 PG 4 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 445VG UT WOS:000266079000007 PM 19404223 ER PT J AU Pieretti-Vanmarcke, R Pieretti, A Pieretti, RV AF Pieretti-Vanmarcke, Rafael Pieretti, Alberto Pieretti, Rafael V. TI Megacalycosis: a rare condition SO PEDIATRIC NEPHROLOGY LA English DT Article DE Megacalycosis; Hydronephrosis; Ultrasound; Intravenous; Pyelogram; Diuretic renogram ID CONGENITAL MEGACALYCOSIS; ASSOCIATION AB Megacalycosis is an extremely rare condition. We report our experience with two cases and discuss its pathogenesis, diagnosis and management in children. Our two patients had presented a prior diagnosis of congenital hydronephrosis. An increased number of calyces with a significant disproportion between the degree of calyceal dilatation and a mildly dilated renal pelvis were found in each case. Megacalycosis must be considered in the differential diagnosis of congenital hydronephrosis, polycalycosis, and infundibular stenosis. The diagnosis is suggested by ultrasound and confirmed by diuretic renography, intravenous pyelography or magnetic resonance urography. Voiding cystourethrography should be performed to rule out vesicoureteral reflux. A high index of suspicion is needed for the diagnosis of this condition. C1 [Pieretti, Rafael V.] Massachusetts Gen Hosp Children, Sect Pediat Urol, Dept Pediat Surg, Boston, MA 02114 USA. [Pieretti-Vanmarcke, Rafael] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Pieretti, Alberto] Cent Univ Venezuela, Caracas, Venezuela. RP Pieretti, RV (reprint author), Massachusetts Gen Hosp Children, Sect Pediat Urol, Dept Pediat Surg, Warren 1157, Boston, MA 02114 USA. EM rpieretti@partners.org NR 7 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD MAY PY 2009 VL 24 IS 5 BP 1077 EP 1079 DI 10.1007/s00467-008-1039-z PG 3 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 423ZQ UT WOS:000264535700021 PM 19002724 ER PT J AU Moore, MA Wallace, EC Westra, SJ AF Moore, Michael A. Wallace, E. Christine Westra, Sjirk J. TI The imaging of paediatric thoracic trauma SO PEDIATRIC RADIOLOGY LA English DT Review DE Chest; Trauma; Multidetector CT; Children ID BLUNT CHEST TRAUMA; COMPUTED-TOMOGRAPHY; BRONCHIAL RUPTURE; AORTIC INJURIES; DOSE REDUCTION; LUNG CONTUSION; DIAPHRAGMATIC RUPTURE; DIAGNOSTIC-RADIOLOGY; OCCULT PNEUMOTHORAX; PULMONARY CONTUSION AB Major chest trauma in a child is associated with significant morbidity and mortality. It is most frequently encountered within the context of multisystem injury following high-energy trauma such as a motor vehicle accident. The anatomic-physiologic make-up of children is such that the pattern of ensuing injuries differs from that in their adult counterparts. Pulmonary contusion, pneumothorax, haemothorax and rib fractures are most commonly encountered. Although clinically more serious and potentially life threatening, tracheobronchial tear, aortic rupture and cardiac injuries are seldom observed. The most appropriate imaging algorithm is one tailored to the individual child and is guided by the nature of the traumatic event as well as clinical parameters. Chest radiography remains the first and most important imaging tool in paediatric chest trauma and should be supplemented with US and CT as indicated. Multidetector CT allows for the accurate diagnosis of most traumatic injuries, but should be only used in selected cases as its routine use in all paediatric patients would result in an unacceptably high radiation exposure to a large number of patients without proven clinical benefit. When CT is used, appropriate modifications should be incorporated so as to minimize the radiation dose to the patient whilst preserving diagnostic integrity. C1 [Moore, Michael A.; Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wallace, E. Christine] UMass Mem Med Ctr, Dept Radiol, Worcester, MA USA. [Wallace, E. Christine] Univ Massachusetts, Sch Med, Worcester, MA USA. [Moore, Michael A.; Westra, Sjirk J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Westra, SJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM swestra@partners.org NR 78 TC 20 Z9 20 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD MAY PY 2009 VL 39 IS 5 BP 485 EP 496 DI 10.1007/s00247-008-1093-5 PG 12 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 423ZS UT WOS:000264535900008 PM 19151969 ER PT J AU Barrett, LF AF Barrett, Lisa Feldman TI Understanding the Mind by Measuring the Brain: Lessons From Measuring Behavior (Commentary on Vul et al., 2009) SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article ID CONSTRUCTION; MODEL AB Throughout the history of psychology, the path of transforming the physical (muscle movements, verbal behavior, or physiological changes) into the mental has been fraught with difficulty. Over the decades, psychologists have risen to the challenge and learned a few things about how to infer the mental from measuring the physical. The Vul, Harris, Winkielman, and Pashler article (2009, this issue) points out that some of these lessons could be helpful to those of us who measure blood flow in the brain in a quest to understand the mind. Three lessons from psychometrics are discussed. C1 [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Barrett, LF (reprint author), Massachusetts Gen Hosp, Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. EM barretli@bc.edu FU NIA NIH HHS [R01 AG030311, R01 AG030311-03]; NIH HHS [DP1 OD003312, DP1 OD003312-02] NR 10 TC 7 Z9 7 U1 13 U2 16 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD MAY PY 2009 VL 4 IS 3 BP 314 EP 318 DI 10.1111/j.1745-6924.2009.01131.x PG 5 WC Psychology, Multidisciplinary SC Psychology GA 445EA UT WOS:000266031300012 PM 19672318 ER PT J AU Cristian, A Greenwald, BD AF Cristian, Adrian Greenwald, Brian D. TI Fatigue Preface SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 [Cristian, Adrian] James J Peters Vet Affairs Med Ctr, Dept Rehabil Med, Bronx, NY 10468 USA. [Cristian, Adrian] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Greenwald, Brian D.] Mt Sinai Med Ctr, Dept Rehabil Med, New York, NY 10029 USA. RP Cristian, A (reprint author), James J Peters Vet Affairs Med Ctr, Dept Rehabil Med, 3d-22,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM acristianmd@msn.com; brian.greenwald@mountsinai.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 J9 PHYS MED REHABIL CLI JI Phys. Med. Rehabil. Clin. N. Am. PD MAY PY 2009 VL 20 IS 2 BP XI EP XII DI 10.1016/j.pmr.2009.02.001 PG 2 WC Rehabilitation SC Rehabilitation GA 450KC UT WOS:000266398400002 PM 19389612 ER PT J AU Kalapatapu, RK Cristian, A AF Kalapatapu, Raj K. Cristian, Adrian TI Assessment of Fatigue in Adults with Disabilities SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Fatigue; Etiology; Adult; Rating scale; Assessment ID TRAUMATIC BRAIN-INJURY; CANCER-RELATED FATIGUE; FIBROMYALGIA IMPACT QUESTIONNAIRE; QUALITY-OF-LIFE; 1ST 2 YEARS; PRIMARY-CARE; MULTIPLE-SCLEROSIS; FAMILY-PRACTICE; VALIDATION; SYMPTOMS AB Fatigue is common among patients presenting to physicians. Fatigue can lead to serious public health consequences and may be caused by a vast array of etiologies. This article reviews the assessment of fatigue from the physical medicine and rehabilitation physician's perspective. The importance of a history and physical examination is emphasized, complemented by the use of laboratory studies. Rating scales used to assess fatigue from different etiologies are discussed, and patient-friendly Internet resources about fatigue are included. C1 [Kalapatapu, Raj K.] Mt Sinai Sch Med, New York, NY 10029 USA. [Cristian, Adrian] Mt Sinai Sch Med, Dept Rehabil Med, James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Kalapatapu, RK (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM rajkumar.kalapatapu@mssm.edu NR 67 TC 0 Z9 0 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 J9 PHYS MED REHABIL CLI JI Phys. Med. Rehabil. Clin. N. Am. PD MAY PY 2009 VL 20 IS 2 BP 313 EP + DI 10.1016/j.pmr.2008.12.001 PG 13 WC Rehabilitation SC Rehabilitation GA 450KC UT WOS:000266398400003 PM 19389613 ER PT J AU Tatlidede, SH Murphy, AD McCormack, MC Nguyen, JT Eberlin, KR Randolph, MA Moore, FD Austen, WG AF Tatlidede, Soner H. Murphy, Adrian D. McCormack, Michael C. Nguyen, John T. Eberlin, Kyle R. Randolph, Mark A. Moore, Francis D., Jr. Austen, William G., Jr. TI Improved Survival of Murine Island Skin Flaps by Prevention of Reperfusion Injury SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the New-England-Society-of-Plastic-and-Reconstructive-Surgeons CY JUN 04-07, 2008 CL Manchester, VT SP New England Soc Plast & Reconstruct Surg ID COMPLEMENT INHIBITORY PROTEIN; REMOTE ORGAN INJURY; C-REACTIVE PROTEIN; SKELETAL-MUSCLE; ISCHEMIA/REPERFUSION INJURY; ISCHEMIA-REPERFUSION; MYOCARDIAL-ISCHEMIA; NATURAL ANTIBODY; INTESTINAL ISCHEMIA/REPERFUSION; RECEPTOR TYPE-1 AB Background: Studies have demonstrated that blocking a single specificity of self-reactive immunoglobulin M with a 12-amino acid peptide mimic of the antigen of immunoglobulin M can attenuate murine intestinal and skeletal muscle injury following ischemia and reperfusion. The aim of this study was to ascertain whether peptide (P8) had protective effects in an axial island skin flap model, where tissue loss is attributed to ischemia-reperfusion injury. Methods: Dorsal lateral thoracic artery island skin flaps (3.5 X 1.5 cm) were elevated in 82 male C57BL/6 mice and rendered ischemic for 10 hours by placing a 7-mm microclamp on the vascular pedicle followed by 7 days of reperfusion. Group I (n = 7), the sham group, had no clamp placed. Group II (n = 21) had clamp placement but no other treatment. Thirty minutes before clamp placement, group III (n = 18) received 0.25 cc of saline intravenously, group IV (n = 18) received 25 mu g/0.25 cc P8 peptide, and group V (n = 7) received 25 mu g/0.25 cc random 12-mer peptide. Animals in group VI (n = 11) underwent two cycles of 20 minutes of ischemic preconditioning before 10 hours of ischemia. After 1 week of reperfusion, percent necrosis was measured and results were compared using analysis of variance and an unpaired t test. Results: In animals treated with P8 peptide, flap necrosis was 14.61 +/- 2.77 percent. This represents a statistically significant, 56 percent reduction in flap necrosis compared with controls (p < 0.001). Conclusion: These data demonstrate that prevention of ischemia-reperfusion injury with P8 peptide produces a significant reduction in necrosis of treated flaps. (Plast. Reconstr. Surg. 123: 1431, 2009.) C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. RP McCormack, MC (reprint author), 15 Parkman St,Wellman Bldg,Room 629, Boston, MA 02114 USA. EM mcmccormack@partners.org NR 43 TC 7 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD MAY PY 2009 VL 123 IS 5 BP 1431 EP 1439 DI 10.1097/PRS.0b013e3181a071e8 PG 9 WC Surgery SC Surgery GA 445QZ UT WOS:000266067900005 PM 19407613 ER PT J AU Cheng, CY Kao, WHL Patterson, N Tandon, A Haiman, CA Harris, TB Xing, C John, EM Ambrosone, CB Brancati, FL Coresh, J Press, MF Parekh, RS Klag, MJ Meoni, LA Hsueh, WC Fejerman, L Pawlikowska, L Freedman, ML Jandorf, LH Bandera, EV Ciupak, GL Nalls, MA Akylbekova, EL Orwoll, ES Leak, TS Miljkovic, I Li, RL Ursin, G Bernstein, L Ardlie, K Taylor, HA Boerwinckle, E Zmuda, JM Henderson, BE Wilson, JG Reich, D AF Cheng, Ching-Yu Kao, W. H. Linda Patterson, Nick Tandon, Arti Haiman, Christopher A. Harris, Tamara B. Xing, Chao John, Esther M. Ambrosone, Christine B. Brancati, Frederick L. Coresh, Josef Press, Michael F. Parekh, Rulan S. Klag, Michael J. Meoni, Lucy A. Hsueh, Wen-Chi Fejerman, Laura Pawlikowska, Ludmila Freedman, Matthew L. Jandorf, Lina H. Bandera, Elisa V. Ciupak, Gregory L. Nalls, Michael A. Akylbekova, Ermeg L. Orwoll, Eric S. Leak, Tennille S. Miljkovic, Iva Li, Rongling Ursin, Giske Bernstein, Leslie Ardlie, Kristin Taylor, Herman A. Boerwinckle, Eric Zmuda, Joseph M. Henderson, Brian E. Wilson, James G. Reich, David TI Admixture Mapping of 15,280 African Americans Identifies Obesity Susceptibility Loci on Chromosomes 5 and X SO PLOS GENETICS LA English DT Article ID GENOME-WIDE SCAN; BODY-WEIGHT; FTO GENE; CART GENE; UNITED-STATES; DISEASE GENES; FAT MASS; ASSOCIATION; VARIANTS; RISK AB The prevalence of obesity (body mass index (BMI) >= 30 kg/m(2)) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6 x 10(-7)). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI. C1 [Cheng, Ching-Yu; Kao, W. H. Linda; Brancati, Frederick L.; Coresh, Josef; Klag, Michael J.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Dept Ophthalmol, Taipei 112, Taiwan. [Cheng, Ching-Yu] Taipei Vet Gen Hosp, Taipei, Taiwan. [Kao, W. H. Linda; Brancati, Frederick L.; Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Patterson, Nick; Tandon, Arti; Freedman, Matthew L.; Ardlie, Kristin; Reich, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Tandon, Arti; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Haiman, Christopher A.; Ursin, Giske; Bernstein, Leslie; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Harris, Tamara B.; Nalls, Michael A.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Xing, Chao] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Xing, Chao] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [Xing, Chao] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [John, Esther M.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Ctr, Stanford, CA USA. [Ambrosone, Christine B.; Ciupak, Gregory L.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Parekh, Rulan S.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Parekh, Rulan S.; Klag, Michael J.; Meoni, Lucy A.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA. [Klag, Michael J.] Johns Hopkins Univ, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. [Meoni, Lucy A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21218 USA. [Hsueh, Wen-Chi; Fejerman, Laura] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Fejerman, Laura; Pawlikowska, Ludmila] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Fejerman, Laura] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Pawlikowska, Ludmila] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jandorf, Lina H.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Akylbekova, Ermeg L.] Jackson State Univ, Jackson Heart Study Anal Grp, Jackson, MS USA. [Orwoll, Eric S.] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97201 USA. [Leak, Tennille S.; Miljkovic, Iva; Zmuda, Joseph M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Li, Rongling] Univ Tennessee, Dept Prevent Med, Div Biostat & Epidemiol, Memphis, TN USA. [Ursin, Giske] Univ Oslo, Dept Nutr, Oslo, Norway. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Canc Etiol, Div Populat Sci, Duarte, CA 91010 USA. [Ardlie, Kristin] Genom Collaborat, Cambridge, MA USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS USA. [Taylor, Herman A.] Tougaloo Coll, Tougaloo, MS USA. [Taylor, Herman A.; Wilson, James G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Boerwinckle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Wilson, James G.] GV Sonny Montgomery Vet Affairs Med Ctr, Jackson, MS USA. RP Cheng, CY (reprint author), Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. EM cycheng@jhsph.edu; wkao@jhsph.edu; reich@genetics.med.harvard.edu RI Cheng, Ching-Yu/K-7017-2013; Bandera, Elisa/M-4169-2014; OI Cheng, Ching-Yu/0000-0003-0655-885X; Bandera, Elisa/0000-0002-8789-2755; Miljkovic, Iva/0000-0002-3155-9777; Fejerman, Laura/0000-0003-3179-1151; Orwoll, Eric/0000-0002-8520-7355 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R21DK073482, Kol DK067207, N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Cancer Institute (NCI), National Institutes of Health (NIH) [RFA-CA-06-503, N01-CO-12400]; Northern California BCFR site [U01 CA6941 7]; National Institute of Child Health and Human Development [NOl-HD-3-31 75]; NCI [NOl-PC-6701 0, CA 74847, CA63464, R01-CA100598]; California Department of Health Services [OSOG 8709]; National Institute of Environmental Health Sciences [R01-ES-07084]; California Breast Cancer Research Program [PB-0051]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK070657, U01DK57304, K01DK067207, U01DK57292]; National Center for Research Resources; National Center on Minority Health and Health Disparities; United States Army Medical Research Program; Center of Excellence for Biobehavioral Breast Cancer Research [DAMD17-01-1-0334]; Susan Komen Foundation for Breast Cancer Research [KG080165]; Burroughs Wellcome Career Development Award in the Biomedical Sciences [U01-HG0041]; [RL-1 HL092550]; [U54-RR020278]; [CA 17054]; [4PB-0092]; [CA54281]; [U01 AR45580]; [U01 AR45614]; [U01 AR45632]; [U01 AR45647]; [U01 AR45654]; [U01 AR45583]; [U01 AG18197]; [U01-AG027810]; [ULl RR024140]; [R01-AR051124]; [R01-CA63446]; [R01-CA77305]; [DAMD1 7-96-607]; [7PB-0068]; [AG05407]; [AG05394]; [AR35584]; [AR35583]; [5T32AG0001 81-19] FX The ARIC Study was carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022 with support for this analysis by R21DK073482 and Kol DK067207 (WHLK). The BCFR was supported by the National Cancer Institute (NCI), National Institutes of Health (NIH) under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and PIs. The Northern California BCFR site was funded by U01 CA6941 7. The Los Angeles component of the Women's Contraceptive and Reproductive Experiences study received support from contracts with the National Institute of Child Health and Human Development (NOl -HD-3-31 75), the NCI (NOl-PC-6701 0) and the California Department of Health Services (OSOG 8709), and grants from the National Institute of Environmental Health Sciences (R01-ES-07084) and the California Breast Cancer Research Program (PB-0051). The DHS was supported by the Donald W. Reynolds Foundation and grant 1 RL-1 HL092550 from the NIH. The FIND Study included in this analysis was supported by the following research grants: U01 DK070657, U01DK57304, K01DK067207 (WHLK), and U01DK57292 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and, in part, by the Intramural Research Program of the NIDDK; this research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and has been funded in part with federal funds from the NCI, NIH, under contract N01-CO-12400. Research support for Health ABC was provided by the Intramural Research Program of the National Institute on Aging, and contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. Genotyping in Health ABC was supported by National Center for Research Resources grant U54-RR020278. Research support for JHS studies was provided by R01-HL084107 (JGW) from the NHLBI and contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the NHLBI and the National Center on Minority Health and Health Disparities. The LIFE Study was supported by grants CA 17054, CA 74847 from the NCI, and by grant 4PB-0092 from the California Breast Cancer Research Program of the University of California. The MEC Study was supported by NCI grants CA63464 and CA54281. MrOS is supported by grants: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, ULl RR024140 and R01-AR051124. SFBABCS was supported by grants R01-CA63446 and R01-CA77305 from the NCI, grant DAMD1 7-96-607 from the United States Army Medical Research Program, and grant 7PB-0068 from the California Breast Cancer Research Program. SOF was supported by grants AG05407, AR35582, AG05394, AR35584, and AR35583. The WCHS was initially funded as part of a Center of Excellence for Biobehavioral Breast Cancer Research (United States Army Medical Research Program, DAMD17-01-1-0334) and subsequently by R01-CA100598 from the NCI. Genotyping for SFBABCS and WCHS was supported by grant KG080165 from the Susan Komen Foundation for Breast Cancer Research. DR was supported by a Burroughs Wellcome Career Development Award in the Biomedical Sciences, and methodological work was supported by grant U01-HG0041 68 to DR, NP and AT. TL is postdoctoral fellow funded on 5T32AG0001 81-19, Training in the Epidemiology of Aging. NR 50 TC 45 Z9 45 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2009 VL 5 IS 5 AR e1000490 DI 10.1371/journal.pgen.1000490 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 459EH UT WOS:000267083000012 PM 19461885 ER PT J AU Namekawa, SH Lee, JT AF Namekawa, Satoshi H. Lee, Jeannie T. TI XY and ZW: Is Meiotic Sex Chromosome Inactivation the Rule in Evolution? SO PLOS GENETICS LA English DT Editorial Material ID DOSAGE COMPENSATION; CHROMATIN; MEIOSIS; SPERMATOGENESIS; MAMMALS; MOUSE C1 [Namekawa, Satoshi H.; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Namekawa, Satoshi H.; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Namekawa, SH (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu FU Howard Hughes Medical Institute NR 24 TC 21 Z9 21 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2009 VL 5 IS 5 AR e1000493 DI 10.1371/journal.pgen.1000493 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 459EH UT WOS:000267083000001 PM 19461890 ER PT J AU Lotter, H Gonzalez-Roldan, N Lindner, B Winau, F Isibasi, A Moreno-Lafont, M Ulmer, AJ Holst, O Tannich, E Jacobs, T AF Lotter, Hannelore Gonzalez-Roldan, Nestor Lindner, Buko Winau, Florian Isibasi, Armando Moreno-Lafont, Martha Ulmer, Artur J. Holst, Otto Tannich, Egbert Jacobs, Thomas TI Natural Killer T Cells Activated by a Lipopeptidophosphoglycan from Entamoeba histolytica Are Critically Important To Control Amebic Liver Abscess SO PLOS PATHOGENS LA English DT Article ID INNATE IMMUNE-RESPONSE; INVARIANT NKT CELLS; PHENOL-WATER METHOD; ALPHA-GALACTOSYLCERAMIDE; INTERFERON-GAMMA; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORS; MONOCLONAL-ANTIBODY; CD1D MOLECULES; HK-9 STRAIN; LIPOPHOSPHOGLYCAN AB The innate immune response is supposed to play an essential role in the control of amebic liver abscess (ALA), a severe form of invasive amoebiasis due to infection with the protozoan parasite Entamoeba histolytica. In a mouse model for the disease, we previously demonstrated that J alpha 18(-/-) mice, lacking invariant natural killer T (iNKT) cells, suffer from more severe abscess development. Here we show that the specific activation of iNKT cells using alpha-galactosylceramide (alpha-GalCer) induces a significant reduction in the sizes of ALA lesions, whereas CD1d(-/-) mice develop more severe abscesses. We identified a lipopeptidophosphoglycan from E. histolytica membranes (EhLPPG) as a possible natural NKT cell ligand and show that the purified phosphoinositol (PI) moiety of this molecule induces protective IFN-gamma but not IL-4 production in NKT cells. The main component of EhLPPG responsible for NKT cell activation is a diacylated PI, (1-O-[(28: 0)-lyso-glycero-3-phosphatidyl-]2-O(C16:0)-Ins). IFN-gamma production by NKT cells requires the presence of CD1d and simultaneously TLR receptor signalling through MyD88 and secretion of IL-12. Similar to alpha-GalCer application, EhLPPG treatment significantly reduces the severity of ALA in ameba-infected mice. Our results suggest that EhLPPG is an amebic molecule that is important for the limitation of ALA development and may explain why the majority of E. histolytica-infected individuals do not develop amebic liver abscess. C1 [Lotter, Hannelore; Gonzalez-Roldan, Nestor; Tannich, Egbert; Jacobs, Thomas] Bernhard Nocht Inst Trop Med, Hamburg, Germany. [Gonzalez-Roldan, Nestor; Holst, Otto] Leibniz Ctr Med & Biosci, Res Ctr Borstel, Div Struct Biochem, Borstel, Germany. [Gonzalez-Roldan, Nestor; Isibasi, Armando] Hosp Especialidades Ctr Med Nacl Siglo XXI, Unidad Invest Med Immunoquim, IMSS, Mexico City, DF, Mexico. [Gonzalez-Roldan, Nestor; Moreno-Lafont, Martha] Inst Politecn Nacl, Dept Inmunol, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. [Lindner, Buko] Leibniz Ctr Med & Biosci, Div Immunochem, Res Ctr Borstel, Borstel, Germany. [Winau, Florian] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Winau, Florian] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Ulmer, Artur J.] Leibniz Ctr Med & Biosci, Res Ctr Borstel, Div Immunol & Cell Biol, Borstel, Germany. RP Lotter, H (reprint author), Bernhard Nocht Inst Trop Med, Hamburg, Germany. EM lotter@bni-hamburg.de; oholst@fz-borstel.de RI Lindner, Buko/G-9731-2014 FU Deutsche Forschungsgemeinschaft (www.dfg.de) [TA 110/8-1]; SFB [470, LI 448/4-1] FX We are grateful to the Deutsche Forschungsgemeinschaft (www.dfg.de) for funding TA 110/8-1 to ET and the materials and position of HL; the funding of SFB 470 to TJ, and materials and expertise for the immunological parts; and for supporting the project LI 448/4-1 to BL and providing mass and gas chromatography materials. We also thank the Consejo Nacional de Ciencia y Tecnologica (www.conacyt.mx) for grant 50545-M to AI and the financial support to NGR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 42 Z9 42 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2009 VL 5 IS 5 AR e1000434 DI 10.1371/journal.ppat.1000434 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 459FH UT WOS:000267085800037 PM 19436711 ER PT J AU York, RM Perell-Gerson, KL Barr, M Durham, J Roper, JM AF York, Robyn M. Perell-Gerson, Karen L. Barr, Michele Durham, Jayson Roper, Janice M. TI Motor Learning of a Gait Pattern to Reduce Forefoot Plantar Pressures in Individuals with Diabetic Peripheral Neuropathy SO PM&R LA English DT Article AB Objective: To examine the role of visual feedback in the reduction of plantar pressures through teaching a "new" gait pattern to diabetic peripheral neuropathy subjects. Immediate, next day, and 1-week retention were studied to determine if motor pattern changes could occur. Design: Randomized controlled trial. Setting: VA Urban Healthcare System. Participants: Twenty-nine community-dwelling older adults with diabetic peripheral neuropathy volunteered. Interventions: Subjects were randomized into feedback and no-feedback groups. All subjects received instruction and 2 days of practice and returned for a 1-week retention test. Instruction to pull the leg forward from the hip to initiate swing rather than push off the ground with the foot while walking was given to all subjects. The feedback group received visual feedback regarding peak plantar pressures after each practice trial. The no-feedback group received no feedback. Main Outcome Measures: Peak plantar pressures in the forefoot region for immediate retention (retention 1), next day retention (retention 2), and long-term retention (1-week retention). Results: Peak plantar pressures were significantly (P < .01) reduced from baseline to retention 2 testing at the first metatarsal area in the feedback group. The feedback group walked significantly (P < .01) slower at retention 1 and 1-week testing compared with baseline. Conclusions: Individuals with diabetic peripheral neuropathy were unable to use a "new" strategy gait pattern to reduce peak plantar pressures long term (1 week). The use of visual feedback following the trial did not assist in the learning of a new walking pattern. C1 [York, Robyn M.; Perell-Gerson, Karen L.; Roper, Janice M.] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA. [York, Robyn M.; Perell-Gerson, Karen L.; Barr, Michele] Calif State Univ Fullerton, Dept Kinesiol, Fullerton, CA 92634 USA. [Durham, Jayson] Space & Naval Warfare Syst Ctr, San Diego, CA USA. RP Perell-Gerson, KL (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA. EM kperell@fullerton.edu FU VA Rehabilitation Research and Development Service [A2372K, A3117R] FX Supported by a Career Development Award (A2372K) from the VA Rehabilitation Research and Development Service to K.L.P.-G. and a grant (A3117R) from the VA Rehabilitation Research and Development Service to K.L.P.-G. and J.M.R. NR 22 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD MAY PY 2009 VL 1 IS 5 BP 434 EP 441 DI 10.1016/j.pmrj.2009.03.001 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA V24LI UT WOS:000208411500006 PM 19627930 ER PT J AU Goldfine, AB Fonseca, VA AF Goldfine, Allison B. Fonseca, Vivian A. TI The Use of Colesevelam HCl in Patients with Type 2 Diabetes Mellitus: Combining Glucose- and Lipid-Lowering Effects SO POSTGRADUATE MEDICINE LA English DT Article DE bile acid sequestrant; cardiovascular; colesevelam HCl; glycemic control; lipid lowering; type 2 diabetes mellitus ID CORONARY HEART-DISEASE; GLYCEMIC CONTROL; DOUBLE-BLIND; BILE-ACIDS; THERAPY; HYPERCHOLESTEROLEMIA; HYDROCHLORIDE; CHOLESTEROL; COLESTIMIDE; EFFICACY AB Therapy is often required to manage the hyperglycemia, hypertension, and dyslipidemia that occur in patients with type 2 diabetes mellitus (T2DM) in order to control the risk of cardiovascular (CV) events. The importance of managing these risk factors is underscored by the recommendation from the American Diabetes Association and the American Association of Clinical Endocrinologists for treatment of these CV risk factors to target levels. However, relatively few patients achieve simultaneous control of these risk factors. As such, therapy that has positive effects on more than I risk factor is of potential benefit. Initially approved as a lipid-lowering agent, the bile acid sequestrant colesevelam hydrochloride (HCl) is now also approved as an adjunct therapy to improve glycemic control in patients with T2DM. This review summarizes the major findings of clinical studies that investigated the glucose- and lipid-lowering effects of colesevelam HCl when added to stable metformin-, sulfonylurea-, or insulin-based antidiabetes therapies in patients with T2DM. C1 [Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Fonseca, Vivian A.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. RP Goldfine, AB (reprint author), 1 Joslin Pl, Boston, MA 02115 USA. EM allison.goldfine@joslin.harvard.edu FU Daiichi Sankyo, Inc FX Acknowledgments Funding for the preparation of this manuscript was provided by Daiichi Sankyo, Inc. Editorial assistance was provided by Luana Atherly, PhD and Karen Stauffer, PhD. NR 26 TC 3 Z9 3 U1 0 U2 0 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD MAY PY 2009 VL 121 IS 3 BP 13 EP 18 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 467TN UT WOS:000267766100003 PM 19494473 ER PT J AU Goldfine, AB Fonseca, VA AF Goldfine, Allison B. Fonseca, Vivian A. TI The Use of Colesevelam HCl in Patients with Type 2 Diabetes Mellitus: Combining Glucose- and Lipid-Lowering Effects SO POSTGRADUATE MEDICINE LA English DT Article DE bile acid sequestrant; cardiovascular; colesevelam HCl; glycemic control; lipid lowering; type 2 diabetes mellitus ID CORONARY HEART-DISEASE; GLYCEMIC CONTROL; DOUBLE-BLIND; BILE-ACIDS; THERAPY; HYPERCHOLESTEROLEMIA; HYDROCHLORIDE; CHOLESTEROL; COLESTIMIDE; EFFICACY AB Therapy is often required to manage the hyperglycemia, hypertension, and dyslipidemia that occur in patients with type 2 diabetes mellitus (T2DM) in order to control the risk of cardiovascular (CV) events. The importance of managing these risk factors is underscored by the recommendation from the American Diabetes Association and the American Association of Clinical Endocrinologists for treatment of these CV risk factors to target levels. However, relatively few patients achieve simultaneous control of these risk factors. As such, therapy that has positive effects on more than I risk factor is of potential benefit. Initially approved as a lipid-lowering agent, the bile acid sequestrant colesevelam hydrochloride (HCl) is now also approved as an adjunct therapy to improve glycemic control in patients with T2DM. This review summarizes the major findings of clinical studies that investigated the glucose- and lipid-lowering effects of colesevelam HCl when added to stable metformin-, sulfonylurea-, or insulin-based antidiabetes therapies in patients with T2DM. C1 [Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Fonseca, Vivian A.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. RP Goldfine, AB (reprint author), 1 Joslin Pl, Boston, MA 02115 USA. EM allison.goldfine@joslin.harvard.edu FU Daiichi Sankyo, Inc FX Funding for the preparation of this manuscript was provided by Daiichi Sankyo, Inc. Editorial assistance was provided by Luana Atherly, PhD and Karen Stauffer, PhD. NR 26 TC 0 Z9 0 U1 0 U2 0 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD MAY PY 2009 BP 13 EP 18 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 493NA UT WOS:000269742500003 ER PT J AU Allen, JD Mohllajee, AP Shelton, RC Othus, MKD Fontenot, HB Hanna, R AF Allen, Jennifer D. Mohllajee, Anshu P. Shelton, Rachel C. Othus, Megan K. D. Fontenot, Holly B. Hanna, Richard TI Stage of adoption of the human papillomavirus vaccine among college women SO PREVENTIVE MEDICINE LA English DT Article DE Cervical neoplasia; Human papillomavirus vaccine; Intention; Attitudes; Knowledge; Social norms ID TRANSMITTED INFECTION VACCINATION; PARENTAL ATTITUDES; HPV VACCINATION; TRANSTHEORETICAL MODEL; ADOLESCENT CHILDREN; SMOKING CESSATION; HEALTH BEHAVIOR; UNITED-STATES; YOUNG-ADULTS; ACCEPTABILITY AB Background. Certain types of human papillomavirus (HPV) can cause cervical and other cancers. A vaccine that protects against HPV types responsible for 70% of cervical cancers is available to females ages 9-26. Objective. To examine correlates of stage of vaccine adoption among women ages 18-22. Methods. In 2007, female students (n = 4774) at a New England University in the U.S. were invited to complete an on-line survey that assessed knowledge of HPV, perceived susceptibility, severity, vaccine benefits/barriers, social and subjective norms, and stage of vaccine adoption Results. 1897 women (40%) responded; complete data were available for 1401. About half (53%) were planning to be vaccinated, 12% had received the vaccine, 15% were undecided, and 7% had decided against vaccination. HPV knowledge was low (mean 58%). In multivariate analyses, social norms was the strongest correlate of stage; each standard deviation increase in social norms score was associated with more than four times the odds of intending to be vaccinated within the next 30 days, compared with those who had decided against vaccination (OR=4.15: 95% CI 2.17-6.36). Conclusions. Acceptance of the vaccine was high, although misconceptions about viral transmission, availability of treatment, and the role of Pap tests were common. Perceived norms were strongly associated with intentions. Interventions on college campuses should stress vaccination as a normative behavior, provide information about viral transmission, and stress the role of continued Pap screening. (C) 2008 Elsevier Inc. All rights reserved. C1 [Allen, Jennifer D.; Mohllajee, Anshu P.; Shelton, Rachel C.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Allen, Jennifer D.; Fontenot, Holly B.; Hanna, Richard] Boston Coll, Chestnut Hill, MA 02167 USA. [Allen, Jennifer D.; Mohllajee, Anshu P.; Shelton, Rachel C.; Othus, Megan K. D.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hanna, Richard] Northeastern Univ, Boston, MA 02115 USA. RP Allen, JD (reprint author), Boston Coll, William Connell Sch Nursing, 140 Commonwealth Ave, Boston, MA 02167 USA. EM jennifer.allen.5@bc.edu RI Hanna, Richard/A-4342-2010; Allen, Jennifer/M-2113-2015 NR 54 TC 70 Z9 70 U1 4 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD MAY PY 2009 VL 48 IS 5 BP 420 EP 425 DI 10.1016/j.ypmed.2008.12.005 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 451LB UT WOS:000266470600004 PM 19133288 ER PT J AU Wakchoure, S Swain, TM Hentunen, TA Bauskin, AR Brown, DA Breit, SN Vuopala, KS Harris, KW Selander, KS AF Wakchoure, Savita Swain, Telisha Millender Hentunen, Teuvo A. Bauskin, Asne R. Brown, David A. Breit, Samuel N. Vuopala, Katri S. Harris, Kevin W. Selander, Katri S. TI Expression of Macrophage Inhibitory Cytokine-1 in Prostate Cancer Bone Metastases Induces Osteoclast Activation and Weight Loss SO PROSTATE LA English DT Article DE MIC-1; prostate cancer; bone metastases ID TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; TUMOR-CELLS; MAP KINASE; IN-VITRO; MIC-1; SERUM; PROGRESSION AB BACKGROUND. Macrophage inhibitory cytokine-1 (MIC-1) belongs to the bone morphogenic protein/transforming growth factor-beta (BMP/TGF-beta) superfamily. Serum MIC-1 concentrations are elevated in patients with advanced prostate cancer. The effects of MIC-1 on prostate cancer bone metastases are unknown. METHODS. In vitro effects of MIC-1 on osteoblast differentiation and activity were analyzed with alkaline phosphatase and mineralization assays; osteoclast numbers were counted microscopically. MIC-1 effects on TLR9 expression were studied with Western blotting. Human Du-145 prostate cancer cells were stably transfected with a cDNA encoding for mature MIC-1 or with an empty vector. The in vivo growth characteristics of the characterized cells were studied with the intra-tibial model of bone metastasis. Tumor associated bone changes were viewed with X-rays, histology, and histomorphometry. Bone formation was assayed by measuring serum PINP. RESULTS. MIC-1 induced osteoblast differentiation and activity and osteoclast formation in vitro. These effects were independent of TLR9 expression, which was promoted by MIC-1. Both MIC-1 and control tumors induced mixed sclerotic/lytic bone lesions, but MIC-1 increased the osteolytic component of tumors. Osteoclast formation at the tumor-bone interface was significantly higher in the MIC-1 tumors, whereas bone formation was significantly higher in the control mice. At sacrifice, the mice bearing MIC-1 tumors were significantly lighter with significantly smaller tumors. CONCLUSIONS. MIC-1 up-regulates TLR9 expression in various cells. MIC-1 stimulates both osteoblast and osteoclast differentiation in vitro, independently of TLR9. MIC-1 over-expressing prostate cancer cells that grow in bone induce osteoclast formation and cachexia. Prostate 69: 652-661, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Selander, Katri S.] Univ Alabama, Dept Med, Div Hematol Oncol, UAB, Birmingham, AL 35294 USA. [Hentunen, Teuvo A.] Univ Turku, Inst Biomed, Dept Anat, FIN-20520 Turku, Finland. [Bauskin, Asne R.; Brown, David A.; Breit, Samuel N.] St Vincents Hosp, Ctr Immunol, Sydney, NSW 2010, Australia. [Bauskin, Asne R.; Brown, David A.; Breit, Samuel N.] Univ New S Wales, Sydney, NSW, Australia. [Vuopala, Katri S.] Lapland Cent Hosp, Rovaniemi, Finland. [Harris, Kevin W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Selander, KS (reprint author), Univ Alabama, Dept Med, Div Hematol Oncol, UAB, WTI T558,1824 6th Ave S, Birmingham, AL 35294 USA. EM katri.selander@ccc.uab.edu FU National Health & Medical Research Council, Australia; New South Wales Health Research and Development Infrastructure; Department of Defense [W81XWH-05-1-0066] FX National Health & Medical Research Council, Australia; Grant sponsor: New South Wales Health Research and Development Infrastructure; Grant sponsor: Department of Defense; Grant number: W81XWH-05-1-0066. NR 52 TC 32 Z9 36 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY 1 PY 2009 VL 69 IS 6 BP 652 EP 661 DI 10.1002/pros.20913 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 437YU UT WOS:000265523600009 PM 19152406 ER PT J AU Rho, JH Roehrl, MHA Wang, JY AF Rho, Jung-Hyun Roehrl, Michael H. A. Wang, Julia Y. TI Glycoproteomic Analysis of Human Lung Adenocarcinomas Using Glycoarrays and Tandem Mass Spectrometry: Differential Expression and Glycosylation Patterns of Vimentin and Fetuin A Isoforms SO PROTEIN JOURNAL LA English DT Article DE Lung cancer; Lectin affinity; Mass spectrometry; Glycoproteins; Vimentin; Fetuin A ID GROWTH-FACTOR-BETA; N-GLYCANS; PROTEIN GLYCOSYLATION; COLORECTAL-CANCER; TUMOR PROGRESSION; IMMUNE-RESPONSE; ANNEXIN-II; OLIGOSACCHARIDES; ALPHA-2HS-GLYCOPROTEIN; ALPHA-1-ANTITRYPSIN AB Human lung cancer is a major cause of cancer mortality worldwide. Advances in pathophysiologic understanding and novel biomarkers for diagnosis and treatment are significant tasks. We have undertaken a comprehensive glycoproteomic analysis of human lung adenocarcinoma tissues. Glycoproteins from paired lung adenocarcinoma and normal tissues were enriched by the lectins Con A, WGA, and AIL. 2-D PAGE revealed 30 differentially expressed protein spots, and 15 proteins were identified by MS/MS, including 8 up- (A1AT, ALDOA, ANXA1, CALR, ENOA, PDIA1, PSB1 and SODM) and 7 down-regulated (ANXA3, CAH2, FETUA, HBB, PRDX2, RAGE and VIME) proteins in lung cancer. By reverse-transcription PCR, nine proteins showed positive correlation between mRNA and glycoprotein expression. Vimentin and fetuin A (alpha(2)-HS-glycoprotein) were selected for further investigation. While for vimentin there was little correlation between total protein and mRNA abundance, expression of WGA-captured glycosylated vimentin protein was frequently decreased in cancer. Glycoarray analysis suggested that vimentins from normal and cancerous lung tissue differ in their contents of sialic acid and terminal GlcNAc. For fetuin A, both total protein and mRNA abundance showed concordant decrease in cancer. WGA- and AIL-binding glycosylated fetuin A was also consistently decreased in cancer. Glycoarray analysis suggested that high mannose glycan structures on fetuin A were only detectable in cancer but not normal tissue. The intriguing expression patterns of different isoforms of glycosylated vimentin and fetuin A in lung cancer illustrate the complexities and benefits of in-depth glycoproteomic analysis. In particular, the discovery of differentially glycosylated protein isoforms in lung adenocarcinoma may represent avenues towards new functional biomarkers for diagnosis, treatment guidance, and response monitoring. C1 [Roehrl, Michael H. A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Rho, Jung-Hyun; Wang, Julia Y.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Rho, Jung-Hyun; Roehrl, Michael H. A.; Wang, Julia Y.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Roehrl, MHA (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM michael_roehrl@hms.harvard.edu FU NIAID/NIH FX We acknowledge financial support from the NIAID/NIH. We thank Drs. Bin Ye, Brian Liu, and Sam Mok of Brigham and Women's Hospital for use of proteomic equipment. We thank the Taplin Biological Mass Spectrometry Center of Harvard Medical School for expert advice. NR 46 TC 32 Z9 36 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1572-3887 J9 PROTEIN J JI Protein J. PD MAY PY 2009 VL 28 IS 3-4 BP 148 EP 160 DI 10.1007/s10930-009-9177-0 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469LE UT WOS:000267898900005 PM 19412661 ER PT J AU Thomas, JJ Vartanian, LR Brownell, KD AF Thomas, Jennifer J. Vartanian, Lenny R. Brownell, Kelly D. TI The Relationship Between Eating Disorder Not Otherwise Specified (EDNOS) and Officially Recognized Eating Disorders: Meta-Analysis and Implications for DSM SO PSYCHOLOGICAL BULLETIN LA English DT Review DE eating disorder not otherwise specified (EDNOS); eating disorder classification; DSM; Meta-analysis ID SUBTHRESHOLD BULIMIA-NERVOSA; RANDOMIZED CONTROLLED-TRIAL; ANOREXIA-NERVOSA; DIAGNOSTIC-CRITERIA; CHINESE PATIENTS; PERSONALITY-DISORDERS; HONG-KONG; FOLLOW-UP; COMMUNITY SAMPLE; SELF-REPORT AB Eating disorder not otherwise specified (EDNOS) is the most prevalent eating disorder (ED) diagnosis. In this meta-analysis, the authors aimed to inform Diagnostic and Statistical Manual of Mental Disorders revisions by comparing the psychopathology of EDNOS with that of the officially recognized EDs: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). A comprehensive literature search identified 125 eligible studies (Published and unpublished) appearing in the literature from 1987 to 2007. Random effects analyses indicated that whereas EDNOS did not differ significantly from AN and BED on eating pathology or general psychopathology, BN exhibited greater eating and general psychopathology than EDNOS. Moderator analyses indicated that EDNOS groups who met all diagnostic criteria for AN except for amenorrhea did not differ significantly from full syndrome cases. Similarly, EDNOS groups who met all criteria for BN or BED except for binge frequency did not differ significantly from full syndrome cases. Results suggest that EDNOS represents a set of disorders associated with substantial psychological and physiological morbidity. Although certain EDNOS subtypes could be incorporated into existing Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) categories, others-such as purging disorder and non-fat-phobic AN-may be best conceptualized as distinct syndromes. C1 [Thomas, Jennifer J.] Harvard Univ, McLean Hosp, Sch Med, Eating Disorders Ctr, Cambridge, MA 02138 USA. [Thomas, Jennifer J.; Brownell, Kelly D.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Vartanian, Lenny R.] Syracuse Univ, Dept Psychol, Syracuse, NY 13244 USA. RP Thomas, JJ (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, WAC 816D,15 Parkman St, Boston, MA 02114 USA. EM jjthomas@partners.org FU National Institutes of Mental Health; National Research Service [F31MH078394] FX We thank the National Institutes of Mental Health for their financial support of this research project through the auspices of Ruth L. Kirschstein National Research Service Award F31MH078394. We also acknowledge the meticulous work of our study coders, Andres De Los Reyes, Kate A. McLaughlin, and Jessica M. Cronce. Lastly, we thank the investigators who contributed their in-press and unpublished studies for inclusion in our meta-analysis. NR 232 TC 111 Z9 114 U1 10 U2 26 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0033-2909 J9 PSYCHOL BULL JI Psychol. Bull. PD MAY PY 2009 VL 135 IS 3 BP 407 EP 433 DI 10.1037/a0015326 PG 27 WC Psychology; Psychology, Multidisciplinary SC Psychology GA 436RW UT WOS:000265433900006 PM 19379023 ER PT J AU Thomas, JJ Roberto, CA Brownell, KD AF Thomas, J. J. Roberto, C. A. Brownell, K. D. TI Eighty-five per cent of what? Discrepancies in the weight cut-off for anorexia nervosa substantially affect the prevalence of underweight SO PSYCHOLOGICAL MEDICINE LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the Association-of-Behavioral-and-Cognitive-Therapies CY NOV 17, 2007 CL Philadelphia, PA SP Assoc Behav & Cognit Therapies DE Anorexia nervosa; expected body weight; body mass index; DSM-IV criteria for eating disorders; Centers for Disease Control and Prevention (CDC); National Health and Nutrition Examination Survey (NHANES) ID EATING DISORDER PATIENTS; CHINESE PATIENTS; CONTROLLED-TRIAL; DOUBLE-BLIND; HONG-KONG; AMENORRHEA; CRITERION; ADOLESCENTS; FLUOXETINE; CHILDREN AB Background. DSM-IV cites <85% of expected body weight (EBW) as a guideline for the diagnosis of anorexia nervosa (AN) but does not require a specific method for calculating EBW. The purpose of the present Study was to determine the degree to which weight cut-off calculations vary across studies, and to evaluate whether differential cut-offs lead to discrepancies in the prevalence of individuals who are eligible for the AN diagnosis. Method. Two coders independently recorded the EBW Calculation methods from 99 Studies that either (a) compared individuals with AN to those With subclinical eating disorders or (b) conducted AN treatment trials. Each weight Cutoff was applied to a nationally representative (n = 12001) and treatment-seeking (n = 189) sample to determine the impact of EBW calculation on the proportion who met the AN weight criterion. Results. Coders identified 10 different EBW methods, each of which produced different weight cut-offs for the diagnosis of AN. Although only 0.23%, of the national sample met the lowest cut-off, this number increased 43-fold to 10.10% under the highest cut-off. Similarly, only 48.1% of treatment seekers met the lowest cut-off, whereas 89.4%, met the highest. Conclusions. There is considerable variance across studies in the determination of the AN weight cut-off. Discrepancies Substantially affect the proportion of individuals who are eligible for diagnosis, treatment and insurance reimbursement. However, differences may not be fully appreciated because the ubiquitous citation of the 85%, criterion creates a sense of false consensus. C1 [Thomas, J. J.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, J. J.; Roberto, C. A.; Brownell, K. D.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Thomas, J. J.] Harvard Univ, McLean Hosp, Klarman Eating Disorders Ctr, Sch Med, Cambridge, MA 02138 USA. RP Thomas, JJ (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, WAC-816D,15 Parkman St, Boston, MA 02114 USA. EM jjthomas@partners.org FU NIMH NIH HHS [1F31 MH078394, F31 MH078394, F31 MH078394-01, F31 MH078394-02] NR 56 TC 12 Z9 12 U1 4 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD MAY PY 2009 VL 39 IS 5 BP 833 EP 843 DI 10.1017/S0033291708004327 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 438QA UT WOS:000265569200015 PM 18775087 ER PT J AU Zhang, XY Zhou, DF Qi, LY Chen, S Cao, LY Chen, DC Xiu, MH Wang, F Wu, GY Lu, L Kosten, TA Kosten, TR AF Zhang, Xiang Yang Zhou, Dong Feng Qi, Ling Yan Chen, Song Cao, Lian Yuan Chen, Da Chun Xiu, Mei Hong Wang, Fan Wu, Gui Ying Lu, Lin Kosten, Therese A. Kosten, Thomas R. TI Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics SO PSYCHOPHARMACOLOGY LA English DT Article DE Schizophrenia; Immune; Cytokine; Oxidative stress; Antioxidant enzymes; Antipsychotic; Psychopathology ID NEUROLEPTIC-FREE SCHIZOPHRENIA; ANTIOXIDANT DEFENSE SYSTEM; FREE-RADICAL PATHOLOGY; IN-VITRO PRODUCTION; TRANSCRIPTION FACTOR; SERUM INTERLEUKIN-6; TARDIVE-DYSKINESIA; FATTY-ACIDS; CSF LEVELS; DRUG-FREE AB Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels. SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males. Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation. C1 [Zhang, Xiang Yang; Kosten, Thomas R.] Baylor Coll Med, VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Zhou, Dong Feng] Peking Univ, Inst Mental Hlth, Beijing 100083, Peoples R China. [Zhang, Xiang Yang; Qi, Ling Yan; Chen, Song; Cao, Lian Yuan; Chen, Da Chun; Xiu, Mei Hong; Wang, Fan] Beijing HuiLongGuan Hosp, Ctr Biol Psychiat, Beijing 100096, Peoples R China. [Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 10083, Peoples R China. RP Zhang, XY (reprint author), Baylor Coll Med, VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu FU Stanley Medical Institute Foundation [03T-459, 05T-726]; Mental Illness Research, Education and Clinical Center (MIRECC); National Institute on Drug Abuse [K05-DA0454, P50-DA18827] FX This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726; XYZ), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK). NR 55 TC 43 Z9 45 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2009 VL 204 IS 1 BP 177 EP 184 DI 10.1007/s00213-008-1447-6 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 436AT UT WOS:000265385700017 PM 19139851 ER PT J AU Sandt, AR Sloan, DM Johnson, KJ AF Sandt, Arthur R. Sloan, Denise M. Johnson, Kareem J. TI Measuring appetitive responding with the postauricular reflex SO PSYCHOPHYSIOLOGY LA English DT Article DE Emotion; Startle blink; Normal volunteers; EMG; Motivation ID AFFECTIVE STARTLE MODULATION; FEAR-POTENTIATED STARTLE; PREPULSE INHIBITION; EMOTION; ATTENTION; RATS; LY354740; AGONIST; PROBE AB Recent research has provided evidence that the postauricular reflex (PAR) is potentiated while people view pleasant images relative to unpleasant and neutral images. The present study sought to extend these findings by investigating whether the PAR is more robustly modulated by the appetitive salience of the stimuli. Eyeblink startle and PAR responses of 51 participants were recorded while they viewed images that varied in valence and thematic content. Participants displayed significantly greater mean PAR magnitude during appetitive-related images (e.g., food, erotica, families) compared with non-appetitive-related pleasant images. These findings support the contention that the PAR is a useful tool for measuring appetitive responding in humans. C1 [Sloan, Denise M.] Natl Ctr PTSD, VA Boston Healthcare Syst, Boston, MA USA. [Sandt, Arthur R.; Johnson, Kareem J.] Temple Univ, Dept Psychol, Philadelphia, PA USA. [Sloan, Denise M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Sloan, DM (reprint author), Natl Ctr PTSD 116B 2, VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM Denise.Sloan@va.gov OI Sloan, Denise/0000-0002-0962-478X NR 29 TC 12 Z9 12 U1 1 U2 13 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAY PY 2009 VL 46 IS 3 BP 491 EP 497 DI 10.1111/j.1469-8986.2009.00797.x PG 7 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 430SG UT WOS:000265008200007 PM 19496218 ER PT J AU Chao, CP Walker, TG Kalva, SP AF Chao, Christine P. Walker, T. Gregory Kalva, Sanjeeva P. TI Natural History and CT Appearances of Aortic Intramural Hematoma SO RADIOGRAPHICS LA English DT Article ID MULTIDETECTOR ROW CT; THORACIC AORTA; IMAGING FEATURES; RETROPERITONEAL FIBROSIS; ATHEROSCLEROTIC ULCER; IMPENDING RUPTURE; ASCENDING AORTA; HELICAL CT; DISSECTION; DIAGNOSIS AB Rupture of the vasa vasorum into the media of the aortic wall results in an aortic intramural hematoma. Characteristic findings of an aortic intramural hematoma include a crescentic hyperattenuating fluid collection at unenhanced computed tomography (CT) and a smooth, nonenhancing, thickened aortic wall at contrast material-enhanced CT. The CT appearance of untreated intramural hematomas evolves over time, and decreased attenuation is a clue to the chronicity of a hematoma. CT is particularly useful for evaluating aortic intramural hematomas because it allows their differentiation from aortic dissections, which have similar clinical manifestations, and permits an exact determination of their location-crucial information for surgical planning. On the basis of CT findings, some hematomas may be expected to resolve spontaneously, whereas others may be identified as posing a high risk for serious complications such as aortic dissection, aneurysm, and rupture. Appropriate clinical management is aided by accurate recognition of diagnostically specific CT features and awareness of their significance. (C) RSNA, 2009. radiographics.rsnajnls.org C1 [Chao, Christine P.; Walker, T. Gregory; Kalva, Sanjeeva P.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Chao, CP (reprint author), Kaiser Permanente, 99 Montecillo Rd, San Rafael, CA 94903 USA. EM c.chao.md@gmail.com NR 37 TC 37 Z9 43 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAY-JUN PY 2009 VL 29 IS 3 BP 791 EP 804 DI 10.1148/rg.293085122 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 455UC UT WOS:000266790800014 PM 19448116 ER PT J AU Dupuis, CS Westra, SJ Makris, J Wallace, EC AF Dupuis, Carolyn S. Westra, Sjirk J. Makris, Joseph Wallace, E. Christine TI Injuries and Conditions of the Extensor Mechanism of the Pediatric Knee SO RADIOGRAPHICS LA English DT Article; Proceedings Paper CT 93rd Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2007 CL Chicago, IL SP Radiol Soc N Amer ID AVULSION FRACTURES; SLEEVE FRACTURE; CHILDREN; PATELLA AB The extensor mechanism of the knee is essential to ambulation and is subject to a number of traumatic, congenital, and inflammatory processes. In the pediatric population, the spectrum of pathologic conditions affecting the extensor mechanism is specific to skeletally immature patients. In addition, certain congenital and developmental disorders may further predispose the knee extensor mechanism to injury. The pathologic processes can be subdivided into categories: conditions of the attachments and insertions of the quadriceps and patellar tendons, conditions of the patella, conditions of the quadriceps muscle group, and avulsions of the superior attachments of the quadriceps. Cases of conditions affecting the extensor mechanism of the pediatric knee were collected at two large trauma centers, and the clinical and radiologic features were reviewed. Initial evaluation of these conditions is performed with radiography, but magnetic resonance imaging has evolved into a useful adjunct for assessing the soft tissues for a more precise evaluation of the true extent of an injury, thereby affecting decisions about surgical intervention and prognosis. (C) RSNA, 2009. radiographics.rsnajnls.org C1 [Dupuis, Carolyn S.] Univ Massachusetts, Sch Med, Dept Radiol, Worcester, MA 01655 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Dupuis, CS (reprint author), Univ Massachusetts, Sch Med, Dept Radiol, 55 Lake Ave N, Worcester, MA 01655 USA. EM dupuisc@ummhc.org NR 17 TC 19 Z9 20 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAY-JUN PY 2009 VL 29 IS 3 BP 877 EP 886 DI 10.1148/rg.293085163 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 455UC UT WOS:000266790800020 PM 19448122 ER PT J AU Sosnovik, DE AF Sosnovik, David E. TI Will Molecular MR Imaging Play a Role in Identification and Treatment of Patients with Vulnerable Atherosclerotic Plaques? SO RADIOLOGY LA English DT Article AB Although the translation of experimental molecular MR imaging agents is highly compelling, it is substantially more complex than the translation of radiolabeled imaging agents. The prognostic value, safety, and cost-effectiveness of molecular MR imaging for the detection of plaque inflammation will need to be demonstrated and will require a robust and collaborative effort among basic scientists, clinicians, epidemiologists, and industry. The well-conducted and valuable study reported by Amirbekian et al (1) in this issue of Radiology adds further momentum to this important endeavor. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res,Dept Radiol, Boston, MA 02129 USA. RP Sosnovik, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res,Dept Radiol, 149 13th St, Boston, MA 02129 USA. EM sosnovik@nmr.mgh.harvard.edu NR 8 TC 2 Z9 3 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2009 VL 251 IS 2 BP 309 EP 310 DI 10.1148/radiol.2512090268 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QW UT WOS:000265643100001 PM 19401565 ER PT J AU Rybak, LD Rosenthal, DI Wittig, JC AF Rybak, Leon D. Rosenthal, Daniel I. Wittig, James C. TI Chondroblastoma: Radiofrequency Ablation-Alternative to Surgical Resection in Selected Cases SO RADIOLOGY LA English DT Article ID METASTASES INVOLVING BONE; OSTEOID OSTEOMA; ELECTRODE AB Purpose: To demonstrate that radiofrequency (RF) ablation can be used safely and effectively to treat selected cases of chondroblastoma. Materials and Methods: Approval was obtained from institutional review boards, research was in compliance with HIPAA protocol. The need to obtain informed consent was waived for retrospective review of patient records. The records of patients with biopsy-proved chondroblastoma who were treated with RF ablation at two academic centers from July 1995 to July 2007 were reviewed. RF ablation was performed with a single-tip electrode by using computed tomography for guidance. Lesion characteristics were determined from imaging studies obtained at the time of the procedure. Symptoms were assessed before and 1 day after the procedure. Longer-term follow-up was obtained from medical records. Results: Thirteen male and four female patients were treated (mean age, 17.3 years). The lesions were located in the proximal humerus (n = 7), proximal tibia (n = 4), proximal femur (n = 3), and distal femur (n = 3). The mean volume of the lesions was 2.46 mL. All patients reported relief of symptoms on postprocedure day 1. Three patients were lost to follow-up. Of the 14 patients for whom longer-term (mean, 41.3 months; range, 4-134 months) follow-up was available, 12 had complete relief of symptoms with no need for medications and full return to all activities. The patient who had the largest lesion of the study required surgical intervention because of collapse of the articular surface in the treatment area. Residual viable tumor was found at surgery. Another patient experienced mechanical problems that were thought to be unrelated to the RF ablation and was rendered pain-free after subsequent surgical treatment. Conclusion: Percutaneous RF ablation is an alternative to surgery for treatment of selected chondroblastomas. Larger lesions beneath weight-bearing surfaces should be approached with caution due to an increased risk of articular collapse and recurrence. C1 [Rybak, Leon D.] NYU, Hosp Joint Dis, Dept Radiol, New York, NY 10003 USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wittig, James C.] Mt Sinai Med Ctr, Dept Orthoped Surg, New York, NY 10029 USA. RP Rybak, LD (reprint author), NYU, Hosp Joint Dis, Dept Radiol, 301 E 17th St,6th Floor, New York, NY 10003 USA. EM Leon.rybak@med.nyu.edu OI RYBAK, Leon/0000-0003-0467-577X NR 16 TC 35 Z9 37 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2009 VL 251 IS 2 BP 599 EP 604 DI 10.1148/radiol.2512080500 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QW UT WOS:000265643100036 PM 19304917 ER PT J AU Liu, SS Wu, CL Ballantyne, JC Buvanendran, A Rathmell, JP Warren, DT Viscusi, ER Ginsberg, B Rosenquist, RW Yadeau, JT Liguori, GA AF Liu, Spencer S. Wu, Christopher L. Ballantyne, Jane C. Buvanendran, Asokumar Rathmell, James P. Warren, Daniel T. Viscusi, Eugene R. Ginsberg, Brian Rosenquist, Richard W. Yadeau, Jacques T. Liguori, Gregory A. TI Where in the World Is ASRA AcutePOP? SO REGIONAL ANESTHESIA AND PAIN MEDICINE LA English DT Article AB Progress continues on American Society of Regional Anesthesia (ASRA) AcutePOP Highlights include selection of data fields and creation of definitions for complications jointly accepted by clinical registries for ASRA, American Society of Anesthesiologists, Regional Anesthesia Surveillance System, Society for Obstetric Anesthesia and Perinatology, and Society for Pediatric Anesthesia. Development of a Web site and applications continues, and a demonstration is planned for the ASRA 2009 meeting. C1 [Liu, Spencer S.; Yadeau, Jacques T.; Liguori, Gregory A.] Hosp Special Surg, Dept Anesthesiol, New York, NY 10021 USA. [Liu, Spencer S.; Yadeau, Jacques T.; Liguori, Gregory A.] Weill Cornell Med Coll, New York, NY USA. [Wu, Christopher L.] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Ballantyne, Jane C.] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Buvanendran, Asokumar] Rush Univ, Med Ctr, Dept Anesthesiol, Chicago, IL 60612 USA. [Rathmell, James P.] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Warren, Daniel T.] Virginia Mason Med Ctr, Dept Anesthesiol, Seattle, WA 98101 USA. [Warren, Daniel T.] Univ Washington, Seattle, WA 98195 USA. [Viscusi, Eugene R.] Thomas Jefferson Univ, Dept Anesthesiol, Philadelphia, PA 19107 USA. [Ginsberg, Brian] Duke Univ, Dept Anesthesiol, Durham, NC USA. [Rosenquist, Richard W.] Univ Iowa, Dept Anesthesia, Iowa City, IA 52242 USA. RP Liu, SS (reprint author), Hosp Special Surg, Dept Anesthesiol, 535 E 70th St, New York, NY 10021 USA. EM iusp@hss.edu NR 2 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-7339 J9 REGION ANESTH PAIN M JI Region. Anesth. Pain Med. PD MAY-JUN PY 2009 VL 34 IS 3 BP 269 EP 274 DI 10.1097/AAP.0b013e3181a39597 PG 6 WC Anesthesiology SC Anesthesiology GA 444FH UT WOS:000265965600019 PM 19591261 ER PT J AU Levitt, JJ Styner, M Niethammer, M Bouix, S Koo, MS Voglmaier, MM Dickey, CC Niznikiewicz, MA Kikinis, R McCarley, RW Shenton, ME AF Levitt, James J. Styner, Martin Niethammer, Marc Bouix, Sylvain Koo, Min-Seong Voglmaier, Martina M. Dickey, Chandlee C. Niznikiewicz, Margaret A. Kikinis, Ron McCarley, Robert W. Shenton, Martha E. TI Shape abnormalities of caudate nucleus in schizotypal personality disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizotypal personality disorder; Caudate nucleus; Striatum; MRI; Shape; Spherical harmonics ID ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; BASAL GANGLIA VOLUMES; ADULT HUMAN BRAIN; NEUROLEPTIC-NAIVE; SCHIZOPHRENIC-PATIENTS; MORPHOMETRIC-ANALYSIS; ANTIPSYCHOTIC-DRUGS; HUMAN STRIATUM; MRI DATA AB Background: Previously, we reported abnormal volume and global shape in the caudate nucleus in schizotypal personality disorder (SPD). Here, we use a new shape measure which importantly permits local in addition to global shape analysis, as well as local correlations with behavioral measures. Methods: Thirty-two female and 15 male SPDs, and 29 female and 14 male normal controls (NCLs), underwent brain magnetic resonance imaging (MRI). We assessed caudate shape measures using spherical harmonic-point distribution model (SPHARM-PDM) methodology. Results: We found more pronounced global shape differences in the right caudate in male and female SPD, compared with NCLs. Local shape differences, principally in the caudate head, survived statistical correction on the right. Also, we performed correlations between local surface deformations with clinical measures and found significant correlations between local shape deflated deformations in the anterior medial surface of the caudate with verbal learning capacity in female SPD. Conclusions: Using SPHARM-PDM methodology, we found both global and local caudate shape abnormalities in male and female SPD, particularly right-sided, and largely restricted to limbic and cognitive anterior caudate. The most important and novel findings were bilateral statistically significant correlations between local surface deflations in the anterior medial surface of the head of the caudate and verbal learning capacity in female SPD. By extension, these local caudate correlation findings implicate the ventromedial prefrontal cortex (vmPFC), which innervates that area of the caudate, and demonstrate the utility of local shape analysis to investigate the relationship between specific subcortical and cortical brain structures in neuropsychiatric conditions. (c) 2008 Published by Elsevier B.V. C1 [Levitt, James J.; Voglmaier, Martina M.; Dickey, Chandlee C.; Niznikiewicz, Margaret A.; McCarley, Robert W.; Shenton, Martha E.] Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Psychiat,Brockton Div,Lab Neurosci, Brockton, MA 02301 USA. [Levitt, James J.; Bouix, Sylvain; Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Kikinis, Ron; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Radiol, Surg Planning Lab,Magnet Resonance Imaging Div, Boston, MA 02115 USA. [Styner, Martin; Niethammer, Marc] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA. [Styner, Martin; Niethammer, Marc] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Koo, Min-Seong] Kwandong Univ, Coll Med, Seoul, South Korea. [Voglmaier, Martina M.] Cambridge Hlth Alliance, Dept Psychiat, Cambridge, MA USA. RP Levitt, JJ (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Psychiat 116A, 940 Belmont St, Brockton, MA 02301 USA. EM james_levitt@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Styner, Martin/0000-0002-8747-5118; Bouix, Sylvain/0000-0003-1326-6054 FU National Institute of Health [K05MH070047, R01 MH50740, R01 MH 40799, R01 MH 052807, U54 EB005149, P50MH080272] FX This work was supported in part by Department of Veteran Affairs Awards (Merits, JJL, MES, RWM: Research Enhancement Award Program, RWM, MES), and National Institute of Health grants K05MH070047 and R01 MH50740 (MES) and R01 MH 40799 and R01 MH 052807 (RWM), Grant U54 EB005149 (RK, CC, MES, MS, MR), P50MH080272 (RWM MES, MK,SB). NR 63 TC 20 Z9 20 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAY PY 2009 VL 110 IS 1-3 BP 127 EP 139 DI 10.1016/j.schres.2008.11.012 PG 13 WC Psychiatry SC Psychiatry GA 463MZ UT WOS:000267437600016 PM 19328654 ER PT J AU Niznikiewicz, MA Spencer, KM Dickey, C Voglmaier, M Seidman, LJ Shenton, ME McCarley, RW AF Niznikiewicz, Margaret A. Spencer, Kevin M. Dickey, Chandlee Voglmaier, Martina Seidman, Larry J. Shenton, Martha E. McCarley, Robert W. TI Abnormal pitch mismatch negativity in individuals with schizotypal personality disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article DE MMN; SPD; Schizophrenia; Auditory processing; Auditory cortex ID AUDITORY SENSORY MEMORY; CHRONIC-SCHIZOPHRENIA; GYRUS VOLUME; GENERATION; DEFICITS; 1ST-EPISODE; ONSET; DYSFUNCTION; POTENTIALS; MODULATION AB Background: The goal of the study was to examine mismatch negativity (MMN) in schizotypal personality disorder (SPD) individuals. Abnormal MMN has been a consistent finding in chronic schizophrenia and there also have been reports of reduced duration MMN in first episode schizophrenia patients [Umbricht, D., Krljes, S., Mismatch negativity in schizophrenia: a meta-analysis. Schizophrenia Research (2005); 76(1):1-23], with some studies finding no pitch MMN amplitude differences [Salisbury, D.F., Shenton, M.E., Griggs, C.B., Bonner-Jackson, A., McCarley, R.W., Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Archives of General Psychiatry (2002); 59(8):686-694.], while others reporting a modest reduction [Umbricht, D.S., Bates, J.A., Lieberman, J.A., Kane, J.M., Javitt, D.C., Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biological Psychiatry (2006); 59(8):762-772], in recent onset schizophrenia patients. To our knowledge no reports exist of MMN in SPD individuals. Methods: Twenty six normal (14 females) control and 23 SPD (12 females) individuals were tested using the pitch MMN paradigm. Normal control (NC) and SPD individuals were recruited from the general population and assessed using DSM-IV. SPD individuals were included if they met 5 or more criteria for SPD disorder. The subjects listened to 2000 frequent 1 kHz pure tones and 100 rare 1.2 kHz pure tones while reading a magazine article. MMN was measured from a difference waveform within the latency window of 175-276 ms. Results: Reduced MMN amplitude was found in SPD relative to NC subjects (p < 0.045). Conclusions: These results point to potential differences between SPD and schizophrenia, where no reduction in MMN was found in most studies of first episode patients. Published by Elsevier B.V. C1 [Niznikiewicz, Margaret A.; Spencer, Kevin M.; Dickey, Chandlee; Voglmaier, Martina; Seidman, Larry J.; Shenton, Martha E.; McCarley, Robert W.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Brockton, MA 02301 USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Boston VA Healthcare Syst, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston VA Healthcare Syst, Boston, MA 02114 USA. RP Niznikiewicz, MA (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Psychiat 116A,940 Belmont St, Brockton, MA 02301 USA. EM margaret_niznikiewicz@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Spencer, Kevin/0000-0002-5500-7627 FU MAN [R01 MH 63360]; RWM [R01 MH 52807] FX The research has been funded with grants awarded to MAN (R01 MH 63360) and to RWM (R01 MH 52807). The NIMH had no further role in study design: in the collection, analysis and interpretation of the data; in the writing ofthe report: and in the decision to submit the paper for publication. NR 41 TC 16 Z9 16 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAY PY 2009 VL 110 IS 1-3 BP 188 EP 193 DI 10.1016/j.schres.2008.10.017 PG 6 WC Psychiatry SC Psychiatry GA 463MZ UT WOS:000267437600023 PM 19327968 ER PT J AU Livingston, DM AF Livingston, David M. TI Complicated Supercomplexes SO SCIENCE LA English DT Editorial Material ID CANCER SUSCEPTIBILITY GENE; BREAST-CANCER; FANCONI-ANEMIA; PALB2; MUTATIONS; PARTNER C1 [Livingston, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. [Livingston, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. EM david_livingston@dfci.harvard.edu NR 14 TC 12 Z9 12 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 1 PY 2009 VL 324 IS 5927 BP 602 EP 603 DI 10.1126/science.1174839 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 439DW UT WOS:000265608800031 PM 19407191 ER PT J AU Schweitzer, MH Zheng, WX Organ, CL Avci, R Suo, ZY Freimark, LM Lebleu, VS Duncan, MB Heiden, MGV Neveu, JM Lane, WS Cottrell, JS Horner, JR Cantley, LC Kalluri, R Asara, JM AF Schweitzer, Mary H. Zheng, Wenxia Organ, Chris L. Avci, Recep Suo, Zhiyong Freimark, Lisa M. Lebleu, Valerie S. Duncan, Michael B. Heiden, Matthew G. Vander Neveu, John M. Lane, William S. Cottrell, John S. Horner, John R. Cantley, Lewis C. Kalluri, Raghu Asara, John M. TI Biomolecular Characterization and Protein Sequences of the Campanian Hadrosaur B. canadensis SO SCIENCE LA English DT Article ID TYRANNOSAURUS-REX; SOFT-TISSUE; CELLULAR PRESERVATION; MASS-SPECTROMETRY; IDENTIFICATION; MASTODON; BONE; OSTEOCYTE; BACTERIAL; COLLAGEN AB Molecular preservation in non-avian dinosaurs is controversial. We present multiple lines of evidence that endogenous proteinaceous material is preserved in bone fragments and soft tissues from an 80-million-year-old Campanian hadrosaur, Brachylophosaurus canadensis [Museum of the Rockies (MOR) 2598]. Microstructural and immunological data are consistent with preservation of multiple bone matrix and vessel proteins, and phylogenetic analyses of Brachylophosaurus collagen sequenced by mass spectrometry robustly support the bird-dinosaur clade, consistent with an endogenous source for these collagen peptides. These data complement earlier results from Tyrannosaurus rex (MOR 1125) and confirm that molecular preservation in Cretaceous dinosaurs is not a unique event. C1 [Schweitzer, Mary H.; Zheng, Wenxia] N Carolina State Univ, Raleigh, NC 27695 USA. [Schweitzer, Mary H.] N Carolina Museum Nat Sci, Raleigh, NC 27601 USA. [Organ, Chris L.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Avci, Recep; Suo, Zhiyong] Montana State Univ, Imaging & Chem Anal Lab, Bozeman, MT 59717 USA. [Freimark, Lisa M.; Cantley, Lewis C.; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Lebleu, Valerie S.; Duncan, Michael B.; Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Div Matrix Biol, Boston, MA 02115 USA. [Lebleu, Valerie S.; Duncan, Michael B.; Kalluri, Raghu] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Heiden, Matthew G. Vander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Neveu, John M.; Lane, William S.] Harvard Univ, Ctr Syst Biol, Fac Arts & Sci, Cambridge, MA 02138 USA. [Cottrell, John S.] Matrix Sci Ltd, London W1U 7GB, England. [Horner, John R.] Museum Rockies, Bozeman, MT 59717 USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Kalluri, Raghu] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Cambridge, MA 02139 USA. [Kalluri, Raghu] Harvard Univ, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Asara, John M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Schweitzer, MH (reprint author), N Carolina State Univ, Raleigh, NC 27695 USA. EM schweitzer@ncsu.edu; jasara@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014; LeBleu, Valerie /E-2991-2015; Kalluri, Raghu/E-2677-2015 OI Cantley, Lewis/0000-0002-1298-7653; Kalluri, Raghu/0000-0002-2190-547X FU NSF [EAR 0722702, EAR 0634136, EAR 0548847, EAR-0541744]; David and Lucile Packard Foundation; United Negro College Fund Merck Postdoctoral Science Research Fellowship; Taplin Funds for Discovery (Harvard Medical School); NASA Expermental Project to Simulate Competitive Research [NCC5-579]; Damon Runyon Cancer Research Foundation; NIH [DK 55001, DK 62987, AA 13913, DK 61866, CA 125550]; Department of Medicine for the Division of Matrix Biology at the Beth Israel Deaconess Medical Center FX We acknowledge funding from NSF [awards EAR 0722702 and EAR 0634136 (J.M.A.) and EAR 0548847 and EAR-0541744 (M.H.S.)]; the David and Lucile Packard Foundation (M.H.S.); United Negro College Fund Merck Postdoctoral Science Research Fellowship (M.B.D.); the Taplin Funds for Discovery (Harvard Medical School); partial support by NASA Expermental Project to Simulate Competitive Research under grant NCC5-579 (R.A. and Z.S.); Damon Runyon Cancer Research Foundation (M.G.V.H.); NIH grants DK 55001, DK 62987, AA 13913, DK 61866, and CA 125550; and the Department of Medicine for the Division of Matrix Biology at the Beth Israel Deaconess Medical Center. Correspondence and requests for materials should be addressed to M.H.S. for biochemical and morphological analyses and to J.M.A. for mass spectrometry and molecular phylogenetics analyses. NR 24 TC 80 Z9 85 U1 3 U2 40 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 1 PY 2009 VL 324 IS 5927 BP 626 EP 631 DI 10.1126/science.1165069 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 439DW UT WOS:000265608800039 PM 19407199 ER PT J AU Serneels, L Van Biervliet, J Craessaerts, K Dejaegere, T Horre, K Van Houtvin, T Esselmann, H Paul, S Schafer, MK Berezovska, O Hyman, BT Sprangers, B Sciot, R Moons, L Jucker, M Yang, ZX May, PC Karran, E Wiltfang, J D'Hooge, R De Strooper, B AF Serneels, Lutgarde Van Biervliet, Jerome Craessaerts, Katleen Dejaegere, Tim Horre, Katrien Van Houtvin, Tine Esselmann, Hermann Paul, Sabine Schaefer, Martin K. Berezovska, Oksana Hyman, Bradley T. Sprangers, Ben Sciot, Raf Moons, Lieve Jucker, Mathias Yang, Zhixiang May, Patrick C. Karran, Eric Wiltfang, Jens D'Hooge, Rudi De Strooper, Bart TI gamma-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease SO SCIENCE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; MODERATE REDUCTION; TRANSGENIC MODEL; IN-VIVO; MICE; PRESENILIN-1; COMPLEXES; DEFICIENCY; EXPRESSION; CLEAVAGE AB The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease. C1 [Serneels, Lutgarde; Van Biervliet, Jerome; Craessaerts, Katleen; Dejaegere, Tim; Horre, Katrien; Van Houtvin, Tine; De Strooper, Bart] Katholieke Univ Leuven VIB, Dept Mol & Dev Genet, B-3000 Louvain, Belgium. [Serneels, Lutgarde; Van Biervliet, Jerome; Craessaerts, Katleen; Dejaegere, Tim; Horre, Katrien; Van Houtvin, Tine; De Strooper, Bart] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium. [Esselmann, Hermann; Paul, Sabine; Wiltfang, Jens] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany. [Esselmann, Hermann; Paul, Sabine; Wiltfang, Jens] Univ Duisburg Essen, Rhine State Hosp Essen, Dept Psychiat & Psychotherapy, D-45147 Essen, Germany. [Schaefer, Martin K.] Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-35032 Marburg, Germany. [Berezovska, Oksana; Hyman, Bradley T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Disorders, Charlestown, MA 02129 USA. [Sprangers, Ben] Katholieke Univ Leuven, Lab Expt Transplantat, B-3000 Louvain, Belgium. [Sciot, Raf] Katholieke Univ Leuven, Lab Morphol & Mol Pathol, B-3000 Louvain, Belgium. [Moons, Lieve] Katholieke Univ Leuven, Lab Neural Circuit Dev & Regenerat, Dept Biol, B-3000 Louvain, Belgium. [Jucker, Mathias] Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. [Yang, Zhixiang; May, Patrick C.] Eli Lilly & Co, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. [Karran, Eric] Lilly Res Ctr Ltd, Windlesham GU20 6PH, Surrey, England. [D'Hooge, Rudi] Katholieke Univ Leuven, Dept Psychol, Lab Biol Psychol, B-3000 Louvain, Belgium. RP De Strooper, B (reprint author), Katholieke Univ Leuven VIB, Dept Mol & Dev Genet, Herestr 49, B-3000 Louvain, Belgium. EM bart.destrooper@med.kuleuven.be RI De Strooper, Bart/F-6507-2012; OI De Strooper, Bart/0000-0001-5455-5819; Wiltfang, Jens/0000-0003-1492-5330 FU Alzheimers Association; Fund for Scientific Research Flanders; KULeuven (Geconcerteerde onderzoeksacties); Federal Office for Scientific Affairs, Belgium; Flemish Government [Methusalem]; MEMOSAD of the European Union [F2-2007-200611]; NIH [P01AG015379, R01AG026593, AG026593, AG 13579] FX We thank C. Peeters for assistance in pathological evaluations, C. Mathieu for FACS analysis, L. Van Aerschot for assistance with behavioral testing, S. Terclavers and H. Schieb for technical assistance, and A. Thathiah for proofreading the manuscript. This work was supported by a Pioneer award from the Alzheimers Association; the Fund for Scientific Research Flanders (to R.D. and B.D.S.); KULeuven (Geconcerteerde onderzoeksacties); Federal Office for Scientific Affairs, Belgium; a Methusalem grant of the Flemish Government; MEMOSAD (F2-2007-200611) of the European Union; and NIH grants P01AG015379, R01AG026593, and AG026593 (to B.T.H.) and NIH AG 13579 (to B.T.H. and O.B.). B.D.S. is a paid consultant for Eli Lilly and Envivo Pharmaceuticals; B.T.H. is a paid consultant for Elan, Genentech, Pfizer, Takeda, Link, and Neurophage. NR 24 TC 124 Z9 135 U1 2 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 1 PY 2009 VL 324 IS 5927 BP 639 EP 642 DI 10.1126/science.1171176 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 439DW UT WOS:000265608800043 PM 19299585 ER PT J AU Ng, AKL Wang, JH Shaw, PC AF Ng, Andy Ka-Leung Wang Jia-Huai Shaw, Pang-Chui TI Structure and sequence analysis of influenza A virus nucleoprotein SO SCIENCE IN CHINA SERIES C-LIFE SCIENCES LA English DT Review DE Influenza H5N1; nucleoprotein; oligomerization; RNA binding ID RNA-BINDING; MUTATIONAL ANALYSIS; AVIAN INFLUENZA; IDENTIFICATION; OLIGOMERIZATION; TRANSCRIPTION; REPLICATION; POLYMERASE; PANHANDLE; COMPLEX AB Influenza A virus nucleoprotein (NP) forms homo-oligomers and multiple copies of NP wrap around genomic RNA, along with a trimeric polymerase making up ribonucleoprotein (RNP) complex. Sequence comparison of more than 2500 influenza A NP showed that this protein contains 30.1 % of polymorphic residues. NP is composed of a head and a body domain and a tail loop/ linker region. The head domain is more conserved than the body domain, as revealed from the structure-based sequence alignment. NP oligomerization is mediated by the insertion of the non-polymorphic and structurally conserved tail loop of one NP molecule to a groove of another NP. The different form of NP oligomers is due to the flexibility of the polymorphic linkers that join the tail loop to the rest of the protein. The RNA binding property of NP is known to involve the protruding element and the flexible basic loop between the head and body domains, both having high degree of primary sequence conservation. To bind RNA, NP may first capture the RNA by the flexible basic loop and then the RNA is clamped by the protruding element. C1 [Ng, Andy Ka-Leung; Shaw, Pang-Chui] Chinese Univ Hong Kong, Dept Biochem, Mol Biotechnol Programme, Shatin, Hong Kong, Peoples R China. [Ng, Andy Ka-Leung; Shaw, Pang-Chui] Chinese Univ Hong Kong, Ctr Prot Sci & Crystallog, Shatin, Hong Kong, Peoples R China. [Wang Jia-Huai] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Dana Farber Canc Inst,Dept Pediat, Boston, MA 02115 USA. RP Shaw, PC (reprint author), Chinese Univ Hong Kong, Dept Biochem, Mol Biotechnol Programme, Shatin, Hong Kong, Peoples R China. EM pcshaw@cuhk.edu.hk NR 36 TC 30 Z9 35 U1 2 U2 10 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1006-9305 J9 SCI CHINA SER C JI Sci. China Ser. C-Life Sci. PD MAY PY 2009 VL 52 IS 5 BP 439 EP 449 DI 10.1007/s11427-009-0064-x PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 451FW UT WOS:000266457100006 PM 19471866 ER PT J AU Meeker, JD Johnson, PI Camann, D Hauser, R AF Meeker, John D. Johnson, Paula I. Camann, David Hauser, Russ TI Polybrominated diphenyl ether (PBDE) concentrations in house dust are related to hormone levels in men SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Endocrine disruption; Exposure; Flame retardant; Human; Male ID BROMINATED FLAME RETARDANTS; VOLUME SURFACE SAMPLER; DEVELOPMENTAL EXPOSURE; INDOOR AIR; MIXTURE; METABOLITES; PESTICIDES; DE-71; RATS AB Despite documented widespread human exposure to polybrominated diphenyl ethers (PBDEs) through dietary intake and contact with or inhalation of indoor dust, along with growing laboratory evidence for altered endocrine function following exposure, human Studies of PBDE exposure and endocrine effects remain limited. We conducted a preliminary study within an ongoing study on the impact of environmental exposures on male reproductive health. We measured serum hormone levels and PBDE concentrations (BDE 47, 99 and 100) in house dust from 24 men recruited through a US infertility clinic. BDE 47 and 99 were detected in 100% of dust samples, and BDE 100 was detected in 67% of dust samples, at concentrations similar to those reported in previous US studies. In multivariable regression models adjusted for age and BMI, there was a statistically significant inverse relationship between dust PBDE concentrations and free androgen index. Dust PBDE concentrations were also strongly and inversely associated with luteinizing hormone (LH) and follicle stimulating hormone (FSH), and positively associated with inhibin B and sex hormone binding globulin (SHBG). Finally, consistent with limited recent human studies of adults, PBDEs were positively associated with free T4. In conclusion, the present study provides compelling evidence of altered hormone levels in relation to PBDE exposures estimated as concentrations in house dust, and that house dust is an important source of human PBDE exposure, but more research is urgently needed. (C) 2009 Elsevier B.V. All rights reserved. C1 [Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Camann, David] SW Res Inst, San Antonio, TX USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Androl Lab, Vincent Mem Obstet & Gynecol Serv, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, In Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 6635 SPH Tower,109 S Observ St, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Meeker, John/0000-0001-8357-5085 FU National Institute of Environmental Health Sciences (NIEHS) [ES009718, ES00002]; National Institutes of Health (NIH) FX This work was supported by grant ES009718 and ES00002 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). NR 39 TC 125 Z9 134 U1 6 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD MAY 1 PY 2009 VL 407 IS 10 BP 3425 EP 3429 DI 10.1016/j.scitotenv.2009.01.030 PG 5 WC Environmental Sciences SC Environmental Sciences & Ecology GA 437VV UT WOS:000265515900021 PM 19211133 ER PT J AU Khademhosseini, A Vacanti, JP Langer, R AF Khademhosseini, Ali Vacanti, Joseph P. Langer, Robert TI PROGRESS IN TISSUE ENGINEERING SO SCIENTIFIC AMERICAN LA English DT Article C1 [Khademhosseini, Ali] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Khademhosseini, Ali; Vacanti, Joseph P.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Vacanti, Joseph P.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Langer, Robert] MIT, Cambridge, MA 02139 USA. RP Khademhosseini, A (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RI Khademhosseini, Ali/A-9435-2010 OI Khademhosseini, Ali/0000-0002-2692-1524 NR 4 TC 167 Z9 174 U1 4 U2 80 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD MAY PY 2009 VL 300 IS 5 BP 64 EP + PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 434LO UT WOS:000265276400035 PM 19438051 ER PT J AU Mount, DB AF Mount, David B. TI Hyponatremia: Introduction SO SEMINARS IN NEPHROLOGY LA English DT Editorial Material ID NONCARDIOGENIC PULMONARY-EDEMA; BRAIN-BARRIER DISRUPTION; INAPPROPRIATE ANTIDIURESIS; NEPHROGENIC SYNDROME; INADVERTENT OVERCORRECTION; INDUCED DEMYELINATION; ENCEPHALOPATHY; RATS; MICE; ASSOCIATION C1 [Mount, David B.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Mount, David B.] Harvard Univ, Sch Med, Div Renal, VA Boston Healthcare Syst, Boston, MA USA. RP Mount, DB (reprint author), Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. NR 27 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2009 VL 29 IS 3 BP 175 EP 177 DI 10.1016/j.semnephrol.2009.03.007 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 461AX UT WOS:000267237000001 PM 19523567 ER PT J AU Mount, DB AF Mount, David B. TI The Brain in Hyponatremia: Both Culprit and Victim SO SEMINARS IN NEPHROLOGY LA English DT Review DE Vasopressin; thirst; magnocellular; TRP1; TRP4; cell volume; aquaporin; K-Cl cotransport; osmotic demyelination; hyponatremia ID CENTRAL PONTINE MYELINOLYSIS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; ESTROGEN-RECEPTOR-BETA; NONCARDIOGENIC PULMONARY-EDEMA; PLASMA VASOPRESSIN RESPONSE; NONSELECTIVE CATION CHANNEL; CONVERTING ENZYME-INHIBITOR; NORMAL THIRST RESPONSES; PITUITARY-ADRENAL AXIS; CELL-VOLUME REGULATION AB Abnormalities in thirst and vasopressin (AVP) release play key roles in the genesis of hyponatremia; both processes are under the control of osmoreceptive neurons in the central nervous system (CNS). The acute development of hyponatremia ill turn leads to profound cerebral edema, whereas treatment of chronic hyponatremia call be associated with osmotic demyelination syndrome (ODS). The brain is thus both "culprit" and "victim" in hyponatremia. This review Summarizes recent advances in the understanding of osmoreception in the brain, the CNS response to acute and chronic hyponatremia, and the pathophysiology of ODS. Semin Nephrol 29:196-215 (C) 2009 Elsevier Inc. All rights reserved. C1 [Mount, David B.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Mount, David B.] Harvard Univ, Sch Med, Div Renal, VA Boston Healthcare Syst, Boston, MA USA. RP Mount, DB (reprint author), Brigham & Womens Hosp, Div Renal, Room 540,4 Blackfan Circle, Boston, MA 02115 USA. EM dmount@rics.bwh.harvard.edu FU National Institutes of Health [DK57708, DK070756]; American Heart Association; Veterans Administration FX Supported by National Institutes of Health grants (DK57708 and DK070756). the American Heart Association and the Veterans Administration. NR 134 TC 16 Z9 16 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2009 VL 29 IS 3 BP 196 EP 215 DI 10.1016/j.semnephrol.2009.03.021 PG 20 WC Urology & Nephrology SC Urology & Nephrology GA 461AX UT WOS:000267237000003 PM 19523569 ER PT J AU Mount, DB Krahn, TA AF Mount, David B. Krahn, Thomas A. TI Hyponatremia: Case Vignettes SO SEMINARS IN NEPHROLOGY LA English DT Review DE Beer potomania; thiazide; pregnancy; olfactory neuroblastoma; hypopituitarism; SIADH; conivaptan; tolvaptan; DDAVP; hypertonic saline ID ANTIDIURETIC-HORMONE SECRETION; DIURETIC-INDUCED HYPONATREMIA; THIAZIDE-INDUCED HYPONATREMIA; CENTRAL PONTINE MYELINOLYSIS; BEER-DRINKERS; INAPPROPRIATE ANTIDIURESIS; INADVERTENT OVERCORRECTION; NEUROENDOCRINE CARCINOMA; OLFACTORY NEUROBLASTOMA; ADRENAL INSUFFICIENCY AB The diagnosis and management of hyponatremia can be intimidating, for both trainees and clinicians alike. We present five clinical scenarios of patients with hyponatremia. These discussions reinforce concepts reviewed elsewhere in this issue of Seminars in Nephrology and/or emphasize specific causes and management issues. Semin Nephrol 29:300-317 (C) 2009 Elsevier Inc. All rights reserved. C1 [Mount, David B.] Harvard Univ, Div Renal, Brigham & Womens Hosp, Sch Med, Boston, MA 02215 USA. [Mount, David B.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Krahn, Thomas A.] Brown Univ, Div Kidney Dis & Hypertens, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Mount, DB (reprint author), Harvard Univ, Div Renal, Brigham & Womens Hosp, Sch Med, Room 540,4 Blackfan Circle, Boston, MA 02215 USA. EM dmount@rics.bwh.harvard.edu FU National Institutes of Health [DK57708, DK070756]; American Heart Association; Veterans Administration FX Supported by National Institutes of Health grants (DK57708 and DK070756). the American Heart Association, and the Veterans Administration. NR 75 TC 5 Z9 5 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2009 VL 29 IS 3 BP 300 EP 317 DI 10.1016/j.semnephrol.2009.04.001 PG 18 WC Urology & Nephrology SC Urology & Nephrology GA 461AX UT WOS:000267237000010 PM 19523576 ER PT J AU Platt, AB Kuna, ST AF Platt, Alec B. Kuna, Samuel T. TI To Adhere or Not to Adhere-Patients Selectively Decide SO SLEEP LA English DT Editorial Material ID POSITIVE AIRWAY PRESSURE; OBSTRUCTIVE SLEEP-APNEA; CARDIOVASCULAR OUTCOMES; MORTALITY; THERAPY; HYPOPNEA; TRIAL; RISK; MEN C1 [Kuna, Samuel T.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Platt, Alec B.] Reading Hosp Med Ctr, Reading, PA USA. [Platt, Alec B.] Resp Specialists LTD, Wyomissing, PA USA. [Kuna, Samuel T.] Univ Penn, Sch Med, Ctr Sleep & Resp Neurobiol, Philadelphia, PA 19104 USA. RP Kuna, ST (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM skuna@mail.med.upenn.edu NR 15 TC 2 Z9 2 U1 0 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD MAY 1 PY 2009 VL 32 IS 5 BP 583 EP 584 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 438FS UT WOS:000265541900002 PM 19480222 ER PT J AU Rice, I Impink, B Niyonkuru, C Boninger, M AF Rice, I. Impink, B. Niyonkuru, C. Boninger, M. TI Manual wheelchair stroke characteristics during an extended period of propulsion SO SPINAL CORD LA English DT Article DE spinal cord injury; biomechanics; propulsion; fatigue; kinetics; wheelchair dynamometer ID MECHANICAL EFFICIENCY; PUSHRIM FORCES; KINETICS; USERS; BIOMECHANICS; FATIGUE; MOTION AB Study Design: Cross-sectional study. Objectives: The purpose of this study was to examine stroke characteristics of long-term manual wheelchair users during an extended manual wheelchair propulsion trial and the extent to which changes in propulsion biomechanics occurred. Setting: Human Engineering Research Laboratories, VA Rehabilitation Research and Development Center, VA Pittsburgh Healthcare Systems, Pittsburgh, PA, USA. Methods: Kinetic data were recorded from 21 subjects with paraplegia at four time points over the course of a 10-min propulsion trial at a steady state speed of 1.4 ms(-1). Upper extremity kinetic parameters were recorded using Smartwheels, force and torque sensing pushrims. Results: Subjects for propulsion biomechanics changed from early to late during the 10-min trial. Individuals displayed decreased maximum rate of rise of resultant force (P=0.0045) with a simultaneous increase in push time (P=0.043) and stroke time (P=0.023), whereas stroke frequency remained static. In addition, there was a decrease in out of plane moment application (P=0.032). Conclusion: Individuals seemed to naturally accommodate their propulsive stroke, using less injurious propulsion biomechanics over the course of a 10-minute trial on a dynamometer. The findings may have occurred as a result of both biomechanical compensations to a challenging propulsion trial and accommodation to propelling on a dynamometer. These results suggest that subjects may be capable of independently incorporating favorable biomechanical strategies to meet the demands of a challenging propulsion scenario. Spinal Cord (2009) 47, 413 - 417; doi:10.1038/sc.2008.139; published online 11 November 2008 C1 [Rice, I.] Univ Pittsburgh, Rehabil Sci Human Engn Res Lab, VA Pittsburgh Healthcare Syst, VA Rehabil Res & Dev Ctr,Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Rice, I.; Boninger, M.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA 15206 USA. [Impink, B.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15206 USA. [Boninger, M.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15206 USA. RP Rice, I (reprint author), Univ Pittsburgh, Rehabil Sci Human Engn Res Lab, VA Pittsburgh Healthcare Syst, VA Rehabil Res & Dev Ctr,Human Engn Res Labs, VA Pittsburgh 7180 Highland Dr 151R-1, Pittsburgh, PA 15206 USA. EM ricei@herlpitt.org OI Boninger, Michael/0000-0001-6966-919X FU Office of Research and Development; Rehabilitation Research and Development Service; Department of Veterans Affairs [B3142C] FX This study was supported by the Office of Research and Development, Rehabilitation Research and Development Service, Department of Veterans Affairs, Grant# B3142C'. NR 18 TC 9 Z9 9 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD MAY PY 2009 VL 47 IS 5 BP 413 EP 417 DI 10.1038/sc.2008.139 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 443DM UT WOS:000265890400012 PM 19002155 ER PT J AU Chou, R Loeser, JD Owens, DK Rosenquist, RW Atlas, SJ Baisden, J Carragee, EJ Grabois, M Murphy, DR Resnick, DK Stanos, SP Shaffer, WO Wall, EM AF Chou, Roger Loeser, John D. Owens, Douglas K. Rosenquist, Richard W. Atlas, Steven J. Baisden, Jamie Carragee, Eugene J. Grabois, Martin Murphy, Donald R. Resnick, Daniel K. Stanos, Steven P. Shaffer, William O. Wall, Eric M. CA Amer Pain Soc Low Back Pain Guidel TI Interventional Therapies, Surgery, and Interdisciplinary Rehabilitation for Low Back Pain An Evidence-Based Clinical Practice Guideline From the American Pain Society SO SPINE LA English DT Review DE low back pain; guideline; evidence-based; surgery; fusion; laminectomy; discectomy; injection; radiofrequency denervation; intradiscal electrothermal therapy; botulinum toxin; interdisciplinary therapy; multidisciplinary therapy; spinal cord stimulation ID RANDOMIZED CONTROLLED-TRIAL; SPINAL-CORD STIMULATION; LUMBAR-DISK HERNIATION; EXTRADURAL CORTICOSTEROID INJECTION; EPIDURAL STEROID INJECTION; INTERACTIVE VIDEO PROGRAM; DOUBLE-BLIND EVALUATION; NERVE ROOT COMPRESSION; UNITED-STATES TRENDS; PROVOCATIVE DISCOGRAPHY AB Study Design. Clinical practice guideline. Objective. To develop evidence-based recommendations on use of interventional diagnostic tests and therapies, surgeries, and interdisciplinary rehabilitation for low back pain of any duration, with or without leg pain. Summary of Background Data. Management of patients with persistent and disabling low back pain remains a clinical challenge. A number of interventional diagnostic tests and therapies and surgery are available and their use is increasing, but in some cases their utility remains uncertain or controversial. Interdisciplinary rehabilitation has also been proposed as a potentially effective noninvasive intervention for persistent and disabling low back pain. Methods. A multidisciplinary panel was convened by the American Pain Society. Its recommendations were based on a systematic review that focused on evidence from randomized controlled trials. Recommendations were graded using methods adapted from the US Preventive Services Task Force and the Grading of Recommendations, Assessment, Development, and Evaluation Working Group. Results. Investigators reviewed 3348 abstracts. A total of 161 randomized trials were deemed relevant to the recommendations in this guideline. The panel developed a total of 8 recommendations. Conclusion. Recommendations on use of interventional diagnostic tests and therapies, surgery, and interdisciplinary rehabilitation are presented. Due to important trade-offs between potential benefits, harms, costs, and burdens of alternative therapies, shared decision-making is an important component of a number of the recommendations. C1 [Chou, Roger] Oregon Hlth & Sci Univ, Dept Med, Oregon Evidence Based Practice Ctr, Portland, OR 97201 USA. [Loeser, John D.] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [Owens, Douglas K.] Vet Affairs Med Ctr, Palo Alto, CA 94304 USA. [Carragee, Eugene J.] Stanford Univ, Dept Orthoped Surg, Stanford, CA 94305 USA. [Rosenquist, Richard W.] Univ Iowa, Dept Anesthesiol, Iowa City, IA USA. [Atlas, Steven J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Gen Med Div, Boston, MA USA. [Baisden, Jamie] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Grabois, Martin] Baylor Coll Med, Inst Rehabil & Res, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [Murphy, Donald R.] Brown Univ, Alpert Med Sch, Rhode Isl Spine Ctr, Dept Community Hlth, Pawtucket, RI USA. [Resnick, Daniel K.] Univ Wisconsin, Dept Neurosurg, Madison, WI USA. [Stanos, Steven P.] Northwestern Univ, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. [Shaffer, William O.] Univ Kentucky, Dept Orthopaed, Lexington, KY USA. [Wall, Eric M.] Qualis Hlth, Seattle, WA USA. RP Chou, R (reprint author), 3181 SW Sam Jackson Pk Rd,Mail Code BICC, Portland, OR 97239 USA. EM chour@ohsu.edu FU American Pain Society (APS) FX Supported by the American Pain Society (APS). NR 143 TC 205 Z9 214 U1 6 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD MAY 1 PY 2009 VL 34 IS 10 BP 1066 EP 1077 DI 10.1097/BRS.0b013e3181a1390d PG 12 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 440DB UT WOS:000265677900013 PM 19363457 ER PT J AU Latorre, JGS Chou, SHY Nogueira, RG Singhal, AB Carter, BS Ogilvy, CS Rordorf, GA AF Latorre, Julius Gene S. Chou, Sherry Hsiang-Yi Nogueira, Raul Gomes Singhal, Aneesh B. Carter, Bob S. Ogilvy, Christopher S. Rordorf, Guy A. TI Effective Glycemic Control With Aggressive Hyperglycemia Management Is Associated With Improved Outcome in Aneurysmal Subarachnoid Hemorrhage SO STROKE LA English DT Article DE critical care; hyperglycemia; intracranial aneurysm; outcome; subarachnoid hemorrhage ID INTENSIVE INSULIN THERAPY; TRAUMATIC BRAIN-INJURY; CRITICALLY-ILL; CEREBRAL GLUCOSE; MICRODIALYSIS; IMPACT; LACTATE; STROKE; RATES AB Background and Purpose-Hyperglycemia strongly predicts poor outcome in patients with aneurysmal subarachnoid hemorrhage, but the effect of hyperglycemia management on outcome is unclear. We studied the impact of glycemic control on outcome of patients with aneurysmal subarachnoid hemorrhage. Methods-A prospective intensive care unit database was used to identify 332 patients with hyperglycemic aneurysmal subarachnoid hemorrhage admitted between January 2000 and December 2006. Patients treated with an aggressive hyperglycemia management (AHM) protocol after 2003 (N = 166) were compared with 166 patients treated using a standard hyperglycemia management before 2003. Within the AHM group, outcome was compared between patients who achieved good (mean glucose burden <1.1 mmol/L) and poor (mean glucose burden <1.1 mmol/L) glycemic control. Poor outcome was defined as modified Rankin scale >= 4 at 3 to 6 months. Multivariable logistic regression models correcting for temporal trend were used to quantify the effect of AHM on poor outcome. Results-Poor outcome in AHM-treated patients was lower (28.31% versus 40.36%) but was not statistically significant after correcting for temporal trend. However, good glycemic control significantly reduced the incidence of poor outcome (OR, 0.25; 95% CI, 0.08 to 0.80; P=0.02) compared with patients with poor glycemic control within the AHM group. No difference in the rate of clinical vasospasm or the development of delayed ischemic neurological deficit was seen before and after AHM protocol implementation. Conclusion-AHM results in good glucose control and significantly reduces the odds for poor outcome after aneurysmal subarachnoid hemorrhage in glucose-controlled patients. Further studies are needed to confirm these results. (Stroke. 2009; 40: 1644-1652.) C1 [Latorre, Julius Gene S.] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Chou, Sherry Hsiang-Yi] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med, Boston, MA 02115 USA. [Nogueira, Raul Gomes] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Intervent Neuroradiol, Boston, MA USA. [Carter, Bob S.; Ogilvy, Christopher S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Singhal, Aneesh B.; Rordorf, Guy A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Latorre, JGS (reprint author), SUNY Upstate Med Univ, Dept Neurol, 7134UH,750 E Adams St, Syracuse, NY 13210 USA. EM latorrej@upstate.edu RI Chou, Sherry/G-5779-2015 FU National Institutes of Health [NCRR K30-RR022292-07] FX We express gratitude to National Institutes of Health for NCRR K30-RR022292-07 grant support to S.H.-Y.C. NR 27 TC 28 Z9 32 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP 1644 EP 1652 DI 10.1161/STROKEAHA.108.535534 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800019 PM 19286596 ER PT J AU Earnshaw, SR Jackson, D Farkouh, R Schwamm, L AF Earnshaw, Stephanie R. Jackson, Dan Farkouh, Ray Schwamm, Lee TI Cost-Effectiveness of Patient Selection Using Penumbral-Based MRI for Intravenous Thrombolysis SO STROKE LA English DT Article DE ischemic stroke; MRI; cost-effectiveness analysis; economics; stroke management ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; INTRACEREBRAL HEMORRHAGE; RANDOMIZED-TRIAL; UNITED-STATES; 3 H; THERAPY; DIFFUSION; EMERGENCY; MODEL AB Background and Purpose-Better selection of patients for intravenous recombinant tissue plasminogen activator (IV tPA) treatment may improve clinical outcomes. We examined the cost-effectiveness of adding penumbral-based MRI to usual computed tomography (CT)-based methods to identify patients for IV tPA treatment. Methods-A decision-analytic model estimated the lifetime costs and outcomes associated with penumbral-based MRI selection in a patient population similar to that enrolled in the IV tPA clinical trials. Inputs were obtained from published literature, clinical trial data, claims databases, and expert opinion. Outcomes included cost per life-year saved and cost per quality-adjusted life-year (QALY) gained. Costs and outcomes were discounted at 3% annually. Sensitivity analyses were conducted. Results-The addition of penumbral-based MRI selection increased total cost by $103 over the patient's remaining lifetime. Penumbral-based MRI selection resulted in favorable outcomes (modified Rankin Scale <= 1) more often than CT-based selection (36.66% versus 35.06%) with an incremental cost per life year of $1840 and an incremental cost per QALY of $1004. Multivariate sensitivity analysis predicted cost-effectiveness (<=$50 000 per QALY) in 99.7% of simulation runs. Conclusions-Selecting ischemic stroke patients for IV tPA treatment using penumbral-based MRI after routine CT may increase overall acute care costs, but the benefit is large enough to make this highly cost-effective. This economic analysis lends further support to the consideration of a paradigm shift in acute stroke evaluation. (Stroke. 2009; 40: 1710-1720.) C1 [Earnshaw, Stephanie R.; Farkouh, Ray] RTI Hlth Solut, Res Triangle Pk, NC 27709 USA. [Jackson, Dan] GE Healthcare, Chalfont St Giles, Bucks, England. [Schwamm, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Earnshaw, SR (reprint author), RTI Hlth Solut, POB 12194,Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM searnshaw@rti.org OI Schwamm, Lee/0000-0003-0592-9145 FU GE Healthcare FX This work was supported by GE Healthcare. NR 43 TC 28 Z9 28 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP 1710 EP 1720 DI 10.1161/STROKEAHA.108.540138 PG 11 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800030 PM 19286581 ER PT J AU Gropen, T Magdon-Ismail, Z Day, D Melluzzo, S Schwamm, LH AF Gropen, Toby Magdon-Ismail, Zainab Day, David Melluzzo, Shannon Schwamm, Lee H. CA NECC Advisory Grp TI Regional Implementation of the Stroke Systems of Care Model Recommendations of the Northeast Cerebrovascular Consortium SO STROKE LA English DT Article DE regional implementation; stroke; stroke systems ID INTERNATIONAL EXPERIENCE; REGISTRIES AB Background and Purpose-The Northeast Cerebrovascular Consortium was established to examine regional disparities and recommend strategies to improve stroke care based on the Stroke Systems of Care Model. Methods-An annual summit was first held in 2006, bringing together public health officials, researchers, physicians, nurses, health professionals, state legislators, and advocacy organizations. Best practices and evidence-based interventions within each of the Stroke Systems of Care Model components were presented. Six writing groups were tasked with cataloging each state's current activities and identifying goals for the region. Results-There were significant variations in the delivery of stroke care, particularly in urban versus rural areas, as evidenced by the availability of designated stroke centers and neurologists, and stroke-related death rates. Recommendations to address variations in care delivery included the use of a common stroke data collection system, unified community education criteria, improvements to emergency medical services dispatch and training, adoption of prehospital care measures, creation of a web-based central repository of acute stroke protocols and order sets, a regional atlas of stroke resources and capabilities, a stroke patient "report card" to promote adherence to secondary prevention strategies, and explicit standards for rehabilitation services. Conclusions-Significant disparities in the delivery of stroke care across the 8 state-region have been identified. Northeast Cerebrovascular Consortium demonstrates that multistate regional collaboration is a viable process for developing specific regional recommendations to address those disparities. Northeast Cerebrovascular Consortium is assessing the usefulness of the Stroke Systems of Care Model as a framework for implementing a regional approach to stroke across the continuum of care. (Stroke. 2009; 40: 1793-1802.) C1 [Gropen, Toby] Long Isl Coll Hosp, Dept Neurol, Brooklyn, NY 11201 USA. [Magdon-Ismail, Zainab; Day, David; Melluzzo, Shannon] Amer Stroke Assoc, Dallas, TX USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gropen, T (reprint author), Long Isl Coll Hosp, Dept Neurol, 339 Hicks St, Brooklyn, NY 11201 USA. EM tgropen@chpnet.org OI Schwamm, Lee/0000-0003-0592-9145 FU NCCDPHP CDC HHS [5 U13 DP001176-02] NR 20 TC 35 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP 1793 EP 1802 DI 10.1161/STROKEAHA.108.531053 PG 10 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800041 PM 19299641 ER PT J AU Ross, JS Halm, EA Bravata, DM AF Ross, Joseph S. Halm, Ethan A. Bravata, Dawn M. TI Use of Stroke Secondary Prevention Services Are There Disparities in Care? SO STROKE LA English DT Article DE health care; prevention; women and minorities; quality of care ID TRANSIENT ISCHEMIC ATTACK; PHYSICAL-ACTIVITY; RISK-FACTORS; HEALTH; BEHAVIORS; MORTALITY; OUTCOMES; DISEASE; CANCER AB Background and Purpose-The purpose of this study was to examine whether there are disparities in use of stroke secondary prevention services because disparities in stroke outcomes have been found among older adults, women, racial minorities, and within Stroke Belt states. Methods-Using the nationally-representative 2005 Behavior Risk Factor Surveillance System, we examined self-reported use of 11 stroke secondary prevention services queried in the survey. We used multivariable logistic regression to examine the association between service use and age, sex, race, and Stroke Belt state residence, controlling for other socio-demographic and health care access characteristics. Results-Among 11 862 adults with a history of stroke, 16% were 80 or older, 54% were women, 13% were non-Hispanic black, and 23% lived within a Stroke Belt state. Overall service use varied: 31% reported poststroke outpatient rehabilitation, 57% regular exercise, 66% smoking cessation counseling, and 91% current use of antihypertensive medications. Age 80 or older was not associated with lower use of any of the 11 services. Women were less likely to report poststroke outpatient rehabilitation and regular exercise when compared with men (probability values <= 0.005); there were no sex-based differences in use of the 9 other services. Blacks were less likely to report pneumococcal vaccination when compared with whites, but were more likely to report poststroke outpatient rehabilitation (probability values <= 0.005); there were no race-based differences in use of the 9 other services. Stroke Belt state residence was not associated with lower use of any of the 11 services. Conclusions-Use of many stroke secondary prevention services was suboptimal. We did not find consistent age, sex, racial, or Stroke Belt state residence disparities in care. (Stroke. 2009; 40: 1811-1819.) C1 [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, Bronx, NY USA. James J Peter VA Med Ctr, HSR&D Res Enhancement Award Program, Bronx, NY USA. James J Peter VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Bravata, Dawn M.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. Richard L Roudebush Vet Adm Med Ctr, HSR&D Ctr Excellence, Indianapolis, IN 46202 USA. RP Ross, JS (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. EM joseph.ross@mssm.edu FU NINDS NIH HHS [R01 NS056028-02, R01 NS056028-04, R01 NS056028-03, R01 NS056028-01A1, R01 NS056028] NR 26 TC 14 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP 1811 EP 1819 DI 10.1161/STROKEAHA.108.539619 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800043 PM 19265044 ER PT J AU Romero, JM Babiarz, LS Forero, NP Murphy, EK Schaefer, PW Gonzalez, RG Lev, MH AF Romero, Javier M. Babiarz, Lukasz S. Forero, N. Paola Murphy, Erin K. Schaefer, Pamela W. Gonzalez, R. Gilberto Lev, Michael H. TI Arterial Wall Enhancement Overlying Carotid Plaque on CT Angiography Correlates With Symptoms in Patients With High Grade Stenosis SO STROKE LA English DT Article DE cerebrovascular disease; CT; risk factors; carotid artery ID COMPUTED-TOMOGRAPHY; VASA VASORUM; ATHEROSCLEROSIS AB Background and Purpose-The degree of internal carotid artery (ICA) stenosis is an established primary risk factor for embolic stroke. Recent publications suggest that inflammatory features may also play an important role. Our purpose was to correlate acute neurological symptoms with either carotid artery wall enhancement or plaque calcification, on axial CT angiographic source images (CTA-SI) of patients with severe (>= 70%) ICA stenosis. Methods-75 consecutive patients with >= 70% ICA stenosis on CTA-SI were identified. Each case was classified as symptomatic (n=37) or asymptomatic (n=38), and as having either calcified or noncalcified plaque. The latter group was stratified into those with versus without arterial wall enhancement, measured in absolute and relative Hounsfield Units (HU). Results-Calcified plaque was present in 39% (15/38) of the symptomatic patients and in 62% (23/37) of the asymptomatic patients (P=0.065). Of the 37 patients without calcified plaque, carotid wall enhancement was observed in 83% (19/23) of the symptomatic, but only in 57% (8/14) of the asymptomatic patients (P=0.041). When the "calcified plaque" and "no carotid wall enhancement" groups were pooled, versus the "carotid wall enhancement" group, enhancement was more likely in symptomatic patients (OR 3.625, CI 95% 1.3229 to 9.93, P=0.01 Fisher Exact test). Conclusions-In patients with severe ICA stenosis, additional stratification of stroke risk may be possible based on the presence of carotid wall enhancement on CTA-SI. Patients with carotid wall enhancement are more likely to be symptomatic, compared to those with either calcified plaque or no enhancement. (Stroke. 2009; 40: 1894-1896.) C1 [Romero, Javier M.; Babiarz, Lukasz S.; Forero, N. Paola; Murphy, Erin K.; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Lev, Michael H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Romero, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM jmromero@partners.org NR 9 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP 1894 EP 1896 DI 10.1161/STROKEAHA.108.529008 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800055 PM 19182087 ER PT J AU Heiss, WD Sorensen, AG AF Heiss, Wolf-Dieter Sorensen, A. Gregory TI Advances in Imaging SO STROKE LA English DT Editorial Material DE imaging; advances ID ACUTE ISCHEMIC-STROKE; PERFUSION-DIFFUSION MISMATCH; MAGNETIC-RESONANCE; CT-ANGIOGRAPHY; PENUMBRA; THROMBOLYSIS; OXYGEN; BRAIN; RISK; MRI C1 [Heiss, Wolf-Dieter] Max Planck Inst Neurol Res, D-50931 Cologne, Germany. [Sorensen, A. Gregory] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sorensen, A. Gregory] Harvard Univ, Sch Med, Boston, MA USA. RP Heiss, WD (reprint author), Max Planck Inst Neurol Res, Gleueler Str 50, D-50931 Cologne, Germany. EM wdh@nf.mpg.de NR 30 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2009 VL 40 IS 5 BP E313 EP E314 DI 10.1161/STROKEAHA.108.545434 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 438UB UT WOS:000265579800079 PM 19359627 ER PT J AU Regenbogen, SE Greenberg, CC Resch, SC Kollengode, A Cima, RR Zinner, MJ Gawande, AA AF Regenbogen, Scott E. Greenberg, Caprice C. Resch, Stephen C. Kollengode, Anantha Cima, Robert R. Zinner, Michael J. Gawande, Atul A. TI Prevention of retained surgical sponges: A decision-analytic model predicting relative cost-effectiveness SO SURGERY LA English DT Article ID FOREIGN-BODIES; PATIENT SAFETY; OPERATING-ROOM; SURGERY; INSTRUMENTS; TECHNOLOGY; IMPACT AB Background. New technologies are available to reduce or prevent retained surgical sponges (RSS), but their relative cost effectiveness are unknown. We developed an empirically calibrated decision-analytic model comparing standard. counting against alternative strategies: universal or selective x-ray, bar-coded sponges (BCS), and radiofrequency-tagged (RF) sponges. Methods. Key model parameters were obtained front field observations during a randomized-controlled BCS trial (n = 298), an observational study of RSS (n = 191,168), and clinical experience with BCS (n similar to 60,000). Because no comparable data exist for RF, we modeled its performance under 2 alternative assumptions. Only incremental sponge tracking costs, excluding those common to all strategies, were considered. Main outcomes were RSS incidence and cost-effectiveness ratios for each strategy, front the institutional decision maker's perspective. Results. Standard counting detects 82% of RSS. Bar coding prevents >= 97.5% for an additional $95,000 per RSS averted. If RF were as effective as bar coding, it would cost $720,000 per additional RSS averted (versus standard counting). Universal and selective x-rays for high-risk operations are more costly, but less effective than BCS-$1.1 to 1.4 million per RSS event prevented. In sensitivity analyses, results were robust over the plausible range of effectiveness assumptions, but sensitive to cost. Conclusion. Using currently available data, this analysis provides a useful model for comparing the relative cost effectiveness of existing sponge tracking strategies. Selecting the best method for an institution depends on its priorities: ease of use, cost reduction., or ensuring RSS are truly "never events." Given medical and liability costs of >$200,000 per incident, novel technologies can substantially reduce the incidence of RSS at an acceptable cost. (Surgery 2009;145:527-35.) C1 [Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Regenbogen, Scott E.; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Greenberg, Caprice C.; Zinner, Michael J.; Gawande, Atul A.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Resch, Stephen C.] ABT Associates Inc, Cambridge, MA 02138 USA. [Kollengode, Anantha] Mayo Clin, Off Qual Management, Rochester, MN USA. [Cima, Robert R.] Mayo Clin, Dept Surg, Rochester, MN USA. RP Regenbogen, SE (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02114 USA. EM sregenbogen@partners.org OI Gawande, Atul/0000-0002-1824-9176 FU Agency for Healthcare Research and Quality [T32-HS000020]; SurgiCount Medical, Temecula, CA FX S.E.R. was supported by Kirschstein National Research Service Award T32-HS000020 from the Agency for Healthcare Research and Quality. Drs Greenberg and Gawande have received research grant support from SurgiCount Medical, Temecula, CA. The funding agencies were not involved in the conduct, analysis, or composition of this study, and were not given the opportunity to approve or edit the manuscript before submission. Accepted for publication January 28, 2009. NR 38 TC 36 Z9 36 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAY PY 2009 VL 145 IS 5 BP 527 EP 535 DI 10.1016/j.surg.2009.01.011 PG 9 WC Surgery SC Surgery GA 439VK UT WOS:000265655300011 PM 19375612 ER PT J AU Levine, A Ramos, A Escalona, A Rodriguez, L Greve, JW Janssen, I Rothstein, R Nepomnayshy, D Gersin, KS Melanson, D Lamport, R Fishman, E Malomo, K Kaplan, LM Neto, MG AF Levine, Andy Ramos, Almino Escalona, Alex Rodriguez, Leonardo Greve, Jan Willem Janssen, Ignace Rothstein, Richard Nepomnayshy, Dmitry Gersin, Keith S. Melanson, David Lamport, Ronald Fishman, Ezra Malomo, Kenneth Kaplan, Lee M. Galvao Neto, Manoel TI Radiographic appearance of endoscopic duodenal-jejunal bypass liner for treatment of obesity and type 2 diabetes SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Editorial Material DE Bariatric; Endoluminal; Radiographic; Obesity; Duodenum; Diabetes ID SLEEVE; EXPERIENCE; SURGERY C1 [Levine, Andy; Melanson, David; Lamport, Ronald; Fishman, Ezra; Malomo, Kenneth] GI Dynam Inc, Lexington 02421, MA USA. [Ramos, Almino; Galvao Neto, Manoel] Gastro Obeso Ctr, Sao Paulo, Brazil. [Escalona, Alex] Pontificia Univ Catolica Chile, Hosp Univ Catolica, Santiago, Chile. [Rodriguez, Leonardo] Hosp DIPRECA, Ctr Cirugia Obesidad, Santiago, Chile. [Greve, Jan Willem] Univ Hosp, Maastricht, Netherlands. [Janssen, Ignace] Ziekenluis Rijnstate, Arnhem, Netherlands. [Rothstein, Richard] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Nepomnayshy, Dmitry] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Gersin, Keith S.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Levine, A (reprint author), GI Dynam Inc, 1 Maguire Rd, Lexington 02421, MA USA. EM alevine@gidynamics.com NR 6 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 1550-7289 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD MAY-JUN PY 2009 VL 5 IS 3 BP 371 EP 374 DI 10.1016/j.soard.2009.02.010 PG 4 WC Surgery SC Surgery GA 454GO UT WOS:000266670600014 PM 19460677 ER PT J AU Tarazi, FI Choi, YK Gardner, M Wong, EHF Henry, B Shahid, M AF Tarazi, Frank I. Choi, Yong Kee Gardner, Matthew Wong, Erik H. F. Henry, Brian Shahid, Mohammed TI Asenapine Exerts Distinctive Regional Effects on Ionotropic Glutamate Receptor Subtypes in Rat Brain SO SYNAPSE LA English DT Article DE asenapine; caudate putamen; frontal cortex; hippocampus; glutamate receptor ID MEDIAL PREFRONTAL CORTEX; ANTIPSYCHOTIC-DRUGS; NEGATIVE SYMPTOMS; EMERGING ROLE; D-SERINE; SCHIZOPHRENIA; EXPRESSION; RISPERIDONE; DOPAMINE; HALOPERIDOL AB Asenapine, a new pyschopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has a unique human receptor binding signature with strong affinity for dopaminergic, alpha-adrenergic, and, in particular, serotonergic receptors raising the possibility of interactions with glutamatergic receptors. Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA) receptors and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were quantified after repeated administration of multiple doses of asenapine (0.03, 0.1, or 0.3 mg/kg, subcutaneous, twice/day) or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP), and processed for in vitro receptor autoradiography. Four weeks of treatment with 0.03, 0.1, or 0.3 mg/kg of asenapine significantly (P < 0.01) decreased binding of [(3)H]MK-801 to NMDA/MK-801 modulatory sites in NAc (by 27%, 29%, and 26%, respectively), medial CPu (by 25%, 28%, and 24%), and lateral CPu (by 24%, 31%, and 26%). In contrast, the same doses of asenapine did not alter binding of [(3)H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [(3)H]AMPA binding to AMPA receptors was selectively and significantly (P < 0.001) elevated in hippocampal CA(1) (41%) and CA(3) (40%) regions but only at the highest dose tested. These results indicate that chronic treatment with asenapine has region-specific and dose-dependent effects on ionotropic Glu-receptor subtypes in rat forebrain, which might contribute to the unique psychopharmacologic properties of asenapine. Synapse 63:413-420, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Tarazi, Frank I.; Choi, Yong Kee; Gardner, Matthew] Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. [Tarazi, Frank I.; Choi, Yong Kee] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tarazi, Frank I.; Choi, Yong Kee] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Wong, Erik H. F.] Pfizer Global R&D, Ann Arbor, MI USA. [Henry, Brian; Shahid, Mohammed] Schering Plough Corp, Newhouse, Lanark, Scotland. RP Tarazi, FI (reprint author), Harvard Univ, Sch Med, McLean Hosp, Lab Psychiat Neurosci, 115 Mill St, Belmont, MA 02478 USA. EM ftarazi@hms.harvard.edu FU NICHD [HD-052752]; Schering-Plough FX NICHD; Contract grant number: HD-052752; Contract grant sponsor: Schering-Plough. NR 45 TC 23 Z9 23 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAY PY 2009 VL 63 IS 5 BP 413 EP 420 DI 10.1002/syn.20618 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 424NZ UT WOS:000264574700006 PM 19177511 ER PT J AU Yeung, A Johnson, DP Trinh, NH Weng, WCC Kvedar, J Fava, M AF Yeung, Albert Johnson, Daniel P. Trinh, Nhi-Ha Weng, Wan-Chen Claire Kvedar, Joseph Fava, Maurizio TI Feasibility and Effectiveness of Telepsychiatry Services for Chinese Immigrants in a Nursing Home SO TELEMEDICINE JOURNAL AND E-HEALTH LA English DT Article DE nursing home; telemedicine; psychiatric consultation; Chinese immigrants ID CARE AB This study investigates the feasibility and effectiveness of providing telepsychiatry services to Chinese immigrants in a nursing home. The psychiatrist interviewed patients face-to-face for the initial consultation, and encouraged them to participate in this study to receive telepsychiatry-based follow-up visits. The feasibility and outcomes of telepsychiatry visits and satisfaction of the subjects, their families, and the nursing home staff were assessed. Nine monolingual Chinese immigrants, 8 women and 1 man, ranging from 54 to 88 years of age, were enrolled. The main reasons for psychiatric consultation were mood and behavioral problems. Eight of the 9 (88.9%) subjects participated in videoconference follow-up visits, and 1 subject (11.1%) declined. Among the 8 subjects, 6 were referred for psychiatric intervention, 1 for differential diagnosis, and 1 for suicide assessment. At the end of the study, all 6 subjects referred for intervention had greatly improved; the subjects, their families, and the nursing staff were highly satisfied with the telepsychiatry service. It is feasible to provide psychiatry consultations to ethnic immigrants in a nursing home despite the fact that many of them are unfamiliar with the technology and suffer from dementia and psychotic symptoms. Telepsychiatry provides an efficient way for ethnic elders in nursing homes to connect with mental health professionals with the appropriate language and cultural background, regardless of location. Telepsychiatry may decrease the disparities in treatment of mental illnesses among ethnic immigrants in nursing homes. C1 [Yeung, Albert; Johnson, Daniel P.; Trinh, Nhi-Ha; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Weng, Wan-Chen Claire] Boston Coll, Boston, MA USA. [Kvedar, Joseph] Ctr Connected Hlth, Boston, MA USA. RP Yeung, A (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 50 Staniford St,Suite 401, Boston, MA 02114 USA. EM ayeung@partners.org FU Center of Connected Health, Partners HealthCare System, Boston, Massachusetts FX Research was funded by the Center of Connected Health, Partners HealthCare System, Boston, Massachusetts. NR 14 TC 18 Z9 18 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED J E-HEALTH JI Telemed. J. e-Health PD MAY PY 2009 VL 15 IS 4 BP 336 EP 341 DI 10.1089/tmj.2008.0138 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 446GN UT WOS:000266110200005 PM 19441951 ER PT J AU Zhou, J Liu, SC Ma, M Hou, JX Yu, HJ Lu, CF Gilbert, GE Shi, JL AF Zhou, Jin Liu, Shuchuan Ma, Ming Hou, Jinxiao Yu, Hongjuan Lu, Chengfang Gilbert, Gary E. Shi, Jialan TI Procoagulant activity and phosphatidylserine of amniotic fluid cells SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Amniotic fluid cells; phosphatidylserine; procoagulant activity; lactadherin ID TISSUE FACTOR PATHWAY; BLOOD-COAGULATION; MEMBRANE-SURFACE; BINDING-SITE; FACTOR-VIII; PROTEIN-C; FACTOR VA; L-SERINE; EMBOLISM; INHIBITOR AB Amniotic fluid (AF) may induce disseminated intravascular coagulation (DIC) when it enters maternal circulation by breaching the placental-maternal circulation barrier. The precise mechanism of the procoagulant activity of AF is unclear, but tissue factor (TF) has been proposed to be the main cause. As one constituent of AF, AF cells accumulate and undergo apoptosis continuously. Therefore, we speculate that AF cells have procoagulant activity due to the externalisation of phosphatidylserine (PS). The present study aims to demonstrate that, in addition to TF, the PS that is externalised on AF cells is important for the procoagulant activity of AF. Ten AF samples from parturient women were analysed using lactadherin as the probe for PS. Anti-TF antibody also was used to identify TF and its associated coagulation functions in AF cells. Normal platelets, neutrophils, and lymphocytes were harvested as controls. Confocal microscopy and flow cytometry was used to assess PS expression on AF cells. The procoagulant activity of AF cells was demonstrated by a plasma coagulation assay and further confirmed by factor Xase/prothrombinase assays. PS and TF were present on most AF cells, providing substantial procoagulant activity. Furthermore, factor Xase and prothrombinase assays showed that AF cells substantially enforced the activation of factor X and prothrombin. PS on AF cells is an important procoagulant source for AF. Lactadherin is an ideal anticoagulant for inhibiting the procoagulant activity of AF cells. C1 [Zhou, Jin; Liu, Shuchuan; Ma, Ming; Hou, Jinxiao; Yu, Hongjuan; Lu, Chengfang; Shi, Jialan] Haibin Med Univ, Affiliated Hosp 1, Dept Hematol, Harbin 150001, Peoples R China. [Gilbert, Gary E.; Shi, Jialan] Harvard Univ, Sch Med, Boston, MA USA. [Gilbert, Gary E.; Shi, Jialan] Brigham & Womens Hosp, Dept Med, VA Boston Hlth Care Syst, Boston, MA 02115 USA. RP Shi, JL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. EM jinzhouh85@163.com; jialan_shi@hms.harvard.edu NR 30 TC 17 Z9 19 U1 1 U2 5 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD MAY PY 2009 VL 101 IS 5 BP 845 EP 851 DI 10.1160/TH08-08-0531 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 446VA UT WOS:000266148300012 PM 19404537 ER PT J AU Delaney, M Cutler, CS Haspel, RL Yeap, BY McAfee, SL Dey, BR Attar, E Kao, G Alyea, EP Koreth, J Ho, VT Saidman, S Liney, D Sese, D Soiffer, RJ Spitzer, TR Antin, JH Ballen, KK AF Delaney, Meghan Cutler, Corey S. Haspel, Richard L. Yeap, Beow Y. McAfee, Steven L. Dey, Bimalangshu R. Attar, Eyal Kao, Grace Alyea, Edwin P. Koreth, John Ho, Vincent T. Saidman, Susan Liney, Deborah Sese, Doreen Soiffer, Robert J. Spitzer, Thomas R. Antin, Joseph H. Ballen, Karen K. TI High-resolution HLA matching in double-umbilical-cord-blood reduced-intensity transplantation in adults SO TRANSFUSION LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; MARROW-TRANSPLANTATION; CLASS-I; DONOR; OUTCOMES; RECONSTITUTION; RECIPIENT; IMPACT AB Double-cord-blood transplantation (DCBT) offers an option for patients receiving reduced-intensity transplants. These unique transplants have two donors, both of whom are usually HLA mismatched at one to two loci. Fifty-three patients were recipients of a reduced-intensity DCBT. Cords were at least 4/6 allele-level HLA-A, -B, and -DR match with the patient and each other with a minimum combined cell dose of more than 3.7 x 10(7) total nucleated cells per kg. Twenty-one patients received cyclosporine/mycophenolate mofetil and 32 patients received sirolimus/tacrolimus (SIR/TAC) for graft-versus-host disease prophylaxis. The effect of allele level HLA typing on clinical endpoints of overall survival (OS), disease-free survival (DFS), engraftment, and acute graft-versus-host disease (aGVHD) were assessed. Neutrophil (p = 0.001) engraftment and platelet engraftment (p = 0.027) were significantly faster in patients who have closer Class I (HLA-A, -B, -C) matching. Neutrophil engraftment was faster in patients who had closer HLA-B matching to their combined cords (p = 0.007). There was a low incidence of aGVHD overall, especially in the SIR/TAC group. Class I HLA matching had no effect on aGVHD. HLA-DR and -DQ had no effect on engraftment or aGVHD. Class I allele matching, and HLA-B matching specifically, were associated with faster neutrophil engraftment. High-resolution HLA matching did not affect OS or DFS. C1 [Delaney, Meghan] Puget Sound Blood Ctr, Seattle, WA 98104 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Histocompatibil Lab, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. Brigham & Womens Hosp, Tissue Typing Lab, Boston, MA 02115 USA. RP Delaney, M (reprint author), Puget Sound Blood Ctr, 921 Terry Ave, Seattle, WA 98104 USA. EM meghand@psbc.org FU NHLBI NIH HHS [P01 HL070149, U54 HL081030-01, U54 HL081030, HL070149] NR 24 TC 23 Z9 24 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAY PY 2009 VL 49 IS 5 BP 995 EP 1002 DI 10.1111/j.1537-2995.2008.02077.x PG 8 WC Hematology SC Hematology GA 436JQ UT WOS:000265410800026 PM 19159415 ER PT J AU McClatchey, AI Fehon, RG AF McClatchey, Andrea I. Fehon, Richard G. TI Merlin and the ERM proteins - regulators of receptor distribution and signaling at the cell cortex SO TRENDS IN CELL BIOLOGY LA English DT Review ID NF2 TUMOR-SUPPRESSOR; MEMBRANE-CYTOSKELETON ADHESION; GROWTH-FACTOR; ADHERENS JUNCTIONS; ACTIN CYTOSKELETON; FERM DOMAIN; NEUROFIBROMATOSIS TYPE-2; INTERCELLULAR-ADHESION; IMMUNOLOGICAL SYNAPSE; CONTACT INHIBITION AB Recent studies highlight the importance of the distribution of membrane receptors in controlling receptor output and in contributing to complex biological processes. The cortical cytoskeleton is known to affect membrane protein distribution but the molecular basis of this is largely unknown. Here, we discuss the functions of Merlin and the ERM proteins both in linking membrane proteins to the underlying cortical cytoskeleton and in controlling the distribution of and signaling from membrane receptors. We also propose a model that could account for the intricacies of Merlin function across model organisms. C1 [McClatchey, Andrea I.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [McClatchey, Andrea I.] Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. [Fehon, Richard G.] Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA. RP McClatchey, AI (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu FU NIH [RO1 CA113733, RO1 NS034738]; DOD [W81XWH-05-1-0189] FX The authors would like to thank the members of the McClatchey and Fehon laboratories for helpful comments and discussions. This work was supported by NIH RO1 CA113733 and DOD W81XWH-05-1-0189 to A.I.M. and NIH RO1 NS034738 to R.G.F. NR 92 TC 93 Z9 94 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD MAY PY 2009 VL 19 IS 5 BP 198 EP 206 DI 10.1016/j.tcb.2009.02.006 PG 9 WC Cell Biology SC Cell Biology GA 453PN UT WOS:000266623500002 PM 19345106 ER PT J AU Yoo, SD Cho, YH Sheen, J AF Yoo, Sang-Dong Cho, Younghee Sheen, Jen TI Emerging connections in the ethylene signaling network SO TRENDS IN PLANT SCIENCE LA English DT Review ID HISTIDINE KINASE-ACTIVITY; F-BOX PROTEINS; RECEPTOR FAMILY-MEMBERS; RAF-LIKE KINASE; ARABIDOPSIS-THALIANA; RESPONSE PATHWAY; AUXIN BIOSYNTHESIS; GENE FAMILY; ENDOPLASMIC-RETICULUM; TRANSCRIPTION FACTOR AB The gaseous plant hormone ethylene acts as a pivotal mediator to respond to and coordinate internal and external cues in modulating plant growth dynamics and developmental programs. Genetic analysis of Arabidopsis thaliana has been used to identify key components and to build a linear ethylene-signaling pathway from the receptors through to the nuclear transcription factors. Studies applying integrative approaches have revealed new regulators, molecular connections and mechanisms in ethylene signaling and unexpected links to other plant hormones. Here, we review and discuss recent discoveries about the functional mode of ethylene receptor complexes, dual mitogen-activated protein kinase cascade signaling, stability control of the master nuclear transcription activator ETHYLENE INSENSITIVE 3 (EIN3), and the contextual relationships between ethylene and other plant hormones, such as auxin and gibberellins, in organ-specific growth regulation. C1 [Yoo, Sang-Dong; Cho, Younghee; Sheen, Jen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. [Yoo, Sang-Dong] Sungkyunkwan Univ, Dept Biol Sci, Suwon, South Korea. RP Sheen, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard.edu RI allasia, valerie/B-4214-2009 FU US National Science Foundation; National Institutes of Health; SungKyunKwan University FX We apologize to authors whose work could not be cited here because of space constraints. We thank C. Chang, S. Zhang and W.H. Cheng for sharing information before publication. This work was supported by grants from the US National Science Foundation and the National Institutes of Health (J.S.) and SungKyunKwan University (S.D.Y.). NR 90 TC 101 Z9 109 U1 1 U2 54 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1360-1385 J9 TRENDS PLANT SCI JI Trends Plant Sci. PD MAY PY 2009 VL 14 IS 5 BP 270 EP 279 DI 10.1016/j.tplants.2009.02.007 PG 10 WC Plant Sciences SC Plant Sciences GA 449YR UT WOS:000266367600006 PM 19375376 ER PT J AU Gee, MS Harisinghani, MG Tabatabaei, S AF Gee, Michael S. Harisinghani, Mukesh G. Tabatabaei, Shahin TI Molecular Imaging in Urologic Surgery SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Radiology; MRI; Optical imaging ID POSITRON-EMISSION-TOMOGRAPHY; OPTICAL COHERENCE TOMOGRAPHY; SUPERPARAMAGNETIC IRON-OXIDE; URINARY-BLADDER CANCER; LYMPH-NODE DISSECTION; GERM-CELL TUMORS; PROSTATE-CANCER; CONTRAST AGENTS; MR; FLUORESCENCE AB Recently, advances in imaging technology have made possible the ability to image noninvasively specific molecular pathways in vivo that are involved in disease processes. Molecular imaging evaluates changes in cellular physiology and function rather than anatomy, which are likely to be earlier and more sensitive manifestations of disease. In addition, as newer drugs to treat disease become increasingly molecule specific, molecular imaging has become necessary to provide noninvasive determination of patients likely to benefit from treatment and early therapy response. This article reviews current and emerging molecular imaging technologies relevant to urologic surgery. C1 [Gee, Michael S.; Harisinghani, Mukesh G.; Tabatabaei, Shahin] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tabatabaei, S (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM stabatabaei@partners.org NR 41 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD MAY PY 2009 VL 36 IS 2 BP 125 EP + DI 10.1016/j.ucl.2009.02.007 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 452YR UT WOS:000266577600003 PM 19406314 ER PT J AU Kupelian, V McVary, KT Barry, MJ Link, CL Rosen, RC Aiyer, LP Mollon, P McKinlay, JB AF Kupelian, Varant McVary, Kevin T. Barry, Michael J. Link, Carol L. Rosen, Raymond C. Aiyer, Lalitha Padmanabhan Mollon, Patrick McKinlay, John B. TI Association of C-reactive Protein and Lower Urinary Tract Symptoms in Men and Women: Results From Boston Area Community Health Survey SO UROLOGY LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; QUALITY-OF-LIFE; BACH SURVEY; PREVALENCE; INDEX; INFLAMMATION; GENDER; SAMPLE; SCALE AB OBJECTIVES: To determine whether an association exists between C reactive protein (CRP) levels and lower urinary tract symptoms (LUTS) as assessed by the American Urological Association Symptom Index (AUA-SI) among both men and women, and to determine the association of CRP levels with the individual urologic symptoms comprising the AUA-SI among both men and women. METHODS: The Boston Area Community Health survey used a multistage stratified design to recruit a random sample of 5502 adults aged 30-79 years. Blood samples were obtained from 3752 participants. The analyses were conducted on 1898 men and 1854 women with complete data on CRP levels. Overall LUTS was defined as an AUA-SI of >= 8 (moderate to severe LUTS). The urologic symptoms comprising the AUA-SI were included in the analysis as reports of fairly often to almost always vs non/rarely/a few times. RESULTS: A statistically significant association was observed between the CRP levels and overall LUTS among both men and women. The pattern of associations between the individual symptoms and CRP levels varied by sex. Nocturia and straining were associated with greater CRP levels among men, and incomplete emptying and weak stream were associated with greater CRP levels among women. CONCLUSIONS: The results of this study have demonstrated an association between CRP levels and LUTS in both men and women. The dose-response relationship between increased CRP levels and an increased odds of LUTS supports the hypothesized role of inflammatory processes in the etiology of LUTS. UROLOGY 73: 950-957, 2009. (C) 2009 Elsevier Inc. C1 [McKinlay, John B.] New England Res Inst, Watertown, MA 02472 USA. Northwestern Univ, Sch Med, Dept Urol, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Pfizer Inc, New York, NY USA. Pfizer Ltd, Sandwich CT13 9NJ, Kent, England. RP McKinlay, JB (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM bach@neriscience.com FU NIDDK NIH HHS [R01 DK056842, U01 DK056842, DK 56842] NR 31 TC 46 Z9 48 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD MAY PY 2009 VL 73 IS 5 BP 950 EP 957 DI 10.1016/j.urology.2008.12.012 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 443PU UT WOS:000265923100009 PM 19394490 ER PT J AU Buchanan, J Fleischmann, R Genovese, MC Kay, J Hsia, EC Doyle, MK Rahman, MU Han, C Parasuraman, S AF Buchanan, J. Fleischmann, R. Genovese, M. C. Kay, J. Hsia, E. C. Doyle, M. K. Rahman, M. U. Han, C. Parasuraman, S. TI GOLIMUMAB, A HUMAN ANTI-TNF-ALPHA MONOCLONAL ANTIBODY, SIGNIFICANTLY IMPROVES SELF-REPORTED PRODUCTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM THREE PHASE 3 STUDIES SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Buchanan, J.; Han, C.; Parasuraman, S.] Johnson & Johnson Pharmaceut Serv LLC, Malvern, PA USA. [Fleischmann, R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Genovese, M. C.] Stanford Univ, Palo Alto, CA 94304 USA. [Kay, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hsia, E. C.; Doyle, M. K.; Rahman, M. U.] U Penn Med Sch, Centocor Res & Dev Inc, Malvern, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD MAY PY 2009 VL 12 IS 3 BP A72 EP A72 DI 10.1016/S1098-3015(10)73423-9 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 433WO UT WOS:000265236700355 ER PT J AU Parikh, NM Shah, DH Deswal, A Ashton, CM Agarwal, SJ Chen, H Johnson, M AF Parikh, N. M. Shah, D. H. Deswal, A. Ashton, C. M. Agarwal, S. J. Chen, H. Johnson, M. TI THE ASSOCIATION OF ASPIRIN USE ON RISK OF HOSPITALIZATION IN CHF PATIENTS TAKING ACE INHIBITORS: A RETROSPECTIVE ANALYSIS OF A NATIONAL COHORT OF VETERANS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Parikh, N. M.] Anal Grp Inc, Boston, MA USA. [Shah, D. H.] Abt Bio Pharma Solut Inc, Waltham, MA USA. [Deswal, A.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Ashton, C. M.] Methodist Inst Technol Innovat & Educ, Houston, TX USA. [Agarwal, S. J.; Chen, H.; Johnson, M.] Univ Houston, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD MAY PY 2009 VL 12 IS 3 BP A146 EP A146 DI 10.1016/S1098-3015(10)73792-X PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 433WO UT WOS:000265236700724 ER PT J AU Toy, EL Porter, CL Books, P Vekeman, F Barghout, V Duh, M Skarin, AT AF Toy, E. L. Porter, C. L. Books, P. Vekeman, F. Barghout, V Duh, M. Skarin, A. T. TI BUDGET IMPACT ANALYSIS OF SARGRAMOSTIM USE IN PATIENTS WITH CHEMOTHERAPY-INDUCED NEUTROPENIA SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Toy, E. L.; Porter, C. L.; Books, P.] Anal Grp Inc, Lakewood, CO USA. [Vekeman, F.] Grp Analyse Ltee, Montreal, PQ, Canada. [Barghout, V] Bayer HealthCare Pharmaceut Inc, Wayne, NJ USA. [Duh, M.] Anal Grp Inc, Boston, MA USA. [Skarin, A. T.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD MAY PY 2009 VL 12 IS 3 BP A39 EP A39 DI 10.1016/S1098-3015(10)73256-3 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 433WO UT WOS:000265236700188 ER PT J AU Vekeman, F Laliberte, F Afonja, O Lafeuille, MH Barghout, V Duh, MS Skarin, AT AF Vekeman, F. Laliberte, F. Afonja, O. Lafeuille, M. H. Barghout, V Duh, M. S. Skarin, A. T. TI PATTERN OF UTILIZATION OF PEGFILGRASTIM IN PATIENTS WITH CHEMOTHERAPY-INDUCED NEUTROPENIA: A RETROSPECTIVE ANALYSIS OF ADMINISTRATIVE CLAIMS DATA SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Vekeman, F.; Laliberte, F.; Lafeuille, M. H.] Grpe Analyse Ltee, Montreal, PQ, Canada. [Afonja, O.; Barghout, V] Bayer HealthCare Pharmaceut Inc, Wayne, NJ USA. [Duh, M. S.] Anal Grp Inc, Boston, MA USA. [Skarin, A. T.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD MAY PY 2009 VL 12 IS 3 BP A3 EP A3 DI 10.1016/S1098-3015(10)73079-5 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 433WO UT WOS:000265236700011 ER PT J AU Yeh, SY Doupis, J Rahangdale, S Horr, S Malhotra, A Veves, A AF Yeh, Susie Yim Doupis, John Rahangdale, Shilpa Horr, Samuel Malhotra, Atul Veves, Aristidis TI Total serum bilirubin does not affect vascular reactivity in patients with diabetes SO VASCULAR MEDICINE LA English DT Article DE bilirubin; diabetes; endothelial function ID FLOW-MEDIATED VASODILATION; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR EVENTS; HEART-DISEASE; RISK; HEALTH; ATHEROSCLEROSIS; ASSOCIATION; ADULTS AB Bilirubin may have a major role in the prevention of cardiovascular disease based on recent data regarding its anti-oxidant properties. We determined the relationship between total serum bilirubin and vascular reactivity in a large cohort of individuals with diabetes, a disease associated with known oxidant stress. We studied 302 individuals: 52 controls, 37 with type 1 diabetes, 213 with type 2 diabetes. High-resolution ultrasound was used to measure flow-mediated dilation (FMD; endotheliumdependent) and nitroglycerin-induced dilation (NID, endothelium-independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure microvascular reactivity in the forearm skin before and after iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium- independent). Bilirubin levels were higher in the type 2 diabetes group (0.71 +/- 0.34 mg/dl) compared to controls (0.56 +/- 0.26 mg/dl, p < 0.0001). A weak inverse correlation was observed between bilirubin and FMD (r = -0.125, p = 0.032) and skin endothelium- dependent vasodilation (r = -0.157, p = 0.019). In multivariate analyses, however, these correlations were not statistically significant. There is no association between bilirubin levels and vascular reactivity in the macro- and microcirculation of individuals with diabetes. Bilirubin, therefore, does not correlate with predictors of cardiovascular risk in the diabetic population. C1 [Horr, Samuel; Veves, Aristidis] Harvard Univ, Sch Med, Microcirculat Lab, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Yeh, Susie Yim; Rahangdale, Shilpa; Malhotra, Atul] Harvard Univ, Sch Med, Sleep Disorders Program, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Doupis, John] Joslin Diabet Ctr, Boston, MA USA. RP Veves, A (reprint author), Harvard Univ, Sch Med, Microcirculat Lab, Beth Israel Deaconess Med Ctr, Palmer 317,1 Deaconess Rd, Boston, MA 02215 USA. EM aveves@caregroup.harvard.edu FU NCRR NIH HHS [M01 RR001032, RR 01032]; NHLBI NIH HHS [K24 HL093218, R01 HL073146, R01 HL073146-04, R01 HL075678, R01 HL75678, R01-HL73146]; NIA NIH HHS [K23 AG024837, K23 AG024837-04] NR 24 TC 10 Z9 10 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD MAY PY 2009 VL 14 IS 2 BP 129 EP 136 DI 10.1177/1358863X08098273 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 433PR UT WOS:000265218500005 PM 19366819 ER PT J AU Gul, KM Ahmadi, N Wang, ZY Jamieson, C Nasir, K Metcalfe, R Hecht, HS Hartley, CJ Naghavi, M AF Gul, Khawar M. Ahmadi, Naser Wang, Zhiying Jamieson, Craig Nasir, Khurram Metcalfe, Ralph Hecht, Harvey S. Hartley, Craig J. Naghavi, Morteza TI Digital thermal monitoring of vascular function: a novel tool to improve cardiovascular risk assessment SO VASCULAR MEDICINE LA English DT Article DE coronary heart disease; digital thermal monitoring; endothelial function; Framingham risk score; reactive hyperemia; vascular reactivity ID REACTIVE HYPEREMIA; MICROVASCULAR FUNCTION; ATHEROSCLEROSIS; DISEASE; FLOW; SKIN AB Digital thermal monitoring (DTM) of vascular function during cuff-occlusive reactive hyperemia relies on the premise that changes in fingertip temperature during and after an ischemic stimulus reflect changes in blood flow. To determine its utility in individuals with and without known coronary heart disease (CHD), 133 consecutive individuals (age 54 +/- 10 years, 50% male, 19 with known CHD) underwent DTM during and after 2 minutes of supra-systolic arm cuff inflation. Fingertip temperatures of the occluded and non-occluded fingertips were measured simultaneously. Post-cuff deflation temperature rebound (TR) was lower in the CHD patients and in those with an increased Framingham risk score (FRS) compared to the normal group. After adjustment for age, sex, and cardiac risk factors, TR was significantly lower in those with CHD compared to those without CHD (p < 0.05). This study demonstrates that vascular dysfunction measured by DTM is associated with CHD and an increased FRS, and could potentially be used to identify high-risk patients. C1 [Gul, Khawar M.; Ahmadi, Naser] Harbor UCLA Med Ctr, Torrance, CA USA. [Wang, Zhiying] Univ Texas Houston Hlth Sci Ctr, Houston, TX USA. [Nasir, Khurram] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MRI PET CT Program, Cambridge, MA 02138 USA. [Metcalfe, Ralph] Univ Houston, Houston, TX 77004 USA. [Hartley, Craig J.] Baylor Coll Med, Houston, TX 77030 USA. RP Naghavi, M (reprint author), 8275 El Rio,Suite 100, Houston, TX 77054 USA. EM mn@vp.org FU NHLBI NIH HHS [R01 HL022512] NR 16 TC 20 Z9 23 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD MAY PY 2009 VL 14 IS 2 BP 143 EP 148 DI 10.1177/1358863X08098850 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 433PR UT WOS:000265218500007 PM 19366821 ER PT J AU Isayama, T England, SLM Crouch, RK Zimmerman, AL Makino, CL AF Isayama, Tomoki England, S. L. McCabe Crouch, R. K. Zimmerman, A. L. Makino, C. L. TI beta-ionone activates and bleaches visual pigment in salamander photoreceptors SO VISUAL NEUROSCIENCE LA English DT Article DE Retinoids; Phototransduction; Rhodopsin; Cyclic nucleotide-gated channel; Neurophysiology ID PROTEIN-COUPLED RECEPTORS; ROD OUTER SEGMENT; RETINAL CONES; BINDING-SITE; ALLOSTERIC MODULATION; OPSIN; RHODOPSIN; ADAPTATION; CHANNELS; PHOTOTRANSDUCTION AB Vision begins with photoisomerization of 11-cis retinal to the all-trans conformation within the chromophore-binding pocket of opsin, leading to activation of a biochemical cascade. Release of all-trans retinal from the binding pocket curtails but does not fully quench file ability of opsin to activate transducin. All-trans retinal and some other analogs, Such as beta-ionone, enhance opsin's activity, presumably oil binding the empty chromophore-binding pocket. By recording from isolated salamander photoreceptors and from patches of rod outer segment membrane, we now show that high concentrations of beta-ionone suppressed circulating current in dark-adapted green-sensitive rods by inhibiting the cyclic nucleotide-gated channels. There were also decreases in circulating current and flash sensitivity, and accelerated flash response kinetics in dark-adapted blue-sensitive (BS) rods and cones. and in Ultraviolet-sensitive cones, at concentrations too low to inhibit the channels. These effects persisted in BS rods even after incubation with 9-cis retinal to ensure complete regeneration of their visual pigment, After long exposures to high concentrations of beta-ionone. recovery was incomplete unless 9-cis retinal was given, indicating that visual pigment had been bleached. Therefore, we propose that beta-ionone activates and bleaches some types of visual pigments, mimicking the effects of light. C1 [Isayama, Tomoki; Makino, C. L.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [England, S. L. McCabe; Zimmerman, A. L.] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. [Crouch, R. K.] Med Univ S Carolina, Dept Ophthalmol, Storm Eye Res Inst, Charleston, SC 29425 USA. RP Isayama, T (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM tomoki_isayama@meei.harvard.edu OI Makino, Clint/0000-0002-6005-9069 FU Medical University of South Carolina (MUSC); [NEI EY11358]; [EY12944]; [EY07774]; [EY04939]; [EY014793]; [EY014104] FX We thank William N. Zagotta for the CNGA1 clone, Michael Varnum tor the CNGA3 clone. and V. Ketalov and M.C. Cornwall for helpful discussions. This work was supported by NEI EY11358, EY12944, EY07774, EY04939, EY014793, EY014104, and an unrestricted grant to Medical University of South Carolina (MUSC) flour Research to Prevent Blindness, Inc. R.K.C. is an Research to Prevent Blindness Senior Scientific Investigator. NR 43 TC 3 Z9 3 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD MAY-JUN PY 2009 VL 26 IS 3 BP 267 EP 274 DI 10.1017/S0952523809090105 PG 8 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 485DV UT WOS:000269102000002 PM 19500430 ER PT J AU Chatterjee, S Rath, ME Spiro, A Eisen, S Sloan, KL Rosen, AK AF Chatterjee, Sharmila Rath, Maria E. Spiro, Avron, III Eisen, Susan Sloan, Kevin L. Rosen, Amy K. TI GENDER DIFFERENCES IN VETERANS HEALTH ADMINISTRATION MENTAL HEALTH SERVICE USE Effects of Age and Psychiatric Diagnosis SO WOMENS HEALTH ISSUES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL COMORBIDITY SURVEY; GULF-WAR VETERANS; WOMEN VETERANS; FEMALE VETERANS; SEXUAL ASSAULT; UNITED-STATES; CARE UTILIZATION; SUBSTANCE-ABUSE; IN-SERVICE AB Purpose. The objective of this study was to compare gender differences in mental health disease burden and outpatient mental health utilization among veterans utilizing Veterans Health Administration (VHA) mental health services in fiscal year 1999 (FY99), after the first Gulf War and significant restructuring of VHA services. Methods. We used logistic regression to examine the relationships among gender, age, diagnostic groups, and utilization of mental health and specialty mental health services in a national sample of veterans. The sample included 782,789 veterans with at least 1 outpatient visit in the VHA in FY99 associated with a mental health or substance abuse (SA) diagnosis. Subgroup analyses were performed for 4 diagnostic categories: 1) posttraumatic stress disorder (PTSD), 2) SA disorders, 3) bipolar and psychotic disorders, and 4) mood and anxiety disorders. Main Findings. Younger women veterans (<35 years old) were significantly less likely and older women (>= 35) more likely to use any mental health services in comparison with their male counterparts. Similar findings were observed for younger women diagnosed with SA or mood and anxiety disorders, but not among veterans with PTSD or bipolar and psychotic disorders, among whom no there were no gender or age differences. In the case of specialized services for SA or PTSD, women younger than 55 with SA or PTSD were significantly less likely to use services than men. Conclusion. Women veterans underutilized specialty mental health services in relation to men but receipt of mental health care overall in FY99 varied by age and diagnosis. Examining gender differences alone, without taking other factors into account, may not provide an adequate picture of women veterans' current mental health service needs. C1 [Chatterjee, Sharmila] Bedford VAMC 152, Ctr Hlth Qual Outcomes & Econ Res, Dept Hlth Policy & Management, Bedford, MA 01730 USA. [Chatterjee, Sharmila; Eisen, Susan; Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Rath, Maria E.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Spiro, Avron, III] Boston VA Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Sloan, Kevin L.] VA Puget Sound Healthcare Syst, Seattle, WA USA. [Sloan, Kevin L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Chatterjee, S (reprint author), Bedford VAMC 152, Ctr Hlth Qual Outcomes & Econ Res, Dept Hlth Policy & Management, Bedford, MA 01730 USA. EM sharmcha@bu.edu OI Spiro III, Avron/0000-0003-4080-8621 NR 53 TC 11 Z9 11 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAY-JUN PY 2009 VL 19 IS 3 BP 176 EP 184 DI 10.1016/j.whi.2009.03.002 PG 9 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 454RH UT WOS:000266699700003 PM 19447322 ER PT J AU Letai, A AF Letai, Anthony TI Hiding from ABT-737 in lymph nodes SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SURVIVAL C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 30 PY 2009 VL 113 IS 18 BP 4132 EP 4133 DI 10.1182/blood-2008-12-192831 PG 4 WC Hematology SC Hematology GA 442MW UT WOS:000265846300004 PM 19406997 ER PT J AU Morel, P Duhamel, A Gobbi, P Dimopoulos, MA Dhodapkar, MV McCoy, J Crowley, J Ocio, EM Garcia-Sanz, R Treon, SP Leblond, V Kyle, RA Barlogie, B Merlini, G AF Morel, Pierre Duhamel, Alain Gobbi, Paolo Dimopoulos, Meletios A. Dhodapkar, Madhav V. McCoy, Jason Crowley, John Ocio, Enrique M. Garcia-Sanz, Ramon Treon, Steven P. Leblond, Veronique Kyle, Robert A. Barlogie, Bart Merlini, Giampaolo TI International prognostic scoring system for Waldenstrom macroglobulinemia SO BLOOD LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Hematology CY DEC 09-12, 2006 CL Orlando, FL SP Amer Soc Hematol ID CONSENSUS PANEL RECOMMENDATIONS; CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTIPLE-MYELOMA; MODEL; RITUXIMAB; WORKSHOP; SURVIVAL; THERAPY; CLASSIFICATION; VALIDATION AB Recently, many new drugs have been developed for the treatment of Waldenstrom macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (> 65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 x 10(9)/L, beta 2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P<.001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance. (Blood. 2009; 113: 4163-4170) C1 [Morel, Pierre] Hop Schaffner, Lens, France. [Morel, Pierre; Leblond, Veronique] French Cooperat Grp Chron Lymphocyt Leukaemia Wal, Paris, France. [Duhamel, Alain] Fac Med Lille, F-59045 Lille, France. [Gobbi, Paolo; Merlini, Giampaolo] Univ Pavia, Fdn IRCCS, Policlin San Matteo, I-27100 Pavia, Italy. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Dhodapkar, Madhav V.] Rockefeller Univ, New York, NY 10021 USA. [McCoy, Jason; Crowley, John] SW Oncol Grp, Seattle, WA USA. [Ocio, Enrique M.; Garcia-Sanz, Ramon] Spanish Grp Study Waldenstrom Macroglobulinaemia, Salamanca, Spain. [Treon, Steven P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Leblond, Veronique] Univ Paris 06, Hop Pitie Salpetriere, Paris, France. [Kyle, Robert A.] Mayo Clin, Rochester, MN USA. [Barlogie, Bart] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP Morel, P (reprint author), Ctr Hosp Schaffner, Serv Hematol Clin, 99 Route Bassee, F-62300 Lens, France. EM pmorel@ch-lens.fr RI Duhamel, Alain/B-8624-2011; 2009, Secribsal/A-1266-2012; Duhamel, Alain/A-4899-2013; Garcia-Sanz, Ramon/B-7986-2017; OI Garcia-Sanz, Ramon/0000-0003-4120-2787; Merlini, Giampaolo/0000-0001-7680-3254 NR 34 TC 121 Z9 129 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 30 PY 2009 VL 113 IS 18 BP 4163 EP 4170 DI 10.1182/blood-2008-08-174961 PG 8 WC Hematology SC Hematology GA 442MW UT WOS:000265846300011 PM 19196866 ER PT J AU Azab, AK Runnels, JM Pitsillides, C Moreau, AS Azab, F Leleu, X Jia, X Wright, R Ospina, B Carlson, AL Alt, C Burwick, N Roccaro, AM Ngo, HT Farag, M Melhem, MR Sacco, A Munshi, NC Hideshima, T Rollins, BJ Anderson, KC Kung, AL Lin, CP Ghobrial, IM AF Azab, Abdel Kareem Runnels, Judith M. Pitsillides, Costas Moreau, Anne-Sophie Azab, Feda Leleu, Xavier Jia, Xiaoying Wright, Renee Ospina, Beatriz Carlson, Alicia L. Alt, Clemens Burwick, Nicholas Roccaro, Aldo M. Ngo, Hai T. Farag, Mena Melhem, Molly R. Sacco, Antonio Munshi, Nikhil C. Hideshima, Teru Rollins, Barrett J. Anderson, Kenneth C. Kung, Andrew L. Lin, Charles P. Ghobrial, Irene M. TI CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy SO BLOOD LA English DT Article ID MEDIATED DRUG-RESISTANCE; NON-HODGKINS-LYMPHOMA; STEM-CELLS; MOBILIZATION; MECHANISMS; BORTEZOMIB; ADHESION; GROWTH; FACTOR-1-ALPHA; INVOLVEMENT AB The interaction of multiple myeloma (MM) cells with their microenvironment in the bone marrow (BM) provides a protective environment and resistance to therapeutic agents. We hypothesized that disruption of the interaction of MM cells with their BM milieu would lead to their sensitization to therapeutic agents such as bortezomib, melphalan, doxorubicin, and dexamethasone. We report that the CXCR4 inhibitor AMD3100 induces disruption of the interaction of MM cells with the BM reflected by mobilization of MM cells into the circulation in vivo, with kinetics that differed from that of hematopoietic stem cells. AMD3100 enhanced sensitivity of MM cell to multiple therapeutic agents in vitro by disrupting adhesion of MM cells to bone marrow stromal cells (BMSCs). Moreover, AMD3100 increased mobilization of MM cells to the circulation in vivo, increased the ratio of apoptotic circulating MM cells, and enhanced the tumor reduction induced by bortezomib. Mechanistically, AMD3100 significantly inhibited Akt phosphorylation and enhanced poly(ADP-ribose) polymerase (PARP) cleavage as a result of bortezomib, in the presence of BMSCs in coculture. These experiments provide a proof of concept for the use of agents that disrupt interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy. (Blood. 2009; 113: 4341-4351) C1 [Azab, Abdel Kareem; Runnels, Judith M.; Pitsillides, Costas; Carlson, Alicia L.; Alt, Clemens; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Azab, Abdel Kareem; Runnels, Judith M.; Pitsillides, Costas; Carlson, Alicia L.; Alt, Clemens; Lin, Charles P.] Massachusetts Gen Hosp, Adv Microscopy Program, Ctr Syst Biol, Boston, MA 02114 USA. [Azab, Abdel Kareem; Runnels, Judith M.; Moreau, Anne-Sophie; Azab, Feda; Leleu, Xavier; Jia, Xiaoying; Wright, Renee; Ospina, Beatriz; Burwick, Nicholas; Roccaro, Aldo M.; Ngo, Hai T.; Farag, Mena; Melhem, Molly R.; Sacco, Antonio; Munshi, Nikhil C.; Hideshima, Teru; Rollins, Barrett J.; Anderson, Kenneth C.; Kung, Andrew L.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Boston, MA USA. [Azab, Abdel Kareem; Runnels, Judith M.; Moreau, Anne-Sophie; Azab, Feda; Leleu, Xavier; Jia, Xiaoying; Wright, Renee; Ospina, Beatriz; Burwick, Nicholas; Roccaro, Aldo M.; Ngo, Hai T.; Farag, Mena; Melhem, Molly R.; Sacco, Antonio; Munshi, Nikhil C.; Hideshima, Teru; Rollins, Barrett J.; Anderson, Kenneth C.; Ghobrial, Irene M.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lin, CP (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM lin@helix.mgh.harvard.edu; Irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128; Kung, Andrew/0000-0002-9091-488X FU National Institutes of Health (NIH, Bethesda, MD) [R01CA125690, EB000664]; Leukemia & Lymphoma Society (White Plains, NY); Multiple Myeloma Research Foundation (MMRF, Nowalk, CT) FX This work was supported in part by R01CA125690, National Institutes of Health (NIH, Bethesda, MD) EB000664, the Leukemia & Lymphoma Society (White Plains, NY), and Multiple Myeloma Research Foundation (MMRF, Nowalk, CT). NR 41 TC 211 Z9 215 U1 5 U2 22 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 30 PY 2009 VL 113 IS 18 BP 4341 EP 4351 DI 10.1182/blood-2008-10-186668 PG 11 WC Hematology SC Hematology GA 442MW UT WOS:000265846300030 PM 19139079 ER PT J AU Roccaro, AM Sacco, A Chen, CZ Runnels, J Leleu, X Azab, F Azab, AK Jia, XY Ngo, HT Melhem, MR Burwick, N Varticovski, L Novina, CD Rollins, BJ Anderson, KC Ghobrial, IM AF Roccaro, Aldo M. Sacco, Antonio Chen, Changzhong Runnels, Judith Leleu, Xavier Azab, Feda Azab, Abdel Kareem Jia, Xiaoying Ngo, Hai T. Melhem, Molly R. Burwick, Nicholas Varticovski, Lyuba Novina, Carl D. Rollins, Barrett J. Anderson, Kenneth C. Ghobrial, Irene M. TI microRNA expression in the biology, prognosis, and therapy of Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID NF-KAPPA-B; MULTIPLE-MYELOMA; CELL LYMPHOMAS; TARGET; REVEALS; MIR-155; PATHWAY; PROTEIN; KINASE; CANCER AB Multilevel genetic characterization of Waldenstrom macroglobulinemia (WM) is required to improve our understanding of the underlying molecular changes that lead to the initiation and progression of this disease. We performed microRNA-expression profiling of bone marrow-derived CD19(+) WM cells, compared with their normal cellular counterparts and validated data by quantitative reverse-transcription-polymerase chain reaction (qRT-PCR). We identified a WM-specific microRNA signature characterized by increased expression of microRNA-363*/-206/-494/-155/-184/-542-3p, and decreased expression of microRNA-9* (ANOVA; P < .01). We found that microRNA-155 regulates proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-kappa B pathways. Potential microRNA-155 target genes were identified using gene-expression profiling and included genes involved in cell-cycle progression, adhesion, and migration. Importantly, increased expression of the 6 miRNAs significantly correlated with a poorer outcome predicted by the International Prognostic Staging System for WM. We further demonstrated that therapeutic agents commonly used in WM alter the levels of the major miRNAs identified, by inducing downmodulation of 5 increased miRNAs and up-modulation of patient-downexpressed miRNA-9*. These data indicate that microRNAs play a pivotal role in the biology of WM; represent important prognostic marker; and provide the basis for the development of new microRNA-based targeted therapies in WM. (Blood. 2009; 113: 4391-4402) C1 [Ghobrial, Irene M.] Dana Farber Canc Inst, Kirsch Lab Waldenstrom Macroglobulinemia, Dept Med Oncol, Boston, MA 02115 USA. [Roccaro, Aldo M.; Sacco, Antonio; Chen, Changzhong; Runnels, Judith; Leleu, Xavier; Azab, Feda; Azab, Abdel Kareem; Jia, Xiaoying; Ngo, Hai T.; Melhem, Molly R.; Burwick, Nicholas; Novina, Carl D.; Rollins, Barrett J.; Anderson, Kenneth C.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Boston, MA USA. [Roccaro, Aldo M.] Univ Bari, Dept Internal Med & Clin Oncol, Sch Med, Bari, Italy. [Roccaro, Aldo M.] Univ Brescia, Sch Med, Unit Blood Dis & Cell Therapies, Brescia, Italy. [Varticovski, Lyuba] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, Kirsch Lab Waldenstrom Macroglobulinemia, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128 FU NIH [R21 1R21CA126119-01]; International Waldenstrom Macroglobulinemia Foundation (IWMF); Kirsch Laboratory for Waldenstrom Macroglobulinemia; Italian Association for Cancer Research; Berlucchi Foundation FX This work was supported in part by NIH (Washington, DC) grant R21 1R21CA126119-01, International Waldenstrom Macroglobulinemia Foundation (IWMF), Kirsch Laboratory for Waldenstrom Macroglobulinemia, Italian Association for Cancer Research (A. M. R.), and Berlucchi Foundation (A. M. R.). NR 42 TC 62 Z9 66 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 30 PY 2009 VL 113 IS 18 BP 4391 EP 4402 DI 10.1182/blood-2008-09-178228 PG 12 WC Hematology SC Hematology GA 442MW UT WOS:000265846300035 PM 19074725 ER PT J AU Romeo, HE Tio, DL Taylor, AN AF Romeo, Horacio E. Tio, Delia L. Taylor, Anna N. TI Effects of superior cervical ganglionectomy on body temperature and on the lipopolysaccharide-induced febrile response in rats SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Fever; Superior cervical ganglionectomy; Biotelemetry; Lipopolysaccharide; Sprague-Dawley rat ID CORTICOTROPIN-RELEASING HORMONE; SUBMAXILLARY LYMPH-NODES; BROWN ADIPOSE-TISSUE; SYMPATHETIC NEURONS; BRAIN COMMUNICATION; LOCUS-COERULEUS; PITUITARY-GLAND; PREOPTIC AREA; NEUROENDOCRINE; HYPOTHALAMUS AB The involvement of the cervical sympathetic ganglia (SCG) on body temperature and during the occurrence of the induced febrile response was investigated in rats. Bilateral superior cervical gaglionectomy (SCGx) attenuated the daily dark-phase temperature compared to that of the sham-operated rats during the first 2 days post surgery. Body temperatures returned to pre-surgery levels by Day-3. Ten days after surgery, a febrile response was induced by lipopolysaccharide (LPS) immune challenge. SCGx significantly blunted the LPS-induced febrile response. These data suggest that obliteration of the cervical sympathetic peripheral innervation impairs the capability to produce an induced febrile response. (C) 2009 Elsevier B.V. All rights reserved. C1 [Romeo, Horacio E.] Univ Buenos Aires, Fac Med, Dept Fisiol, RA-2155 Buenos Aires, DF, Argentina. [Romeo, Horacio E.; Tio, Delia L.; Taylor, Anna N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Tio, Delia L.; Taylor, Anna N.] W Los Angeles Healthcare Ctr, Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Romeo, HE (reprint author), Univ Buenos Aires, Fac Med, Dept Fisiol, 1121BA, RA-2155 Buenos Aires, DF, Argentina. EM hromeo@fmed.uba.ar FU National Institute of Dental and Craniofacial Research [DE016063-01] FX This work is supported by The National Institute of Dental and Craniofacial Research; Grant number: DE016063-01 (H.E. Romeo). NR 56 TC 3 Z9 3 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD APR 30 PY 2009 VL 209 IS 1-2 BP 81 EP 86 DI 10.1016/j.jneuroim.2009.01.027 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 448ZG UT WOS:000266299900009 PM 19251325 ER PT J AU Liu, HS Agam, Y Madsen, JR Kreiman, G AF Liu, Hesheng Agam, Yigal Madsen, Joseph R. Kreiman, Gabriel TI Timing, Timing, Timing: Fast Decoding of Object Information from Intracranial Field Potentials in Human Visual Cortex SO NEURON LA English DT Article ID INFERIOR TEMPORAL NEURONS; SINGLE NEURONS; INFEROTEMPORAL CORTEX; PREFRONTAL CORTEX; FACE PERCEPTION; HUMAN BRAIN; RECOGNITION; MEMORY; RESPONSES; CATEGORY AB The difficulty of visual recognition stems from the need to achieve high selectivity while maintaining robustness to object transformations within hundreds of milliseconds. Theories of visual recognition differ in whether the neuronal circuits invoke recurrent feedback connections or not. The timing of neurophysiological responses in visual cortex plays a key role in distinguishing between bottom-up and top-down theories. Here, we quantified at millisecond resolution the amount of visual information conveyed by intracranial field potentials from 912 electrodes in 11 human subjects. We could decode object category information from human visual cortex in single trials as early as 100 ms poststimulus. Decoding performance was robust to depth rotation and scale changes. The results suggest that physiological activity in the temporal lobe can account for key properties of visual recognition. The fast decoding in single trials is compatible with feedforward theories and provides strong constraints for computational models of human vision. C1 [Liu, Hesheng; Agam, Yigal; Kreiman, Gabriel] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurosci & Ophthalmol, Boston, MA 02115 USA. [Liu, Hesheng] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02115 USA. [Madsen, Joseph R.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurosurg, Boston, MA 02129 USA. [Kreiman, Gabriel] Harvard Univ, Ctr Brain Sci, Boston, MA 02115 USA. [Kreiman, Gabriel] Harvard Univ, Swartz Ctr Theoret Neurosci, Boston, MA 02115 USA. RP Kreiman, G (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurosci & Ophthalmol, Boston, MA 02115 USA. EM gabriel.kreiman@tch.harvard.edu OI Liu, Hesheng/0000-0002-7233-1509 FU Epilepsy Foundation; Whitehall Foundation; Klingenstein Fund; Children's Hospital Boston Ophthalmology Foundation FX We would like to thank the patients for their cooperation in these studies. We also thank Margaret Livingstone, Ethan Meyers, and Thomas Serre for comments on the manuscript, and Calin Buia, Sheryl Manganaro, Paul Dionne, and Malena Espanol for technical assistance. We also acknowledge the financial support from the Epilepsy Foundation, the Whitehall Foundation, the Klingenstein Fund, and Children's Hospital Boston Ophthalmology Foundation. NR 56 TC 179 Z9 180 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 30 PY 2009 VL 62 IS 2 BP 281 EP 290 DI 10.1016/j.neuron.2009.02.025 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 441MU UT WOS:000265774100015 PM 19409272 ER PT J AU Gaissert, HA Piyavisetpat, N Mark, EJ AF Gaissert, Henning A. Piyavisetpat, Nitra Mark, Eugene J. TI A Man with Chest Pain, Dysphagia, and Pleural and Mediastinal Calcifications Diffuse malignant mesothelioma, with extensive osseous differentiation, involving the pleura, chest wall, lung, mediastinum, esophagus, and pericardium. Acute myocardial infarction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; ASBESTOS EXPOSURE; CARTILAGINOUS DIFFERENTIATION; TUMOR; OSTEOSARCOMA; HYPERPLASIA; MORTALITY; DIAGNOSIS; FEATURES; BRITAIN C1 [Gaissert, Henning A.] Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. [Piyavisetpat, Nitra] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mark, Eugene J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gaissert, Henning A.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Piyavisetpat, Nitra] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Mark, Eugene J.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Gaissert, HA (reprint author), Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. NR 36 TC 2 Z9 2 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 30 PY 2009 VL 360 IS 18 BP 1886 EP 1895 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 438MU UT WOS:000265560300012 PM 19403907 ER PT J AU Kaufman, RE Ostacher, MJ Marks, EH Simon, NM Sachs, GS Jensen, JE Renshaw, PF Pollack, MH AF Kaufman, Rebecca E. Ostacher, Michael J. Marks, Elizabeth H. Simon, Naomi M. Sachs, Gary S. Jensen, J. Eric Renshaw, Perry F. Pollack, Mark H. TI Brain GABA levels in patients with bipolar disorder SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Anxiety; Bipolar disorder; GABA; Glutamate; Magnetic resonance spectroscopy; Neuroimaging ID MAGNETIC-RESONANCE-SPECTROSCOPY; ANTERIOR CINGULATE CORTEX; AMINOBUTYRIC-ACID CONCENTRATIONS; DORSOLATERAL PREFRONTAL CORTEX; MOOD DISORDERS; ELECTROCONVULSIVE-THERAPY; SCHIZOPHRENIC-PATIENTS; DEPRESSED-PATIENTS; GABAERGIC NEURONS; ANXIETY DISORDERS AB Purpose: A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. General methods: We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls. Findings: There were no significant differences in GABA, glutamate or glutamine between patients and controls. Conclusions: Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder. (C) 2009 Elsevier Inc. All rights reserved. C1 [Pollack, Mark H.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, Boston, MA 02114 USA. [Jensen, J. Eric; Renshaw, Perry F.] McLean Hosp, Dept Psychiat, Belmont, MA 02478 USA. RP Pollack, MH (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, Simches Res Bldg,2nd Floor,185 Cambridge St, Boston, MA 02114 USA. EM mpollack@partners.org OI Ostacher, Michael/0000-0003-0353-7535; Sripada, Rebecca/0000-0002-2844-3458 FU NARSAD Independent Investigator Grant FX This study was funded by a NARSAD Independent Investigator Grant. NR 49 TC 27 Z9 27 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD APR 30 PY 2009 VL 33 IS 3 BP 427 EP 434 DI 10.1016/j.pnpbp.2008.12.025 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 437EY UT WOS:000265470500007 PM 19171176 ER PT J AU Healy, BC Engler, D AF Healy, Brian C. Engler, David TI Modeling disease-state transition heterogeneity through Bayesian variable selection SO STATISTICS IN MEDICINE LA English DT Article DE Bayesian variable selection; Markov transition models; multinomial logit models; Multiple sclerosis ID MULTIPLE-SCLEROSIS; PROGRESSION; DISABILITY; TIME AB In many diseases, Markov transition models are useful in describing transitions between discrete disease states. Often the probability of transitioning from one state to another varies widely across subjects. This heterogeneity is driven, in part, by a possibly unknown number of previous disease states and by potentially complex relationships between clinical data and these states. We propose use of Bayesian variable selection in Markov transition models to allow estimation of subject-specific transition probabilities. Our approach simultaneously estimates the order of the Markov process and the transition-specific covariate effects. The methods are assessed using Simulation studies and applied to model disease-state transition on the expanded disability status scale (EDSS) in multiple sclerosis (MS) patients from the Partners MS Center in Boston, MA. The proposed methodology is shown to accurately identify complex covariate-transition relationships in simulations and identifies a clinically significant interaction between relapse history and EDSS history in MS patients. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Healy, Brian C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol,Partners MS Ctr, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Engler, David] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. RP Engler, D (reprint author), 223 TMCB, Provo, UT 84602 USA. EM engler@byu.edu FU Partners MS Center FX We would like to thank Micha Mandel and the reviewers for helpful comments, and the Partners MS Center for access to the data and funding this research. NR 24 TC 3 Z9 3 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD APR 30 PY 2009 VL 28 IS 9 BP 1353 EP 1368 DI 10.1002/sim.3545 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 434YG UT WOS:000265309600003 PM 19206077 ER PT J AU Smith, MJ Culhane, AC Donovan, M Coffey, JC Barry, BD Kelly, MA Higgins, DG Wang, JH Kirwan, WO Cotter, TG Redmond, HP AF Smith, M. J. Culhane, A. C. Donovan, M. Coffey, J. C. Barry, B. D. Kelly, M. A. Higgins, D. G. Wang, J. H. Kirwan, W. O. Cotter, T. G. Redmond, H. P. TI Analysis of differential gene expression in colorectal cancer and stroma using fluorescence-activated cell sorting purification SO BRITISH JOURNAL OF CANCER LA English DT Article DE colorectal cancer; fluorescence-activated cell sorting; gene expression microarray analysis; humans ID BREAST-CANCER; MICROARRAY DATA; HEPATOCELLULAR-CARCINOMA; CLINICAL-APPLICATION; SIGNATURE; PROFILES; MICRODISSECTION; PREDICTION; TUMORS; RECURRENCE AB Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e. g., COL6A3, COL1A2, POSTN, TIMP2). Genes characteristic of colorectal carcinoma were overexpressed in the FACS- purified cells (e. g., HOX2D and RHOB). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes. C1 [Smith, M. J.; Coffey, J. C.; Barry, B. D.; Kelly, M. A.; Wang, J. H.; Kirwan, W. O.; Redmond, H. P.] Natl Univ Ireland Univ Coll Cork, Acad Dept Surg, Cork, Ireland. [Smith, M. J.; Donovan, M.; Cotter, T. G.] Natl Univ Ireland Univ Coll Cork, Dept Biochem, Cork, Ireland. [Culhane, A. C.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Culhane, A. C.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Higgins, D. G.] Univ Coll Dublin, Conway Inst, Dublin 2, Ireland. RP Redmond, HP (reprint author), Natl Univ Ireland Univ Coll Cork, Cork Univ Hosp, Acad Dept Surg, Cork, Ireland. EM Henry.Redmond@hse.ie RI Smith, Myles/B-7803-2009; Higgins, des/J-6314-2012; OI Smith, Myles/0000-0002-3254-4817; Higgins, Des/0000-0002-3952-3285 NR 55 TC 19 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD APR 28 PY 2009 VL 100 IS 9 BP 1452 EP 1464 DI 10.1038/sj.bjc.6604931 PG 13 WC Oncology SC Oncology GA 438SH UT WOS:000265575200013 PM 19401702 ER PT J AU Thangaroopan, M Truong, QA Kalra, MK Yared, K Abbara, S AF Thangaroopan, Molly Truong, Quynh A. Kalra, Mannudeep K. Yared, Kibar Abbara, Suhny TI Rare Case of an Unroofed Coronary Sinus Diagnosis by Multidetector Computed Tomography SO CIRCULATION LA English DT Editorial Material C1 [Truong, Quynh A.] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, Boston, MA 02114 USA. [Thangaroopan, Molly; Kalra, Mannudeep K.; Abbara, Suhny] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. RP Truong, QA (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NHLBI NIH HHS [T32 HL076136-05, K23 HL098370, L30 HL093806, L30 HL093806-01, T32 HL076136] NR 2 TC 17 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 28 PY 2009 VL 119 IS 16 BP E518 EP E520 DI 10.1161/CIRCULATIONAHA.107.707018 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 438UG UT WOS:000265580300019 PM 19398672 ER PT J AU Friedrich, MG Sechtem, U Schulz-Menger, J Holmvang, G Alakija, P Cooper, LT White, JA Abdel-Aty, H Gutberlet, M Prasad, S Aletras, A Laissy, JP Paterson, I Filipchuk, NG Kumar, A Pauschinger, M Liu, P AF Friedrich, Matthias G. Sechtem, Udo Schulz-Menger, Jeanette Holmvang, Godtfred Alakija, Pauline Cooper, Leslie T. White, James A. Abdel-Aty, Hassan Gutberlet, Matthias Prasad, Sanjay Aletras, Anthony Laissy, Jean-Pierre Paterson, Ian Filipchuk, Neil G. Kumar, Andreas Pauschinger, Matthias Liu, Peter CA Int Consensus Grp Cardiovasc Magne TI Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular magnetic resonance; myocarditis; consensus ID SUDDEN CARDIAC DEATH; AMERICAN-HEART-ASSOCIATION; ENDOMYOCARDIAL BIOPSY; ECHOCARDIOGRAPHIC FINDINGS; SUSPECTED MYOCARDITIS; DELAYED ENHANCEMENT; VIRAL MYOCARDITIS; GADOLINIUM-DTPA; ENZYME-RELEASE; CHEST-PAIN AB Cardiovascular magnetic resonance (CMR) has become the primary tool for noninvasive assessment of myocardial inflammation in patients with suspected myocarditis. The International Consensus Group on CMR Diagnosis of Myocarditis was founded in 2006 to achieve consensus among CMR experts and develop recommendations on the current state-of-the-art use of CMR for myocarditis. The recommendations include indications for CMR in patients with suspected myocarditis, CMR protocol standards, terminology for reporting CMR findings, and diagnostic CMR criteria for myocarditis (i.e., "Lake Louise Criteria"). C1 [Friedrich, Matthias G.; Filipchuk, Neil G.; Kumar, Andreas] Univ Calgary, Stephenson Cardiovasc MR Ctr, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci & Radiol, Calgary, AB T2N 2T9, Canada. [Alakija, Pauline] Univ Calgary, Dept Pathol, Calgary, AB T2N 2T9, Canada. [Sechtem, Udo] Robert Bosch Krankenhaus, Dept Cardiol, Stuttgart, Germany. [Schulz-Menger, Jeanette; Abdel-Aty, Hassan] Charite Univ Med Berlin, HELIOS Klinikum Berlin Buch, Franz Volhard Klin, Berlin, Germany. [Holmvang, Godtfred] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cooper, Leslie T.] Mayo Clin, Coll Med, Rochester, MN USA. [White, James A.] London Hlth Sci Ctr, London, ON, Canada. [Gutberlet, Matthias] Univ Leipzig, Dept Diagnost & Intervent Radiol, Leipzig, Germany. [Prasad, Sanjay] Royal Brompton Hosp, London SW3 6LY, England. [Aletras, Anthony] NHLBI, NIH, Bethesda, MD 20892 USA. [Laissy, Jean-Pierre] Hop Bichat Claude Bernard, Dept Radiol, F-75877 Paris, France. [Paterson, Ian] Univ Alberta, Div Cardiol, Edmonton, AB, Canada. [Pauschinger, Matthias] Klinikum Nurnberg Sud, Dept Cardiol, Nurnberg, Germany. [Liu, Peter] Toronto Gen Hosp, Max Bell Res Ctr, Toronto, ON, Canada. RP Friedrich, MG (reprint author), Univ Calgary, Stephenson Cardiovasc MR Ctr, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci & Radiol, 1403 29th St NW, Calgary, AB T2N 2T9, Canada. EM matthias.friedrich@ucalgary.ca OI Aletras, Anthony/0000-0002-3786-3817 FU Intramural NIH HHS [Z99 HL999999] NR 65 TC 538 Z9 571 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 28 PY 2009 VL 53 IS 17 BP 1475 EP 1487 DI 10.1016/j.jacc.2009.02.007 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 437VN UT WOS:000265515100001 PM 19389557 ER PT J AU Wilson, SR Scirica, BM Braunwald, E Murphy, SA Karwatowska-Prokopczuk, E Buros, JL Chaitman, BR Morrow, DA AF Wilson, Sean R. Scirica, Benjamin M. Braunwald, Eugene Murphy, Sabina A. Karwatowska-Prokopczuk, Ewa Buros, Jacqueline L. Chaitman, Bernard R. Morrow, David A. TI Efficacy of Ranolazine in Patients With Chronic Angina Observations From the Randomized, Double-Blind, Placebo-Controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angina; exercise tolerance; ranolazine; recurrent ischemia ID MYOCARDIAL-INFARCTION; HEART-DISEASE; AMLODIPINE; PREVENTION; COMMITTEE; PECTORIS; UPDATE; 1-YEAR AB Objectives We aimed to evaluate the efficacy and safety of ranolazine in a larger and more diverse group of patients with angina than previously studied. Background Ranolazine is an antianginal shown to reduce angina and improve exercise performance in selected patients with early-positive exercise testing and those with frequent angina. Methods We investigated the antianginal effects of ranolazine in the subgroup of patients with prior chronic angina (n = 3,565, 54%) enrolled in the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 36 trial of patients with acute coronary syndrome. Follow-up was a median of 350 days. Results Patients with prior angina received evidence-based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents). The primary end point (cardiovascular death, myocardial infarction, recurrent ischemia) was less frequent with ranolazine (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75 to 0.97; p = 0.017), due entirely to a significant reduction in recurrent ischemia (HR: 0.78; 95% CI: 0.67 to 0.91; p = 0.002). Ranolazine also reduced worsening angina (HR: 0.77; 95% CI: 0.59 to 1.00; p = 0.048) and intensification of antianginal therapy (HR: 0.77; 95% CI: 0.64 to 0.92, p = 0.005). Exercise duration at 8 months was greater with ranolazine (514 s vs. 482 s, p = 0.002). Cardiovascular death or myocardial infarction did not differ between treatment groups (HR: 0.97; 95% CI: 0.80 to 1.16; p = 0.71). Symptomatic documented arrhythmias (2.9% vs. 2.9%, p = 0.92) and total mortality (6.2% vs. 6.4%, p = 0.96) were similar with ranolazine or placebo. Conclusions In this largest study of ranolazine in patients with established coronary artery disease, ranolazine was effective in reducing angina with favorable safety in a substantially broader group of patients with angina than previously studied. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788) (J Am Coll Cardiol 2009;53:1510-6) (C) 2009 by the American College of Cardiology Foundation C1 [Morrow, David A.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Karwatowska-Prokopczuk, Ewa] CV Therapeut, Palo Alto, CA USA. [Chaitman, Bernard R.] St Louis Univ, Sch Med, St Louis, MO USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org FU CV Therapeutics (CVT) (Palo Alto, California) FX The MERLIN-TIMI 36 trial was supported by CV Therapeutics (CVT) (Palo Alto, California). Dr. Scirica has received research funding and honoraria for educational presentations and consulting for CVT. Dr. Braunwald received research grant support from CVT for the MERLIN-TIMI 36 trial. NR 24 TC 74 Z9 78 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 28 PY 2009 VL 53 IS 17 BP 1510 EP 1516 DI 10.1016/j.jacc.2009.01.037 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 437VN UT WOS:000265515100005 PM 19389561 ER PT J AU Weyman, AE AF Weyman, Arthur E. TI The Year in Echocardiography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE echocardiography; year; 2008 ID CARDIAC-RESYNCHRONIZATION THERAPY; VENTRICULAR FILLING PATTERN; RADIAL 2-DIMENSIONAL STRAIN; PATENT FORAMEN OVALE; HEART-FAILURE; ORIFICE AREA; TRACKING; TORSION; NEOVASCULARIZATION; DYSSYNCHRONY C1 Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Weyman, AE (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Yawkey 5E, Boston, MA 02114 USA. EM aweyman@partners.org NR 34 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 28 PY 2009 VL 53 IS 17 BP 1558 EP 1567 DI 10.1016/j.jacc.2009.01.042 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 437VN UT WOS:000265515100013 PM 19389569 ER PT J AU Lentz, MR Kim, WK Lee, V Bazner, S Halpern, EF Venna, N Williams, K Rosenberg, ES Gonzalez, RG AF Lentz, M. R. Kim, W. K. Lee, V. Bazner, S. Halpern, E. F. Venna, N. Williams, K. Rosenberg, E. S. Gonzalez, R. G. TI Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection SO NEUROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA COMPLEX; MAGNETIC-RESONANCE-SPECTROSCOPY; CEREBROSPINAL-FLUID; METABOLITE ABNORMALITIES; ANTIRETROVIRAL THERAPY; IMMUNE-RESPONSES; H-1 MRS; BRAIN AB Objective: To determine if changes in brain metabolites are observed during early HIV infection and correlate these changes with immunologic alterations. Methods: Eight subjects with early HIV infection, 9 HIV-seronegative controls, and 10 chronically HIV-infected subjects without neurologic impairment underwent (1)H magnetic resonance spectroscopy. Subjects with early stage infection were identified near the time of HIV seroconversion and imaged within 60 days of an evolving Western blot, while still having detectable plasma virus. Subjects had blood drawn for viral RNA and T cell quantification. Results: Both N-acetylaspartate (NAA) and Glx (glutamate + glutamine) were decreased in the frontal cortical gray matter of seropositive subjects. NAA levels were found to be decreased in the centrum semiovale white matter of chronically HIV-infected subjects, but not in those with early infection. Both HIV-infected cohorts demonstrated a lower number of CD4(+) T lymphocytes and a higher number of CD8(+) T lymphocytes in their blood. Lower NAA levels in the frontal cortex of subjects with early infection were associated with an expansion of CD8(+) T cells, especially effector CD8(+) T cells. Conclusions: These results verify metabolism changes occurring in the brain early during HIV infection. Lower NAA and Glx levels in the cortical gray matter suggests that HIV causes neuronal dysfunction soon after infection, which correlates to the expansion of CD8(+) T cells, specifically to an activated phenotype. Utilizing magnetic resonance spectroscopy to track NAA levels may provide important information on brain metabolic health while allowing better understanding of the virus-host interactions involved in CNS functional deficits. Neurology (R) 2009; 72: 1465-1472 C1 [Lentz, M. R.; Lee, V.; Halpern, E. F.; Gonzalez, R. G.] Massachusetts Gen Hosp, Dept Neuroradiol, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Venna, N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bazner, S.; Rosenberg, E. S.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Dept Med, Boston, MA 02114 USA. [Bazner, S.; Rosenberg, E. S.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Dept Pathol, Boston, MA 02114 USA. [Williams, K.] Boston Coll, Dept Biol, Boston, MA USA. [Kim, W. K.] Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23501 USA. RP Lentz, MR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bldg 149,13th St,Rm 2301, Charlestown, MA 02129 USA. EM mlentz@nmr.mgh.harvard.edu FU NIH [NS040237, NS037654, U19MH81835, NS050041, AI040873]; National Center for Research Resources [P41 RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute FX Supported by NIH grants NS051129 (M.R.L.), NS040237 (K.W.), NS037654 and U19MH81835 (K.W.), NS050041 (R.G.G.), AI040873 (E.S.R.), the National Center for Research Resources (P41 RR14075), and the Mental Illness and Neuroscience Discovery (MIND) Institute. NR 40 TC 55 Z9 57 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 28 PY 2009 VL 72 IS 17 BP 1465 EP 1472 DI 10.1212/WNL.0b013e3181a2e90a PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 438UD UT WOS:000265580000004 PM 19398702 ER PT J AU Wua, M Jung, L Cooper, AB Fleet, C Chen, LH Breault, L Clark, K Cai, ZH Vincent, S Bottega, S Shen, Q Richardson, A Bosenburg, M Naber, SP DePinho, RA Kuperwasserf, C Robinson, MO AF Wua, Min Jung, Lina Cooper, Adrian B. Fleet, Christina Chen, Lihao Breault, Lyne Clark, Kimberly Cai, Zuhua Vincent, Sylvie Bottega, Steve Shen, Qiong Richardson, Andrea Bosenburg, Marcus Naber, Stephen P. DePinho, Ronald A. Kuperwasserf, Charlotte Robinson, Murray O. TI Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer model; human in mouse; tissue reconstitution ID EXPRESSION; CELLS; TRANSFORMATION; APOPTOSIS; MUTATION; MOUSE AB Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies. C1 [Kuperwasserf, Charlotte] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Wua, Min; Jung, Lina; Cooper, Adrian B.; Fleet, Christina; Chen, Lihao; Breault, Lyne; Clark, Kimberly; Cai, Zuhua; Vincent, Sylvie; Bottega, Steve; Shen, Qiong; Robinson, Murray O.] Aveo Pharmaceut Inc, Cambridge, MA 02139 USA. [Richardson, Andrea] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Richardson, Andrea] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bosenburg, Marcus] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. [Naber, Stephen P.] Tufts Univ New England Med Ctr, Dept Pathol, Boston, MA 02111 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. RP Kuperwasserf, C (reprint author), Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. EM Charlotte.Kuperwasser@tufts.edu; mrobinson@aveopharma.com OI Robinson, Murray/0000-0003-4462-0685 NR 23 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 28 PY 2009 VL 106 IS 17 BP 7022 EP 7027 DI 10.1073/pnas.0811785106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 438VS UT WOS:000265584500029 ER PT J AU Muller, MR Sasaki, Y Stevanovic, I Lamperti, ED Ghosh, S Sharma, S Gelinas, C Rossi, DJ Pipkin, ME Rajewsky, K Hogan, PG Rao, A AF Mueller, Martin R. Sasaki, Yoshiteru Stevanovic, Irena Lamperti, Edward D. Ghosh, Srimoyee Sharma, Sonia Gelinas, Curtis Rossi, Derrick J. Pipkin, Matthew E. Rajewsky, Klaus Hogan, Patrick G. Rao, Anjana TI Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEPENDENT TRANSCRIPTIONAL PATHWAY; PATERNAL X-CHROMOSOME; EARLY MOUSE EMBRYOS; T-CELL DEVELOPMENT; NF-ATC; MYELOID DIFFERENTIATION; NUCLEAR-LOCALIZATION; CD34(+) CELLS; FACTOR NFAT1; CALCINEURIN AB NFAT transcription factors are highly phosphorylated proteins residing in the cytoplasm of resting cells. Upon dephosphorylation by the phosphatase calcineurin, NFAT proteins translocate to the nucleus, where they orchestrate developmental and activation programs in diverse cell types. NFAT is rephosphorylated and inactivated through the concerted action of at least 3 different kinases: CK1, GSK-3, and DYRK. The major docking sites for calcineurin and CK1 are strongly conserved throughout vertebrate evolution, and conversion of either the calcineurin docking site to a high-affinity version or the CK1 docking site to a low-affinity version results in generation of hyperactivable NFAT proteins that are still fully responsive to stimulation. In this study, we generated transgenic mice expressing hyperactivable versions of NFAT1 from the ROSA26 locus. We show that hyperactivable NFAT increases the expression of NFAT-dependent cytokines by differentiated T cells as expected, but exerts unexpected signal-dependent effects during T cell differentiation in the thymus, and is progressively deleterious for the development of B cells from hematopoietic stem cells. Moreover, progressively hyperactivable versions of NFAT1 are increasingly deleterious for embryonic development, particularly when normal embryos are also present in utero. Forced expression of hyperactivable NFAT1 in the developing embryo leads to mosaic expression in many tissues, and the hyperactivable proteins are barely tolerated in organs such as brain, and cardiac and skeletal muscle. Our results highlight the need for balanced Ca/NFAT signaling in hematopoietic stem cells and progenitor cells of the developing embryo, and emphasize the evolutionary importance of kinase and phosphatase docking sites in preventing inappropriate activation of NFAT. C1 [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. EM arao@idi.harvard.edu FU National Institutes of Health; Deutsche Krebshilfe postdoctoral fellowship; Cancer Research Institute postdoctoral fellowship; Canadian Institutes of Health Research postdoctoral fellowship FX We thank D. Ghitza for help with blastocyst injections of ES cells and K. Ketman for help with cell sorting. This study was supported by grants (to K. R. and A. R.); a T32 training grant (to S. G.), a Deutsche Krebshilfe postdoctoral fellowship (to M. R. M.), a Cancer Research Institute postdoctoral fellowship (to M. R. M.), a Canadian Institutes of Health Research postdoctoral fellowship (to S. S.), and a (to S. S.). NR 45 TC 28 Z9 29 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 28 PY 2009 VL 106 IS 17 BP 7034 EP 7039 DI 10.1073/pnas.0813296106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 438VS UT WOS:000265584500031 PM 19351896 ER PT J AU Schnipper, JL Hamann, C Ndumele, CD Liang, CL Carty, MG Karson, AS Bhan, I Coley, CM Poon, E Turchin, A Labonville, SA Diedrichsen, EK Lipsitz, S Broverman, CA McCarthy, P Gandhi, TK AF Schnipper, Jeffrey L. Hamann, Claus Ndumele, Chima D. Liang, Catherine L. Carty, Marcy G. Karson, Andrew S. Bhan, Ishir Coley, Christopher M. Poon, Eric Turchin, Alexander Labonville, Stephanie A. Diedrichsen, Ellen K. Lipsitz, Stuart Broverman, Carol A. McCarthy, Patricia Gandhi, Tejal K. TI Effect of an Electronic Medication Reconciliation Application and Process Redesign on Potential Adverse Drug Events A Cluster-Randomized Trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT Summer Meeting of the American-Society-of-Health-System-Pharmacists CY JUN 25-26, 2007 CL San Francisco, CA SP Amer Soc Hlth Syst Pharmacists ID HOSPITAL ADMISSION; ERRORS; DISCREPANCIES; SYSTEM; PREVENTION AB Background: Medication reconciliation at transitions in care is a national patient safety goal, but its effects on important patient outcomes require further evaluation. We sought to measure the impact of an information technology -based medication reconciliation intervention on medication discrepancies with potential for harm (potential adverse drug events [PADEs]). Methods: We performed a controlled trial, randomized by medical team, on general medical inpatient units at 2 academic hospitals from May to June 2006. We enrolled 322 patients admitted to 14 medical teams, for whom amedication history could be obtained before discharge. The intervention was a computerized medication reconciliation tool and process redesign involving physicians, nurses, and pharmacists. The main outcome was unintentional discrepancies between preadmission medications and admission or discharge medications that had potential for harm (PADEs). Results: Among 160 control patients, there were 230 PADEs (1.44 per patient), while among 162 intervention patients there were 170 PADEs (1.05 per patient) (adjusted relative risk [ARR], 0.72; 95% confidence interval [CI], 0.52-0.99). A significant benefit was found at hospital 1 (ARR, 0.60; 95% CI, 0.38-0.97) but not at hospital 2 (ARR, 0.87; 95% CI, 0.57-1.32) (P=.32 for test of effect modification). Hospitals differed in the extent of integration of the medication reconciliation tool into computerized provider order entry applications at discharge. Conclusions: A computerized medication reconciliation tool and process redesign were associated with a decrease in unintentional medication discrepancies with potential for patient harm. Software integration issues are likely important for successful implementation of computerized medication reconciliation tools. Trial Registration: clinicaltrials. gov Identifier: NCT00296426 C1 [Schnipper, Jeffrey L.] Brigham & Womens Hosp, Div Gen Med, Brigham & Womens Acad Hosp Serv, Boston, MA 02120 USA. [McCarthy, Patricia; Gandhi, Tejal K.] Brigham & Womens Hosp, Ctr Clin Excellence, Boston, MA 02120 USA. [Labonville, Stephanie A.; Diedrichsen, Ellen K.] Brigham & Womens Hosp, Serv Pharm, Boston, MA 02120 USA. [Hamann, Claus; Karson, Andrew S.; Bhan, Ishir; Coley, Christopher M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hamann, Claus] Massachusetts Gen Hosp, Geriatr Med Unit, Boston, MA 02114 USA. [Karson, Andrew S.; McCarthy, Patricia] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Poon, Eric; Turchin, Alexander; Broverman, Carol A.] Partners Informat Syst Clin Informat Res & Dev, Boston, MA USA. [Schnipper, Jeffrey L.; Hamann, Claus; Carty, Marcy G.; Karson, Andrew S.; Bhan, Ishir; Coley, Christopher M.; Poon, Eric; Turchin, Alexander; Lipsitz, Stuart; Gandhi, Tejal K.] Harvard Univ, Sch Med, Boston, MA USA. [Diedrichsen, Ellen K.] Massachusetts Gen Hosp, Serv Pharm, Boston, MA 02114 USA. RP Schnipper, JL (reprint author), Brigham & Womens Hosp, Div Gen Med, Brigham & Womens Acad Hosp Serv, 1620 Tremont St, Boston, MA 02120 USA. EM jschnipper@partners.org RI Tao, Youyou/D-2367-2014; Vila, Vanessa/B-4982-2014 FU NHLBI NIH HHS [K08 HL072806] NR 36 TC 107 Z9 107 U1 1 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 27 PY 2009 VL 169 IS 8 BP 771 EP 780 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 438FE UT WOS:000265540500007 PM 19398689 ER PT J AU Linder, JA Rigotti, NA Schneider, LI Kelley, JHK Brawarsky, P Haas, JS AF Linder, Jeffrey A. Rigotti, Nancy A. Schneider, Louise I. Kelley, Jennifer H. K. Brawarsky, Phyllis Haas, Jennifer S. TI An Electronic Health Record-Based Intervention to Improve Tobacco Treatment in Primary Care A Cluster-Randomized Controlled Trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Society-of-General-Internal-Medicine CY APR 09-12, 2008 CL Pittsburgh, PA SP Soc Gen Internal Med ID CLINICAL DECISION-SUPPORT; SMOKING-CESSATION; MEDICAL-RECORD; TREATMENT GUIDELINES; QUALITY IMPROVEMENT; AMBULATORY-CARE; UNITED-STATES; SMOKERS; PHYSICIANS; PATIENT AB Background: To improve the documentation and treatment of tobacco use in primary care, we developed and implemented a 3-part electronic health record enhancement: (1) smoking status icons, (2) tobacco treatment reminders, and (3) a Tobacco Smart Form that facilitated the ordering of medication and fax and e-mail counseling referrals. Methods: We performed a cluster-randomized controlled trial of the enhancement in 26 primary care practices between December 19, 2006, and September 30, 2007. The primary outcome was the proportion of documented smokers who made contact with a smoking cessation counselor. Secondary outcomes included coded smoking status documentation and medication prescribing. Results: During the 9-month study period, 132 630 patients made 315 962 visits to study practices. Coded documentation of smoking status increased from 37% of patients to 54% (+ 17%) in intervention practices and from 35% of patients to 46% (+ 11%) in control practices (P <. 001 for the difference in differences). Among the 9589 patients who were documented smokers at the start of the study, more patients in the intervention practices were recorded as nonsmokers by the end of the study (5.3% vs 1.9% in control practices; P <. 001). Among 12 207 documented smokers, more patients in the intervention practices made contact with a cessation counselor(3.9% vs 0.3% in control practices; P <. 001). Smokers in the intervention practices were no more likely to be prescribed smoking cessation medication (2% vs 2% in control practices; P=.40). Conclusion: This electronic health record-based intervention improved smoking status documentation and increased counseling assistance to smokers but not the prescription of cessation medication. Trial Registration: clinicaltrials. gov Identifier: NCT00383461 C1 [Linder, Jeffrey A.; Schneider, Louise I.; Kelley, Jennifer H. K.; Brawarsky, Phyllis; Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Linder, Jeffrey A.; Rigotti, Nancy A.; Schneider, Louise I.; Haas, Jennifer S.] Harvard Univ, Sch Med, Boston, MA USA. RP Linder, JA (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St,BC 3-2X, Boston, MA 02120 USA. EM jlinder@partners.org FU AHRQ HHS [K08 HS014563]; NCI NIH HHS [R21 CA121906, R21 CA121906-02]; NHLBI NIH HHS [K24 HL04440, K24 HL004440-09, K24 HL004440] NR 38 TC 33 Z9 33 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 27 PY 2009 VL 169 IS 8 BP 781 EP 787 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 438FE UT WOS:000265540500008 PM 19398690 ER PT J AU Obeso, EG Murphy, E Brugge, W Deshpande, V AF Obeso, Elvira Gonzalez Murphy, Erin Brugge, William Deshpande, Vikram TI Pseudocyst of the Pancreas The Role of Cytology and Special Stains for Mucin SO CANCER CYTOPATHOLOGY LA English DT Article DE Alcian blue; mucicarmine; intraductal; papillary-mucinous neoplasms; pseudocyst ID NEEDLE-ASPIRATION-CYTOLOGY; CYSTIC NEOPLASMS; CLINICOPATHOLOGICAL CHARACTERISTICS; SYMPTOMATIC PATIENTS; DIAGNOSIS; LESIONS; BIOPSY AB BACKGROUND: Currently, the preoperative diagnosis of a pancreatic cyst is based on clinical and imaging findings, frequently in conjunction with chemical analysis of cyst fluid and cytologic evaluation. The purpose of these diagnostic tests is to distinguish benign from malignant cysts of the pancreas. Accordingly, it is imperative to distinguish pancreatic pseudocysts from their mimics. In this study, the authors explored the cytomorphologic features of pseudocyst of the pancreas and evaluated the role of Alcian blue and mucicarmine stains in the cytologic evaluation of pancreatic cysts, METHODS: Forty-two patients were identified who had an eventual diagnosis of pancreatic pseudocyst and had an endoscopic ultrasoundguided fine-needle aspirate available. Clinical and imaging findings and chemical analyses of cyst fluid were recorded. The cytologic preparations were evaluated for gastrointestinal contamination, inflammatory cells, mucin, and pigmented material. The cytomorphologic features of 110 neoplastic mucinous cysts (intraductal papillary-mucinous neoplasms/mucinous cystic neoplasms of the pancreas) were evaluated and compared with the pseudocysts. RESULTS: The majority of patients (95%) had a prior episode of pancreatitis. On imaging, the pseudocysts were unilocular (92%). In 69% of cases, the endosonographic diagnosis was that of a pseudocyst. The mean carcinoembryonic antigen level was 41 ng/mL. In contrast, the cytopathologist rendered a definitive diagnosis of pseudocyst in only 10% of cases. The majority of smears (75%) revealed neutrophils and/or histiocytes. Atypical epithelial clusters were identified in 3 cases, I of which was diagnosed as suspicious for carcinoma. Yellow pigmented material, which was identified in 13 pseudocysts (31%), was not observed in neoplastic mucinous cysts. Alcian blue- and mucicarmine-positive material was identified in 64% and 40% of pseudocysts, respectively, and in 57% and 38% of neoplastic mucinous cysts, respectively. CONCLUSIONS: The diagnosis of a pseudocyst depended primarily on clinical and imaging findings and on chemical analysis of cyst fluid. The cytologic features frequently were nonspecific. The presence of yellow pigmented material served as a surrogate marker of a pseudocyst. Special stains for mucin did not distinguish pseudocysts from neoplastic mucinous cysts. Cancer (Cancer Cytopathol) 2009;117:101-7. (C) 2009 American Cancer Society. C1 [Deshpande, Vikram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Brugge, William] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Deshpande, V (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM vdeshpande@partners.org NR 15 TC 14 Z9 15 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD APR 25 PY 2009 VL 117 IS 2 BP 101 EP 107 DI 10.1002/cncy.20000 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 430RJ UT WOS:000265005900004 ER PT J AU Awazawa, M Ueki, K Inabe, K Yamauchi, T Kaneko, K Okazaki, Y Bardeesy, N Ohnishi, S Nagai, R Kadowaki, T AF Awazawa, Motoharu Ueki, Kohjiro Inabe, Kazunori Yamauchi, Toshimasa Kaneko, Kazuma Okazaki, Yukiko Bardeesy, Nabeel Ohnishi, Shin Nagai, Ryozo Kadowaki, Takashi TI Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Diabetes mellitus; Adipocytokine; Adiponectin; SREBP1c; Fatty acid synthesis; AMPK ID ACTIVATED PROTEIN-KINASE; ADIPOSE-SPECIFIC PROTEIN; INSULIN-SENSITIVITY; FATTY LIVERS; MICE; RECEPTOR; GLUCOSE; BINDING; RESISTANCE; GENE AB Adiponectin, one of the insulin-sensitizing adipokines, has been shown to activate fatty acid oxidation in liver and skeletal muscle, thus maintaining insulin sensitivity. However, the precise roles of adiponectin in fatty acid synthesis are poorly understood. Here we show that adiponectin administration acutely suppresses expression of sterol regulatory element-binding protein (SREBP) I c, the master regulator which controls and upregulates the enzymes involved in fatty acid synthesis, in the liver of +Lepr(db)/+Lep(db) (db/db) mouse as well as in Cultured hepatocytes. We also show that adiponectin suppresses SREBP1c by AdipoR1, one of the functional receptors for adiponetin, and furthermore that suppressing either AMP-activated protein kinase (AMPK) via its upstream kinase LKB1 deletion cancels the negative effect of adiponectin on SREBP1c expression. These data show that adiponectin suppresses SREBP1c through the AdipoR1/LKB1/AMPK pathway, and suggest a possible role for adiponectin in the regulation of hepatic fatty acid synthesis. (C) 2009 Elsevier Inc. All rights reserved. C1 [Awazawa, Motoharu; Ueki, Kohjiro; Yamauchi, Toshimasa; Kaneko, Kazuma; Okazaki, Yukiko; Kadowaki, Takashi] Univ Tokyo, Grad Sch Med, Dept Metab Dis, Bunkyo Ku, Tokyo 1138655, Japan. [Awazawa, Motoharu; Kadowaki, Takashi] Natl Inst Hlth & Nutr, Sinjuku Ku, Tokyo 1628636, Japan. [Inabe, Kazunori] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan. [Bardeesy, Nabeel] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02114 USA. [Ohnishi, Shin] Univ Tokyo, Dept Gastroenterol, Grad Sch Med, Tokyo 1138655, Japan. [Nagai, Ryozo] Univ Tokyo, Dept Cardiovasc Dis, Grad Sch Med, Tokyo 1138655, Japan. RP Kadowaki, T (reprint author), Univ Tokyo, Grad Sch Med, Dept Metab Dis, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM kadowaki-3im@h.u-tokyo.ac.jp FU Japan Society for the Promotion of Science [10NP0201]; juvenile Diabetes Foundation International [1-2003-746]; Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health and Welfare; Takeda Science Foundation FX We thank Dr. H. Shimano for the reporter plasmid used for the measurement of SREBP1c promoter activity, and F. Takahashi and H. Chiyonobu for their excellent technical assistance. This work was supported by a Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (10NP0201) (to T.K.), a grant from Special Coordination Funds for Promoting Science and Technology, a grant from the juvenile Diabetes Foundation International (1-2003-746) (to T.K.), a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T.K. and K.U.), Health Science Research grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare, a grant from Takeda Science Foundation (to K.U.). NR 27 TC 68 Z9 74 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 24 PY 2009 VL 382 IS 1 BP 51 EP 56 DI 10.1016/j.bbrc.2009.02.131 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 432HO UT WOS:000265124300011 PM 19254698 ER PT J AU Avruch, J Xavier, R Bardeesy, N Zhang, XF Praskova, M Zhou, D Xia, F AF Avruch, Joseph Xavier, Ramnik Bardeesy, Nabeel Zhang, Xian-Feng Praskova, Maria Zhou, Dawang Xia, Fan TI Rassf Family of Tumor Suppressor Polypeptides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ORGAN SIZE CONTROL; MICROTUBULE STABILITY; BIOCHEMICAL-ANALYSIS; HIPPO PATHWAY; KINASE MST1; APOPTOSIS; PROTEIN; ACTIVATION; DOMAINS; NORE1 AB The Rassf1-6 polypeptides each contain a Ras/Rap association domain, which enables binding to several GTP-charged Ras-like GTPases, at least in vitro or when overexpressed. The Ras/Rap association domains are followed by SARAH domains, which mediate Rassf heterodimerization with the Mst1/2 protein kinases. Rassf1A is unequivocally a tumor suppressor, and all Rassf proteins behave like tumor suppressors, exhibiting epigenetic silencing of expression in many human cancers and proapoptotic and/or anti-proliferative effects when re-expressed in tumor cell lines. Herein, we review the binding of the Rassf polypeptides to Ras-like GTPases and the Mst1/2 kinases and their role in Rassf function. C1 [Avruch, Joseph; Zhang, Xian-Feng; Praskova, Maria; Zhou, Dawang; Xia, Fan] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Bardeesy, Nabeel] Harvard Univ, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Xavier, Ramnik] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Avruch, Joseph; Zhang, Xian-Feng; Praskova, Maria; Zhou, Dawang; Xia, Fan] Harvard Univ, Sch Med, Diabet Unit, Med Serv, Boston, MA 02114 USA. [Xavier, Ramnik] Harvard Univ, Sch Med, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. [Avruch, Joseph; Xavier, Ramnik; Bardeesy, Nabeel; Zhang, Xian-Feng; Praskova, Maria; Zhou, Dawang; Xia, Fan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Avruch, J (reprint author), Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. EM avruch@molbio.mgh.harvard.edu OI Zhou, Dawang/0000-0002-9053-5249 FU National Institutes of Health [DK17776, P30 DK57521, HL088297, DK043351, T32 DK007028] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK17776 and P30 DK57521 (to J. A.), HL088297 and DK043351 (to R. X.), and T32 DK007028 (to D. Z.). This is the second article of three in the Thematic Minireview Series on Novel Ras Effectors. This minireview will be reprinted in the 2009 Minireview Compendium, which will be available in January, 2010. NR 40 TC 62 Z9 65 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 24 PY 2009 VL 284 IS 17 BP 11001 EP 11005 DI 10.1074/jbc.R800073200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500003 PM 19091744 ER PT J AU Gobert, RP van den Eijnden, M Szyndralewiez, C Jorand-Lebrun, C Swinnen, D Chen, LF Gillieron, C Pixley, F Juillard, P Gerber, P Johnson-Leger, C Halazy, S Camps, M Bombrun, A Shipp, M Vitte, PA Ardissone, V Ferrandi, C Perrin, D Rommel, C van Huijsduijnen, RH AF Gobert, Rosanna Pescini van den Eijnden, Monique Szyndralewiez, Cedric Jorand-Lebrun, Catherine Swinnen, Dominique Chen, Linfeng Gillieron, Corine Pixley, Fiona Juillard, Pierre Gerber, Patrick Johnson-Leger, Caroline Halazy, Serge Camps, Montserrat Bombrun, Agnes Shipp, Margaret Vitte, Pierre-Alain Ardissone, Vittoria Ferrandi, Chiara Perrin, Dominique Rommel, Christian van Huijsduijnen, Rob Hooft TI GLEPP1/Protein-tyrosine Phosphatase phi Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative Colitis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; RECEPTOR-TYPE-O; GROWTH-HORMONE RECEPTOR; MOLECULAR-CLONING; IMMUNE-RESPONSE; PTP-OC; EXPRESSION; IDENTIFICATION; SYK; PROMOTER AB We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase phi. Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of neutrophils, lymphocytes, and macrophages. In murine disease models, the GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative colitis, a model for inflammatory bowel disease. Taken together, our data provide confirmation that GLEPP1 plays an important role in controlling chemotaxis of multiple types of leukocytes and that pharmacological inhibition of this phosphatase may have therapeutic use. C1 [Gobert, Rosanna Pescini; van den Eijnden, Monique; Szyndralewiez, Cedric; Jorand-Lebrun, Catherine; Swinnen, Dominique; Gillieron, Corine; Juillard, Pierre; Gerber, Patrick; Johnson-Leger, Caroline; Halazy, Serge; Camps, Montserrat; Bombrun, Agnes; Vitte, Pierre-Alain; Perrin, Dominique; Rommel, Christian; van Huijsduijnen, Rob Hooft] Merck Serono Int, CH-1211 Geneva, Switzerland. [Chen, Linfeng; Shipp, Margaret] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pixley, Fiona] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia. [Ardissone, Vittoria; Ferrandi, Chiara] Merck Serono Ist Ric Biomed Antoine Marxer, I-10010 Colleretto Giacosa, TO, Italy. RP van Huijsduijnen, RH (reprint author), Merck Serono Int, 9 Chemin Mines, CH-1211 Geneva, Switzerland. EM rob.hooft@merckserono.net FU European Union Research Training Network [MRTN-CT-2006-035830] FX Supported by European Union Research Training Network Grant MRTN-CT-2006-035830. NR 53 TC 7 Z9 8 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 24 PY 2009 VL 284 IS 17 BP 11385 EP 11395 DI 10.1074/jbc.M807241200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500043 PM 19233845 ER PT J AU Neel, BG Cross, FR Pellman, D AF Neel, Benjamin G. Cross, Frederick R. Pellman, David TI Hidesaburo Hanafusa 1929-2009 Obituary SO MOLECULAR CELL LA English DT Biographical-Item C1 [Neel, Benjamin G.] Univ Toronto, Ontario Canc Inst, Toronto, ON M4W 2V1, Canada. [Cross, Frederick R.] Rockefeller Univ, New York, NY 10065 USA. [Pellman, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Neel, BG (reprint author), Univ Toronto, Ontario Canc Inst, Toronto, ON M4W 2V1, Canada. EM bneel@uhnresearch.ca; fcross@rockefeller.edu; david_pellman@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 24 PY 2009 VL 34 IS 2 BP 141 EP 143 DI 10.1016/j.molcel.2009.04.005 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 437XX UT WOS:000265521300005 ER PT J AU Zhu, J Luo, BH Barth, P Schonbrun, J Baker, D Springer, TA AF Zhu, Jieqing Luo, Bing-Hao Barth, Patrick Schonbrun, Jack Baker, David Springer, Timothy A. TI The Structure of a Receptor with Two Associating Transmembrane Domains on the Cell Surface: Integrin alpha(IIb)beta(3) SO MOLECULAR CELL LA English DT Article ID GROWTH-FACTOR RECEPTOR; CYTOPLASMIC DOMAINS; PROTEIN STRUCTURES; SPATIAL STRUCTURE; HELIX PACKING; GLYCOPHORIN-A; RESTING STATE; ACTIVATION; PREDICTION; MECHANISM AB Structures of intact receptors with single-pass transmembrane domains are essential to understand how extracellular and cytoplasmic domains regulate association and signaling through transmembrane domains. A chemical and computational method to determine structures of the membrane regions of such receptors on the cell surface is developed here and validated with glycophorin A. An integrin heterodimer structure reveals association over most of the lengths of the alpha and beta transmembrane domains and shows that the principles governing association of hetero and homo transmembrane dimers differ. A turn at the Gly of the juxtamembrane GFFKR motif caps the alpha TM helix and brings the two Phe of GFFKR into the alpha/beta interface. A juxtamembrane Lys residue in beta also has an important role in the interface. The structure shows how transmembrane association/dissociation regulates integrin signaling. A joint ectodomain and membrane structure shows that substantial flexibility between the extracellular and TM domains is compatible with TM signaling. C1 [Zhu, Jieqing; Luo, Bing-Hao; Springer, Timothy A.] Harvard Univ, Sch Med, Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Zhu, Jieqing; Luo, Bing-Hao; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Barth, Patrick; Schonbrun, Jack; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Barth, Patrick; Schonbrun, Jack; Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM springeroffice@idi.harvard.edu RI Baker, David/K-8941-2012 OI Baker, David/0000-0001-7896-6217 FU NIH [HL-48675]; HHMI FX We thank Junichi Takagi and Guo-hui Li for early help with the project, This work was supported by NIH grant HL-48675 and HHMI. NR 40 TC 87 Z9 89 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 24 PY 2009 VL 34 IS 2 BP 234 EP 249 DI 10.1016/j.molcel.2009.02.022 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 437XX UT WOS:000265521300014 PM 19394300 ER PT J AU Coleman, JJ Mylonakis, E AF Coleman, Jeffrey J. Mylonakis, Eleftherios TI The Tangled Web of Signaling in Innate Immunity SO CELL HOST & MICROBE LA English DT Editorial Material ID KINASE-C-DELTA; CAENORHABDITIS-ELEGANS AB Similarities in innate immune signaling exist between mammals and the nematode Caenorhabditis elegans. Now, Ziegler et al. (2009) and Ren et al. (2009) demonstrate that a protein kinase C 8 homolog in C. elegans is involved in innate immunity, providing evidence that the conservation of immune signaling networks extends further than previously thought. C1 [Coleman, Jeffrey J.; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Mylonakis, E (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM emylonakis@partners.org RI Coleman, Jeffrey/E-2981-2015; OI Coleman, Jeffrey/0000-0001-8579-1996 FU NIAID NIH HHS [R01 AI075286, T32 AI007061] NR 12 TC 4 Z9 4 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD APR 23 PY 2009 VL 5 IS 4 BP 313 EP 315 DI 10.1016/j.chom.2009.04.002 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 438QX UT WOS:000265571600003 PM 19380109 ER PT J AU Sin, MLY Gau, V Liao, JC Haake, DA Wong, PK AF Sin, Mandy L. Y. Gau, Vincent Liao, Joseph C. Haake, David A. Wong, Pak Kin TI Active Manipulation of Quantum Dots using AC Electrokinetics SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID ELECTRIC-FIELDS; FLUID-FLOW; DNA; MICROELECTRODES; DIELECTROPHORESIS; NANOPARTICLES; ELECTROLYTES; BIOMOLECULES; NANOTUBES; BIOSENSOR AB The superior optical and electrical properties of quantum dot (QD) nanoparticles are being applied in a new generation of QD devices for microelectronic, nanophotonic, and biomedical systems. Research on integrated QD-based systems has been focused on passive manipulation of QDs including template-guided self-assembly, molecular scaffold-based assembly, and microbead-based assembly. However, little effort has been devoted to development of methods for active manipulation, such as positioning and concentration, of QDs. In this study, we show that 20 nm colloidal QDs can be effectively positioned and concentrated using a combination of dielectrophoresis (DEP) and AC electro-osmosis (ACEO). The long-range fluid motion generated by ACEO entrains QDs to the area near the electrode surface, which facilitates the trapping of QDs by DEP. A systematic investigation was performed to examine electrokinetic processes at different applied frequencies and voltages using a concentric electrode configuration. We demonstrate that QDs can be dynamically positioned with an electric field strength as small as 10 kV/m and define the operating parameters for increasing the concentration of colloidal QDs by 2 orders of magnitude within one minute. C1 [Sin, Mandy L. Y.; Wong, Pak Kin] Univ Arizona, Dept Aerosp & Mech Engn, Tucson, AZ 85721 USA. [Gau, Vincent] Genefluidics Inc, Monterey Pk, CA 91754 USA. [Liao, Joseph C.] Stanford Univ, Dept Urol, Stanford, CA 94305 USA. [Liao, Joseph C.] Stanford Univ, Bio X Program, Stanford, CA 94305 USA. [Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA 90095 USA. [Wong, Pak Kin] Univ Arizona, Biomed Engn Interdisciplinary Program, Tucson, AZ 85721 USA. [Wong, Pak Kin] Univ Arizona, Inst Bio5, Tucson, AZ 85721 USA. RP Wong, PK (reprint author), Univ Arizona, Dept Aerosp & Mech Engn, Tucson, AZ 85721 USA. EM pak@email.arizona.edu RI Wong, Pak Kin/A-7974-2012; Liao, Joseph/J-5874-2015 OI Wong, Pak Kin/0000-0001-7388-2110; FU American Chemical Society Petroleum Research Fund [47507-G7]; Arizona Biomedical Research Commission; Arizona Research Laboratories Center for Insect Science [AI075565]; National Institute of Allergy and Infectious Disease [1U01AI082457-01]; Veterans Affairs RRD Merit Review [4872] FX The authors thank V. Constantino, C. S. Chen, and M. Junkin for technical assistance. This work was supported by the American Chemical Society Petroleum Research Fund (47507-G7), Arizona Biomedical Research Commission, Arizona Research Laboratories Center for Insect Science, Cooperative Agreement Award AI075565 (to D.A.H.) from the National Institute of Allergy and Infectious Disease (1U01AI082457-01), and Veterans Affairs RR&D Merit Review 4872 (to J.C.L.). NR 39 TC 22 Z9 22 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD APR 23 PY 2009 VL 113 IS 16 BP 6561 EP 6565 DI 10.1021/jp9004423 PG 5 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 435ZV UT WOS:000265383300032 ER PT J AU Canto, C Gerhart-Hines, Z Feige, JN Lagouge, M Noriega, L Milne, JC Elliott, PJ Puigserver, P Auwerx, J AF Canto, Carles Gerhart-Hines, Zachary Feige, Jerome N. Lagouge, Marie Noriega, Lilia Milne, Jill C. Elliott, Peter J. Puigserver, Pere Auwerx, Johan TI AMPK regulates energy expenditure by modulating NAD(+) metabolism and SIRT1 activity SO NATURE LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; MITOCHONDRIAL-FUNCTION; GLUCOSE-HOMEOSTASIS; SKELETAL-MUSCLE; RECEPTOR-GAMMA; PGC-1-ALPHA; MECHANISM; OXIDATION AB AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio(1). Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin(2,3), thiazolidinediones(4) and exercise(5), which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP(1). This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD(+)-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD(+) levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism. C1 [Canto, Carles; Feige, Jerome N.; Lagouge, Marie; Noriega, Lilia; Auwerx, Johan] CNRS INSERM ULP, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. [Canto, Carles; Noriega, Lilia; Auwerx, Johan] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland. [Gerhart-Hines, Zachary; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Gerhart-Hines, Zachary; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Milne, Jill C.; Elliott, Peter J.] Sirtris Pharmaceut Inc, Cambridge, MA 02139 USA. [Auwerx, Johan] Inst Clin Souris, F-67404 Illkirch Graffenstaden, France. RP Auwerx, J (reprint author), CNRS INSERM ULP, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. EM admin.auwerx@epfl.ch OI Canto, Carles/0000-0002-5167-7922 FU CNRS; Ecole Polytechnique Federale de Lausanne; INSERM; ULP; NIH [DK59820, DK069966]; EU [LSHM-CT-2004-512013, ERC-2008-AdG-23118]; Fondation de la Recherche Medicale (FRM); EMBO; FEBS FX This work was supported by grants of CNRS, Ecole Polytechnique Federale de Lausanne, INSERM, ULP, NIH (DK59820 and DK069966), EU FP6 (EUGENE2; LSHM-CT-2004-512013) and EU Ideas programme (sirtuins; ERC-2008-AdG-23118). C. C. has been supported by grants of Fondation de la Recherche Medicale (FRM) and EMBO. J. N. F. was supported by a FEBS grant. The authors thank F. Foufelle and P. Ferre, B. Spiegelman, D. P. Kelly, S.-i. Imai, G. Hardie, C. Ammann (Topotarget) and F. Alt for providing materials, and members of the Auwerx and Puigserver laboratories for discussion. NR 33 TC 1089 Z9 1135 U1 36 U2 217 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 23 PY 2009 VL 458 IS 7241 BP 1056 EP U140 DI 10.1038/nature07813 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 436KL UT WOS:000265412900049 PM 19262508 ER PT J AU Weinblatt, ME Abbott, GF Koreishi, AF AF Weinblatt, Michael E. Abbott, Gerald F. Koreishi, Aashiyana F. TI A Woman with Respiratory Failure and a Cavitary Lesion in the Lung Invasive group A beta-hemolytic streptococcal infection, with acute necrotizing bronchopneumonia with cavitation and with evidence of the toxic shock syndrome, in a patient treated with anti-TNF antibody. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID NECROSIS-FACTOR-ALPHA; SERIOUS BACTERIAL-INFECTIONS; RHEUMATOID-ARTHRITIS; PNEUMOCOCCAL PNEUMONIA; FACTOR ANTAGONISTS; DEFICIENT MICE; THERAPY; RISK; TUBERCULOSIS; ETANERCEPT C1 [Weinblatt, Michael E.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Koreishi, Aashiyana F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Weinblatt, Michael E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Abbott, Gerald F.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Koreishi, Aashiyana F.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Weinblatt, ME (reprint author), Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. NR 29 TC 6 Z9 6 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 23 PY 2009 VL 360 IS 17 BP 1770 EP 1779 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 435XY UT WOS:000265377800013 PM 19387019 ER PT J AU Bakirtzi, K Belfort, G Lopez-Coviella, I Kuruppu, D Cao, L Abel, ED Brownell, AL Kandror, KV AF Bakirtzi, Kyriaki Belfort, Gabriel Lopez-Coviella, Ignacio Kuruppu, Darshini Cao, Lei Abel, E. Dale Brownell, Anna-Liisa Kandror, Konstantin V. TI Cerebellar Neurons Possess a Vesicular Compartment Structurally and Functionally Similar to Glut4-Storage Vesicles from Peripheral Insulin-Sensitive Tissues SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GLUCOSE-TRANSPORTER GLUT4; CENTRAL-NERVOUS-SYSTEM; REGULATED MEMBRANE AMINOPEPTIDASE; SKELETAL-MUSCLE; GLUT4-CONTAINING VESICLES; SUBCELLULAR-LOCALIZATION; RAT ADIPOCYTES; PC12 CELLS; RESPONSIVE AMINOPEPTIDASE; STIMULATED TRANSLOCATION AB The insulin-sensitive isoform of the glucose transporting protein, Glut4, is expressed in fat as well as in skeletal and cardiac muscle and is responsible for the effect of insulin on blood glucose clearance. Recent studies have revealed that Glut4 is also expressed in the brain, although the intracellular compartmentalization and regulation of Glut4 in neurons remains unknown. Using sucrose gradient centrifugation, immunoadsorption and immunofluorescence staining, we have shown that Glut4 in the cerebellum is localized in intracellular vesicles that have the sedimentation coefficient, the buoyant density, and the protein composition similar to the insulin-responsive Glut4-storage vesicles from fat and skeletal muscle cells. In cultured cerebellar neurons, insulin stimulates glucose uptake and causes translocation of Glut4 to the cell surface. Using (18)FDG ((18)fluoro-2-deoxyglucose) positron emission tomography, we found that physical exercise acutely increases glucose uptake in the cerebellum in vivo. Prolonged physical exercise increases expression of the Glut4 protein in the cerebellum. Our results suggest that neurons have a novel type of translocation-competent vesicular compartment which is regulated by insulin and physical exercise similar to Glut4-storage vesicles in peripheral insulin target tissues. C1 [Bakirtzi, Kyriaki; Belfort, Gabriel; Kandror, Konstantin V.] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Lopez-Coviella, Ignacio] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Kuruppu, Darshini; Cao, Lei; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Abel, E. Dale] Univ Utah, Div Endocrinol Diabet & Metab, Salt Lake City, UT 84112 USA. [Abel, E. Dale] Univ Utah, Program Human Mol Biol & Genet, Salt Lake City, UT 84112 USA. RP Kandror, KV (reprint author), Boston Univ, Sch Med, Dept Biochem, K124D,715 Albany St, Boston, MA 02118 USA. EM kandror@biochem.bumc.bu.edu RI Cao, Lei/B-3254-2012; OI Cao, Lei/0000-0003-4018-9496; Kandror, Konstantin/0000-0002-8601-9313 FU National Institutes of Health [EB001850, DK52057, DK56736]; American Diabetes Association FX This work was supported by research grants from the National Institutes of Health [Grants EB001850 (A.L.B.) and DK52057 and DK56736 (K.V.K.)], and by an Innovation Award from the American Diabetes Association (K.V. K.). We are grateful to Dr. Paul Toselli, Dr. Daniela Pellegrino, Dr. Aijun Zhu, and Mark Jedrychowski for help with some experiments. NR 67 TC 22 Z9 22 U1 1 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 22 PY 2009 VL 29 IS 16 BP 5193 EP 5201 DI 10.1523/JNEUROSCI.0858-09.2009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 436XV UT WOS:000265450300017 PM 19386915 ER PT J AU Zhu, TF Szostak, JW AF Zhu, Ting F. Szostak, Jack W. TI Coupled Growth and Division of Model Protocell Membranes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID FATTY-ACID VESICLES; MURCHISON CARBONACEOUS CHONDRITE; MONOCARBOXYLIC ACIDS; SELF-REPRODUCTION; TRANSFORMATION; COMPETITION; COMPONENTS; PARTICLES; LIPOSOMES; NETWORKS AB The generation of synthetic forms of cellular life requires solutions to the problem of how biological processes such as cyclic growth and division could emerge from purely physical and chemical systems. Small unilamellar fatty acid vesicles grow when fed with fatty acid micelles and can be forced to divide by extrusion, but this artificial division process results in significant loss of protocell contents during each division cycle. Here we describe a simple and efficient pathway for model protocell membrane growth and division. The growth of large multilamellar fatty acid vesicles fed with fatty acid micelles, in a solution where solute permeation across the membranes is slow, results in the transformation of initially spherical vesicles into long thread-like vesicles, a process driven by the transient imbalance between surface area and volume growth. Modest shear forces are then sufficient to cause the thread-like vesicles to divide into multiple daughter vesicles without loss of internal contents. In an environment of gentle shear, protocell growth and division are thus coupled processes. We show that model protocells can proceed through multiple cycles of reproduction. Encapsulated RNA molecules, representing a primitive genome, are distributed to the daughter vesicles. Our observations bring us closer to the laboratory synthesis of a complete protocell consisting of a self-replicating genome and a self-replicating membrane compartment. In addition, the robustness and simplicity of this pathway suggests that similar processes might have occurred under the prebiotic conditions of the early Earth. C1 [Zhu, Ting F.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Zhu, Ting F.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Zhu, Ting F.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NASA [EXB020031-0018] FX We thank R. Bruckner, I. Chen, S. Chung, M. Elenko, R. Irwin, P. L. Luisi, A. Luptak, S. Mansy, D. Treco, C. Wong, and S. Zhou for helpful discussions and comments on the manuscript. This work was supported in part by grant EXB020031-0018 from the NASA Exobiology Program. J.W.S. is an Investigator of the Howard Hughes Medical Institute. NR 38 TC 128 Z9 134 U1 66 U2 128 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD APR 22 PY 2009 VL 131 IS 15 BP 5705 EP 5713 DI 10.1021/ja900919c PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 434IJ UT WOS:000265268100055 PM 19323552 ER PT J AU Shekelle, PG AF Shekelle, Paul G. TI Supplementation with vitamin E or vitamin C did not differ from placebo for major cardiovascular events and mortality SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PREVENTION; DISEASE; METAANALYSIS C1 W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Shekelle, PG (reprint author), W Los Angeles Vet Affairs Med Ctr, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 21 PY 2009 VL 150 IS 8 AR JC4-12 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 437AD UT WOS:000265457000027 PM 19391226 ER PT J AU Winkler, DD Schuermann, JP Cao, XH Holloway, SP Borchelt, DR Carroll, MC Proescher, JB Culotta, VC Hart, PJ AF Winkler, Duane D. Schuermann, Jonathan P. Cao, Xiaohang Holloway, Stephen P. Borchelt, David R. Carroll, Mark C. Proescher, Jody B. Culotta, Valeria C. Hart, P. John TI Structural and Biophysical Properties of the Pathogenic SOD1 Variant H46R/H48Q SO BIOCHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; ZINC SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; COPPER CHAPERONE CCS; CU,ZN-SUPEROXIDE DISMUTASE; TRANSGENIC MICE; BINDING-SITE; FAMILIAL ALS; IN-VITRO; DISULFIDE AB Over 100 mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Two pathogenic SOD1 mutations, His46Arg (H46R) and His48Gln (H48Q), affect residues that act as copper ligands in the wild type enzyme. Transgenic mice expressing a human SOD1 variant containing both mutations develop paralytic disease akin to ALS. Here we show that H46R/H48Q SOD1 possesses multiple characteristics that distinguish it from the wild type. These properties include the following: (1) an ablated copper-binding site, (2) a substantially weakened affinity for zinc, (3) a binding site for a calcium ion, (4) the ability to form stable heterocomplexes with the copper chaperone for SOD1 (CCS), and (5) compromised CCS-mediated oxidation of the intrasubunit disulfide bond in vivo. The results presented here, together with data on pathogenic SOD1 proteins coming from cell culture and transgenic mice, suggest that incomplete posttranslational modification of nascent SOD1 polypeptides via CCS may be a characteristic shared by familial ALS SOD1 mutants, leading to a population of destabilized, off-pathway folding intermediates that are toxic to motor neurons. C1 [Winkler, Duane D.; Schuermann, Jonathan P.; Cao, Xiaohang; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Winkler, Duane D.; Schuermann, Jonathan P.; Cao, Xiaohang; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Audie Murphy Div, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Borchelt, David R.] Univ Florida, Dept Neurosci, McKnight Brain Inst, Gainesville, FL 32610 USA. [Carroll, Mark C.; Proescher, Jody B.; Culotta, Valeria C.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. RP Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM pjhart@biochem.uthscsa.edu FU NIH-NINDS [R01-NS39112, P01-NS04913]; NIHGMS [GM50016]; JHU NIEHS center; American Foundation for Aging Research (AFAR).; NIH [T32AG021890-03]; NIEHS [ES 07141]; William and Ella Owens Medical Research Foundation; Judith and Jean Pape Adams Charitable Foundation FX This work was supported by grants NIH-NINDS R01-NS39112 (P.J.H.), P01-NS04913 (Joan S. Valentine, D.R.B., and P.J.H.), NIHGMS GM50016 (V.C.C.), and the JHU NIEHS center (V.C.C.). D.D.W. was supported in part by the American Foundation for Aging Research (AFAR). J.P.S. was supported by NIH T32AG021890-03. J.B.P. was supported by NIEHS training grant ES 07141. X.C. was supported in part by the William and Ella Owens Medical Research Foundation and the Judith and Jean Pape Adams Charitable Foundation. Support for the X-ray Crystallography Core Laboratory and the Center for Analytical Ultracentrifugation of Macromolecular Assemblies by the UTHSCSA Executive Research Committee and the San Antonio Cancer Institute is also gratefully acknowledged. NR 58 TC 18 Z9 18 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 21 PY 2009 VL 48 IS 15 BP 3436 EP 3447 DI 10.1021/bi8021735 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432YL UT WOS:000265170200020 PM 19227972 ER PT J AU Scirica, BM Morrow, DA Budaj, A Dalby, AJ Mohanavelu, S Aroesty, J Hedgepeth, CM Stone, PH Braunwald, E AF Scirica, Benjamin M. Morrow, David A. Budaj, Andrzej Dalby, Anthony J. Mohanavelu, Satishkumar Aroesty, Julian Hedgepeth, Chester M. Stone, Peter H. Braunwald, Eugene TI Ischemia Detected on Continuous Electrocardiography After Acute Coronary Syndrome Observations From the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome; ischemia; electrocardiography; Holter; ranolazine ID UNSTABLE ANGINA; CARDIOVASCULAR EVENTS; RECURRENT ISCHEMIA; RANDOMIZED-TRIAL; PROGNOSTIC VALUE; ARTERY-DISEASE; HEART-FAILURE; HIGH-RISK; AMLODIPINE; BIOMARKERS AB Objectives The purpose of this study was to assess the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS). Background The small size of prior studies evaluating cECG prevented full evaluation of the risk associated with ischemia across subpopulations and compared with other methods of risk stratification. Ranolazine, a new antianginal agent, reduces ischemic symptoms in patients with chronic angina and after ACS but the anti-ischemic effect, as detected by cECG, is not known. Methods In all, 6,560 patients hospitalized with non-ST-segment elevation ACS were randomly assigned to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) trial. The cECG was performed for 7 days after randomization. Outcomes were followed for a median of 348 days. Clinical events that occurred during cECG recording were excluded from analysis. Results A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with >= 1 episode of ischemia on cECG (n = 1,271, 20%) were at increased risk of cardiovascular death ( 7.7% vs. 2.7%, p < 0.001), MI (9.4% vs. 5.0%, p < 0.001), and recurrent ischemia (17.5% vs. 12.3%, p < 0.001). The relationship with cardiovascular death was independent of baseline characteristics or elevated biomarkers ( adjusted hazard ratio: 2.46, p < 0.001). Ischemia on cECG was associated with significantly worse outcomes in several subgroups. Ranolazine did not reduce the rate of ischemia detected on cECG (19.9% vs. 21.0%, hazard ratio: 0.93, p = 0.21). Conclusions In more than 6,300 patients with ACS, ischemia detected on cECG occurred frequently and was strongly and independently associated with poor cardiovascular outcomes, including cardiovascular death. Continuous ECG monitoring to detect ischemia after ACS may help to identify patients at increased risk. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes [MERLIN]; NCT00099788) (J Am Coll Cardiol 2009; 53: 1411-21) (C) 2009 by the American College of Cardiology Foundation C1 [Scirica, Benjamin M.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Budaj, Andrzej] Grochowski Hosp, Postgrad Med Sch, Warsaw, Poland. [Dalby, Anthony J.] Milpark Hosp, Johannesburg, South Africa. RP Scirica, BM (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM bscirica@partners.org FU CV Therapeutics; Accumetrics; Amgen; AstraZeneca; Bayer Healthcare; Beckman Coulter; Biosite; Bristol-Myers Squibb; Eli Lilly; Michael Lerner FX The MERLIN-TIMI 36 study was supported by CV Therapeutics. The TIMI Study Group reports receiving significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck & Co., Merck-Schering Plough Joint Venture, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, OrthoClinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, and Schering-Plough. Dr. Scirica receives honoraria for consulting and educational presentations from CV Therapeutics, and is supported in part by an unrestricted research grant from Michael Lerner. Dr. Morrow receives honoraria for educational presentations from CV Therapeutics and Sanofi-Aventis, serves as a consultant for GlaxoSmithKline and Sanofi-Aventis, and is on the advisory board for Genentech. Dr. Budaj receives honoraria from CV Therapeutics, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Sanofi-Aventis, and serves as a consultant to GlaxoSmithKline and Sanofi-Aventis. Dr. Aroesty serves as a consultant to Fibrogen, which has no commercial products and is conducting no research that could bear any relationship to this paper. Dr. Stone receives a research grant from CV Therapeutics. Dr. Braunwald receives honoraria from and serves as a consultant to AstraZeneca, Bayer AG, CV Therapeutics, Daichii Sankyo, Merck, Pfizer, and Schering-Plough. NR 25 TC 23 Z9 26 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 21 PY 2009 VL 53 IS 16 BP 1411 EP 1421 DI 10.1016/j.jacc.2008.12.053 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432UR UT WOS:000265160200003 PM 19371824 ER PT J AU Arsava, EM Rahman, R Rosand, J Lu, J Smith, EE Rost, NS Singhal, AB Lev, MH Furie, KL Koroshetz, WJ Sorensen, AG Ay, H AF Arsava, E. M. Rahman, R. Rosand, J. Lu, J. Smith, E. E. Rost, N. S. Singhal, A. B. Lev, M. H. Furie, K. L. Koroshetz, W. J. Sorensen, A. G. Ay, H. TI Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke SO NEUROLOGY LA English DT Article ID WHITE-MATTER CHANGES; SCALE SCORE; MRI; AGE; LESIONS; BRAIN; CT; REHABILITATION; ENCEPHALOPATHY; CONNECTIVITY AB Background: Leukoaraiosis (LA) is closely associated with aging, a major determinant of clinical outcome after ischemic stroke. In this study we sought to identify whether LA, independent of advancing age, affects outcome after acute ischemic stroke. Methods: LA volume was quantified in 240 patients with ischemic stroke and MRI within 24 hours of symptom onset. We explored the relationship between LA volume at admission and clinical outcome at 6 months, as assessed by the modified Rankin Scale (mRS). An ordinal logistic regression model was developed to analyze the independent effect of LA volume on clinical outcome. Results: Bivariate analyses showed a significant correlation between LA volume and mRS at 6 months (r = 0.19, p = 0.003). Mean mRS was 1.7 +/- 1.8 among those in the lowest (<= 1.2 mL) and 2.5 +/- 1.9 in the highest (>9.9 mL) quartiles of LA volume (p = 0.01). The unfavorable prognostic effect of LA volume on clinical outcome was retained in the multivariable model (p = 0.002), which included age, gender, stroke risk factors (hypertension, diabetes mellitus, atrial fibrillation), previous history of brain infarction, admission plasma glucose level, admission NIH Stroke Scale score, IV rtPA treatment, and acute infarct volume on MRI as covariates. Conclusions: The volume of leukoaraiosis is a predictor of clinical outcome after ischemic stroke and this relationship persists after adjustment for important prognostic factors including age, initial stroke severity, and infarct volume. Neurology(R) 2009; 72: 1403-1410 C1 [Arsava, E. M.; Lu, J.; Lev, M. H.; Sorensen, A. G.; Ay, H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.; Smith, E. E.; Rost, N. S.; Singhal, A. B.; Furie, K. L.; Ay, H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke Serv,Dept Neurol, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.; Rost, N. S.] MIT & Harvard, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Koroshetz, W. J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Ay, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, 149 13th St,Room 2301, Boston, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; OI Arsava, Ethem Murat/0000-0002-6527-4139; Smith, Eric/0000-0003-3956-1668 FU NIH [R01-NS059727, R01-NS051412, P50-NS051343, R01-HS011392, R01-NS038477] FX Supported by NIH grants R01-NS059727 (J.R.), R01-NS051412 and P50-NS051343 ( A. B. S.), P50-NS051343 ( M. H. L.), R01-HS011392 and P50-NS051343 ( K. L. F.), and R01-NS038477 ( A. G. S.). NR 39 TC 79 Z9 84 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 21 PY 2009 VL 72 IS 16 BP 1403 EP 1410 DI 10.1212/WNL.0b013e3181a18823 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 436DV UT WOS:000265393700007 PM 19380699 ER PT J AU Bohnen, NI Muller, MLTM Kuwabara, H Constantine, GM Studenski, SA AF Bohnen, N. I. Mueller, M. L. T. M. Kuwabara, H. Constantine, G. M. Studenski, S. A. TI Age-associated leukoaraiosis and cortical cholinergic deafferentation SO NEUROLOGY LA English DT Article ID WHITE-MATTER HYPERINTENSITIES; HUMAN-BRAIN; ACETYLCHOLINESTERASE ACTIVITY; PARKINSONS-DISEASE; ALZHEIMER-DISEASE; RATING-SCALE; IN-VIVO; DENERVATION; PATHWAYS; PERFORMANCE AB Objective: To investigate the relationship between age-associated MRI leukoaraiosis or white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity. Background: One possible mechanism of cognitive decline in elderly individuals with leukoaraiosis is disruption of cholinergic fibers by strategically located white matter lesions. Periventricular lesions may have a higher chance of disrupting cholinergic projections compared with more superficial nonperiventricular white matter lesions because of anatomic proximity to the major cholinergic axonal projection bundles that originate from the basal forebrain. Methods: Community-dwelling, middle-aged and elderly subjects without dementia (mean age 71.0 +/- 9.2 years; 55-84 years; n = 18) underwent brain MRI and AChE PET imaging. The severity of periventricular and nonperiventricular WMH on fluid-attenuated inversion recovery MRI images was scored using the semiquantitative rating scale of Scheltens et al. [(11)C] methyl-4-piperidinyl propionate AChE PET imaging was used to assess cortical AChE activity. Age-corrected Spearman partial rank correlation coefficients were calculated. Results: The severity of periventricular (R = -0.52, p = 0.04) but not nonperiventricular (R = -0.20, not significant) WMH was inversely related to global cortical AChE activity. Regional cortical cholinergic effects of periventricular WMH were most significant for the occipital lobe (R = -0.58, p = 0.02). Conclusions: The presence of periventricular but not nonperiventricular white matter hyperintensities (WMH) is significantly associated with lower cortical cholinergic activity. These findings support a regionally specific disruption of cholinergic projection fibers by WMH. Neurology(R) 2009; 72: 1411-1416 C1 [Bohnen, N. I.; Mueller, M. L. T. M.] Univ Michigan, Funct Neuroimaging Cognit & Mobil Lab, Dept Radiol, Ann Arbor, MI 48105 USA. [Bohnen, N. I.; Mueller, M. L. T. M.] Univ Michigan, Funct Neuroimaging Cognit & Mobil Lab, Dept Neurol, Ann Arbor, MI 48105 USA. [Bohnen, N. I.] GRECC, VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kuwabara, H.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Constantine, G. M.] Univ Pittsburgh, Dept Math & Stat, Pittsburgh, PA 15260 USA. [Studenski, S. A.] GRECC, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Studenski, S. A.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Dept Med, Pittsburgh, PA 15260 USA. RP Bohnen, NI (reprint author), Univ Michigan, Funct Neuroimaging Cognit & Mobil Lab, Dept Radiol, 24 Frank Lloyd Wright Dr,Box 362, Ann Arbor, MI 48105 USA. EM nbohnen@umich.edu RI Muller, Martijn/A-7205-2010 FU Department of Veterans Affairs and National Institute on Aging [AG023641, AG024827] FX Supported by the Department of Veterans Affairs and National Institute on Aging grants AG023641 and AG024827. NR 31 TC 13 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 21 PY 2009 VL 72 IS 16 BP 1411 EP 1416 DI 10.1212/WNL.0b013e3181a187c6 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 436DV UT WOS:000265393700008 PM 19380700 ER PT J AU Yi, CR Goldberg, MB AF Yi, Chae-ryun Goldberg, Marcia B. TI Enterohemorrhagic Escherichia coli raises the I-BAR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ESPF(U); EFFECTOR; PROTEIN; TIR; MEMBRANES; MECHANISM; WASP C1 [Yi, Chae-ryun; Goldberg, Marcia B.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Cambridge, MA 02139 USA. RP Goldberg, MB (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Cambridge, MA 02139 USA. EM mgoldberg1@partners.org FU NIAID NIH HHS [R01 AI081724] NR 12 TC 3 Z9 3 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 21 PY 2009 VL 106 IS 16 BP 6431 EP 6432 DI 10.1073/pnas.0902773106 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437SI UT WOS:000265506800003 PM 19380713 ER PT J AU Letai, A AF Letai, Anthony TI Puma strikes Bax SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; BCL-2 FAMILY-MEMBERS; ACTIVATION; APOPTOSIS; DEATH; P53; LIGAND AB The commitment to programmed cell death via apoptosis is largely made upon activation of the proapoptotic mitochondrial proteins Bax or Bak. In this issue, Gallenne et al. (Gallenne, T., F. Gautier, L. Oliver, E. Hervouet, B. Noel, J.A. Hickman, O. Geneste, P.-F. Cartron, F.M. Vallette, S. Manon, and P. Juin. 2009. J. Cell Biol. 185: 279-290) provide evidence that the p53 up-regulated modulator of apoptosis (Puma) protein can directly activate Bax. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM anthony_letai@dfci.harvard.edu NR 19 TC 21 Z9 23 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD APR 20 PY 2009 VL 185 IS 2 BP 189 EP 191 DI 10.1083/jcb.200903134 PG 3 WC Cell Biology SC Cell Biology GA 439AR UT WOS:000265599200005 PM 19380876 ER PT J AU Kilbridge, KL Fraser, G Krahn, M Nelson, EM Conaway, M Bashore, R Wolf, A Barry, MJ Gong, DA Nease, RF Connors, AF AF Kilbridge, Kerry L. Fraser, Gertrude Krahn, Murray Nelson, Elizabeth M. Conaway, Mark Bashore, Randall Wolf, Andrew Barry, Michael J. Gong, Debra A. Nease, Robert F., Jr. Connors, Alfred F. TI Lack of Comprehension of Common Prostate Cancer Terms in an Underserved Population SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID QUALITY-OF-LIFE; DECISION-ANALYSIS; INFORMED-CONSENT; RADICAL PROSTATECTOMY; HEALTH LITERACY; MEDICARE SURVEY; PATIENT; OUTCOMES; ANTIGEN; MEN AB Purpose To assess the comprehension of common medical terms used in prostate cancer in patient education materials to obtain informed consent, and to measure outcomes after prostate cancer treatment. We address this issue among underserved, African-American men because of the increased cancer incidence and mortality observed in this population. Patients and Methods We reviewed patient education materials and prostate-specific quality-of-life instruments to identify technical terms describing sexual, urinary, and bowel function. Understanding of these terms was assessed in face-to-face interviews of 105, mostly African-American men, age >= 40, from two low-income clinics. Comprehension was evaluated using semiqualitative methods coded by two independent investigators. Demographics were collected and literacy was measured. Results Fewer than 50% of patients understood the terms "erection" or "impotent." Only 5% of patients understood the term "incontinence" and 25% understood the term "bowel habits." More patients recognized word roots than related terms or compound words (eg, "rectum" v "rectal urgency," "intercourse" v "vaginal intercourse"). Comprehension of terms from all domains was statistically significantly correlated with reading level (P < .001). Median literacy level was fourth to sixth grade. Prostate cancer knowledge was poor. Many patients had difficulty locating key anatomic structures. Conclusion Limited comprehension of prostate cancer terms and low literacy create barriers to obtaining informed consent for treatment and to measuring prostate cancer outcomes accurately in our study population. In addition, the level of prostate cancer knowledge was poor. These results highlight the need for prostate cancer education efforts and outcomes measurements that consider literacy and use nonmedical language. J Clin Oncol 27: 2015-2021. (C) 2009 by American Society of Clinical Oncology C1 [Kilbridge, Kerry L.] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. Univ Toronto, Toronto, ON, Canada. MetroHlth Med Ctr, Cleveland, OH USA. Express Scripts, St Louis, MO USA. Washington Univ, St Louis, MO USA. Jesse Brown Vet Adm Med Ctr, Chicago, IL USA. Cent Virginia Community Hlth Ctr, Class 2007, Sch Publ Hlth, New Canton, VA USA. Univ Virginia, Charlottesville, VA USA. Univ N Carolina, Chapel Hill, NC USA. RP Kilbridge, KL (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St,9th Floor 955, Boston, MA 02114 USA. EM kkilbridge@partners.org OI Krahn, Murray/0000-0001-5836-397X FU NCI NIH HHS [K07 CA085754, KO7CA085754] NR 69 TC 32 Z9 33 U1 2 U2 5 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 APR 20 PY 2009 VL 27 IS 12 BP 2015 EP 2021 DI 10.1200/JCO.2008.17.3468 PG 7 WC Oncology SC Oncology GA 447MH UT WOS:000266194700017 PM 19307512 ER PT J AU Egede, LE Frueh, CB Richardson, LK Acierno, R Mauldin, PD Knapp, RG Lejuez, C AF Egede, Leonard E. Frueh, Christopher B. Richardson, Lisa K. Acierno, Ronald Mauldin, Patrick D. Knapp, Rebecca G. Lejuez, Carl TI Rationale and design: telepsychology service delivery for depressed elderly veterans SO TRIALS LA English DT Article ID BEHAVIORAL ACTIVATION TREATMENT; POSTTRAUMATIC-STRESS-DISORDER; LONGITUDINAL PSYCHIATRIC DATA; RANDOM REGRESSION-MODELS; SAMPLE-SIZE FORMULAS; QUALITY-OF-LIFE; ESTABLISH EQUIVALENCE; RANDOMIZED-TRIAL; CLINICAL-TRIALS; NULL HYPOTHESIS AB Background: Older adults who live in rural areas experience significant disparities in health status and access to mental health care. "Telepsychology," (also referred to as " telepsychiatry," or " telemental health") represents a potential strategy towards addressing this longstanding problem. Older adults may benefit from telepsychology due to its: (1) utility to address existing problematic access to care for rural residents; (2) capacity to reduce stigma associated with traditional mental health care; and (3) utility to overcome significant age-related problems in ambulation and transportation. Moreover, preliminary evidence indicates that telepsychiatry programs are often less expensive for patients, and reduce travel time, travel costs, and time off from work. Thus, telepsychology may provide a cost-efficient solution to access-to-care problems in rural areas. Methods: We describe an ongoing four-year prospective, randomized clinical trial comparing the effectiveness of an empirically supported treatment for major depressive disorder, Behavioral Activation, delivered either via in-home videoconferencing technology ("Telepsychology") or traditional face-to-face services ("Same-Room"). Our hypothesis is that inhomeTelepsychology service delivery will be equally effective as the traditional mode (Same-Room). Two-hundred twenty-four (224) male and female elderly participants will be administered protocol-driven individual Behavioral Activation therapy for depression over an 8-week period; and subjects will be followed for 12-months to ascertain longer-term effects of the treatment on three outcomes domains: (1) clinical outcomes (symptom severity, social functioning); (2) process variables (patient satisfaction, treatment credibility, attendance, adherence, dropout); and (3) economic outcomes (cost and resource use). Discussion: Results from the proposed study will provide important insight into whether telepsychology service delivery is as effective as the traditional mode of service delivery, defined in terms of clinical, process, and economic outcomes, for elderly patients with depression residing in rural areas without adequate access to mental health services. Trial registration: National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00324701). C1 [Egede, Leonard E.; Frueh, Christopher B.; Acierno, Ronald; Mauldin, Patrick D.; Knapp, Rebecca G.; Lejuez, Carl] Ralph H Johnson VAMC, Ctr Dis Prevent & Hlth Intervent Div Populat, Charleston, SC USA. [Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Egede, Leonard E.; Mauldin, Patrick D.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Frueh, Christopher B.] Baylor Coll Med, Menninger Clin, Houston, TX 77030 USA. [Frueh, Christopher B.] Baylor Coll Med, Dept Psychiat, Houston, TX 77030 USA. [Frueh, Christopher B.; Richardson, Lisa K.; Acierno, Ronald] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Richardson, Lisa K.] Murdoch Univ, Sch Psychol, Perth, WA, Australia. [Mauldin, Patrick D.] Med Univ S Carolina, Dept Clin Pharm & Outcome Sci, Charleston, SC 29425 USA. [Knapp, Rebecca G.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Lejuez, Carl] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. RP Egede, LE (reprint author), Ralph H Johnson VAMC, Ctr Dis Prevent & Hlth Intervent Div Populat, Charleston, SC USA. EM egedel@musc.edu; frueh@bcm.edu; l.richardson@murdoch.edu.au; acierno@musc.edu; mauldinp@musc.edu; knappr@musc.edu; clejuez@psyc.umd.edu FU Veterans Health Administration Health Services Research and Development program [IIR 04-421] FX The study was funded by grant # IIR 04-421 from the Veterans Health Administration Health Services Research and Development program. NR 89 TC 19 Z9 19 U1 3 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD APR 20 PY 2009 VL 10 AR 22 DI 10.1186/1745-6215-10-22 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 452HS UT WOS:000266531600001 PM 19379517 ER PT J AU Mar, JC Kimura, Y Schroder, K Irvine, KM Hayashizaki, Y Suzuki, H Hume, D Quackenbush, J AF Mar, Jessica C. Kimura, Yasumasa Schroder, Kate Irvine, Katharine M. Hayashizaki, Yoshihide Suzuki, Harukazu Hume, David Quackenbush, John TI Data-driven normalization strategies for high-throughput quantitative RT-PCR SO BMC BIOINFORMATICS LA English DT Article ID REAL-TIME; GENE-EXPRESSION; IDENTIFICATION; VALIDATION; ARRAY AB Background: High-throughput real-time quantitative reverse transcriptase polymerase chain reaction (qPCR) is a widely used technique in experiments where expression patterns of genes are to be profiled. Current stage technology allows the acquisition of profiles for a moderate number of genes (50 to a few thousand), and this number continues to grow. The use of appropriate normalization algorithms for qPCR-based data is therefore a highly important aspect of the data preprocessing pipeline. Results: We present and evaluate two data-driven normalization methods that directly correct for technical variation and represent robust alternatives to standard housekeeping gene-based approaches. We evaluated the performance of these methods against a single gene housekeeping gene method and our results suggest that quantile normalization performs best. These methods are implemented in freely-available software as an R package qpcrNorm distributed through the Bioconductor project. Conclusion: The utility of the approaches that we describe can be demonstrated most clearly in situations where standard housekeeping genes are regulated by some experimental condition. For large qPCR-based data sets, our approaches represent robust, data-driven strategies for normalization. C1 [Mar, Jessica C.; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kimura, Yasumasa; Hayashizaki, Yoshihide; Suzuki, Harukazu] Yokohama Inst, Omics Sci Ctr, RIKEN, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Schroder, Kate; Irvine, Katharine M.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Hume, David] Univ Edinburgh, Roslin Inst, Roslin EH25 9PS, Midlothian, Scotland. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Quackenbush, J (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM jess@jimmy.harvard.edu; y-kimura@gsc.riken.jp; k.schroder@imb.uq.edu.au; k.irvine@imb.uq.edu.au; yoshihide@gsc.riken.jp; harukazu@gsc.riken.jp; David.Hume@roslin.ed.ac.uk; johnq@jimmy.harvard.edu RI Irvine, Katharine/A-5559-2011; Schroder, Kate/C-6132-2008; Kimura, Yasumasa/M-9720-2013; Suzuki, Harukazu/N-9553-2015 OI Schroder, Kate/0000-0001-9261-3805; Suzuki, Harukazu/0000-0002-8087-0836 FU Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government; Ministry of Education, Culture, Sports, Science and Technology, Japan; National Human Genome Research Institute of the US National Institutes of Health [1P50 HG004233] FX We gratefully acknowledge the contribution of Kayoko Murakami for generating the qPCR data. We also acknowledge the support of a research grant for the RIKEN Omics Science Center from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government and a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We also thank Dr Tom Chittenden and Renee Rubio for helpful discussion and valuable feedback; and Dr Razvan Sultana for technical help. We also thank the referees for useful feedback and suggestions that have improved both the method and our presentation. JCM and JQ were supported by a grant from the National Human Genome Research Institute of the US National Institutes of Health (1P50 HG004233). NR 20 TC 47 Z9 47 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD APR 19 PY 2009 VL 10 AR 110 DI 10.1186/1471-2105-10-110 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 453IU UT WOS:000266604900001 PM 19374774 ER PT J AU Neel, BG Cross, FR Pellman, D AF Neel, Benjamin G. Cross, Frederick R. Pellman, David TI Hidesaburo Hanafusa 1929-2009 Obituary SO CELL LA English DT Biographical-Item C1 [Neel, Benjamin G.] Univ Toronto, Ontario Canc Inst, Toronto, ON M4W 2V1, Canada. [Cross, Frederick R.] Rockefeller Univ, New York, NY 10065 USA. [Pellman, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Neel, BG (reprint author), Univ Toronto, Ontario Canc Inst, Toronto, ON M4W 2V1, Canada. EM bneel@uhnresearch.ca; fcross@rockefeller.edu; david_pellman@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD APR 17 PY 2009 VL 137 IS 2 BP 197 EP 199 DI 10.1016/j.cell.2009.04.004 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 437AB UT WOS:000265456800007 ER PT J AU Ng, SYM Yoshida, T Zhang, JW Georgopoulos, K AF Ng, Samuel Yao-Ming Yoshida, Toshimi Zhang, Jiangwen Georgopoulos, Katia TI Genome-wide Lineage-Specific Transcriptional Networks Underscore Ikaros-Dependent Lymphoid Priming in Hematopoietic Stem Cells SO IMMUNITY LA English DT Article ID CHROMATIN REMODELER MI-2-BETA; ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW; PROGENITOR CELLS; MULTIPOTENT PROGENITORS; GENE-EXPRESSION; SELF-RENEWAL; COMMITMENT; RECEPTOR; PROTEINS AB The mechanisms regulating lineage potential during early hematopoiesis were investigated. First, a cascade of lineage-affiliated gene expression signatures, primed in hematopoietic stem cells (HSCs) and differentially propagated in lineage-restricted progenitors, was identified. Lymphoid transcripts were primed as early as the HSC, together with myeloid and erythroid transcripts. Although this multilineage priming was resolved upon subsequent lineage restrictions, an unexpected cosegregation of lymphoid and myeloid gene expression and potential past a nominal myeloid restriction point was identified. Finally, we demonstrated that whereas the zinc finger DNA-binding factor Ikaros was required for induction of lymphoid lineage priming in the HSC, it was also necessary for repression of genetic programs compatible with self-renewal and multipotency downstream of the HSC. Taken together, our studies provide new insight into the priming and restriction of lineage potentials during early hematopoiesis and identify Ikaros as a key bivalent regulator of this process. C1 [Ng, Samuel Yao-Ming; Yoshida, Toshimi; Georgopoulos, Katia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Zhang, Jiangwen] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. RP Georgopoulos, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM katia.georgopoulos@cbrc2.mgh.harvard.edu RI Zhang, Jiangwen/A-7654-2013 FU National Institutes of Health [NIH-R37-AI33062-16, NIH-R01-AI42254-11] FX This work was supported by National Institutes of Health grants NIH-R37-AI33062-16 and NIH-R01-AI42254-11 to K.G. We thank Bob Czyzewski for mouse husbandry, and we thank the K.G. lab and Bruce Morgan for a critical review of the manuscript. NR 56 TC 128 Z9 128 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR 17 PY 2009 VL 30 IS 4 BP 493 EP 507 DI 10.1016/j.immuni.2009.01.014 PG 15 WC Immunology SC Immunology GA 435BT UT WOS:000265319000007 PM 19345118 ER PT J AU Savina, A Peres, A Cebrian, I Carmo, N Moita, C Hacohen, N Moita, LF Amigorena, S AF Savina, Ariel Peres, Audrey Cebrian, Ignacio Carmo, Nuno Moita, Catarina Hacohen, Nir Moita, Luis F. Amigorena, Sebastian TI The Small GTPase Rac2 Controls Phagosomal Alkalinization and Antigen Crosspresentation Selectively in CD8(+) Dendritic Cells SO IMMUNITY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; PHAGOCYTE NADPH OXIDASE; IN-VIVO; CROSS-PRESENTATION; PRESENTING CELLS; RHO-GTPASES; MURINE MACROPHAGES; CATHEPSIN-S; ACTIVATION; LOCALIZATION AB A unique subpopulation of spleen dendritic cells (DCs) that express the CD8 surface marker efficiently present phagocytosed antigens to CD8(+) T lymphocytes in a process called "crosspresentation," which initiates cytotoxic immune responses. We now show that the small GTPase Rac2 plays a critical role in antigen crosspresentation selectively in this DC subpopulation. In CD8(+) DCs, Rac2 determines the subcellular assembly of the NADPH oxidase complex (NOX2) to phagosomes, whereas in CD8(-) DCs, Rac1 mediates the assembly of NOX2 at the plasma membrane. In the absence of Rac2, the production of reactive oxygen species (ROS) in DC-phagosomes was abolished, the phagosomal pH dropped, and the efficiency of antigen crosspresentation was reduced. We conclude that the activity of Racl and 2 control crosspresentation in DC subpopulations through the regulation of phagosomal oxidation and pH. C1 [Savina, Ariel; Peres, Audrey; Cebrian, Ignacio; Amigorena, Sebastian] Inst Curie, INSERM U653, F-75248 Paris 05, France. [Carmo, Nuno; Moita, Catarina; Moita, Luis F.] Univ Lisbon, Fac Med, Inst Mol Med, Cell Biol Immune Syst Unit, P-1649028 Lisbon, Portugal. [Hacohen, Nir] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Hacohen, Nir] Broad Inst Harvard, Cambridge, MA 02142 USA. [Hacohen, Nir] MIT, Cambridge, MA USA. RP Savina, A (reprint author), Inst Curie, INSERM U653, 26 Rue Ulm, F-75248 Paris 05, France. EM ariel.savina@curie.fr; sebastian.amigorena@curie.fr RI Moita, Luis/L-1296-2013; OI Moita, Luis/0000-0003-0707-315X; Ferreira Moita, Catarina/0000-0002-9910-2343 FU Institut National de la Sainte et de la Recherche Medicale (INSERM); Ligue National de Lutte contre le Cancer (LLNC); Institut Curie; Contrat CEE DC-Thera [LSBH-CT-2004-512074, LSHC-CT-2006-518234]; Fondation Bettencourt and Association de Recherche contre le Cancer; Fundacao, Luso-Americana para o Desenvolvimento and Fundacao para a Ciencia e a Tecnologia [PTDC/SAU-MII/69280/2006, PTDC/SAU-MII/78333/2006] FX We are grateful to J. Villadangos and P. Schnorrer (Melbourne University) for help with the DC sorting protocols. We also specially thank A. Boissonnas, C. Hivroz, S. Dogniaux, S. Krumeich, and K. Chemin for experimental help and reagents and A. Lennon for comments on the manuscript. This work was supported by Institut National de la Sainte et de la Recherche Medicale (INSERM), Ligue National de Lutte contre le Cancer (LLNC), the Institut Curie, Contrat CEE DC-Thera No LSBH-CT-2004-512074 "Dendritic Cells for novel immunotherapies" and Contrat CEE CancerImmunotherapy LSHC-CT-2006-518234 "Cancer Immunology and Immunotherapy," Fondation Bettencourt and Association de Recherche contre le Cancer (prix L. Griffuel), and Fundacao, Luso-Americana para o Desenvolvimento and Fundacao para a Ciencia e a Tecnologia (PTDC/SAU-MII/69280/2006 and PTDC/SAU-MII/78333/2006). A.S. was supported by INSERM; A.P. by LLNC. NR 44 TC 121 Z9 124 U1 3 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR 17 PY 2009 VL 30 IS 4 BP 544 EP 555 DI 10.1016/j.immuni.2009.01.013 PG 12 WC Immunology SC Immunology GA 435BT UT WOS:000265319000011 PM 19328020 ER PT J AU Menze, MA Boswell, L Toner, M Hand, SC AF Menze, Michael A. Boswell, Leaf Toner, Mehmet Hand, Steven C. TI Occurrence of Mitochondria-targeted Late Embryogenesis Abundant (LEA) Gene in Animals Increases Organelle Resistance to Water Stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARTEMIA-FRANCISCANA EMBRYOS; SHOCK/ALPHA-CRYSTALLIN PROTEIN; MAMMALIAN-CELLS; INTRACELLULAR TREHALOSE; DESICCATION TOLERANCE; ENHANCED PROTECTION; MEMBRANE INTEGRITY; DIVALENT-CATIONS; IMPORT MACHINERY; IN-VITRO AB Anhydrobiotic animals survive virtually complete loss of cellular water. The mechanisms that explain this phenomenon are not fully understood but often include the accumulation of low molecular weight solutes such as trehalose and macromolecules like Late Embryogenesis Abundant (LEA) proteins. Here we report for the first time the occurrence of a mitochondria-targeted LEA gene (Afrlea3m) product in an animal species. The deduced molecular mass of the 307-amino acid polypeptide from the brine shrimp Artemia franciscana is 34 kDa. Bioinformatic analyses reveal features typical of a Group 3 LEA protein, and subcellular localization programs predict targeting of the mature peptide to the mitochondrial matrix, based on an N-terminal, amphipathic presequence. Real-time quantitative PCR shows that Afralea3m mRNA is expressed manyfold higher in desiccation-tolerant embryonic stages when compared with intolerant nauplius larvae. Mitochondrial localization of the protein was confirmed by transfection of human hepatoma cells (HepG2/C3A) with a nucleotide construct encoding the first 70 N-terminal amino acids of AfrLEA3m in-frame with the nucleotide sequence for green fluorescence protein. The chimeric protein was readily incorporated into mitochondria of these cells. Successful targeting of a protein to human mitochondria by use of an arthropod signaling sequence clearly reveals the highly conserved nature of such presequences, as well as of the import machinery. Finally, mitochondria isolated from A. franciscana embryos, which naturally contain AfrLEA3m and trehalose, exhibit resistance to water stress (freezing) as evidenced by an unchanged capacity for oxidative phosphorylation on succinate + rotenone, a resistance that is absent in mammalian mitochondria lacking AfrLEA3m. C1 [Menze, Michael A.; Boswell, Leaf; Hand, Steven C.] Louisiana State Univ, Dept Biol Sci, Div Cellular Dev & Integrat Biol, Baton Rouge, LA 70803 USA. [Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Charlestown, MA 02129 USA. RP Menze, MA (reprint author), Louisiana State Univ, Dept Biol Sci, Div Cellular Dev & Integrat Biol, 202 Life Sci Bldg, Baton Rouge, LA 70803 USA. EM menze@lsu.edu OI Menze, Michael/0000-0003-1072-5462 FU National Institutes of Health [2 RO1 DK046270-14A1] FX This work was supported, in whole or in part, by National Institutes of Health Grant 2 RO1 DK046270-14A1. NR 59 TC 35 Z9 38 U1 2 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 17 PY 2009 VL 284 IS 16 BP 10714 EP 10719 DI 10.1074/jbc.C900001200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431ZZ UT WOS:000265104600045 PM 19228698 ER PT J AU Kitagaki, H Cowart, LA Matmati, N Montefusco, D Gandy, J de Avalos, SV Novgorodo, SA Zheng, J Obeid, LM Hannun, YA AF Kitagaki, Hiroshi Cowart, L. Ashley Matmati, Nabil Montefusco, David Gandy, Jason de Avalos, Silvia Vaena Novgorodo, Sergei A. Zheng, Jim Obeid, Lina M. Hannun, Yusuf A. TI ISC1-dependent Metabolic Adaptation Reveals an Indispensable Role for Mitochondria in Induction of Nuclear Genes during the Diauxic Shift in Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOSPHINGOLIPID-PHOSPHOLIPASE-C; SPHINGOLIPID BIOSYNTHESIS; RETROGRADE RESPONSE; LINKS METABOLISM; GENOME STABILITY; YEAST LONGEVITY; RTG2 PROTEIN; EXPRESSION; ACTIVATION; KINASE AB Growth of Saccharomyces cerevisiae following glucose depletion ( the diauxic shift) depends on a profound metabolic adaptation accompanied by a global reprogramming of gene expression. In this study, we provide evidence for a heretofore unsuspected role for Isc1p in mediating this reprogramming. Initial studies revealed that yeast cells deleted in ISC1, the gene encoding inositol sphingolipid phospholipase C, which resides in mitochondria in the post-diauxic phase, showed defective aerobic respiration in the post-diauxic phase but retained normal intrinsic mitochondrial functions, including intact mitochondrial DNA, normal oxygen consumption, and normal mitochondrial polarization. Microarray analysis revealed that the Delta isc1 strain failed to up-regulate genes required for nonfermentable carbon source metabolism during the diauxic shift, thus suggesting a mechanism for the defective supply of respiratory substrates into mitochondria in the post-diauxic phase. This defect in regulating nuclear gene induction in response to a defect in a mitochondrial enzyme raised the possibility that mitochondria may initiate diauxic shift-associated regulation of nucleus-encoded genes. This was established by demonstrating that in respiratory-deficient petite cells these genes failed to be upregulated across the diauxic shift in a manner similar to the Delta isc1 strain. Isc1p- and mitochondrial function-dependent genes significantly overlapped with Adr1p-, Snf1p-, and Cat8p-dependent genes, suggesting some functional link among these factors. However, the retrograde response was not activated in Delta isc1, suggesting that the response of Delta isc1 cannot be simply attributed to mitochondrial dysfunction. These results suggest a novel role for Isc1p in allowing the reprogramming of gene expression during the transition from anaerobic to aerobic metabolism. C1 [Kitagaki, Hiroshi; Cowart, L. Ashley; Matmati, Nabil; Montefusco, David; Gandy, Jason; de Avalos, Silvia Vaena; Zheng, Jim; Hannun, Yusuf A.] Med Univ S Carolina, Dept Biochem, Charleston, SC 29425 USA. [Kitagaki, Hiroshi; Cowart, L. Ashley; Matmati, Nabil; Montefusco, David; Gandy, Jason; de Avalos, Silvia Vaena; Zheng, Jim; Hannun, Yusuf A.] Med Univ S Carolina, Dept Mol Biol, Charleston, SC 29425 USA. [Novgorodo, Sergei A.; Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Cowart, L. Ashley; Obeid, Lina M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Kitagaki, Hiroshi] Saga Univ, Fac Agr, Saga 8408502, Japan. RP Hannun, YA (reprint author), Med Univ S Carolina, Dept Biochem, 173 Ashley Ave,POB 250509, Charleston, SC 29425 USA. EM hannun@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [GM43825, R01 AG016583]; Veterans Affairs Merit Award; Merit Review Entry Program Award; Department of Veterans Affairs, Office of Research and Development; Noda Institute for Scientific Research FX This work was supported, in whole or in part, by National Institutes of Health Grant GM43825 ( to Y. A. H.) and Grant R01 AG016583 ( to L. M. O.). This work was also supported by a Veterans Affairs Merit Award ( to L. M. O.), a Merit Review Entry Program Award ( to L. A. C.) from the Department of Veterans Affairs, Office of Research and Development, and in part by an NISR research grant from the Noda Institute for Scientific Research ( to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked " advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 45 TC 40 Z9 40 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 17 PY 2009 VL 284 IS 16 BP 10818 EP 10830 DI 10.1074/jbc.M805029200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431ZZ UT WOS:000265104600056 PM 19179331 ER PT J AU Butt, MU Zacharias, N Velmahos, GC AF Butt, Muhammad U. Zacharias, Nikolaos Velmahos, George C. TI Penetrating abdominal injuries: management controversies SO SCANDINAVIAN JOURNAL OF TRAUMA RESUSCITATION & EMERGENCY MEDICINE LA English DT Review ID SELECTIVE NONOPERATIVE MANAGEMENT; GUNSHOT WOUNDS; STAB WOUNDS; COMPUTED-TOMOGRAPHY; ROUTINE LAPAROTOMY; TRAUMA; ABDOMEN; DIAPHRAGM; DURATION; BACK AB Penetrating abdominal injuries have been traditionally managed by routine laparotomy. New understanding of trajectories, potential for organ injury, and correlation with advanced radiographic imaging has allowed a shift towards non-operative management of appropriate cases. Although a selective approach has been established for stab wounds, the management of abdominal gunshot wounds remains a matter of controversy. In this chapter we describe the rationale and methodology of selecting patients for non-operative management. We also discuss additional controversial issues, as related to antibiotic prophylaxis, management of asymptomatic thoracoabdominal injuries, and the use of colostomy vs. primary repair for colon injuries. C1 [Velmahos, George C.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM umarbutt177@gmail.com; nzacharias@partners.org; gvelmahos@partners.org NR 31 TC 18 Z9 18 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-7241 J9 SCAND J TRAUMA RESUS JI Scand. J. Trauma Resusc. Emerg. Med. PD APR 17 PY 2009 VL 17 AR 19 DI 10.1186/1757-7241-17-19 PG 7 WC Emergency Medicine SC Emergency Medicine GA 665HU UT WOS:000283026800002 PM 19374761 ER PT J AU Treon, SP Branagan, AR Ioakimidis, L Soumerai, JD Patterson, CJ Turnbull, B Wasi, P Emmanouilides, C Frankel, SR Lister, A Morel, P Matous, J Gregory, SA Kimby, E AF Treon, Steven P. Branagan, Andrew R. Ioakimidis, Leukothea Soumerai, Jacob D. Patterson, Christopher J. Turnbull, Barry Wasi, Parveen Emmanouilides, Christos Frankel, Stanley R. Lister, Andrew Morel, Pierre Matous, Jeffrey Gregory, Stephanie A. Kimby, Eva TI Long-term outcomes to fludarabine and rituximab in Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; 3RD INTERNATIONAL WORKSHOP; COOPERATIVE-ONCOLOGY-GROUP; MANTLE-CELL LYMPHOMA; MULTIPLE-MYELOMA; PHASE-II; TREATMENT RECOMMENDATIONS; FOLLICULAR LYMPHOMA; PROGNOSTIC FACTORS; LOW-GRADE AB We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenstrom macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800. (Blood. 2009; 113: 3673-3678) C1 [Treon, Steven P.; Branagan, Andrew R.; Ioakimidis, Leukothea; Soumerai, Jacob D.; Patterson, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Wasi, Parveen] McMaster Univ, Med Ctr, Hamilton, ON, Canada. [Turnbull, Barry] BioBridges, Boston, MA USA. [Emmanouilides, Christos] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Frankel, Stanley R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Lister, Andrew] St Bartholomews Hosp & Canc Res, London, England. [Morel, Pierre] Ctr Hosp Schaffner, Lens, France. [Matous, Jeffrey] Rocky Mt Canc Ctr, Denver, CO USA. [Gregory, Stephanie A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Kimby, Eva] Huddinge Univ Hosp, Karolinska Inst, Stockholm, Sweden. RP Treon, SP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu FU Dana-Farber Cancer Institute; Berlex Pharmaceuticals; Genentech; Biogen IDEC; Bing Fund for Waldenstrom macroglobulinemia; National Institutes of Health Career Development Award [K23CA087977-03] FX This work was supported by the Research Fund for Waldenstrom's at the Dana-Farber Cancer Institute, Berlex Pharmaceuticals, Genentech, Biogen IDEC, the Bing Fund for Waldenstrom macroglobulinemia, and a National Institutes of Health Career Development Award (K23CA087977-03) (S.P.T.). NR 40 TC 69 Z9 71 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3673 EP 3678 DI 10.1182/blood-2008-09-177329 PG 6 WC Hematology SC Hematology GA 436WD UT WOS:000265445900006 PM 19015393 ER PT J AU Ali, N Karlsson, C Aspling, M Hu, G Hacohen, N Scadden, DT Larsson, J AF Ali, Nicole Karlsson, Christine Aspling, Marie Hu, Guang Hacohen, Nir Scadden, David T. Larsson, Jonas TI Forward RNAi screens in primary human hematopoietic stem/progenitor cells SO BLOOD LA English DT Article ID NOD/SCID REPOPULATING CELLS; CULTURE-INITIATING CELLS; VECTOR TRANSDUCTION; GENETIC SCREEN; SECONDARY AB The mechanisms regulating key fate decisions such as self-renewal and differentiation in hematopoietic stem and progenitor cells (HSPC) remain poorly understood. We report here a screening strategy developed to assess modulators of human hematopoiesis using a lentiviral short hairpin RNA (shRNA) library transduced into cord blood-derived stem/progenitor cells. To screen for modifiers of self-renewal/differentiation, we used the limited persistence of HSPCs under ex vivo culture conditions as a baseline for functional selection of shRNAs conferring enhanced maintenance or expansion of the stem/progenitor potential. This approach enables complex, pooled screens in large numbers of cells. Functional selection identified novel specific gene targets (exostoses 1) or shRNA constructs capable of altering human hematopoietic progenitor differentiation or stem cell expansion, respectively, thereby demonstrating the potential of this forward screening approach in primary human stem cell populations. (Blood. 2009; 113: 3690-3695) C1 [Ali, Nicole; Aspling, Marie; Scadden, David T.; Larsson, Jonas] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Ali, Nicole; Aspling, Marie; Scadden, David T.; Larsson, Jonas] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Karlsson, Christine; Larsson, Jonas] Lund Univ, Lund Stem Cell Ctr, Lund, Sweden. [Hu, Guang] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Genet,Ctr Genet & Genom, Boston, MA 02114 USA. [Hu, Guang] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. [Hacohen, Nir] Broad Inst Massachusetts Inst Technol, Cambridge, MA USA. [Hacohen, Nir] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Cambridge, MA 02138 USA. [Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Scadden, DT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St,CPZN 4265A, Boston, MA 02114 USA. EM scadden.david@mgh.harvard.edu; jonas.larsson@med.lu.se RI Hu, Guang/E-7474-2016 OI Hu, Guang/0000-0003-0437-4723 FU National Institutes of Health (Bethesda, MD); Swedish Cancer Foundation (Stockholm, Sweden); Swedish Childhood Cancer Foundation (Stockholm, Sweden) FX This work was supported by National Institutes of Health (Bethesda, MD) grants to D.T.S. and grants from the Swedish Cancer Foundation (Stockholm, Sweden) and the Swedish Childhood Cancer Foundation (Stockholm, Sweden) to J.L. NR 14 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3690 EP 3695 DI 10.1182/blood-2008-10-176396 PG 6 WC Hematology SC Hematology GA 436WD UT WOS:000265445900009 PM 19188664 ER PT J AU Sarantopoulos, S Stevenson, KE Kim, HT Cutler, CS Bhuiya, NS Schowalter, M Ho, VT Alyea, EP Koreth, J Blazar, BR Soiffer, RJ Antin, JH Ritz, J AF Sarantopoulos, Stefanie Stevenson, Kristen E. Kim, Haesook T. Cutler, Corey S. Bhuiya, Nazmim S. Schowalter, Michael Ho, Vincent T. Alyea, Edwin P. Koreth, John Blazar, Bruce R. Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome TI Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease SO BLOOD LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MINOR HISTOCOMPATIBILITY ANTIGENS; BONE-MARROW TRANSPLANTATION; SJOGRENS-SYNDROME; CUTTING EDGE; LYMPHOCYTE STIMULATOR; TOLERANCE CHECKPOINTS; ACTIVATING FACTOR; CHRONIC GVHD; AUTOANTIBODIES AB Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre-germinal center (GC) B cells and post-GC "plasmablast-like" cells, suggesting in vivo BAFF dependence of these 2 CD27(+) B-cell subsets. Circulating CD27(+) B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27(+) B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease. (Blood. 2009; 113: 3865-3874) C1 [Sarantopoulos, Stefanie; Cutler, Corey S.; Bhuiya, Nazmim S.; Schowalter, Michael; Ho, Vincent T.; Alyea, Edwin P.; Koreth, John; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Sarantopoulos, Stefanie; Cutler, Corey S.; Bhuiya, Nazmim S.; Schowalter, Michael; Ho, Vincent T.; Alyea, Edwin P.; Koreth, John; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Stevenson, Kristen E.; Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Bone Marrow Transplantat, Minneapolis, MN 55455 USA. [Blazar, Bruce R.] Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. [Ritz, Jerome] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Ritz, Jerome] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. RP Sarantopoulos, S (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, 44 Binney St,M530, Boston, MA 02115 USA. EM stefanie_sarantopoulos@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU Leukemia & Lymphoma Society; Jock and Bunny Adams Research and Education Endowment; Ted and Eileen Pasquarello Research Fund; National Institutes of Health [AI29530, HL70149, K12CA087723] FX This study was supported by the Leukemia & Lymphoma Society (White Plains, NY), Jock and Bunny Adams Research and Education Endowment (Boston, MA), Ted and Eileen Pasquarello Research Fund (Boston, MA), and National Institutes of Health (Bethesda, MD) grants AI29530, HL70149, and K12CA087723. NR 63 TC 139 Z9 143 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3865 EP 3874 DI 10.1182/blood-2008-09-177840 PG 10 WC Hematology SC Hematology GA 436WD UT WOS:000265445900029 PM 19168788 ER PT J AU Wang, SB Xia, Q Passias, P Wood, K Li, GA AF Wang, Shaobai Xia, Qun Passias, Peter Wood, Kirkham Li, Guoan TI Measurement of geometric deformation of lumbar intervertebral discs under in-vivo weightbearing condition SO JOURNAL OF BIOMECHANICS LA English DT Article DE Lumbar spine; Spine kinematics; Disc deformation; In-vivo weightbearing; Fluoroscopic and MR imaging ID CREEP RESPONSE ANALYSIS; IMAGE MATCHING METHOD; AXIAL-COMPRESSION; MOTION SEGMENT; SHEAR STRAIN; KINEMATICS; ELEMENT; DEGENERATION; HEALTHY; SYSTEM AB Quantitative data of spinal intervertebral disc deformation is instrumental for investigation of spinal disc pathology. In this study, we employed a combined dual fluoroscopic imaging system and the MR imaging technique to determine the lumbar disc deformation in living human subjects. Discs at L2-3, L3-4 and L4-5 levels were investigated in 8 normal subjects. The geometric deformation of the discs under full body weight loading condition (upright standing) was determined using the supine, non-weightbearing condition as a reference. The average maximum tensile deformation was -21% in compression and 24% in tension, and maximum shear deformation on the disc surface reached 26%. The data indicated that different portions of the disc are under different tensile and shear deformation. Further, discs of L2-3, L3-4 and L4-5 have different deformation behavior under the physiological weightbearing condition. In general, the higher level discs have higher deformation values. The technique used in this Study can be used to investigate the deformation behaviors of diseased discs as well as the efficacy of different surgical modalities at restoring normal disc deformation patterns. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Wang, Shaobai; Xia, Qun; Passias, Peter; Wood, Kirkham; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02114 USA. [Wang, Shaobai] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU NASS; Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School FX Support from the NASS grant and the Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School was greatly appreciated. NR 25 TC 18 Z9 23 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD APR 16 PY 2009 VL 42 IS 6 BP 705 EP 711 DI 10.1016/j.jbiomech.2009.01.004 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 436WS UT WOS:000265447400006 PM 19268946 ER PT J AU Chen, CC Kennedy, RD Sidi, S Look, AT D'Andrea, A AF Chen, Clark C. Kennedy, Richard D. Sidi, Samuel Look, A. Thomas D'Andrea, Alan TI CHK1 inhibition as a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors SO MOLECULAR CANCER LA English DT Article ID DEPENDENT KINASE INHIBITOR; CELL-CYCLE CHECKPOINTS; ADVANCED SOLID TUMORS; PHASE-I TRIAL; DAMAGE CHECKPOINT; BRCA PATHWAY; PROTEIN; CANCER; COMBINATION; UCN-01 AB Background: DNA repair deficient tumor cells have been shown to accumulate high levels of DNA damage. Consequently, these cells become hyper-dependent on DNA damage response pathways, including the CHK1-kinase-mediated response. These observations suggest that DNA repair deficient tumors should exhibit increased sensitivity to CHK1 inhibition. Here we offer experimental evidence in support of this hypothesis. Results: Using isogenic pairs of cell lines differing only in the Fanconi Anemia ( FA) DNA repair pathway, we showed that FA deficient cell lines were hypersensitive to CHK1 silencing by independent siRNAs as well as CHK1 pharmacologic inhibition by Go6976 and UCN-01. In parallel, an siRNA screen designed to identify gene silencings synthetically lethal with CHK1 inhibition identified genes required for FA pathway function. To confirm these findings in vivo, we demonstrated that whole zebrafish embryos, depleted for FANCD2 by a morpholino approach, were hypersensitive to Go6976. Silencing of FA genes led to hyper-activation of CHK1 and vice versa. Furthermore, inactivation of CHK1 in FA deficient cell lines caused increased accumulation of DNA strand and chromosomal breakages. These results suggest that the functions subserved by CHK1 and the FA pathway mutually compensate in maintaining genome integrity. As CHK1 inhibition has been under clinical trial in combination with cisplatin, we showed that the FA specific tumoricidal effect of CHK1 inhibition and cisplatin was synergistic. Conclusion: Taken together, these results suggest CHK1 inhibition as a strategy for targeting FA deficient tumors. C1 [Chen, Clark C.; Kennedy, Richard D.; D'Andrea, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Clark C.] Harvard Univ, Sch Med, Beth Israel Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Sidi, Samuel; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP D'Andrea, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM cchen1@partners.org; richard_kennedy@dfci.harvard.edu; samuel_sidi@dfci.harvard.edu; thomas_look@dfci.harvard.edu; Alan_Dandrea@dfci.harvard.edu RI Kennedy, Richard/J-3489-2012; Chen, Clark/C-8714-2013 OI Kennedy, Richard/0000-0003-4737-6163; Chen, Clark/0000-0001-6258-9277 FU NCI NIH HHS [P50CA105009-01]; NHLBI NIH HHS [R01HL52725, P01HL54785, R37 HL052725]; NIDDK NIH HHS [R01DK43889, R01 DK043889]; PHS HHS [(U19A1067751, P01150654] NR 44 TC 52 Z9 54 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD APR 16 PY 2009 VL 8 AR 24 DI 10.1186/1476-4598-8-24 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 449IA UT WOS:000266322900001 PM 19371427 ER PT J AU Devore, S Ihlefeld, A Hancock, K Shinn-Cunningham, B Delgutte, B AF Devore, Sasha Ihlefeld, Antje Hancock, Kenneth Shinn-Cunningham, Barbara Delgutte, Bertrand TI Accurate Sound Localization in Reverberant Environments Is Mediated by Robust Encoding of Spatial Cues in the Auditory Midbrain SO NEURON LA English DT Article ID INTERAURAL TIME DIFFERENCES; AMPLITUDE-MODULATED TONES; INFERIOR COLLICULUS NEURONS; SUPERIOR OLIVARY COMPLEX; LOW-FREQUENCY CELLS; SPEECH-INTELLIGIBILITY; UNANESTHETIZED RABBIT; BINAURAL INTERACTION; RESPONSE PROPERTIES; NEURAL MECHANISMS AB In reverberant environments, acoustic reflections interfere with the direct sound arriving at a listener's ears, distorting the spatial cues for sound localization. Yet, human listeners have little difficulty localizing sounds in most settings. Because reverberant energy builds up overtime, the source location is represented relatively faithfully during the early portion of a sound, but this representation becomes increasingly degraded later in the stimulus. We show that the directional sensitivity of single neurons in the auditory midbrain of anesthetized cats follows a similar time course, although onset dominance in temporal response patterns results in more robust directional sensitivity than expected, suggesting a simple mechanism for improving directional sensitivity in reverberation. In parallel behavioral experiments, we demonstrate that human lateralization judgments are consistent with predictions from a population rate model decoding the observed midbrain responses, suggesting a subcortical origin for robust sound localization in reverberant environments. C1 [Devore, Sasha; Hancock, Kenneth; Delgutte, Bertrand] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Devore, Sasha; Shinn-Cunningham, Barbara; Delgutte, Bertrand] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Ihlefeld, Antje; Shinn-Cunningham, Barbara] Boston Univ, Hearing Res Ctr, Boston, MA 02108 USA. [Delgutte, Bertrand] MIT, Elect Res Lab, Cambridge, MA 02139 USA. RP Devore, S (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. EM sashad@alum.mit.edu OI , /0000-0003-1349-9608; Ihlefeld, Antje/0000-0001-7185-5848 FU National Institutes of Health (NIH) [R01 DC002258, R01 DC05778-02, P30 DC005209, T32 DC00038] FX This work was supported by National Institutes of Health (NIH) Grants R01 DC002258 (B.D.), R01 DC05778-02 (B.S.-C.), and core grant P30 DC005209 to Eaton Peabody Laboratory. S.D. was partially supported by NIH Grant T32 DC00038. We thank Connie Miller for surgical assistance and Lorraine Delhorne and Eric Larson for assistance with the behavioral experiments. Dr. Adrian K.C. Lee provided the ILD-pointer software and Dr. Jay Desloges provided the BRIR-simulation software. We additionally thank three anonymous reviewers who helped us to improve this manuscript. NR 86 TC 42 Z9 44 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 16 PY 2009 VL 62 IS 1 BP 123 EP 134 DI 10.1016/j.neuron.2009.02.018 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 435LZ UT WOS:000265346700014 PM 19376072 ER PT J AU Viel, KR Ameri, A Abshire, TC Iyer, RV Watts, RG Lutcher, C Channell, C Cole, SA Fernstrom, KM Nakaya, S Kasper, CK Thompson, AR Almasy, L Howard, TE AF Viel, Kevin R. Ameri, Afshin Abshire, Thomas C. Iyer, Rathi V. Watts, Raymond G. Lutcher, Charles Channell, Cynthia Cole, Shelley A. Fernstrom, Karl M. Nakaya, Shelley Kasper, Carol K. Thompson, Arthur R. Almasy, Laura Howard, Tom E. TI Inhibitors of Factor VIII in Black Patients with Hemophilia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Hematology CY DEC 09-12, 2006 CL Orlando, FL SP Amer Soc Hematol ID PREVIOUSLY UNTREATED PATIENTS; RECOMBINANT FACTOR-VIII; FACTOR-IX; GENETIC ASSOCIATION; AFRICAN-AMERICANS; UNITED-STATES; F8 GENE; MUTATIONS; RISK; INVERSION AB BACKGROUND Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients. METHODS We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors. RESULTS Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P = 0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups. CONCLUSIONS These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies. C1 [Viel, Kevin R.; Cole, Shelley A.; Almasy, Laura] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Ameri, Afshin; Lutcher, Charles] Med Coll Georgia, Augusta, GA 30912 USA. [Abshire, Thomas C.; Channell, Cynthia; Fernstrom, Karl M.] Emory Univ, Atlanta, GA 30322 USA. [Iyer, Rathi V.] Univ Mississippi, Med Ctr, Jackson, MS USA. [Watts, Raymond G.] Univ Alabama, Birmingham, AL USA. [Nakaya, Shelley; Thompson, Arthur R.] Univ Washington, Seattle, WA 98195 USA. [Kasper, Carol K.; Howard, Tom E.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Kasper, Carol K.] Orthoped Hosp, Los Angeles, CA USA. [Howard, Tom E.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Howard, Tom E.] Greater Los Angeles Vet Affairs Hosp, Los Angeles, CA USA. RP Howard, TE (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, 11301 Wilshire Blvd,Bldg 500,Rm 12S4, Los Angeles, CA 90073 USA. EM tom.howard@va.gov FU NHLBI NIH HHS [HL-07109, HL-70751, HL-71130, HL-72533, K08 HL071130, K08 HL071130-06, R01 HL070751, R01 HL070751-07, R01 HL072533, R01 HL072533-05] NR 53 TC 106 Z9 111 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 16 PY 2009 VL 360 IS 16 BP 1618 EP 1627 DI 10.1056/NEJMoa075760 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 433BH UT WOS:000265178000006 PM 19369668 ER PT J AU Jha, AK DesRoches, CM Campbell, EG Donelan, K Rao, SR Ferris, TG Shields, A Rosenbaum, S Blumenthal, D AF Jha, Ashish K. DesRoches, Catherine M. Campbell, Eric G. Donelan, Karen Rao, Sowmya R. Ferris, Timothy G. Shields, Alexandra Rosenbaum, Sara Blumenthal, David TI Use of Electronic Health Records in U. S. Hospitals SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHYSICIAN ORDER ENTRY; INFORMATION-TECHNOLOGY; UNITED-STATES; CARE; QUALITY; ADOPTION; ORGANIZATIONS; SYSTEMS AB BACKGROUND Despite a consensus that the use of health information technology should lead to more efficient, safer, and higher-quality care, there are no reliable estimates of the prevalence of adoption of electronic health records in U. S. hospitals. METHODS We surveyed all acute care hospitals that are members of the American Hospital Association for the presence of specific electronic-record functionalities. Using a definition of electronic health records based on expert consensus, we determined the proportion of hospitals that had such systems in their clinical areas. We also examined the relationship of adoption of electronic health records to specific hospital characteristics and factors that were reported to be barriers to or facilitators of adoption. RESULTS On the basis of responses from 63.1% of hospitals surveyed, only 1.5% of U. S. hospitals have a comprehensive electronic-records system (i.e., present in all clinical units), and an additional 7.6% have a basic system (i.e., present in at least one clinical unit). Computerized provider-order entry for medications has been implemented in only 17% of hospitals. Larger hospitals, those located in urban areas, and teaching hospitals were more likely to have electronic-records systems. Respondents cited capital requirements and high maintenance costs as the primary barriers to implementation, although hospitals with electronic-records systems were less likely to cite these barriers than hospitals without such systems. CONCLUSIONS The very low levels of adoption of electronic health records in U. S. hospitals suggest that policymakers face substantial obstacles to the achievement of health care performance goals that depend on health information technology. A policy strategy focused on financial support, interoperability, and training of technical support staff may be necessary to spur adoption of electronic-records systems in U. S. hospitals. C1 [Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Jha, Ashish K.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [DesRoches, Catherine M.; Campbell, Eric G.; Donelan, Karen; Rao, Sowmya R.; Ferris, Timothy G.; Shields, Alexandra; Blumenthal, David] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Rosenbaum, Sara] George Washington Univ, Dept Hlth Policy, Washington, DC USA. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu RI Tao, Youyou/D-2367-2014 FU Office of the National Coordinator for Health Information Technology in the Department of Health and Human Services; Robert Wood Johnson Foundation FX Supported by grants from the Office of the National Coordinator for Health Information Technology in the Department of Health and Human Services and the Robert Wood Johnson Foundation. NR 24 TC 574 Z9 581 U1 10 U2 67 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 16 PY 2009 VL 360 IS 16 BP 1628 EP 1638 DI 10.1056/NEJMsa0900592 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 433BH UT WOS:000265178000007 PM 19321858 ER PT J AU Berkowitz, RS Goldstein, DP AF Berkowitz, Ross S. Goldstein, Donald P. TI Molar Pregnancy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GESTATIONAL TROPHOBLASTIC DISEASE; COMPLETE HYDATIDIFORM MOLE; UNDETECTABLE HCG LEVELS; FOLLOW-UP; ORAL-CONTRACEPTIVES; NATURAL-HISTORY; LOW-RISK; DIAGNOSIS; NEOPLASIA; MANAGEMENT AB A healthy 37-year-old woman presents at 10 weeks of pregnancy with vaginal bleeding. Physical examination shows that the uterine size is appropriate for gestational age. The level of serum human chorionic gonadotropin (hCG) is 22,000 mIU per milliliter. Ultrasonography does not show an identifiable fetal heartbeat. After receiving a clinical diagnosis of missed abortion, the patient undergoes evacuation of the uterus; pathological examination indicates a complete molar pregnancy. How should this case be managed? C1 [Berkowitz, Ross S.] Brigham & Womens Hosp, Div Gynecol Oncol, Dept Obstet & Gynecol, Boston, MA 02115 USA. Trophoblast Tumor Registry, New England Trophoblast Dis Ctr, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Berkowitz, RS (reprint author), Brigham & Womens Hosp, Div Gynecol Oncol, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. EM rberkowitz@partners.org NR 56 TC 70 Z9 79 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 16 PY 2009 VL 360 IS 16 BP 1639 EP 1645 DI 10.1056/NEJMcp0900696 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 433BH UT WOS:000265178000008 PM 19369669 ER PT J AU Brass, SD Smith, EE Arboleda-Velasquez, JF Copen, WA Frosch, MP AF Brass, Steven D. Smith, Eric E. Arboleda-Velasquez, Joseph F. Copen, William A. Frosch, Matthew P. TI A Man with Migraine, Aphasia, and Hemiparesis and Similarly Affected Family Members Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SMALL-VESSEL DISEASE; MULTIPLE-SCLEROSIS; NOTCH3 MUTATIONS; DIFFERENTIAL-DIAGNOSIS; HEREDITARY; STROKE; DEMENTIA; SPECTRUM; BINDING; MUSCLE C1 [Brass, Steven D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Copen, William A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Smith, Eric E.] Foothills Prov Gen Hosp, Dept Neurol, Calgary, AB T2N 2T9, Canada. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Brass, Steven D.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Arboleda-Velasquez, Joseph F.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Copen, William A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Brass, SD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 NR 40 TC 9 Z9 9 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 16 PY 2009 VL 360 IS 16 BP 1656 EP 1665 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 433BH UT WOS:000265178000012 PM 19369672 ER PT J AU Spiegel, BMR Farid, M Van Oijen, MGH Laine, L Howden, CW Esrailian, E AF Spiegel, B. M. R. Farid, M. Van Oijen, M. G. H. Laine, L. Howden, C. W. Esrailian, E. TI Adherence to best practice guidelines in dyspepsia: a survey comparing dyspepsia experts, community gastroenterologists and primary-care providers SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID HELICOBACTER-PYLORI INFECTION; PROTON PUMP INHIBITORS; PHYSICIANS PERCEPTIONS; NATIONAL-SURVEY; QUALITY; RISK; MANAGEMENT; DISORDERS; ENDOSCOPY; THERAPY AB Although 'best practice' guidelines for dyspepsia management have been disseminated, it remains unclear whether providers adhere to these guidelines. To compare adherence to 'best practice' guidelines among dyspepsia experts, community gastroenterologists and primary-care providers (PCPs). We administered a vignette survey to elicit knowledge and beliefs about dyspepsia including a set of 16 best practices, to three groups: (i) dyspepsia experts; (ii) community gastroenterologists and (iii) PCPs. The expert, community gastroenterologist and PCP groups endorsed 75%, 73% and 57% of best practices respectively. Gastroenterologists were more likely to adhere with guidelines than PCPs (P < 0.0001). PCPs were more likely to define dyspepsia incorrectly, overuse radiographic testing, delay endoscopy, treat empirically for Helciobacter pylori without confirmatory testing and avoid first-line proton pump inhibitors (PPIs). PCPs had more concerns about adverse events with PPIs [e.g. osteoporosis (P = 0.04), community-acquired pneumonia (P = 0.01)] and higher level of concern predicted lower guideline adherence (P = 0.04). Gastroenterologists are more likely than PCPs to comply with best practices in dyspepsia, although compliance remains incomplete in both groups. PCPs harbour more concerns regarding long-term PPI use and these concerns may affect therapeutic decision making. This suggests that best practices have not been uniformly adopted and persistent guideline-practice disconnects should be addressed. C1 [Spiegel, B. M. R.; Farid, M.; Esrailian, E.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Spiegel, B. M. R.; Farid, M.] VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, Los Angeles, CA USA. [Spiegel, B. M. R.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Spiegel, B. M. R.; Van Oijen, M. G. H.; Esrailian, E.] UCLA VA Ctr Outcomes Res & Educ, Los Angels, CA USA. [Van Oijen, M. G. H.] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands. [Laine, L.] Univ So Calif, Dept Gastroenterol, Keck Sch Med, Los Angels, CA USA. [Howden, C. W.] Northwestern Univ, Div Gastroenterol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Spiegel, BMR (reprint author), 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ulca.edu FU Veteran's Affairs Health Services Research and Development (HSR&D) Career Development Transition Award [RCD 03-179-2]; AstraZeneca; Novartis; Amgen; Procter Gamble; TAP; Takeda; CURE Digestive Disease Research Center [NIH 2P30 DK 041301-17]; Nycomed FX Declaration of personal and funding interests: Dr Spiegel is supported by a Veteran's Affairs Health Services Research and Development (HSR&D) Career Development Transition Award (RCD 03-179-2). Dr Spiegel has served as a consultant to TAP Pharmaceutical Products Inc, Takeda Pharmaceuticals of North America, Novartis, and AstraZeneca. He has received research funding from AstraZeneca, Novartis, Amgen, Procter & Gamble, TAP, Takeda, and AstraZeneca. Drs Esrailian and Spiegel are supported by the CURE Digestive Disease Research Center (NIH 2P30 DK 041301-17). Dr Howden has served as a consultant to TAP Pharmaceutical Products Inc., Takeda Pharmaceuticals of North America, Santarus, Otsuka, Novartis, Biovail, Extera Partners and KV Pharmaceuticals, as a speaker for AstraZeneca, Santarus and Otsuka, and has received research funding from AstraZeneca. Dr Laine has acted as a consultant for AstraZeneca, Eisai, Santarus, Horizon and Pozen, and has received research support from Takeda Pharmaceuticals and GSK. M. G. H. van Oijen is a consultant and has received grant support from AstraZeneca and Nycomed. The authors had complete authority over all aspects of the study, including development of the hypotheses and analysis plan, development of data collection instruments, collection of data, analysis and interpretation of data, and writing of the manuscript. NR 27 TC 15 Z9 15 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD APR 15 PY 2009 VL 29 IS 8 BP 871 EP 881 DI 10.1111/j.1365-2036.2009.03935.x PG 11 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 421QC UT WOS:000264372400009 PM 19183152 ER PT J AU Tung, P Wiviott, SD Cannon, CP Murphy, SA McCabe, CH Gibson, CM AF Tung, Patricia Wiviott, Stephen D. Cannon, Christopher P. Murphy, Sabina A. McCabe, Carolyn H. Gibson, C. Michael TI Seasonal Variation in Lipids in Patients Following Acute Coronary Syndrome on Fixed Doses of Pravastatin (40 mg) or Atorvastatin (80 mg) (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 [PROVE IT-TIMI 22] Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TRIAL PLACEBO GROUP; SERUM-LIPIDS; CHOLESTEROL; STATINS AB Previous studies have shown seasonal variation in lipids. To understand whether this variation exists in patients with acute coronary syndromes receiving statins, we examined data from the PROVE IT-TIMI 22 Study. At baseline, no significant difference in low-density lipoprotein (LDL) cholesterol was observed when stratified by season. However, a statistically significant difference in high-density lipoprotein cholesterol between winter (37 mg/dl) and summer (39 mg/dl) was observed (p <0.001) at baseline. On treatment, median LDL cholesterol was 102 mg/dl in winter versus 96 mg/dl in summer (p <0.001) for the pravastatin group and 68 mg/dl in winter versus 62 mg/dl in summer (p <0.001) for the atorvastatin group. Median high-density lipoprotein cholesterol was 43 mg/dl in summer versus 41 mg/dl in winter in the pravastatin group and 42 mg/dl in summer versus 39 mg/dl in winter in the atorvastatin group (p <0.001). More patients achieved LDL cholesterol <100 mg/dl in summer at 56% versus 47% in winter in the pravastatin group (p <0.001) and 89% versus 87% in winter for the atorvastatin group (p = 0.11). Achievement of LDL cholesterol <70 mg/dl was also higher in summer than winter. In conclusion, this was the first evidence of seasonal variability in cholesterol in patients with acute coronary syndromes treated with statins. This variability affected achievement of National Cholesterol Education Program goals and may affect management decisions based on season of collection. (C) 2009 Elsevier Inc. (Am J Cardiol 2009;103:1056-1060) C1 [Tung, Patricia; Wiviott, Stephen D.; Cannon, Christopher P.; Murphy, Sabina A.; McCabe, Carolyn H.; Gibson, C. Michael] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Tung, Patricia; Wiviott, Stephen D.; Cannon, Christopher P.; Murphy, Sabina A.; McCabe, Carolyn H.; Gibson, C. Michael] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM swiviott@partners.org NR 13 TC 20 Z9 21 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 15 PY 2009 VL 103 IS 8 BP 1056 EP 1060 DI 10.1016/j.amjcard.2008.12.034 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 436RR UT WOS:000265433300003 PM 19361589 ER PT J AU Parashar, S Katz, R Smith, NL Arnold, AM Vaccarino, V Wenger, NK Gottdiener, JS AF Parashar, Susmita Katz, Ronit Smith, Nicholas L. Arnold, Alice M. Vaccarino, Viola Wenger, Nanette K. Gottdiener, John S. TI Race, Gender, and Mortality in Adults >= 65 Years of Age With Incident Heart Failure (from the Cardiovascular Health Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; RACIAL-DIFFERENCES; UNITED-STATES; ELDERLY-PATIENTS; SEX-DIFFERENCES; HOSPITALIZATION; POPULATION; SURVIVAL; OUTCOMES; EPIDEMIOLOGY AB In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults >= 65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15% to 20% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences. (C) 2009 Elsevier Inc. (Am J Cardiol 2009;103:1120-1127) C1 [Parashar, Susmita; Vaccarino, Viola; Wenger, Nanette K.] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. [Katz, Ronit; Smith, Nicholas L.; Arnold, Alice M.] Univ Washington, Dept Epidemiol, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98195 USA. [Smith, Nicholas L.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Gottdiener, John S.] Univ Maryland, Div Cardiol, Baltimore, MD 21201 USA. RP Parashar, S (reprint author), Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. EM susmita.parashar@emory.edu FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-35129, N01-HC45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01 HC15103, N01 HC-55222, U01 HL080295]; National Institute of Neurological Disorders and Stroke. Bethesda, Maryland; American Heart Association, Dallas, Texas [0630084N]; National Center for Research Resources/ National Institutes of Health [1K23RR023171] FX This work was supported by contracts N01-HC-35129, N01-HC45133, N01-HC-75150. N01-HC-85079 through N01-HC-85086, N01 HC15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, with additional contribution from the National Institute of Neurological Disorders and Stroke. Bethesda, Maryland. Dr. Parashar was supported by Scientist Development Award 0630084N from the American Heart Association, Dallas, Texas, and Mentored Clinical Scientist Development Award 1K23RR023171 from the National Center for Research Resources/ National Institutes of Health. NR 30 TC 26 Z9 26 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 15 PY 2009 VL 103 IS 8 BP 1120 EP 1127 DI 10.1016/j.amjcard.2008.12.043 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 436RR UT WOS:000265433300014 PM 19361600 ER PT J AU Blankstein, R Shah, A Pale, R Abbara, S Bezerra, H Bolen, M Mamuya, WS Hoffmann, U Brady, TJ Cury, RC AF Blankstein, Ron Shah, Amar Pale, Rodrigo Abbara, Suhny Bezerra, Hiram Bolen, Michael Mamuya, Wilfred S. Hoffmann, Udo Brady, Thomas J. Cury, Ricardo C. TI Radiation Dose and Image Quality of Prospective Triggering With Dual-Source Cardiac Computed Tomography SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY CT ANGIOGRAPHY AB Prospectively triggered (PT) cardiac computed tomography (CT), whereby radiation is administered only at a predefined phase of the cardiac cycle, has been shown to substantially decrease radiation dose. The aim of our study was to assess the use of this technique in a clinical population using dual-source cardiac CT. Of 312 consecutive patients referred for a dual-source cardiac computed tomographic examination, PT was used in 42 patients for whom, based on physician judgment, it was decided to minimize radiation, whereas retrospective gating was used for 188 patients (coronary artery bypass grafting and pulmonary vein studies were excluded). Kilovolt and milliampere per second were chosen for each patient based on assessment of body habitus and effective radiation dose was calculated. Analysis of nonevaluable vessels was based on clinical readings. For each study, image quality (IQ) was rated on a subjective IQ score and contrast-to-noise and signal-to-noise ratios were calculated. Of the 42 PT examinations (mean age 44.3 years, body mass index 27.8 kg/m(2), 62% men), 28 were referred for coronary evaluation, 11 for aortic disease with/without coronaries, and 3 for other reasons (i.e., suspected mass and congenital disease). Average heart rate was 64.5 beats/min. Average radiation dose of all 42 PT scans was 3.2 +/- 1.6 vs 13.4 +/- 7.8 mSv for the 188 non-PT scans. There was no significant difference in IQ score and contrast-to-noise and signal-to-noise ratios between the 2 groups. Furthermore, the incidence of limited right coronary artery evaluation and of limitations related to right coronary artery motion did not differ between PT and non-PT scans. In conclusion, in selected patients, prospective triggering. with dual-source cardiac CT is feasible and results in a dramatic decrease of radiation dose without compromising IQ. Future advances in cardiac CT may further improve this technique, thus allowing for wider use. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;103:1168-1173) C1 [Blankstein, Ron; Shah, Amar; Pale, Rodrigo; Abbara, Suhny; Bezerra, Hiram; Bolen, Michael; Mamuya, Wilfred S.; Hoffmann, Udo; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Blankstein, Ron; Shah, Amar; Pale, Rodrigo; Abbara, Suhny; Bezerra, Hiram; Bolen, Michael; Mamuya, Wilfred S.; Hoffmann, Udo; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Blankstein, Ron; Shah, Amar; Pale, Rodrigo; Abbara, Suhny; Bezerra, Hiram; Bolen, Michael; Mamuya, Wilfred S.; Hoffmann, Udo; Brady, Thomas J.; Cury, Ricardo C.] Harvard Univ, Sch Med, Boston, MA USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Med & Radiol, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Miami, FL USA. RP Blankstein, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM rblankstein@partners.org FU NHLBI NIH HHS [1T32 HL076136] NR 6 TC 40 Z9 49 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 15 PY 2009 VL 103 IS 8 BP 1168 EP 1173 DI 10.1016/j.amjcard.2008.12.045 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 436RR UT WOS:000265433300023 PM 19361609 ER PT J AU Wilson, KM Mucci, LA Cho, E Hunter, DJ Chen, WY Willett, WC AF Wilson, Kathryn M. Mucci, Lorelei A. Cho, Eunyoung Hunter, David J. Chen, Wendy Y. Willett, Walter C. TI Dietary Acrylamide Intake and Risk of Premenopausal Breast Cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE acrylamide; breast neoplasms; diet ID ONCOGENICITY; EXPOSURE; WOMEN; RATS; FOOD AB Acrylamide, a probable human carcinogen, is formed during high-temperature cooking of many commonly consumed foods. It is widespread; approximately 30% of calories consumed in the United States are from foods containing acrylamide. In animal studies, acrylamide causes mammary tumors, but it is unknown whether the level of acrylamide in foods affects human breast cancer risk. The authors studied the association between acrylamide intake and breast cancer risk among 90,628 premenopausal women in the Nurses' Health Study II. They calculated acrylamide intake from food frequency questionnaires in 1991, 1995, 1999, and 2003. From 1991 through 2005, they documented 1,179 cases of invasive breast cancer. They used Cox proportional hazards models to assess the association between acrylamide and breast cancer risk. The multivariable-adjusted relative risk of premenopausal breast cancer was 0.92 (95% confidence interval: 0.76, 1.11) for the highest versus the lowest quintile of acrylamide intake (P(trend) = 0.61). Results were similar regardless of smoking status or estrogen and progesterone receptor status of the tumors. The authors found no associations between intakes of foods high in acrylamide, including French fries, coffee, cereal, potato chips, potatoes, and baked goods, and breast cancer risk. They found no evidence that acrylamide intake, within the range of US diets, is associated with increased risk of premenopausal breast cancer. C1 [Wilson, Kathryn M.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Wilson, Kathryn M.; Mucci, Lorelei A.; Hunter, David J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wilson, Kathryn M.; Cho, Eunyoung; Hunter, David J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mucci, Lorelei A.; Cho, Eunyoung; Hunter, David J.; Chen, Wendy Y.; Willett, Walter C.] Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Wilson, KM (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave,3rd Floor, Boston, MA 02115 USA. EM kwilson@hsph.harvard.edu FU National Cancer Institute [CA050385]; National Cancer Institute/National Institutes of Health training grant [T32 CA09001] FX This work was supported by a grant from the National Cancer Institute (CA050385) and by a National Cancer Institute/National Institutes of Health training grant (T32 CA09001 to K. M. W.) NR 18 TC 31 Z9 35 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2009 VL 169 IS 8 BP 954 EP 961 DI 10.1093/aje/kwn421 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 425KH UT WOS:000264634900005 PM 19224978 ER PT J AU McCarthy, JF Valenstein, M Kim, HM Ilgen, M Zivin, K Blow, FC AF McCarthy, John F. Valenstein, Marcia Kim, H. Myra Ilgen, Mark Zivin, Kara Blow, Frederic C. TI Suicide Mortality Among Patients Receiving Care in the Veterans Health Administration Health System SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE military medicine; mortality; suicide; veterans ID POSTTRAUMATIC-STRESS-DISORDER; VIETNAM VETERANS; WAR VETERANS; US VETERANS; GULF-WAR; AFFAIRS; RISK; WOMEN; OUTPATIENTS; DEPRESSION AB Understanding and reducing mortality from suicide among veterans is a national priority, particularly for individuals receiving care from the US Veterans Health Administration (VHA). This report examines suicide rates among VHA patients and compares them with rates in the general population. Suicide mortality was assessed in fiscal year 2001 for patients alive at the start of that fiscal year and with VHA use in fiscal years 2000-2001 (n = 4,692,034). Deaths from suicide were identified by using National Death Index data. General population rates were identified by use of the Web-based Injury Statistics Query and Reporting System. VHA rates were 43.13/100,000 person-years for men and 10.41/100,000 person-years for women. For male patients, the age-adjusted standardized mortality ratio was 1.66; for females, it was 1.87. Male patients aged 30-79 years had increased risks relative to men in the general population; standardized mortality ratios ranged from 2.56 (ages 30-39 years) to 1.33 (ages 70-79 years). Female patients aged 40-59 years had greater risks than did women in the general population, with standardized mortality ratios of 2.15 (ages 40-49 years) and 2.36 (ages 50-59 years). Findings offer heretofore unavailable comparison points for health systems. Prior to the conflicts in Afghanistan and Iraq and before recent VHA initiatives, rates were higher among VHA patients than in the general population. Female patients had particularly high relative risks. C1 [McCarthy, John F.; Valenstein, Marcia; Ilgen, Mark; Zivin, Kara; Blow, Frederic C.] Serious Mental Illness Treatment Res & Evaluat Ct, US Dept Vet Affairs, Ann Arbor, MI 48113 USA. [McCarthy, John F.; Valenstein, Marcia; Kim, H. Myra; Ilgen, Mark; Zivin, Kara; Blow, Frederic C.] Ctr Clin Management Res, US Dept Vet Affairs, Ann Arbor, MI USA. [McCarthy, John F.; Valenstein, Marcia; Kim, H. Myra; Ilgen, Mark; Zivin, Kara; Blow, Frederic C.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP McCarthy, JF (reprint author), Serious Mental Illness Treatment Res & Evaluat Ct, US Dept Vet Affairs, POB 13017, Ann Arbor, MI 48113 USA. EM john.mccarthy2@va.gov NR 37 TC 116 Z9 116 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2009 VL 169 IS 8 BP 1033 EP 1038 DI 10.1093/aje/kwp010 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 425KH UT WOS:000264634900014 PM 19251753 ER PT J AU Lott, JP Iwashyna, TJ Christie, JD Asch, DA Kramer, AA Kahn, JM AF Lott, Jason P. Iwashyna, Theodore J. Christie, Jason D. Asch, David A. Kramer, Andrew A. Kahn, Jeremy M. TI Critical Illness Outcomes in Specialty versus General Intensive Care Units SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE critical care; health services; organization; intensive care unit; hospital mortality ID EVALUATION APACHE IV; EMERGENCY-DEPARTMENT; ILL PATIENTS; MECHANICAL VENTILATION; PATIENT OUTCOMES; BURNOUT SYNDROME; ACUTE PHYSIOLOGY; IMPACT; SERVICES; STATES AB Rationale: General intensive care units (ICUs) provide care across a wide range of diagnoses, whereas specialty ICUs provide diagnosis-specific care. Risk-adjusted outcome differences across such units are unknown. Objectives: To determine the association between specialty ICU care and the outcome of critical illness. Methods: We conducted a retrospective cohort study design analyzing patients admitted to 124 ICUs participating in the Acute Physiology and Chronic Health Evaluation IV from January 2002 to December 2005. We examined 84,182 patients admitted to specialty and general ICUs with an admitting diagnosis or procedure of acute coronary syndrome, ischemic stroke, intracranial hemorrhage, pneumonia, abdominal surgery, or coronary-artery bypass graft surgery. ICU type determined by a local data coordinator at each site. Patients were classified by admission to a general ICU, a diagnosis-appropriate ("ideal") specialty ICU, or a diagnosis-inappropriate ("non-ideal") specialty ICU. The primary outcomes were in-hospital mortality and ICU length of stay. Measurements and Main Results: After adjusting for important con-founders, there were no significant differences in risk-adjusted mortality between general versus ideal specialty ICUs for all conditions other than pneumonia. Risk-adjusted mortality was significantly greater for patients admitted to non-ideal specialty ICUs. There was no consistent effect of specialization on length of stay for all patients or for ICU survivors. Conclusions: Ideal specialty ICU care appears to offer no survival benefit over general ICU care for select common diagnoses. Non-ideal specialty ICU care (i.e., "boarding") is associated with increased risk-adjusted mortality. C1 [Christie, Jason D.; Kahn, Jeremy M.] Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. [Christie, Jason D.; Kahn, Jeremy M.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Iwashyna, Theodore J.] Univ Michigan, Sch Med, Div Pulm & Crit Care Med, Ann Arbor, MI USA. [Iwashyna, Theodore J.; Asch, David A.; Kahn, Jeremy M.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. [Kramer, Andrew A.] Cerner Corp, Vienna, VA USA. RP Kahn, JM (reprint author), Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, 723 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM jmkahn@mail.med.upenn.edu OI Kramer, Andrew/0000-0002-5681-5781; Asch, David/0000-0002-7970-286X; Lott, Jason/0000-0002-4097-7225; Iwashyna, Theodore/0000-0002-4226-9310 NR 38 TC 40 Z9 41 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD APR 15 PY 2009 VL 179 IS 8 BP 676 EP 683 DI 10.1164/rccm.200808-1281OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 434BZ UT WOS:000265251500008 PM 19201923 ER PT J AU Collier, DS Kay, J Estey, G Surrao, D Chueh, HC Grant, RW AF Collier, Deborah S. Kay, Jonathan Estey, Greg Surrao, Dominic Chueh, Henry C. Grant, Richard W. TI A Rheumatology-Specific Informatics-Based Application With a Disease Activity Calculator SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID CONTROLLED-TRIAL; ACTIVITY SCORE; ACTIVITY INDEX; ARTHRITIS; VALIDATION; OUTCOMES; STRATEGY AB Objective. To design a rheumatology-specific tool with a disease activity calculator integrated into the electronic medical records (EMRs) at our institution and assess physicians' attitudes toward the use of this tool. Methods. The Rheumatology OnCall (ROC) application culls rheumatology-pertinent data from our institution's laboratory, microbiology, pathology, radiology, and pharmacy information systems. Attending rheumatologists and rheumatology fellows accessed the ROC and disease activity calculator during outpatient visits at the time of the clinical encounter. Results. During the 12-week study period, 15 physicians used the ROC application and the disease activity calculator during 474 and 429 outpatient clinic visits, respectively. In weekly survey responses, physicians reported that use of the ROC interface improved patient care in 140 (78%) of 179 visits, and that the Disease Activity Score in 28 joints (DAS28) results at the time of the visit would not have changed patient management in 157 (88%) of these, although seeing a trend in DAS28 was useful in 149 (96%) of 156 visits. At the study's conclusion, most physicians reported that the ROC application was useful (11 of 12 physicians) and that seeing a trend in DAS28 improved daily patient care (12 of 13 physicians). Conclusion. The ROC application is useful in daily rheumatologic care, and the disease activity calculator facilitates management of patients with rheumatoid arthritis. However, widespread acceptance and use of such tools depend upon the general acceptance of and access to EMRs in the clinical setting. The utility of the disease activity calculator may be limited by the lack of available acute-phase reactant results at the time of the clinical encounter. C1 [Collier, Deborah S.] Massachusetts Gen Hosp, Yawkey Ctr, Boston, MA 02114 USA. [Collier, Deborah S.; Kay, Jonathan; Chueh, Henry C.; Grant, Richard W.] Harvard Univ, Sch Med, Boston, MA USA. RP Collier, DS (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Suite 2C-2100,55 Fruit St, Boston, MA 02114 USA. EM dscollier@partners.org OI Grant, Richard/0000-0002-6164-8025; Kay, Jonathan/0000-0002-8970-4260 FU Centocor; Pfizer FX Dr. Collier's work was supported by an unrestricted educational grant from Centocor. Dr. Kay's work was supported by an unrestricted educational grant from Pfizer. NR 15 TC 9 Z9 10 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2009 VL 61 IS 4 BP 488 EP 494 DI 10.1002/art.24345 PG 7 WC Rheumatology SC Rheumatology GA 431AL UT WOS:000265033600012 PM 19333976 ER PT J AU Collier, DS Grant, RW Estey, G Surrao, D Chueh, HC Kay, J AF Collier, Deborah S. Grant, Richard W. Estey, Greg Surrao, Dominic Chueh, Henry C. Kay, Jonathan TI Physician Ability to Assess Rheumatoid Arthritis Disease Activity Using an Electronic Medical Record-Based Disease Activity Calculator SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID COLLEGE-OF-RHEUMATOLOGY; RANDOMIZED CONTROLLED-TRIAL; ACTIVITY SCORE; CLINICAL-PRACTICE; IMPROVEMENT CRITERIA; ACTIVITY INDEX; JOINT COUNTS; VALIDATION; METHOTREXATE; COMBINATION AB Objective. To assess physicians' concordance with Disease Activity Score in 28 joints (DAS28) categories calculated by an electronic medical record (EMR)-embedded disease activity calculator, as well as attitudes toward this application. Methods. Fifteen rheumatologists used the EMR-embedded disease activity calculator to predict a rheumatoid arthritis (RA) DAS28 disease activity category at the time of each clinical encounter. Results. physician-predicted DAS28 disease activity categories ranged from high (> 5.1, 15% of cohort, 66 of 429 patient visits) to moderate (>3.2-5.1, 21% of cohort, 90 of 429 patient visits) to low (2.6-3.2, 29% of cohort, 123 of 429 patient visits) to remission (<2.6, 35% of cohort, 150 of 429 patient visits). Overall concordance between calculated DAS28 results and physician-predicted RA disease activity was 64%. Using either the physician-predicted or the calculated DAS28 category as the gold standard, accuracy was greatest for patients in remission (75% and 88% accuracy, respectively) and those with high disease activity (68% and 79% accuracy, respectively), and less for patients with moderate (48% and 62% accuracy, respectively) or low disease activity (62% and 31% accuracy, respectively). Conclusion. Accurate physician prediction of DAS28 remission and high disease activity categories, even without immediate availability of the erythrocyte sedimentation rate or the C-reactive protein level at the time of the visit, may be used to guide quantitatively driven outpatient RA management. C1 [Collier, Deborah S.] Massachusetts Gen Hosp, Yawkey Ctr, Boston, MA 02114 USA. [Collier, Deborah S.; Grant, Richard W.; Chueh, Henry C.; Kay, Jonathan] Harvard Univ, Sch Med, Boston, MA USA. RP Collier, DS (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Suite 2C-2100,55 Fruit St, Boston, MA 02114 USA. EM dscollier@partners.org OI Grant, Richard/0000-0002-6164-8025; Kay, Jonathan/0000-0002-8970-4260 FU Centocor; Pfizer FX Dr. Collier's work was supported by an unrestricted educational grant from Centocor. Dr. Kay's work was supported by an unrestricted educational grant from Pfizer. NR 20 TC 8 Z9 8 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2009 VL 61 IS 4 BP 495 EP 500 DI 10.1002/art.24335 PG 6 WC Rheumatology SC Rheumatology GA 431AL UT WOS:000265033600013 PM 19333984 ER PT J AU Taylor, WJ Shewchuk, R Saag, KG Schumacher, HR Singh, JA Grainger, R Edwards, NL Bardin, T Waltrip, RW Simon, LS Burgos-Vargas, R AF Taylor, W. J. Shewchuk, R. Saag, K. G. Schumacher, H. R., Jr. Singh, J. A. Grainger, R. Edwards, N. L. Bardin, T. Waltrip, R. W. Simon, L. S. Burgos-Vargas, R. TI Toward a Valid Definition of Gout Flare: Results of Consensus Exercises Using Delphi Methodology and Cognitive Mapping SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID CONTROLLED-TRIAL; TRIAMCINOLONE ACETONIDE; DOUBLE-BLIND; ARTHRITIS; INDOMETHACIN; ATTACKS; ETORICOXIB; HYPERURICEMIA; EFFICACY; THERAPY AB Objective. To identify, in people known to have gout, the testable, key components of a standard definition of gout flare for use in clinical research. Methods. Consensus methodology was used to identify key elements of a gout flare. Two Delphi exercises were conducted among different groups of rheumatologists. A cognitive mapping technique among 9 gout experts with hierarchical cluster analysis provided a framework to guide the panel discussion, which identified the final set of items that should be tested empirically. Results. From the Delphi exercises, 21 items were presented to the expert panel. Cluster analysis and multidimensional scaling showed that: these items clustered into 5 concepts (joint inflammation, severity of symptoms, stereotypical nature, pain, and gout archetype) distributed along 2 dimensions (objective to subjective features and general features to specific features of gout). Using this analysis, expert panel discussion generated a short list of potential features: joint swelling, joint tenderness, joint warmth, severity of pain, patient global assessment, time to maximum pain, time to complete resolution of pain, an acute-phase marker, and functional impact of the episode. Conclusion. A short list of features has been identified and now requires validation against a patient and physician-defined gout flare in order to determine the best combination of features. C1 [Taylor, W. J.] Univ Otago, Wellington Sch Med & Hlth Sci, Dept Med, Wellington 6242, New Zealand. [Taylor, W. J.; Grainger, R.] Hutt Valley Dist Hlth Board, Wellington Reg Rheumatol Unit, Wellington, New Zealand. [Shewchuk, R.] Univ Alabama, Birmingham, AL USA. [Schumacher, H. R., Jr.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Schumacher, H. R., Jr.] Vet Affairs Med Ctr, Philadelphia, PA USA. [Singh, J. A.] Univ Minnesota, Minneapolis, MN USA. [Singh, J. A.] Minneapolis VA Med Ctr, Minneapolis, MN USA. [Grainger, R.] Malaghan Inst Med Res, Wellington, New Zealand. [Edwards, N. L.] Univ Florida, Gainesville, FL USA. [Bardin, T.] Hop Lariboisiere, F-75475 Paris, France. [Waltrip, R. W.] Savient Pharmaceut, E Brunswick, NJ USA. [Simon, L. S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Burgos-Vargas, R.] Univ Nacl Autonoma Mexico, Hosp Gen Mexico, Mexico City 04510, DF, Mexico. RP Taylor, WJ (reprint author), Univ Otago, Wellington Sch Med & Hlth Sci, Dept Med, POB 7343, Wellington 6242, New Zealand. EM will.taylor@otago.ac.nz RI Grainger, Rebecca/I-1866-2012; OI singh, jasvinder/0000-0003-3485-0006 FU American College of Rheumatology/European League Against Rheumatism; TAP; Savient FX Supported in part by an American College of Rheumatology/European League Against Rheumatism grant. Dr. Singh is recipient of investigator-initiated research grants from TAP and Savient for a different project. NR 25 TC 14 Z9 14 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD APR 15 PY 2009 VL 61 IS 4 BP 535 EP 543 DI 10.1002/art.24166 PG 9 WC Rheumatology SC Rheumatology GA 431AL UT WOS:000265033600018 PM 19333981 ER PT J AU New, AS Hazlett, E aan het Rot, M Liu, X Lazarus, S Goodman, M Zipursky, E Koenigsberg, HW Siever, LJ AF New, Antonia S. Hazlett, Erin aan het Rot, Marije Liu, Xun Lazarus, Sophie Goodman, Marianne Zipursky, Emma Koenigsberg, Harold W. Siever, Larry J. TI The Neuroscience of Alexithymia in Borderline Personality Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [New, Antonia S.; Hazlett, Erin; aan het Rot, Marije; Liu, Xun; Lazarus, Sophie; Goodman, Marianne; Zipursky, Emma; Koenigsberg, Harold W.; Siever, Larry J.] Mt Sinai Sch Med, New York, NY USA. [New, Antonia S.; Goodman, Marianne; Koenigsberg, Harold W.] James J Peters VA Med Ctr, Mental Hlth Care Ctr, Bronx, NY USA. RI Liu, Xun/C-2400-2009 OI Liu, Xun/0000-0003-1366-8926 NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 13 BP 4S EP 4S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200014 ER PT J AU Mathalon, DH Ford, JM Guglielmino, R Roach, BJ Gueorguieva, R Clapp, WC Teyler, TJ Cavus, I AF Mathalon, Daniel H. Ford, Judith M. Guglielmino, Robert Roach, Brian J. Gueorguieva, Ralitza Clapp, Wesley C. Teyler, Timothy J. Cavus, Idil TI Long-Term Potentiation of Visual Evoked Potentials is Impaired in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Mathalon, Daniel H.; Ford, Judith M.; Roach, Brian J.; Gueorguieva, Ralitza] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mathalon, Daniel H.; Ford, Judith M.] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Guglielmino, Robert; Clapp, Wesley C.; Cavus, Idil] Yale Univ, New Haven, CT USA. [Roach, Brian J.] No Calif Inst Res & Educ, San Francisco, CA USA. [Teyler, Timothy J.] Univ Idaho, Moscow, ID 83843 USA. [Teyler, Timothy J.] Washington State Univ, Vcapp, Pullman, WA 99164 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 41 BP 13S EP 13S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200036 ER PT J AU Evans, KC AF Evans, Karleyton C. TI The Cortico-Limbic Neural Response to Air Hunger Shares Temporal Dynamics with Subjective Interoception: A Proof of Concept fMRI Study for Panic Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Evans, Karleyton C.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 101 BP 31S EP 31S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200096 ER PT J AU Wynn, JK Crosby, S Nori, P Green, MF AF Wynn, Jonathan K. Crosby, Shelly Nori, Poorang Green, Michael F. TI Association Between Mismatch Negativity Deficits, Social Cognition and Functional Outcome in Schizoprhenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wynn, Jonathan K.] VA Greater Los Angeles Healthcare Syst, Res & Dev, Los Angeles, CA USA. [Crosby, Shelly; Nori, Poorang; Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RI Wynn, Jonathan/H-3749-2014 OI Wynn, Jonathan/0000-0002-1763-8540 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 176 BP 54S EP 54S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200171 ER PT J AU Yao, J Dougherty, GG Keshavan, MS Montrose, DM Matson, WR McEvoy, J Kaddurah-Daouk, R Condray, R Reddy, RD AF Yao, Jeffrey Dougherty, George G. Keshavan, Matched S. Montrose, Debra M. Matson, Wayne R. McEvoy, Joseph Kaddurah-Daouk, Rima Condray, Ruth Reddy, Ravinder D. TI Homeostatic Imbalance of Purine Catabolism in First-Episode Neuroleptic-Naive Patients with Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Yao, Jeffrey; Dougherty, George G.; Condray, Ruth] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. [Yao, Jeffrey; Dougherty, George G.; Keshavan, Matched S.; Montrose, Debra M.; Condray, Ruth; Reddy, Ravinder D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Keshavan, Matched S.] Wayne State Univ, Dept Psychiat, Detroit, MI USA. [Matson, Wayne R.] Bedford VA Med Ctr, Med Res Serv, Bedford, MA USA. [McEvoy, Joseph; Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 211 BP 65S EP 65S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200205 ER PT J AU Sklar, P Ferreira, MAR Craddock, N Meng, Y Ruderfer, D Fran, J Daly, MJ Holmans, P O'Donovan, M Scolnick, EM Corvin, AP Blackwood, DH Gurling, HM Purcell, SM AF Sklar, Pamela Ferreira, M. A. R. Craddock, N. Meng, Y. Ruderfer, D. Fran, J. Daly, M. J. Holmans, P. O'Donovan, M. Scolnick, E. M. Corvin, A. P. Blackwood, D. H. Gurling, H. M. Purcell, S. M. TI Collaborative Genome-Wide Analysis Supports a Role for ANK3 and CACNA1C in Bipolar Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Sklar, Pamela; Ferreira, M. A. R.; Meng, Y.; Ruderfer, D.; Fran, J.; Daly, M. J.; Purcell, S. M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sklar, Pamela; Ferreira, M. A. R.; Meng, Y.; Ruderfer, D.; Fran, J.; Daly, M. J.; Scolnick, E. M.; Purcell, S. M.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Boston, MA USA. [Craddock, N.; Holmans, P.; O'Donovan, M.] Cardiff Univ, Dept Psychol Med, Cardiff, S Glam, Wales. [Corvin, A. P.] Univ Dublin Trinity Coll, Trinity Ctr Hlth Sci, Dublin 2, Ireland. [Blackwood, D. H.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Gurling, H. M.] Univ Coll London, Dept Mental Hlth Sci, Windeyer Inst Med Sci, Mol Psychiat Lab, Edinburgh, Midlothian, Scotland. RI Gurling, Hugh/A-5029-2010; Holmans, Peter/F-4518-2015; Ruderfer, Douglas/M-5795-2016 OI Holmans, Peter/0000-0003-0870-9412; Ruderfer, Douglas/0000-0002-2365-386X NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 318 BP 95S EP 96S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200306 ER PT J AU Britton, JC Stewart, SE Price, LM Killgore, WDS Jenike, MA Rauch, SL AF Britton, Jennifer C. Stewart, S. Evelyn Price, Lauren M. Killgore, William D. S. Jenike, Michael A. Rauch, Scott L. TI The Neural Correlates of Negative Priming in Pediatric Obsessive Compulsive Disorder. SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Britton, Jennifer C.; Price, Lauren M.; Killgore, William D. S.; Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Stewart, S. Evelyn; Jenike, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Britton, Jennifer/J-4501-2013; Stewart, Evelyn/K-6961-2014 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 344 BP 103S EP 103S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200333 ER PT J AU Koenigsberg, HW AF Koenigsberg, Harold W. TI Neural Network Sensitization and Habituation and Emotional Reactivity in Borderline and Avoidant Personality Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Koenigsberg, Harold W.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Koenigsberg, Harold W.] James J Peters VA Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 347 BP 104S EP 104S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200336 ER PT J AU Hoelzel, BK Carmody, J Evans, KC Hoge, EA Dusek, JA Morgan, L Pitman, RK Lazar, SW AF Hoelzel, Britta K. Carmody, James Evans, Karleyton C. Hoge, Elizabeth A. Dusek, Jeffery A. Morgan, Lucas Pitman, Roger K. Lazar, Sara W. TI Stress Reduction Correlates with Changes in Gray Matter Concentration in the Right Amygdala SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hoelzel, Britta K.; Evans, Karleyton C.; Morgan, Lucas; Pitman, Roger K.; Lazar, Sara W.] Massachusetts Gen Hosp, Charlestown, MA USA. [Carmody, James] Univ Massachusetts, Sch Med, Ctr Mindfulness, Worcester, MA USA. [Hoge, Elizabeth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dusek, Jeffery A.] Abbott NW Hosp, Penny George Inst Hlth & Healing, Minneapolis, MN 55407 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 361 BP 108S EP 108S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200350 ER PT J AU Hezel, DM Jenike, EA Sampaio, A Egan-Stack, D Stewart, SE AF Hezel, Dianne M. Jenike, Eric A. Sampaio, Aline Egan-Stack, Denise Stewart, S. Evelyn TI Gender as a Mediator of Intensive Residential Treatment Response in OCD SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hezel, Dianne M.; Sampaio, Aline; Stewart, S. Evelyn] McLean Hosp, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Egan-Stack, Denise] McLean Hosp, Obsess Compuls Disorder Inst, Belmont, MA 02178 USA. RI Stewart, Evelyn/K-6961-2014 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 396 BP 119S EP 119S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200385 ER PT J AU Sallee, F Spencer, T Connor, D Lopez, F Lyne, A Tremblay, G AF Sallee, Floyd Spencer, Thomas Connor, Daniel Lopez, Frank Lyne, Andrew Tremblay, Gerald TI Effects of Guanfacine Extended Release on Secondary Measures in Children With Attention-Deficit/Hyperactivity Disorder and Oppositional Symptoms SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Sallee, Floyd] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. [Spencer, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin & Res Program Pediat Psychopharmacol, Boston, MA USA. [Connor, Daniel] Univ Connecticut, Sch Med, Farmington, CT USA. [Lopez, Frank] Childrens Dev Ctr, Winter Pk, FL USA. [Lyne, Andrew] Shire Pharmaceut Dev Ltd, Global Biomet, Basingstoke, Hants, England. [Tremblay, Gerald] Shire Dev Inc, Neurosci, Wayne, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 488 BP 149S EP 149S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200477 ER PT J AU Levitt, JJ Alvarado, JL Kubicki, M Nestor, PG McCarley, RW Shenton, ME AF Levitt, James J. Alvarado, Jorge L. Kubicki, Marek Nestor, Paul G. McCarley, Robert W. Shenton, Martha E. TI Decreased Fractional Anisotropy in the Anterior Limb of the Internal Capsule in Schizophrenia and its Cognitive Correlates SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Levitt, James J.; Nestor, Paul G.; McCarley, Robert W.; Shenton, Martha E.] Harvard Univ, Sch Med, VA Boston Hlth Care Syst, Brockton, MA 02401 USA. [Levitt, James J.; Alvarado, Jorge L.; Kubicki, Marek; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Sch Med, Boston, MA 02115 USA. NR 0 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 520 BP 159S EP 160S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200509 ER PT J AU Schwartz, CE Blackford, JU Zald, DH Kalin, N AF Schwartz, Carl E. Blackford, Jennifer Urbano Zald, David H. Kalin, Ned TI Neural Substrates of Developmental Risk for Psychiatric Disorders: Research Methods SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Schwartz, Carl E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Blackford, Jennifer Urbano; Zald, David H.] Vanderbilt Univ, Nashville, TN USA. [Kalin, Ned] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 532 BP 163S EP 163S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200520 ER PT J AU Vinogradov, S Deicken, R Ellman, LM Kern, DM Genevsky, A Poole, JH Kremen, W Schaefer, C Brown, AS AF Vinogradov, Sophia Deicken, Ray Ellman, Lauren M. Kern, David M. Genevsky, Alex Poole, John H. Kremen, William Schaefer, Catherine Brown, Alan S. TI The Interaction of Fetal Hypoxia and Prenatal infection in Schizophrenia: Investigating Effects of Concomitant Obstetric Complications SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Vinogradov, Sophia; Deicken, Ray] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ellman, Lauren M.; Kern, David M.; Brown, Alan S.] Columbia Univ, New York, NY USA. [Genevsky, Alex] San Francisco VA Med Ctr, San Francisco, CA USA. [Poole, John H.] Palo Alto VA, Palo Alto, CA USA. [Kremen, William] Univ Calif San Diego, San Diego, CA 92103 USA. [Kremen, William] Kaiser Permanente, Div Res, Res, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 SU S MA 629 BP 191S EP 192S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200608 ER PT J AU Vinogradov, S Deicken, R Ellman, LM Kern, DM Cook, CL Poole, JH Kremen, W Schaefer, C Brown, AS AF Vinogradov, Sophia Deicken, Ray Ellman, Lauren M. Kern, David M. Cook, Colleen L. Poole, John H. Kremen, William Schaefer, Catherine Brown, Alan S. TI Fetal Hypoxia and Schizophrenia: A Longitudinal Case-Control Study of Cognitive and Brain Volumetric Outcomes SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Vinogradov, Sophia; Deicken, Ray] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ellman, Lauren M.; Kern, David M.; Brown, Alan S.] Columbia Univ, New York, NY USA. [Cook, Colleen L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Poole, John H.] Palo Alto VA, Palo Alto, CA USA. [Kremen, William] Univ Calif San Diego, San Diego, CA 92103 USA. [Schaefer, Catherine] Kaiser Permanente, Div Res, Res, Oakland, CA USA. NR 0 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 SU S MA 628 BP 191S EP 191S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200607 ER PT J AU Levitt, JJ Bobrow, LH Lucia, DM Smith, KM McCarley, RW Shenton, ME AF Levitt, James J. Bobrow, Laurel H. Lucia, Diandra M. Smith, Katherine M. McCarley, Robert W. Shenton, Martha E. TI An MRI Study of Anterior Cingulate Gyrus Subregions in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Levitt, James J.; McCarley, Robert W.; Shenton, Martha E.] Harvard Univ, Sch Med, VA Boston Hlth Care Syst, Brockton, MA 02401 USA. [Levitt, James J.; Bobrow, Laurel H.; Lucia, Diandra M.; Smith, Katherine M.; Shenton, Martha E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Brockton, MA 02401 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 638 BP 194S EP 194S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200616 ER PT J AU Pendergrass, JC Weiss, AR Heckers, S AF Pendergrass, Jo Cara Weiss, Anthony R. Heckers, Stephan TI Abnormal Cortical-Thalamic-Cerebellar Recruitment During Successful Memory Retrieval in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Pendergrass, Jo Cara; Heckers, Stephan] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Weiss, Anthony R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Heckers, Stephan/F-3051-2010 OI Heckers, Stephan/0000-0003-3601-9910 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 640 BP 195S EP 195S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200618 ER PT J AU Melonakos, ED Shenton, M Rathi, Y Bouix, S Kubicki, M AF Melonakos, Eric D. Shenton, Martha Rathi, Yogesh Bouix, Sylvain Kubicki, Marek TI Can Whole Brain Voxel-Based Morphometry Studies Applied to DTI Data Localize White Matter Changes in Schizophrenia? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Melonakos, Eric D.; Shenton, Martha; Rathi, Yogesh; Bouix, Sylvain; Kubicki, Marek] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Shenton, Martha] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Shenton, Martha; Kubicki, Marek] Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 SU S MA 673 BP 204S EP 205S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200649 ER PT J AU Melonakos, ED Shenton, ME Markant, D Alvarado, J Westin, CF Kubicki, M AF Melonakos, Eric D. Shenton, Martha E. Markant, Doug Alvarado, Jorge Westin, Carl-Fredrik Kubicki, Marek TI White Matter Properties of Orbitofrontal Connections in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Melonakos, Eric D.; Shenton, Martha E.; Markant, Doug; Alvarado, Jorge; Kubicki, Marek] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Shenton, Martha E.; Kubicki, Marek] Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 SU S MA 672 BP 204S EP 204S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200648 ER PT J AU Daly, EJ Trivedi, MH Fava, M Shelton, R Wisniewski, SR Morris, DW Stegman, D Preskorn, SH Rush, AJ AF Daly, Ella J. Trivedi, Madhukar H. Fava, Maurizio Shelton, Richard Wisniewski, Stephen R. Morris, David W. Stegman, Diane Preskorn, Sheldon H. Rush, A. J. TI The Relationship Between Adverse Events During SSRI Treatment for MDD and Nonremission - Report from the Suicide Assessment Methodology Study (SAMS) SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Daly, Ella J.; Trivedi, Madhukar H.; Morris, David W.; Stegman, Diane; Rush, A. J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Daly, Ella J.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. [Fava, Maurizio; Shelton, Richard] Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. [Wisniewski, Stephen R.] Vanderbilt Univ, Nashville, TN USA. [Preskorn, Sheldon H.] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Rush, A. J.] Duke Natl Univ Singapore, Singapore, Singapore. RI Preskorn, Sheldon/L-9839-2016 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 715 BP 217S EP 217S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200689 ER PT J AU Nguyen, VT Eskandari, F Duan, ZG Wright, E Cizza, G AF Nguyen, Vi T. Eskandari, Farideh Duan, Zhigang Wright, Elizabeth Cizza, Giovanni TI Premenopausal Women with Major Depressive Disorder (MDD) have Lower 24-hour Adiponectin Levels with Preserved Circadian Rhythm and Higher ACTH vs. Cortisol Correlation: Implications for Greater Metabolic and Cardiovascular Risk SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Nguyen, Vi T.; Cizza, Giovanni] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. [Nguyen, Vi T.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Eskandari, Farideh] NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. [Duan, Zhigang; Wright, Elizabeth] NIDDK, Off Director, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 753 BP 230S EP 230S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200727 ER PT J AU Perlis, RH Houston, JR Adams, DH Heinloth, AN Fijal, B AF Perlis, Roy H. Houston, John R. Adams, David H. Heinloth, Alexandra N. Fijal, Bonnie TI Failure To Replicate Prior Genetic Associations Of SNPs in Candidate Genes With Antidepressant Treatment Response in Patients Treated With Duloxetine SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Houston, John R.; Adams, David H.; Fijal, Bonnie] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Heinloth, Alexandra N.] I3Statprobe, UnitedHlth Grp, Ann Arbor, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 754 BP 230S EP 230S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200728 ER PT J AU Crabbe, JC Metten, P Rhodes, JS Yu, CH Brown, LL Phillips, TJ Finn, DA AF Crabbe, John C. Metten, Pamela Rhodes, Justin S. Yu, Chia-Hua Brown, Lauren Lyon Phillips, Tamara J. Finn, Deborah A. TI A Line of Mice Selected for High Blood Ethanol Concentrations Shows Drinking in the Dark to Intoxication SO BIOLOGICAL PSYCHIATRY LA English DT Article DE DID; ethanol consumption; genetic animal models; HDID; intoxication; mouse; pharmacogenetics; selective breeding ID VOLUNTARY ALCOHOL-CONSUMPTION; C57BL/6J MICE; STRAIN DIFFERENCES; SCHEDULED ACCESS; LATERAL SEPTUM; ANIMAL-MODELS; GENETICS; RAT; SUSCEPTIBILITY; PERCEPTION AB Background: Many animal models of alcoholism have targeted aspects of excessive alcohol intake (abuse) and dependence. In the rodent, models aimed at increasing alcohol self-ad ministration have used genetic or environmental manipulations, or their combination. Strictly genetic manipulations (e.g., comparison of inbred strains or targeted mutants, selective breeding) have not yielded rat or mouse genotypes that will regularly and voluntarily drink alcohol to the point of intoxication. Although some behavioral manipulations (e.g., scheduling or limiting access to alcohol, adding a sweetener)will induce mice or rats to drink enough alcohol to become intoxicated, these typically require significant food or water restriction or a long time to develop. We report progress toward the development of a new genetic animal model for high levels of alcohol drinking. Methods: High Drinking in the Dark (HDID-1) mice have been selectively bred for high blood ethanol concentrations (BEC, ideally exceeding 100 mg%) resulting from the ingestion of a 20% alcohol solution. Results: After 11 generations of selection, more than 56% of the population now exceeds this BEC after a 4-hour drinking session in which a single bottle containing 20% ethanol is available. The dose of ethanol consumed also produced quantifiable signs of intoxication. Conclusions: These mice will be useful for mechanistic studies of the biological and genetic contributions to excessive drinking. C1 [Crabbe, John C.; Metten, Pamela; Yu, Chia-Hua; Brown, Lauren Lyon; Phillips, Tamara J.; Finn, Deborah A.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland Alcohol Res Ctr, Portland, OR 97201 USA. [Crabbe, John C.; Metten, Pamela; Yu, Chia-Hua; Brown, Lauren Lyon; Phillips, Tamara J.; Finn, Deborah A.] VA Med Ctr, Portland, OR USA. [Rhodes, Justin S.] Univ Illinois, Beckman Inst, Dept Psychol, Urbana, IL USA. RP Crabbe, JC (reprint author), Portland VA Med Ctr, R&D 12,3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM crabbe@ohsu.edu FU National Institutes of Health and by the Department of Veterans Affairs [AA010760, AA013478, AA013519] FX These studies were conducted as part of the Integrative Neuroscience Initiative on Alcoholism of the National Institute on Alcohol Abuse and Alcoholism and were supported by Grant Nos. AA010760, AA013478, and AA013519 from the National Institutes of Health and by the Department of Veterans Affairs. We thank Andy Jade Cameron, Alex Henry, Katie Mordarski, Jason Schlumbohm, Michelle Sorensen, and Stephanie Spence for expert technical assistance. NR 36 TC 70 Z9 70 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 BP 662 EP 670 DI 10.1016/j.biopsych.2008.11.002 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 428OG UT WOS:000264857400005 PM 19095222 ER PT J AU Sos, ML Koker, M Weir, BA Heynck, S Rabinovsky, R Zander, T Seeger, JM Weiss, J Fischer, F Frommolt, P Michel, K Peifer, M Mermel, C Girard, L Peyton, M Gazdar, AF Minna, JD Garraway, LA Kashkar, H Pao, W Meyerson, M Thomas, RK AF Sos, Martin L. Koker, Miriam Weir, Barbara A. Heynck, Stefanie Rabinovsky, Rosalia Zander, Thomas Seeger, Jens M. Weiss, Jonathan Fischer, Florian Frommolt, Peter Michel, Kathrin Peifer, Martin Mermel, Craig Girard, Luc Peyton, Michael Gazdar, Adi F. Minna, John D. Garraway, Levi A. Kashkar, Hamid Pao, William Meyerson, Matthew Thomas, Roman K. TI PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR SO CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; ADENOCARCINOMA; SENSITIVITY; MUTATIONS; SURVIVAL; PATHWAY; EXPRESSION; GEFITINIB; CELLS AB Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in I out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. [Cancer Res 2009;69(8):3256-61] C1 [Thomas, Roman K.] Max Planck Soc, Chem Genom Ctr, Dortmund, Germany. [Pao, William] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med & Pharmacol, Dallas, TX 75390 USA. [Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Girard, Luc; Peyton, Michael; Gazdar, Adi F.; Minna, John D.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Garraway, Levi A.; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Rabinovsky, Rosalia; Mermel, Craig; Garraway, Levi A.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Weir, Barbara A.; Mermel, Craig; Garraway, Levi A.; Meyerson, Matthew] Broad Inst Harvard, Cambridge, MA USA. [Weir, Barbara A.; Mermel, Craig; Garraway, Levi A.; Meyerson, Matthew] MIT, Cambridge, MA 02139 USA. [Frommolt, Peter] Inst Med Stat Informat & Epidemiol, Cologne, Germany. [Seeger, Jens M.; Kashkar, Hamid] Inst Med Microbiol Immunol & Hyg, Cologne, Germany. [Sos, Martin L.; Koker, Miriam; Heynck, Stefanie; Weiss, Jonathan; Fischer, Florian; Michel, Kathrin; Peifer, Martin; Thomas, Roman K.] Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany. [Sos, Martin L.; Koker, Miriam; Heynck, Stefanie; Weiss, Jonathan; Fischer, Florian; Michel, Kathrin; Peifer, Martin; Thomas, Roman K.] Univ Cologne, Fac Med, Cologne, Germany. [Zander, Thomas; Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol, Cologne, Germany. [Zander, Thomas; Thomas, Roman K.] Univ Cologne, Dept Internal Med 1, Cologne, Germany. RP Thomas, RK (reprint author), Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, Gleueler Str 50, D-50931 Cologne, Germany. EM nini@nf.mpg.de RI Peyton, Michael/A-8728-2008; Meyerson, Matthew/E-7123-2012; Frommolt, Peter/L-9656-2016 OI Frommolt, Peter/0000-0002-1966-8014 FU International Association for the Study of Lung Cancer; Deutsche Krebshilfe [107954]; Fritz-Thyssen-Stiftung [10.08.2.175]; NGFN-Plus Program of the German Ministry of Science and Education [01GS08100]; Specialized Programs of Research Excellence [P50CA70907]; DOD PROSPECT; Longenbaugh Foundation FX R.K. Thomas is a fellow of the International Association for the Study of Lung Cancer: and is supported by the Deutsche Krebshilfe (107954), the Fritz-Thyssen-Stiftung (10.08.2.175), and the NGFN-Plus Program of the German Ministry of Science and Education (BMBF, 01GS08100). J.D. Minna is supported by grants from the Specialized Programs of Research Excellence P50CA70907, DOD PROSPECT, and the Longenbaugh Foundation. NR 21 TC 233 Z9 254 U1 3 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2009 VL 69 IS 8 BP 3256 EP 3261 DI 10.1158/0008-5472.CAN-08-4055 PG 6 WC Oncology SC Oncology GA 435AF UT WOS:000265314900004 PM 19351834 ER PT J AU Sun, T Wang, QB Balk, S Brown, M Lee, GSM Kantoff, P AF Sun, Tong Wang, Qianben Balk, Steven Brown, Myles Lee, Gwo-Shu Mary Kantoff, Philip TI The Role of microRNA-221 and microRNA-222 in Androgen-Independent Prostate Cancer Cell Lines SO CANCER RESEARCH LA English DT Article ID LUNG-CANCER; EXPRESSION; CARCINOMA; RECEPTOR; GROWTH; PROLIFERATION; PROGRESSION; P27(KIP1); MIR-221; SIGNATURES AB Androgen-dependent prostate cancer typically progresses to castration-resistant prostate cancer (CRPC) after the androgen deprivation therapy. MicroRNAs (mill) are noncoding small RNAs (19-25nt) that play an important role in the regulation of gene expression. Recent studies have shown that mill expression patterns are significantly different in normal and neoplastic prostate epithelial cells. However, the importance of mills in the development of CRPC has not yet been explored. By performing genome-wide expression profiling of mills, we found that expression levels of several mills, in particular miR-221 and miR-222, were significantly increased, in CRPC cells (the LNCaP-derived cell line LNCaP-Abl) compared with those in the androgen-dependent prostate cancer cell line (LNCaP). Overexpression of miR-221 or miR-222 in LNCaP or another androgen-dependent cell line, LAPC-4, significantly reduced the level of the dihydrotestosterone (DHT) induced up-regulation of prostate-specific antigen (PSA) expression and increased androgen-independent growth of LNCaP cells. Knocking down the expression level of miR-221 and miR-222 with antagonist mills in the LNCaP-Abl cell line restored the response to the DHT induction of PSA transcription and also increased the growth response of the LNCaP-Abl cells to the androgen treatment. Changing the expression level of p27/kip1, a known target of miR-221 and miR-222, alone in LNCaP cells affected the DHT-independent cell growth but did not significantly influence the response of PSA transcription to the DHT treatment. In conclusion, our data suggest the involvement of miR-221 and miR-222 in the development or maintenance of the CRPC phenotype. [Cancer Res 2009;69(8):3356-63] C1 [Sun, Tong; Wang, Qianben; Brown, Myles; Lee, Gwo-Shu Mary; Kantoff, Philip] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sun, Tong; Wang, Qianben; Balk, Steven; Brown, Myles; Lee, Gwo-Shu Mary; Kantoff, Philip] Harvard Univ, Sch Med, Boston, MA USA. [Balk, Steven] Beth Israel Deaconess Med Ctr, Dept Med, Canc Biol Program, Boston, MA 02215 USA. RP Lee, GSM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, D710B,44 Binney St, Boston, MA 02115 USA. EM gwo-shu_lee@dfci.harvard.edu RI Wang, Qianben/E-4267-2011; OI Brown, Myles/0000-0002-8213-1658 FU NCI NIH HHS [2 P50 CA090381-06, P50 CA090381-06, P50 CA090381] NR 35 TC 145 Z9 157 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2009 VL 69 IS 8 BP 3356 EP 3363 DI 10.1158/0008-5472.CAN-08-4112 PG 8 WC Oncology SC Oncology GA 435AF UT WOS:000265314900018 PM 19351832 ER PT J AU Ohashi, E Kogai, T Kagechika, H Brent, GA AF Ohashi, Emi Kogai, Takahiko Kagechika, Hiroyuki Brent, Gregory A. TI Activation of the PI3 Kinase Pathway By Retinoic Acid Mediates Sodium/Iodide Symporter Induction and Iodide Transport in MCF-7 Breast Cancer Cells SO CANCER RESEARCH LA English DT Article ID RADIOIODIDE UPTAKE; NONGENOMIC ACTIONS; SIGNALING PATHWAY; ESTROGEN-RECEPTOR; GENE-EXPRESSION; PROTEIN; NUCLEAR; DIFFERENTIATION; 3-KINASE; TARGET AB Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (NIS). NIS activation is used for radioiodide imaging and therapeutic ablation of thyroid carcinoma. NIS is expressed in >70% of breast cancers but at a level insufficient for radioiodine treatment. All-traps retinoic acid (tRA) induces NIS gene expression and functional iodide uptake in human breast cancer cell lines and mouse breast cancer models. tRA usually regulates gene expression by direct interaction of RA receptor (RAR) with a target gene, but it can also act through nongenomic pathways. We report a direct influence of tRA treatment on the phosphoinositide 3-kinase (PI3K) signal transduction pathway that mediates tRA-induced NIS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, alpha, beta, and gamma, and RXR alpha. We previously identified RAR beta and RXR alpha as important for NIS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85 alpha knockdown with siRNA abolished tRA-induced NIS expression. Immunoprecipitation experiments and glutathione S-transferase pull-down assay showed a direct interaction between RAR beta 2, RXR alpha, and p85 alpha. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt knockdown with siRNA reduced NIS expression. These findings indicate that RA induction of NIS in MCF-7 cells is mediated, by rapid activation of the PI3K pathway and involves direct interaction with RAR and retinoid X receptor. Defining these mechanisms should lead to methods to further enhance NIS expression, as well as retinoid targets that influence growth and differentiation of breast cancer. [Cancer Res 2009;69(8):3443-50] C1 [Ohashi, Emi; Kogai, Takahiko; Brent, Gregory A.] Univ Calif Los Angeles, Mol Endocrinol Lab, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med,Dept Med, Los Angeles, CA 90073 USA. [Ohashi, Emi; Kogai, Takahiko; Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. [Kagechika, Hiroyuki] Tokyo Med & Dent Univ, Sch Biomed Sci, Chiyoda Ku, Tokyo, Japan. RP Brent, GA (reprint author), Univ Calif Los Angeles, Mol Endocrinol Lab, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med,Dept Med, Bldg 114,Room 230,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM gbrent@ucla.edu FU NIH [RO1 CA089364] FX Grant support: NIH RO1 CA089364 (GA Brent). NR 37 TC 32 Z9 34 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2009 VL 69 IS 8 BP 3443 EP 3450 DI 10.1158/0008-5472.CAN-08-3234 PG 8 WC Oncology SC Oncology GA 435AF UT WOS:000265314900028 PM 19351850 ER PT J AU Wakimoto, H Kesari, S Farrell, CJ Curry, WT Zaupa, C Aghi, M Kuroda, T Stemmer-Rachamimov, A Shah, K Liu, TC Jeyaretna, DS Debasitis, J Pruszak, J Martuza, RL Rabkin, SD AF Wakimoto, Hiroaki Kesari, Santosh Farrell, Christopher J. Curry, William T., Jr. Zaupa, Cecile Aghi, Manish Kuroda, Toshihiko Stemmer-Rachamimov, Anat Shah, Khalid Liu, Ta-Chiang Jeyaretna, Deva S. Debasitis, Jason Pruszak, Jan Martuza, Robert L. Rabkin, Samuel D. TI Human Glioblastoma-Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors SO CANCER RESEARCH LA English DT Article ID MALIGNANT GLIOMA; DOPAMINERGIC-NEURONS; NEURAL PRECURSORS; EXPRESSION; TUMORS; GROWTH; THERAPY; VIROTHERAPY; IDENTIFICATION; ANGIOGENESIS AB Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem-like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)-deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of gamma 34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of alpha 47. Infection with oHSV G47 Delta (ICP6(-), gamma 34.5(-), alpha 47(-)) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of 6470 significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis. [Cancer Res 2009;69(8):3472-81] C1 [Wakimoto, Hiroaki; Farrell, Christopher J.; Curry, William T., Jr.; Zaupa, Cecile; Aghi, Manish; Kuroda, Toshihiko; Liu, Ta-Chiang; Jeyaretna, Deva S.; Debasitis, Jason; Martuza, Robert L.; Rabkin, Samuel D.] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Mol Neurosurg Lab, Dept Neurosurg, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shah, Khalid] Massachusetts Gen Hosp, Mol Neurotherapy & Imaging Lab, Ctr Mol Imaging Res, Dept Radiol,Dept Neurol, Boston, MA 02114 USA. [Kesari, Santosh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol & Med Oncol,Dept Neurol,Brigham &, Boston, MA 02115 USA. [Pruszak, Jan] Harvard Univ, McLean Hosp, Sch Med, Ctr Neurogenerat Res, Belmont, MA 02178 USA. RP Wakimoto, H (reprint author), Massachusetts Gen Hosp, Brain Tumor Res Ctr, Mol Neurosurg Lab, Dept Neurosurg, CPZN-3800,185 Cambridge St, Boston, MA 02114 USA. EM hwakimoto@partners.org RI rabkin, samuel/C-2443-2012; Kesari, Santosh/E-8461-2013; Pruszak, Jan/G-6972-2015; OI rabkin, samuel/0000-0003-2344-2795; Pruszak, Jan/0000-0003-4297-4009; Kuroda, Toshihiko/0000-0001-6660-8930 FU NIH [NS-032677, K08 CA124804]; Department of Defense [W81XWH-07-1-0359]; Sontag Foundation Distinguished Scientist Grant FX NIH grant NS-032677 (R.L. Martuza), Department of Defense grant W81XWH-07-1-0359 (S.D. Rabkin), and NIH grant K08 CA124804 and a Sontag Foundation Distinguished Scientist Grant (S. Kesari). NR 50 TC 138 Z9 143 U1 4 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2009 VL 69 IS 8 BP 3472 EP 3481 DI 10.1158/0008-5472.CAN-08-3886 PG 10 WC Oncology SC Oncology GA 435AF UT WOS:000265314900032 PM 19351838 ER PT J AU Braggio, E Keats, JJ Leleu, X Van Wier, S Jimenez-Zepeda, VH Valdez, R Schop, RFJ Price-Troska, T Henderson, K Sacco, A Azab, F Greipp, P Gertz, M Hayman, S Rajkumar, SV Carpten, J Chesi, M Barrett, M Stewart, AK Dogan, A Bergsagel, L Ghobrial, IM Fonseca, R AF Braggio, Esteban Keats, Jonathan J. Leleu, Xavier Van Wier, Scott Jimenez-Zepeda, Victor H. Valdez, Riccardo Schop, Roelandt F. J. Price-Troska, Tammy Henderson, Kimberly Sacco, Antonio Azab, Feda Greipp, Philip Gertz, Morie Hayman, Suzanne Rajkumar, S. Vincent Carpten, John Chesi, Marta Barrett, Michael Stewart, A. Keith Dogan, Ahmet Bergsagel, Leif Ghobrial, Irene M. Fonseca, Rafael TI Identification of Copy Number Abnormalities and Inactivating Mutations in Two Negative Regulators of Nuclear Factor-kappa B Signaling Pathways in Waldenstrom's Macroglobulinemia SO CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; RECEPTOR-ASSOCIATED FACTOR-3; MULTIPLE-MYELOMA; CELL LYMPHOMA; CHROMOSOMAL TRANSLOCATION; MALT LYMPHOMA; 6Q DELETIONS; TARGET GENES; ACTIVATION; BORTEZOMIB AB Waldenstrom's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 61) was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor-associated factor 3 and TNF alpha-induced protein 3, two negative regulators of the nuclear factor-kappa B (NF-kappa B) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kappa B target genes. Mutational activation of the NF-kappa B pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-kappa B pathway activation in the treatment of WM. [Cancer Res 2009;69(8):3579-88] C1 [Braggio, Esteban; Keats, Jonathan J.; Van Wier, Scott; Jimenez-Zepeda, Victor H.; Valdez, Riccardo; Schop, Roelandt F. J.; Chesi, Marta; Stewart, A. Keith; Bergsagel, Leif; Fonseca, Rafael] Mayo Clin, Ctr Canc, Scottsdale, AZ 85259 USA. [Leleu, Xavier; Sacco, Antonio; Azab, Feda; Ghobrial, Irene M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Price-Troska, Tammy; Henderson, Kimberly; Greipp, Philip; Gertz, Morie; Hayman, Suzanne; Rajkumar, S. Vincent; Dogan, Ahmet] Mayo Clin, Rochester, MI USA. [Carpten, John; Barrett, Michael] Translat Genom, Phoenix, AZ USA. RP Fonseca, R (reprint author), Mayo Clin, Ctr Canc, 13400 E Shea Blvd,Collaborat Res Bldg 3-006, Scottsdale, AZ 85259 USA. EM fonseca.rafael@mayo.edu RI Bergsagel, Peter/A-7842-2011; Sacco, Antonio/K-4681-2016 OI Bergsagel, Peter/0000-0003-1523-7388; Fonseca, Rafael/0000-0002-5938-3769; Sacco, Antonio/0000-0003-2945-9416 FU IWMF 2S; MMRF Fellowship; Mary-Lou Kurtz Fellowship [R01-AG020686, CA83724-01, SPORE P50-CA100707-01]; National Cancer Institute [P01-CA62242]; Donaldson Charitable Trust Fund; International Waldenstrom Macroglobulinemia Foundation; Damon Runyon Cancer Research Fund FX IWMF 2S grant (E. Braggio). MMRF Fellowship and Gene and Mary-Lou Kurtz Fellowship (J.J. Keats), grants R01-AG020686 and SPORE P50-CA100707-01 (P.L. Bergsagel), grant R01-CA83724-01, SPORE P50-CA100707-01 and P01-CA62242 from the National Cancer Institute, and the Donaldson Charitable Trust Fund (R. Fonseca), and the International Waldenstrom Macroglobulinemia Foundation. R. Fonseca is a clinical investigator of the Damon Runyon Cancer Research Fund. NR 49 TC 68 Z9 70 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 15 PY 2009 VL 69 IS 8 BP 3579 EP 3588 DI 10.1158/0008-5472.CAN-08-3701 PG 10 WC Oncology SC Oncology GA 435AF UT WOS:000265314900044 PM 19351844 ER PT J AU Sakamoto, KM Frank, DA AF Sakamoto, Kathleen M. Frank, David A. TI CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; ELEMENT-BINDING-PROTEIN; CHRONIC MYELOID-LEUKEMIA; MULTIPLE SIGNALING PATHWAYS; GRANULOCYTE-MACROPHAGE; FACTOR-RECEPTOR; POLYCYTHEMIA-VERA; LUNG-CANCER; CELL-LINE; PROGENITOR CELLS AB Transcription factors are key regulators of the pattern of gene expression in a cell and directly control central processes such as proliferation, survival, self-renewal, and invasion. Given this critical role, the function of transcription factors is normally regulated closely, often through transient phosphorylation. Although transcription factors are not often directly modified by mutations in cancer cells, they frequently become activated constitutively through mutations affecting "upstream" pathways. By continually driving the expression of key target genes, these oncogenic transcription factors play a central role in tumor pathogenesis. One such transcription factor is the cAMP-regulatory element-binding protein (CREB), which can be activated through phosphorylation by a number of kinases, including Akt, p90Rsk, protein kinase A, and calcium/calmodulin-dependent kinases and regulates genes whose deregulated expression promotes oncogenesis, including cyclins, Bcl-2 family members, and Egr-1. CREB is overexpressed and constitutively phosphorylated in a number of forms of human cancer, including acute myeloid leukemia (AML) and non-small cell lung cancer, and appears to play a direct role in disease pathogenesis and prognosis. Although transcription factors have not been a central focus of drug development, recent advances suggest that CREB and other such proteins may be worthwhile targets for cancer therapy. C1 [Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sakamoto, Kathleen M.] Univ Calif Los Angeles, Mattel Childrens Hosp, Jonsson Comprehens Canc Ctr, Gwynne Hazen Cherry Mem Labs,Div Hematol Oncol, Los Angeles, CA USA. [Sakamoto, Kathleen M.] David Geffen Sch Med, Dept Pathol & Lab Med, Brooklyn, NY USA. [Sakamoto, Kathleen M.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Sakamoto, Kathleen M.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Frank, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Frank, David A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Mayer 522B, Boston, MA 02115 USA. EM david_frank@dfci.harvard.edu FU National Institutes of Health [HL75826, HL83077]; American Cancer Society [RSG-99-081-01-LIB]; Department of Defense [CM050077]; Leukemia and Lymphoma Society Translational Research [6019-07] FX Grant support: National Institutes of Health grants HL75826 and HL83077, American Cancer Society grant RSG-99-081-01-LIB, the Department of Defense (CM050077), and the Leukemia and Lymphoma Society Translational Research Grant 6019-07 (K.M. Sakamoto). NR 46 TC 107 Z9 111 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2009 VL 15 IS 8 BP 2583 EP 2587 DI 10.1158/1078-0432.CCR-08-1137 PG 5 WC Oncology SC Oncology GA 435AC UT WOS:000265314600002 PM 19351775 ER PT J AU Kuang, Y Rogers, A Yeap, BY Wang, L Makrigiorgos, M Vetrand, K Thiede, S Distel, RJ Janne, PA AF Kuang, Yanan Rogers, Andrew Yeap, Beow Y. Wang, Lilin Makrigiorgos, Mike Vetrand, Kristi Thiede, Sara Distel, Robert J. Jaenne, Pasi A. TI Noninvasive Detection of EGFR T790M in Gefitinib or Erlotinib Resistant Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; CHEMOTHERAPY-NAIVE PATIENTS; PROSPECTIVE PHASE-II; ACQUIRED-RESISTANCE; CIRCULATING DNA; GENE-MUTATIONS; AMPLIFICATION; PLASMA; TRIAL; PREDICTOR AB Purpose: Tumors from 50% of epidermal growth factor receptor (EGFR) mutant non - small cell lung cancer patients that develop resistance to gefitinib or erlotinib will contain a secondary EGFR T790M mutation. As most patients do not undergo repeated tumor biopsies we evaluated whether EGFR T790M could be detected using plasma DNA. Experimental Design: DNA from plasma of 54 patients with known clinical response to gefitinib or erlotinib was extracted and used to detect both EGFR-activating and EGFR T790M mutations. Forty-three (80%) of patients had tumor EGFR sequencing (EGFR mutant/wild type: 30/13) and seven patients also had EGFR T790M gefitinib/erlotinib-resistant tumors. EGFR mutations were detected using two methods, the Scorpion Amplification Refractory Mutation System and the WAVE/Surveyor, combined with whole genome amplification. Results: Both EGFR-activating and EGFR T790M were identified in 70% of patients with known tumor EGFR-activating (21 of 30) or T790M (5 of 7) mutations. EGFR T790M was identified from plasma DNA in 54% (15 of 28) of patients with prior clinical response to gefitinib/erlotinib, 29% (4 of 14) with prior stable disease, and in 0% (0 of 12) that had primary progressive disease or were untreated with gefitinib/erlotinib. Conclusions: EGFR T790M can be detected using plasma DNA from gefitinib- or erlotinib-resistant patients. This noninvasive method may aid in monitoring drug resistance and in directing the course of subsequent therapy. C1 [Vetrand, Kristi; Thiede, Sara; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Kuang, Yanan; Rogers, Andrew; Distel, Robert J.; Jaenne, Pasi A.] Dana Farber Canc Inst, Ctr Clin & Translat Res, Translat Res Lab, Boston, MA 02115 USA. [Wang, Lilin] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Vetrand, Kristi; Thiede, Sara; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Yeap, Beow Y.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D820,44 Binney St, Boston, MA 02115 USA. EM pjanne@partners.org FU NIH [RO1CA114465-03]; National Cancer Institute Lung SPORE [P50CA090578]; Hazel and Samuel Bellin research fund; Department of Defense [W81 XOSH06-1-0303] FX NIH RO1CA114465-03 (P.A. Janne, B.Y. Yeap), National Cancer Institute Lung SPORE P50CA090578 (P.A. Janne, BY Yeap), the Hazel and Samuel Bellin research fund (P.A. Janne), and Department of Defense W81 XOSH06-1-0303 (P.A. Janne). NR 26 TC 123 Z9 127 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2009 VL 15 IS 8 BP 2630 EP 2636 DI 10.1158/1078-0432.CCR-08-2592 PG 7 WC Oncology SC Oncology GA 435AC UT WOS:000265314600008 PM 19351754 ER PT J AU Lun, XQ Jang, JH Tang, N Deng, H Head, R Bell, JC Stojdl, DF Nutt, CL Senger, DL Forsyth, PA McCart, JA AF Lun, Xue Qing Jang, Ji-Hyun Tang, Nan Deng, Helen Head, Renee Bell, John C. Stojdl, David F. Nutt, Catherine L. Senger, Donna L. Forsyth, Peter A. McCart, J. Andrea TI Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-I TRIAL; BLOOD-BRAIN-BARRIER; REGULATORY T-CELLS; MYXOMA-VIRUS; ANTITUMOR-ACTIVITY; TUMOR; PATHWAY; CANCER; MUTANT; GLIOBLASTOMA AB Purpose: The oncolytic effects of a systemically delivered, replicating, double-deleted vaccinia virus has been previously shown for the treatment of many cancers, including colon, ovarian, and others. The purpose of this study was to investigate the oncolytic potential of double-deleted vaccinia virus alone or in combination with rapamycin or cyclophosphamide to treat malignant gliomas in vitro and in vivo. Experimental Design: Rat (RG2, F98, C6) and human (A172, U87MG, U118) glioma cell lines were cultured in vitro and treated with live or UV-inactivated vaccinia virus. Viral gene [enhanced green fluorescent protein (EGFP)] expression by fluorescence-activated cell sorting, relative cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and assays for cytopathic effects were examined. S.c. murine tumor xenografts (U87MG, U118, C6) and i.c. (RG2, F98) tumor models in immunocompetent rats were treated with systemic administration of EGFP-expressing vaccinia virus (vvDD-EGFP), alone or in combination with rapamycin or cyclophosphamide, or controls. Tumor size, viral biodistribution, and animal survival were assessed. Lastly, the oncolytic effects of vvDD-EGFP on human malignant glioma explants were evaluated. Results: vvDD-EGFP was able to infect and kill glioma cells in vitro. A single systemic dose of vvDD-EGFP significantly inhibited the growth of xenografts in athymic mice. Systemic delivery of vvDD-EGFP alone was able to target solitary and multifocal i.c. tumors and prolong survival of immunocompetent rats, whereas combination therapy with rapamycin or cyclophosphamide enhanced viral replication and further prolonged survival. Finally, vvDD-EGFP was able to infect and kill ex vivo primary human malignant gliomas. Conclusions: These results suggest that vvDD-EGFP is a promising novel agent for human malignant glioma therapy, and in combination with immunosuppressive agents, may lead to prolonged survival from this disease. C1 [Jang, Ji-Hyun; Tang, Nan; Deng, Helen; Head, Renee; McCart, J. Andrea] Toronto Gen Res Inst, Div Expt Therapeut, Toronto, ON, Canada. [Lun, Xue Qing; Senger, Donna L.; Forsyth, Peter A.] Univ Calgary, Clark H Smith Brain Tumor Ctr, Calgary, AB T2N 1N4, Canada. [Lun, Xue Qing; Senger, Donna L.; Forsyth, Peter A.] Univ Calgary, Tom Baker Canc Ctr, Dept Oncol, Calgary, AB T2N 1N4, Canada. [Lun, Xue Qing; Senger, Donna L.; Forsyth, Peter A.] Univ Calgary, Tom Baker Canc Ctr, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. [Lun, Xue Qing; Senger, Donna L.; Forsyth, Peter A.] Univ Calgary, Tom Baker Canc Ctr, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. [McCart, J. Andrea] Mt Sinai Hosp, Dept Surg, Toronto, ON, Canada. [McCart, J. Andrea] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Bell, John C.] Ottawa Hlth Res Inst, Ctr Canc Therapeut, Ottawa, ON, Canada. [Stojdl, David F.] Childrens Hosp Eastern Ontario, Apoptosis Res Ctr, Ottawa, ON K1H 8L1, Canada. [Nutt, Catherine L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Nutt, Catherine L.] Harvard Univ, Sch Med, Boston, MA USA. RP McCart, JA (reprint author), Toronto Gen Res Inst, Div Expt Therapeut, Room 4-408,67 Coll St, Toronto, ON, Canada. EM amccart@uhnres.utoronto.ca RI Nutt, Catherine/K-8794-2012 FU National Cancer Institute of Canada; Terry Fox Foundation; Clark Smith Brain Tumor Center; Faculty of Medicine, University of Toronto; Jennerex FX National Cancer Institute of Canada with funds raised by the Canadian Cancer Society (P.A. Forsyth and D.L. Senger); a Program Project Grant from the Terry Fox Foundation (P.A. Forsyth, D.L. Senger, J.C. Bell, and D.F. Stojdl); the Clark Smith Brain Tumor Center (P.A. Forsyth); a Grant Miller Cancer Research Grant from the Faculty of Medicine, University of Toronto (J.A. McCart); and commercial support from Jennerex (D.F. Stojdl and J.C. Bell). NR 48 TC 64 Z9 65 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2009 VL 15 IS 8 BP 2777 EP 2788 DI 10.1158/1078-0432.CCR-08-2342 PG 12 WC Oncology SC Oncology GA 435AC UT WOS:000265314600024 PM 19351762 ER PT J AU Huang, JM Levitsky, LL Rhoads, DB AF Huang, Jianmin Levitsky, Lynne L. Rhoads, David B. TI Novel P2 promoter-derived HNF4 alpha isoforms with different N-terminus generated by alternate exon insertion SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Alternative splicing; Diabetes; HNF4 alpha; Transcription factor; Variant/isoform; P2 promoter; HNF4 alpha 10/alpha 11/alpha 12; Evolutionary conservation; Exon 1E ID HEPATOCYTE NUCLEAR FACTOR-4-ALPHA; PANCREATIC BETA-CELLS; TRANSCRIPTION FACTOR HNF-4; FACTOR 4-ALPHA ISOFORMS; LIVER DEVELOPMENT; HEPATOCYTE-NUCLEAR-FACTOR-4-ALPHA HNF4A; COMMON VARIANTS; GENE-EXPRESSION; YOUNG GENES; P1 PROMOTER AB Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a critical transcription factor for pancreas and liver development and functions in islet beta cells to maintain glucose homeostasis. Mutations in the human HNF4A gene lead to maturity onset diabetes of the young (MODY1) and polymorphisms are associated with increased risk for type 2 diabetes mellitus (T2DM). Expression of six HNF4 alpha variants, three each from two developmentally regulated promoters, has been firmly established. We have now detected a new set of HNF4 alpha variants designated HNF4 alpha 10-12 expressed from distal promoter P2. These variants, generated by inclusion of previously undetected exon 1E (human =222 nt, rodent =136 nt) following exon 1D have an altered N-terminus but identical remaining reading frame. HNF4 alpha 10-alpha 12 are expressed in pancreatic islets (and liver) and exhibit transactivation potentials similar to the corresponding alpha 7-alpha 9 isoforms. DNA-binding analyses implied much higher protein levels of HNF4 alpha 10-alpha 12 in liver than expected from the RT-PCR data. Our results provide evidence for a more complex expression pattern of HNF4 alpha than previously appreciated. We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4 alpha mutations and polymorphisms in genetic analyses of MODY1 and T2DM. (C) 2009 Elsevier Inc. All rights reserved. C1 [Huang, Jianmin] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Huang, JM (reprint author), MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. EM jmhuang@partners.org; rhoads@helix.mgh.harvard.edu FU American Diabetes Association Research [7-05-RA-121]; Diabetes Action Research & Education Foundation [204]; William F. Milton Fund of Harvard University (DBR); Nicholas Dulong Diabetes Research Fund FX We thank Dr. Yin Xia (MassGeneral Hospital) for comments on the manuscript and assistance in real-time qRT-PCR, and Dr. Sheng Xiao (Brigham and Women's Hospital) for comments on the manuscript. We are grateful to the Islet Cell Resource Centers of the University of Alabama, the University of Miami, and the University of Minnesota. This study was supported by American Diabetes Association Research Grant 7-05-RA-121 (DBR), Diabetes Action Research & Education Foundation Grant #204 (DBR), The William F. Milton Fund of Harvard University (DBR), and the Nicholas Dulong Diabetes Research Fund (LLL). NR 53 TC 10 Z9 11 U1 0 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD APR 15 PY 2009 VL 315 IS 7 BP 1200 EP 1211 DI 10.1016/j.yexcr.2009.01.004 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 432IO UT WOS:000265126900011 PM 19353766 ER PT J AU Zhang, XP Huang, X Olumi, AF AF Zhang, Xiaoping Huang, Xu Olumi, Aria F. TI Repression of NF-kappa B and activation of AP-1 enhance apoptosis in prostate cancer cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE apoptosis; TRAIL; TNF-alpha; mechanisms of resistance ID TRAIL-INDUCED APOPTOSIS; DEATH DOMAIN KINASE; MEDIATED APOPTOSIS; C-FOS; RECEPTOR; EXPRESSION; CASPASE-8; ALPHA; INHIBITION; INDUCTION AB TNF alpha and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNF alpha and TRAIL. We show that inhibition of NF-kappa B or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFa or TRAIL. Inhibition of NF-kappa B by silencing TRAF2, by silencing RIP or by ectopic expression Of I kappa B partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFa or TRAIL. However, concomitant repression of NF-kappa B and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNF alpha and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, to overcome cancers that are resistant to proapoptotic therapies. (c) 2008 Wiley-Liss, Inc. C1 [Zhang, Xiaoping; Huang, Xu; Olumi, Aria F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. [Zhang, Xiaoping] Huazhong Univ Sci & Technol, Tongji Med Sch, Union Hosp, Dept Urol, Wuhan 430074, Peoples R China. RP Olumi, AF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Yawkey Bldg,Suite 7E, Boston, MA 02114 USA. EM aolumi@partners.org FU Howard Hughes Medical Institute/SPORE; National Natural Science Foundation of China (NSFC) FX Financial support from Howard Hughes Medical Institute/SPORE grant to the Biomedical Research Support Program at Harvard Medical School to AFO and the National Natural Science Foundation of China (NSFC) to XZ is acknowledged. NR 46 TC 12 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 15 PY 2009 VL 124 IS 8 BP 1980 EP 1989 DI 10.1002/ijc.24139 PG 10 WC Oncology SC Oncology GA 422UH UT WOS:000264452700029 PM 19123467 ER PT J AU Kahn, SE AF Kahn, Steven E. TI Glucose Control in Type 2 Diabetes Still Worthwhile and Worth Pursuing SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE; AUTONOMIC NEUROPATHY; COMPLICATIONS; MELLITUS; HYPOGLYCEMIA; OUTCOMES C1 [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. RP Kahn, SE (reprint author), VA Puget Sound Hlth Care Syst 151, 1660 S Columbian Way, Seattle, WA 98108 USA. EM skahn@u.washington.edu OI Kahn, Steven/0000-0001-7307-9002 NR 15 TC 9 Z9 9 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 15 PY 2009 VL 301 IS 15 BP 1590 EP 1592 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 432MH UT WOS:000265137900031 PM 19366780 ER PT J AU Nathan, DM AF Nathan, David M. TI Progress in Diabetes Research-What's Next SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID LONG-TERM COMPLICATIONS; BLOOD-GLUCOSE CONTROL; INTENSIVE THERAPY; MELLITUS C1 [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. RP Nathan, DM (reprint author), MGH Diabet Ctr, 50 Staniford St,Ste 340, Boston, MA 02114 USA. EM dnathan@partners.org NR 23 TC 5 Z9 5 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 15 PY 2009 VL 301 IS 15 BP 1599 EP 1601 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 432MH UT WOS:000265137900034 PM 19366783 ER PT J AU Castriotta, RJ Atanasov, S Wilde, MC Masel, BE Lai, JM Kuna, ST AF Castriotta, Richard J. Atanasov, Strahil Wilde, Mark C. Masel, Brent E. Lai, Jenny M. Kuna, Samuel T. TI Treatment of Sleep Disorders after Traumatic Brain Injury SO JOURNAL OF CLINICAL SLEEP MEDICINE LA English DT Article DE Trauma; brain injury; hypersomnia; sleep apnea; narcolepsy; sleep disorders; MSLT; continuous positive airway pressure ID EXCESSIVE DAYTIME SLEEPINESS; POSITIVE AIRWAY PRESSURE; APNEA-HYPOPNEA SYNDROME; MILD HEAD-INJURY; QUALITY-OF-LIFE; CPAP TREATMENT; RESIDUAL SLEEPINESS; DOUBLE-BLIND; MODAFINIL; PLACEBO AB Study Objectives: Determine whether treatment of sleep disorders identified in brain injured adults would result in resolution of those sleep disorders and improvement of symptoms and daytime function. Methods: Prospective evaluation of unselected traumatic brain injury patients with nocturnal polysomnography (NPSG), multiple sleep latency test (MSLT), Epworth Sleepiness Scale (ESS), and neuropsychological testing including Psychomotor Vigilance Test (PVT), Profile of Mood States (POMS), and Functional Outcome of Sleep Questionnaire (FOSQ) before and after treatment with continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA), modafinil (200 mg) for narcolepsy and posttraumatic hypersomnia (PTH), or pramipexole (0.375 mg) for periodic limb movements in sleep (PLMS). Setting: Three academic medical centers. Participants: Fifty-seven (57) adults >= 3 months post traumatic brain injury (TBI). Measurements And Results: Abnormal sleep studies were found in 22 subjects (39%), of whom 13 (23%) had OSA, 2 (3%) had PTH, 3 (5%) had narcolepsy, 4 (7%) had PLMS, and 12 had objective excessive daytime sleepiness with MSLT score < 10 minutes. Apneas, hypopneas, and snoring were eliminated by CPAP in OSA subjects, but there was no significant change in MSLT scores. Periodic limb movements were eliminated with pramipexole. One of 3 narcolepsy subjects and 1 of 2 PTH subjects had resolution of hypersomnia with modafinil. There was no significant change in FOSQ, POMS, or PVT results after treatment. Conclusions: Treatment of sleep disorders after TBI may result in polysomnographic resolution without change in sleepiness or neuropsychological function. C1 [Castriotta, Richard J.] Univ Texas Hlth Sci Ctr Houston, Div Pulm Crit Care & Sleep Med, Houston, TX 77030 USA. [Castriotta, Richard J.; Wilde, Mark C.; Lai, Jenny M.] Mem Hermann Hosp Sleep Disorders Ctr, Houston, TX USA. [Atanasov, Strahil] Univ Texas Med Branch Galveston, Galveston, TX USA. [Masel, Brent E.] Transit Learning Ctr, Galveston, TX USA. [Kuna, Samuel T.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Castriotta, RJ (reprint author), Univ Texas Hlth Sci Ctr Houston, Div Pulm Crit Care & Sleep Med, 6431 Fannin St,MSB 1-274, Houston, TX 77030 USA. EM Richard.J.Castriotta@uth.tmc.edu RI Sanguansri, Luz/B-6630-2011; OI Sanguansri, Luz/0000-0003-1908-7604; Castriotta, Richard/0000-0003-3502-4558 NR 48 TC 40 Z9 40 U1 0 U2 7 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 1550-9389 J9 J CLIN SLEEP MED JI J. Clin. Sleep Med. PD APR 15 PY 2009 VL 5 IS 2 BP 137 EP 144 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 499YN UT WOS:000270262900009 PM 19968047 ER PT J AU Huett, A Ng, A Cao, ZF Kuballa, P Komatsu, M Daly, MJ Podolsky, DK Xavier, RJ AF Huett, Alan Ng, Aylwin Cao, Zhifang Kuballa, Petrie Komatsu, Masaaki Daly, Mark J. Podolsky, Daniel K. Xavier, Ramnik J. TI A Novel Hybrid Yeast-Human Network Analysis Reveals an Essential Role for FNBP1L in Antibacterial Autophagy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SALMONELLA-CONTAINING VACUOLE; PLASMA-MEMBRANE INVAGINATION; PROTEIN-PROTEIN INTERACTIONS; GENOME-WIDE ASSOCIATION; PHOSPHOLIPID SCRAMBLASE-1; SACCHAROMYCES-CEREVISIAE; ACTIN CYTOSKELETON; CROHNS-DISEASE; MACHINERY; CELLS AB Autophagy is a conserved cellular process required for the removal of defective organelles, protein aggregates, and intracellular pathogens. We used a network analysis strategy to identify novel human autophagy components based upon the yeast interactome centered on the core yeast autophagy proteins. This revealed the potential involvement of 14 novel mammalian genes in autophagy, several of which have known or predicted roles in membrane organization or dynamics. We selected one of these membrane interactors, FNBP1L (formin binding protein 1-like), an F-BAR-containing protein (also termed Toca-1), for further study based upon a predicted interaction with ATG3. We confirmed the FNBP1L/ATG3 interaction biochemically and mapped the FNBP1L domains responsible. Using a functional RNA interference approach, we determined that FNBP1L is essential for autophagy of the intracellular pathogen Salmonella enterica serovar Typhimurium and show that the autophagy process serves to restrict the growth of intracellular bacteria. However, FNBP1L appears dispensable for other forms of autophagy induced by serum starvation or rapamycin. We present a model where FNBP1L is essential for autophagy of intracellular pathogens and identify FNBP1L as a differentially used molecule in specific autophagic contexts. By using network biology to derive functional biological information, we demonstrate the utility of integrated genomics to novel molecule discovery in autophagy. The Journal of Immunology, 2009, 182: 4917-4930. C1 [Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol,Richard B Simches Re, Boston, MA 02114 USA. [Huett, Alan; Ng, Aylwin; Cao, Zhifang; Kuballa, Petrie; Podolsky, Daniel K.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit,Ctr Inflammatory Bowel Dis, Boston, MA 02114 USA. [Daly, Mark J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Komatsu, Masaaki] Tokyo Metropolitan Inst Med Sci, Lab Frontier Sci, Tokyo 113, Japan. [Komatsu, Masaaki] Juntendo Univ, Sch Med, Dept Biochem, Tokyo 113, Japan. [Daly, Mark J.; Xavier, Ramnik J.] Broad Inst Massachussetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Podolsky, Daniel K.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Xavier, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol,Richard B Simches Re, 185 Cambridge St,7th Floor, Boston, MA 02114 USA. EM Xavier@molbio.mgh.harvard.edu FU National Institutes of Health [A1062773, DK83756, DK043351, DK060049]; Crohn's and Colitis Foundation of America FX This work was supported National Institutes of Health Grants A1062773, DK83756, and DK043351 (to R.J.X., M.J.D., and A.H.) and DK060049 and DK043351 (to D.K.P.). A.N, is supported by a Crohn's and Colitis Foundation of America fellowship. NR 64 TC 31 Z9 33 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2009 VL 182 IS 8 BP 4917 EP 4930 DI 10.4049/jimmunol.0803050 PG 14 WC Immunology SC Immunology GA 430QX UT WOS:000265004700054 PM 19342671 ER PT J AU Tai, AW Chung, RT AF Tai, Andrew W. Chung, Raymond T. TI Racial Differences in Response to Interferon-Based Antiviral Therapy for Hepatitis C Virus Infection: A Hardwiring Issue? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID CAUCASIAN AMERICAN PATIENTS; AFRICAN-AMERICAN; CONTROLLED TRIAL; PEGINTERFERON; RIBAVIRIN; GENOTYPE-1; EXPRESSION; CYTOKINE-SIGNALING-3; SUPPRESSOR; ALFA C1 [Tai, Andrew W.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, WRN 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org OI Tai, Andrew/0000-0002-6877-450X FU NIAID NIH HHS [F32 AI080122] NR 15 TC 2 Z9 2 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2009 VL 199 IS 8 BP 1101 EP 1103 DI 10.1086/597385 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 422EB UT WOS:000264409000001 PM 19284288 ER PT J AU Schneidewind, A Brumme, ZL Brumme, CJ Power, KA Reyor, LL O'Sullivan, K Gladden, A Hempel, U Kuntzen, T Wang, YYE Oniangue-Ndza, C Jessen, H Markowitz, M Rosenberg, ES Sekaly, RP Kelleher, AD Walker, BD Allen, TM AF Schneidewind, Arne Brumme, Zabrina L. Brumme, Chanson J. Power, Karen A. Reyor, Laura L. O'Sullivan, Kristin Gladden, Adrianne Hempel, Ursula Kuntzen, Thomas Wang, Yaoyu E. Oniangue-Ndza, Cesar Jessen, Heiko Markowitz, Martin Rosenberg, Eric S. Sekaly, Rafick-Pierre Kelleher, Anthony D. Walker, Bruce D. Allen, Todd M. TI Transmission and Long-Term Stability of Compensated CD8 Escape Mutations SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; ACUTE/EARLY HIV-1 INFECTION; VIRAL LOAD; LYMPHOCYTE RESPONSE; CYCLOPHILIN-A; GAG PROTEIN; EVOLUTION; REVERSION; ASSOCIATION AB Human immunodeficiency virus effectively evades CD8(+) T-cell responses through the development of CD8 escape mutations. Recent reports documenting reversion of transmitted mutations and the impact of specific escape mutations upon viral replication suggest that complex forces limit the accumulation of CD8 escape mutations at the population level. However, the presence of compensatory mutations capable of alleviating the impact of CD8 escape mutations on replication capacity may enable their persistence in an HLA-mismatched host. Herein, we illustrate the long-term stability of stereotypic escape mutations in the immunodominant HLA-B27-restricted epitope KK10 in p24/Gag following transmission when accompanied by a specific compensatory mutation. C1 [Allen, Todd M.] Massachusetts Gen Hosp, Div Infect Dis, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. [Schneidewind, Arne] Univ Klinikum Regensburg, Innere Med Klin 1, Regensburg, Germany. [Jessen, Heiko] Jessen Praxis, Berlin, Germany. [Markowitz, Martin] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Sekaly, Rafick-Pierre] Univ Montreal, Montreal, PQ, Canada. [Kelleher, Anthony D.] Univ New S Wales, Sydney, NSW, Australia. RP Allen, TM (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Partners AIDS Res Ctr, Bldg 149,13th St,Rm 6625, Charlestown, MA 02129 USA. EM tallen2@partners.org RI Allen, Todd/F-5473-2011; OI Brumme, Chanson/0000-0003-2722-5288 FU National Institutes of Health [R01-AI054178]; Bill & Melinda Gates Foundation; NHMRC of Australia FX This study was supported by the National Institutes of Health, grant R01-AI054178 (T. M. A.), and a grant from the Bill & Melinda Gates Foundation (B. D. W. and T. M. A.). A. D. K. is supported by a Practitioner grant from the NHMRC of Australia. NR 35 TC 40 Z9 40 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR 15 PY 2009 VL 83 IS 8 BP 3993 EP 3997 DI 10.1128/JVI.01108-08 PG 5 WC Virology SC Virology GA 420ZI UT WOS:000264327300055 PM 19091871 ER PT J AU Ikeda, S He, AB Kong, SW Lu, J Bejar, R Bodyak, N Lee, KH Ma, Q Kang, PM Golub, TR Pu, WT AF Ikeda, Sadakatsu He, Aibin Kong, Sek Won Lu, Jun Bejar, Rafael Bodyak, Natalya Lee, Kyu-Ho Ma, Qing Kang, Peter M. Golub, Todd R. Pu, William T. TI MicroRNA-1 Negatively Regulates Expression of the Hypertrophy-Associated Calmodulin and Mef2a Genes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MUSCLE-SPECIFIC MICRORNA; INDUCED HEART-FAILURE; CARDIAC-HYPERTROPHY; IN-VIVO; TRANSCRIPTION FACTORS; PRESSURE-OVERLOAD; TARGETS; GATA4; DIFFERENTIATION; OVEREXPRESSION AB Calcium signaling is a central regulator of cardiomyocyte growth and function. Calmodulin is a critical mediator of calcium signals. Because the amount of calmodulin within cardiomyocytes is limiting, the precise control of calmodulin expression is important for the regulation of calcium signaling. In this study, we show for the first time that calmodulin levels are regulated posttranscriptionally in heart failure. The cardiomyocyte-restricted microRNA miR-1 inhibited the translation of calmodulin-encoding mRNAs via highly conserved target sites within their 3' untranslated regions. In keeping with its effect on calmodulin expression, miR-1 downregulated calcium-calmodulin signaling through calcineurin to NFAT. miR-1 also negatively regulated the expression of Mef2a and Gata4, key transcription factors that mediate calcium-dependent changes in gene expression. Consistent with the downregulation of these hypertrophy-associated genes, miR-1 attenuated cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes and in the intact adult heart. Our data indicate that miR-1 regulates cardiomyocyte growth responses by negatively regulating the calcium signaling components calmodulin, Mef2a, and Gata4. C1 [Ikeda, Sadakatsu; He, Aibin; Kong, Sek Won; Lee, Kyu-Ho; Ma, Qing; Pu, William T.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Cardiol, Boston, MA 02115 USA. [Ikeda, Sadakatsu; He, Aibin; Kong, Sek Won; Lee, Kyu-Ho; Ma, Qing; Pu, William T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Lu, Jun; Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Lu, Jun; Golub, Todd R.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Bejar, Rafael] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bodyak, Natalya; Kang, Peter M.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02115 USA. [Golub, Todd R.] Childrens Hosp Boston, Dept Med, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Pu, William T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Pu, WT (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Cardiol, Enders 1254,300 Longwood Ave, Boston, MA 02115 USA. EM wpu@enderstch.harvard.edu FU AHA; NIH [PO1 HL074734] FX I. was supported by an AHA fellowship. This work was supported by NIH grant PO1 HL074734 and by a charitable donation from Edward P. Marram and Karen K. Carpenter. NR 46 TC 207 Z9 237 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR 15 PY 2009 VL 29 IS 8 BP 2193 EP 2204 DI 10.1128/MCB.01222-08 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 424HS UT WOS:000264558400018 PM 19188439 ER PT J AU Zhang, Q Strangman, GE Ganis, G AF Zhang, Quan Strangman, Gary E. Ganis, Giorgio TI Adaptive filtering to reduce global interference in non-invasive NIRS measures of brain activation: How well and when does it work? SO NEUROIMAGE LA English DT Article DE Near infrared; Brain; Visual cortex; Vision; Hemodynamics; Adaptive filter; Interference; Cancellation; Physiological noise ID NEAR-INFRARED SPECTROSCOPY; DIFFUSE OPTICAL TOMOGRAPHY; VISUAL-CORTEX; HUMAN ADULTS; HEMODYNAMICS; OXYGENATION; METABOLISM; ARTIFACT; REMOVAL; INFANTS AB In previous work we introduced a novel method for reducing global interference, based on adaptive filtering, to improve the contrast to noise ratio (CNR) of evoked hemodynamic responses measured non-invasively with near infrared spectroscopy (NIRS). Here, we address the issue of how to generally apply the proposed adaptive filtering method. A total of 156 evoked visual response measurements, collected from 15 individuals, were analyzed. The similarity (correlation) between measurements with far and near source-detector separations collected during the rest period before visual stimulation was used as indicator of global interference dominance. A detailed analysis of CNR improvement in oxy-hemoglobin (O(2)Hb) and deoxyhemoglobin (HHb), as a function of the rest period correlation coefficient, is presented. Results show that for O2Hb measurements, 66% exhibited substantial global interference. For this dataset, dominated by global interference, 71% of the measurements revealed CNR improvements after adaptive filtering, with a mean CNR improvement of 60%. No CNR improvement was observed for HHb. This study corroborates our previous finding that adaptive filtering provides an effective method to increase CNR when there is strong global interference, and also provides a practical way for determining when and where to apply this technique. (C) 2009 Elsevier Inc. All rights reserved. C1 [Strangman, Gary E.; Ganis, Giorgio] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Zhang, Quan; Strangman, Gary E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Ganis, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Ganis, Giorgio] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Ganis, G (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM ganis@nmr.mgh.harvard.edu OI Ganis, Giorgio/0000-0001-6175-2618 FU NIMH [R21-MH068610]; NSF [BCS-0322611]; NIBIB [R01-EB006589]; National Space Biomedical Research Institute [NCC 9-58] FX We would like to thank Christina Supelana for technical support. This effort was supported primarily by the NIMH (R21-MH068610 to GG), with contributions from the NSF (BCS-0322611), the NIBIB (R01-EB006589), and the National Space Biomedical Research Institute through NASA Cooperative Agreement NCC 9-58. NR 37 TC 77 Z9 83 U1 3 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 15 PY 2009 VL 45 IS 3 BP 788 EP 794 DI 10.1016/j.neuroimage.2008.12.048 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SK UT WOS:000264378400016 PM 19166945 ER PT J AU Kong, J Kaptchuk, TJ Polich, G Kirsch, I Vangel, M Zyloney, C Rosen, B Gollub, R AF Kong, Jian Kaptchuk, Ted J. Polich, Ginger Kirsch, Irving Vangel, Mark Zyloney, Carolyn Rosen, Bruce Gollub, Randy TI Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia SO NEUROIMAGE LA English DT Review DE Acupuncture; Acupuncture analgesia; Placebo; Placebo analgesia; Expectancy; Expectancy manipulation; Conditioning; Pain; Sham acupuncture needle ID RANDOMIZED CONTROLLED-TRIAL; LOW-BACK-PAIN; CARPAL-TUNNEL-SYNDROME; CONNECTIVE-TISSUE; HUMAN BRAIN; ACUPOINT STIMULATION; PARKINSONS-DISEASE; NEURAL MECHANISMS; OPIOID ACTIVITY; RATIO SCALES AB Recent advances in placebo research have demonstrated the mind's power to alter physiology. In this study, we combined an expectancy manipulation model with both verum and sham acupuncture treatments to address: 1) how and to what extent treatment and expectancy effects - including both subjective pain intensity levels (pain sensory ratings) and objective physiological activations (fMRI) - interact; and 2) if the underlying mechanism of expectancy remains the same whether placebo treatment is given alone or in conjunction with active treatment. The results indicate that although verum acupuncture+high expectation and sham acupuncture+high expectation induced subjective reports of analgesia of equal magnitude, fMRI analysis showed that verum acupuncture produced greater fMRI signal decrease in pain related brain regions during application of calibrated heat pain stimuli on the right arm. We believe our study provides brain imaging evidence for the existence of different mechanisms underlying acupuncture analgesia and expectancy evoked placebo analgesia. Our results also suggest that the brain network involved in expectancy may vary under different treatment situations (verum and sham acupuncture treatment). (c) 2008 Elsevier Inc. All rights reserved. C1 [Kong, Jian; Polich, Ginger; Zyloney, Carolyn; Gollub, Randy] Massachusetts Gen Hosp, Dept Psychiat, Bldg 149,13th St,Suite 2661, Charlestown, MA 02129 USA. [Kong, Jian; Vangel, Mark; Rosen, Bruce; Gollub, Randy] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. [Kaptchuk, Ted J.; Gollub, Randy] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA USA. [Kirsch, Irving] Univ Hull, Kingston Upon Hull HU6 7RX, N Humberside, England. [Vangel, Mark] MGH CRC Biomed Imaging Core, Charlestown, MA USA. RP Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bldg 149,13th St,Suite 2661, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044 FU National Center for Complimentary and Alternative Medicine (NCCAM) [PO1-AT002048]; NCCAM [R21AT00949, KO1AT003883, K24AT004095, M01-RR-01066]; National Center for Research Resources (NCRR) [UL1 RR025758-01]; NCRR [P41RR14075]; MIND Institute FX This work was supported by PO1-AT002048 to Bruce Rosen from National Center for Complimentary and Alternative Medicine (NCCAM), R21AT00949 to Randy Gollub from NCCAM, KO1AT003883 to Jian Kong from NCCAM, K24AT004095 to Ted Kaptchuk from NCCAM, M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR and the MIND Institute. NR 104 TC 69 Z9 80 U1 1 U2 29 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 APR 15 PY 2009 VL 45 IS 3 BP 940 EP 949 DI 10.1016/j.neuroimage.2008.12.025 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SK UT WOS:000264378400029 PM 19159691 ER PT J AU Timbie, JW Shahian, DM Newhouse, JP Rosenthal, MB Normand, SLT AF Timbie, Justin W. Shahian, David M. Newhouse, Joseph P. Rosenthal, Meredith B. Normand, Sharon-Lise T. TI Composite measures for hospital quality using quality-adjusted life years SO STATISTICS IN MEDICINE LA English DT Article DE quality of care; quality-adjusted life years; provider profiling; cardiac bypass graft surgery; hierarchical model ID LONG-TERM-SURVIVAL; BYPASS GRAFT-SURGERY; ADULT CARDIAC-SURGERY; UNINTENDED CONSEQUENCES; MYOCARDIAL-INFARCTION; PERFORMANCE-MEASURES; COST-EFFECTIVENESS; RISK-FACTORS; OF-LIFE; OUTCOMES AB Developing clinically meaningful summary measures of health-care quality is key to inferring quality of care. Current summary measures use a number of different approaches to weight their individual measures but rarely use weights based on clinical 'importance'. Such an approach would help to focus quality improvement efforts on areas likely to have the largest impact On health outcomes. Using coronary artery bypass graft (CABG) surgery as a case study, we weight and combine 11 process, complication, and survival measures to summarize differences in quality-adjusted life expectancy 1 year following surgery for a sample of hospitals. We use a fully Bayesian analysis to estimate 1-year survival outcomes using a hierarchical exponential survival model. We then estimate the expected utility of the year following surgery for each patient using complication probabilities fitted from hierarchical models and utility values from the literature. We estimate quality-adjusted life years (QALYs) for each hospital as the utility-weighted average 1-year survival probability and then estimate 'incremental QALYs' by taking the difference in QALYs for each hospital relative to a comparison group that reflects the average performance of all hospitals in the state. We illustrate our framework by estimating incremental QALYs for 14 hospitals performing CABG surgery in Massachusetts in 2003 and find that a composite measure based on QALYs can change the classification of quality outliers relative to conventional mortality measures. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Timbie, Justin W.] VA Ann Arbor Healthcare Syst, HSR&D Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Shahian, David M.] Massachusetts Gen Hosp, Dept Surg, Ctr Qual & Safety, Boston, MA 02114 USA. [Newhouse, Joseph P.; Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Newhouse, Joseph P.; Rosenthal, Meredith B.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Timbie, JW (reprint author), VA Ann Arbor Healthcare Syst, HSR&D Ctr Clin Management Res, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM justinti@med.umich.edu OI Rosenthal, Meredith/0000-0003-3410-0184 FU Alfred P. Sloan Foundation FX Contract/grant sponsor: Alfred P. Sloan Foundation NR 48 TC 5 Z9 5 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD APR 15 PY 2009 VL 28 IS 8 BP 1238 EP 1254 DI 10.1002/sim.3539 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 425NW UT WOS:000264645400003 PM 19184974 ER PT J AU Bonetti, M Zahrieh, D Cole, BF Gelber, RD AF Bonetti, Marco Zahrieh, David Cole, Bernard F. Gelber, Richard D. TI A small sample study of the STEPP approach to assessing treatment-covariate interactions in survival data SO STATISTICS IN MEDICINE LA English DT Article DE treatment-covariate interaction; clinical trials; permutation-based inference; survival analysis ID NEGATIVE BREAST-CANCER; CLINICAL-TRIALS; ENDOCRINE RESPONSIVENESS; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; SUBSETS; THERAPY; WOMEN; CMF AB A new, intuitive method has recently been proposed to explore treatment-covariate interactions in survival data arising from two treatment arms of a clinical trial. The method is based on constructing overlapping subpopulations of patients with respect to one (or more) covariates of interest and in observing the pattern of the treatment effects estimated across the subpopulations. A plot of these treatment effects is called a subpopulation treatment effect pattern plot. Here, we explore the small sample characteristics of the asymptotic results associated with the method and develop an alternative permutation distribution-based approach to inference that should be preferred for smaller sample sizes. We then describe an extension of the method to the case in which the pattern of estimated quantiles of survivor functions is of interest. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Bonetti, Marco] Bocconi Univ, Dept Decis Sci, I-20136 Milan, Italy. [Zahrieh, David; Gelber, Richard D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cole, Bernard F.] Univ Vermont, Dept Math & Stat, Burlington, VT 05401 USA. [Gelber, Richard D.] Harvard Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02115 USA. RP Bonetti, M (reprint author), Bocconi Univ, Dept Decis Sci, Via Rontgen 1, I-20136 Milan, Italy. EM marco.bonetti@unibocconi.it OI Bonetti, Marco/0000-0003-2304-4180 FU The United States National Cancer Institute [CA-75362]; The Italian Ministry for Research (MIUR) protocol [2007AYHZWC] FX Contract/grant sponsor: The Italian Ministry for Research (MIUR) protocol; contract/grant number: 2007AYHZWC NR 11 TC 18 Z9 18 U1 0 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD APR 15 PY 2009 VL 28 IS 8 BP 1255 EP 1268 DI 10.1002/sim.3524 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 425NW UT WOS:000264645400004 PM 19170050 ER PT J AU Heher, EC Spitzer, TR Goes, NB AF Heher, Eliot C. Spitzer, Thomas R. Goes, Nelson B. TI Light Chains: Heavy Burden in Kidney Transplantation SO TRANSPLANTATION LA English DT Review DE Plasma cell dyscrasia; Multiple myeloma; Monoclonal gammopathy of uncertain significance; Light chain deposition disease; Monoclonal immunoglobulin deposition disease ID STEM-CELL TRANSPLANTATION; DIAGNOSED MULTIPLE-MYELOMA; ACUTE-RENAL-FAILURE; MONOCLONAL GAMMOPATHY; DEPOSITION DISEASE; UNDETERMINED SIGNIFICANCE; PLASMA-EXCHANGE; PLUS DEXAMETHASONE; FOLLOW-UP; IN-VITRO AB Plasma cell dyscrasias are frequently encountered malignancies which are often associated with kidney disease through the production of monoclonal immunoglobulin (Ig). Recent advances in the field include the availability of an assay for free light chains, the introduction of new agents which more effectively target malignant plasma cells, and refinements in the application of stem-cell transplantation. Well-selected patients with plasma cell dyscrasias whose monoclonal Ig is well controlled may be candidates for kidney transplantation. Kidney transplant patients with allograft dysfunction from recurrent or de novo monoclonal Ig deposition can be successfully identified and treated with these new approaches. C1 [Heher, Eliot C.; Goes, Nelson B.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Heher, Eliot C.; Spitzer, Thomas R.; Goes, Nelson B.] Massachusetts Gen Hosp, Transplantat Ctr, Boston, MA 02114 USA. [Spitzer, Thomas R.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Heher, EC (reprint author), MGH GRB 1003,55 Fruit St, Boston, MA 02114 USA. EM eheher@partners.org NR 55 TC 5 Z9 5 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD APR 15 PY 2009 VL 87 IS 7 BP 947 EP 952 DI 10.1097/TP.0b013e31819b9977 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 433DQ UT WOS:000265184900001 PM 19352111 ER PT J AU Christen, T Nahrendorf, M Wildgruber, M Swirski, FK Aikawa, E Waterman, P Shimizu, K Weissleder, R Libby, P AF Christen, Thomas Nahrendorf, Matthias Wildgruber, Moritz Swirski, Filip K. Aikawa, Elena Waterman, Peter Shimizu, Koichi Weissleder, Ralph Libby, Peter TI Molecular Imaging of Innate Immune Cell Function in Transplant Rejection SO CIRCULATION LA English DT Article DE imaging; inflammation; leukocytes; rejection; transplantation ID CARDIAC ALLOGRAFT VASCULOPATHY; IRON-OXIDE PARTICLES; IN-VIVO; PROTEASE ACTIVITY; CONTRAST AGENT; ATHEROSCLEROSIS; ACCUMULATION; INFILTRATION; REPERFUSION; MACROPHAGES AB Background-Clinical detection of transplant rejection by repeated endomyocardial biopsy requires catheterization and entails risks. Recently developed molecular and cellular imaging techniques that visualize macrophage host responses could provide a noninvasive alternative. Yet, which macrophage functions may provide useful markers for detecting parenchymal rejection remains uncertain. Methods and Results-We transplanted isografts from B6 mice and allografts from Balb/c mice heterotopically into B6 recipients. In this allograft across major histocompatability barriers, the transplanted heart undergoes predictable progressive rejection, leading to graft failure after 1 week. During rejection, crucial macrophage functions, including phagocytosis and release of proteases, render these abundant innate immune cells attractive imaging targets. Two or 6 days after transplantation, we injected either a fluorescent protease sensor or a magnetofluorescent phagocytosis marker. Histological and flow cytometric analyses established that macrophages function as the major cellular signal source. In vivo, we obtained a 3-dimensional functional map of macrophages showing higher phagocytic uptake of magnetofluorescent nanoparticles during rejection using magnetic resonance imaging and higher protease activity in allografts than in isografts using tomographic fluorescence. We further assessed the sensitivity of imaging to detect the degree of rejection. In vivo imaging of macrophage response correlated closely with gradually increasing allograft rejection and attenuated rejection in recipients with a genetically impaired immune response resulting from a deficiency in recombinase-1 (RAG-1(-/-)). Conclusions-Molecular imaging reporters of either phagocytosis or protease activity can detect cardiac allograft rejection noninvasively, promise to enhance the search for novel tolerance-inducing strategies, and have translational potential. (Circulation. 2009;119:1925-1932.) C1 [Christen, Thomas; Shimizu, Koichi; Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Nahrendorf, Matthias; Swirski, Filip K.; Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Nahrendorf, Matthias; Wildgruber, Moritz; Swirski, Filip K.; Aikawa, Elena; Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Nahrendorf, Matthias; Wildgruber, Moritz; Swirski, Filip K.; Aikawa, Elena; Waterman, Peter; Weissleder, Ralph] Harvard Univ, Sch Med, Charlestown, MA USA. RP Libby, P (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, NRB 741,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM plibby@rics.bwh.harvard.edu FU Donald W. Reynolds Foundation [U01HL080731]; American Heart Association Scientist Development [0630010N]; American Society of Transplantation Basic Science FX This work was funded in part by the Donald W. Reynolds Foundation, Translational Program of Excellence in Nanotechnology grant U01HL080731, American Heart Association Scientist Development grant 0630010N (to Dr Shimizu), and American Society of Transplantation Basic Science Faculty Development grant (to Dr Shimizu). NR 26 TC 39 Z9 40 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 14 PY 2009 VL 119 IS 14 BP 1925 EP 1932 DI 10.1161/CIRCULATIONAHA.108.796888 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 432BW UT WOS:000265109500011 PM 19332470 ER PT J AU Desai, NR Mega, JL Jiang, ST Cannon, CP Sabatine, MS AF Desai, Nihar R. Mega, Jessica L. Jiang, Songtao Cannon, Christopher P. Sabatine, Marc S. TI Interaction Between Cigarette Smoking and Clinical Benefit of Clopidogrel SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE clopidogrel; cytochrome P450; smoking ID ST-SEGMENT ELEVATION; PLATELET REACTIVITY; MYOCARDIAL-INFARCTION; RESPONSE VARIABILITY; STENT IMPLANTATION; ASPIRIN; EVENTS; TRIAL; AGGREGATION; INHIBITION AB Objectives The aim of this study was to examine the interaction between cigarette smoking and the clinical efficacy of clopidogrel in ST-segment elevation myocardial infarction (STEMI). Background Cigarette smoking induces cytochrome P450 (CYP)1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of >= 10 cigarettes/day. Methods The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in 3,429 STEMI patients in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) randomized trial stratified by smoking intensity as follows: not current smokers (n = 1,732), and smokers of 1 to 9 (n = 206), 10 to 19 (n = 354), 20 to 29 (n = 715), and >= 30 cigarettes/day (n = 422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification. Results Although clopidogrel reduced the rate of the primary end point of a closed infarct-related artery or death/myocardial infarction before angiography in the CLARITY-TIMI 28 trial, the benefit was especially marked among those who smoked >= 10 cigarettes/day (adjusted odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.37 to 0.66; p < 0.0001) compared with those who did not (adjusted OR: 0.72, 95% CI: 0.57 to 0.91; p = 0.006; p(interaction) = 0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, myocardial infarction, or urgent revascularization through 30 days among those who smoked >= 10 cigarettes/ day (adjusted OR: 0.54, 95% CI: 0.38 to 0.76; p = 0.0004) compared with those who did not (adjusted OR: 0.98; 95% CI: 0.75 to 1.28; p = 0.87; p(interaction) = 0.006). Conclusions Cigarette smoking seems to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel might impact its clinical effectiveness. (J Am Coll Cardiol 2009; 53: 1273-8) (c) 2009 by the American College of Cardiology Foundation C1 [Mega, Jessica L.; Cannon, Christopher P.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Desai, Nihar R.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Mega, Jessica L.; Cannon, Christopher P.; Sabatine, Marc S.] Harvard Univ, Sch Med, Boston, MA USA. [Jiang, Songtao] Harvard Clin Res Inst, Boston, MA USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU Bristol-Myers Squibb; AstraZeneca; Bayer Healthcare; Beckman Coulter; Biosite; CV Therapeutics; Eli Lilly; Genentech; GlaxoSmithKline; Integrated Therapeutics Group; Johnson Johnson; Merck; Nanosphere; Novartis; Pfizer; Roche Diagnostics; Sanofi-Aventis; Schering-Plough; Siemens Medical Solutions; Accumetrics; Bristol Myers Squibb/Sanofi Pharmaceuticals Partnership; Merck/Schering-Plough Partnership; Sanofi-Aventis and Schering-Plough FX From the *Department of Medicine and dagger TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; and the Harvard Clinical Research Institute, Boston, Massachusetts. The CLARITY-TIMI 28 trial was funded by Bristol-Myers Squibb. The TIMI Study Group reports receiving significant research grant support from AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, Genentech, GlaxoSmithKline, Integrated Therapeutics Group, Johnson & Johnson, Merck, Nanosphere, Novartis, Pfizer, Roche Diagnostics, Sanofi-Aventis, Schering-Plough, Siemens Medical Solutions, and Singulex. Dr. Mega receives research grant support from Schering-Plough. Dr. Cannon receives research grant support from Accumetrics, AstraZeneca, Bristol Myers Squibb/Sanofi Pharmaceuticals Partnership, GlaxoSmithKline, Merck, and Merck/Schering-Plough Partnership and holds equity in Automedics Medical Systems. Dr. Sabatine reports receiving research grant support from Sanofi-Aventis and Schering-Plough and honoraria from Bristol- Myers Squibb and Sanofi-Aventis. NR 28 TC 71 Z9 73 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 14 PY 2009 VL 53 IS 15 BP 1273 EP 1278 DI 10.1016/j.jacc.2008.12.044 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 430TV UT WOS:000265012600003 PM 19358940 ER PT J AU Kernan, WN Viscoli, CM DeMarco, D Mendes, B Shrauger, K Schindler, JL McVeety, JC Sicklick, A Moalli, D Greco, P Bravata, DM Eisen, S Resor, L Sena, K Story, D Brass, LM Furie, KL Gutmann, L Hinnau, E Gorman, M Lovejoy, AM Inzucchi, SE Young, LH Horwitz, RI AF Kernan, W. N. Viscoli, C. M. DeMarco, D. Mendes, B. Shrauger, K. Schindler, J. L. McVeety, J. C. Sicklick, A. Moalli, D. Greco, P. Bravata, D. M. Eisen, S. Resor, L. Sena, K. Story, D. Brass, L. M. Furie, K. L. Gutmann, L. Hinnau, E. Gorman, M. Lovejoy, A. M. Inzucchi, S. E. Young, L. H. Horwitz, R. I. CA IRIS Trial Investigators TI Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs) SO NEUROLOGY LA English DT Article ID CLINICAL-TRIAL; RECRUITMENT; STROKE AB Objective: Our purpose was to develop a geographically localized, multi-institution strategy for improving enrolment in a trial of secondary stroke prevention. Methods: We invited 11 Connecticut hospitals to participate in a project named the Local Identification and Outreach Network (LION). Each hospital provided the names of patients with stroke or TIA, identified from electronic admission or discharge logs, to researchers at a central coordinating center. After obtaining permission from personal physicians, researchers contacted each patient to describe the study, screen for eligibility, and set up a home visit for consent. Researchers traveled throughout the state to enroll and follow participants. Outside the LION, investigators identified trial participants using conventional recruitment strategies. We compared recruitment success for the LION and other sites using data from January 1, 2005, through June 30, 2007. Results: The average monthly randomization rate from the LION was 4.0 participants, compared with 0.46 at 104 other Insulin Resistance Intervention after Stroke (IRIS) sites. The LION randomized on average 1.52/1,000 beds/month, compared with 0.76/1,000 beds/month at other IRIS sites (p = 0.03). The average cost to randomize and follow one participant was $8,697 for the LION, compared with $7,198 for other sites. Conclusion: A geographically based network of institutions, served by a central coordinating center, randomized substantially more patients per month compared with sites outside of the network. The high enrollment rate was a result of surveillance at multiple institutions and greater productivity at each institution. Although the cost per patient was higher for the network, compared with nonnetwork sites, cost savings could result from more rapid completion of research. Neurology (R) 2009; 72: 1345-1351 C1 [Kernan, W. N.; Viscoli, C. M.; DeMarco, D.; Mendes, B.; Shrauger, K.; Hinnau, E.; Lovejoy, A. M.; Inzucchi, S. E.; Young, L. H.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Schindler, J. L.; McVeety, J. C.; Story, D.; Brass, L. M.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Sicklick, A.] Yale Univ, Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06510 USA. [Horwitz, R. I.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Bravata, D. M.] Indiana Univ, Sch Med, Richard L Roudebush VAMC, Indianapolis, IN USA. [Gorman, M.] Univ Vermont, Dept Neurol, Burlington, VT USA. [Furie, K. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Moalli, D.] Lawrence Mem Hosp, Groton, CT USA. [Greco, P.] St Marys Hosp, Waterbury, CT USA. [Eisen, S.] Waterbury Hosp & Hlth Ctr, Waterbury, CT USA. [Resor, L.] Stamford Hosp, Stamford, CT USA. [Shrauger, K.] Bridgeport Hosp, Bridgeport, CT USA. [Gutmann, L.] NINDS, NIH, Bethesda, MD 20892 USA. RP Kernan, WN (reprint author), Suite 515,2 Church St S, New Haven, CT 06519 USA. EM walter.kernan@yale.edu RI Tanne, David/F-2560-2010; Spence, J. David/K-6396-2013 OI Tanne, David/0000-0002-6699-2220; Spence, J. David/0000-0001-7478-1098 FU National Institute of Neurological Disorders and Stroke [U01 NS044876]; Takeda Pharmaceuticals North America, Inc FX Supported by the National Institute of Neurological Disorders and Stroke (U01 NS044876) and by a grant from Takeda Pharmaceuticals North America, Inc. NR 8 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 14 PY 2009 VL 72 IS 15 BP 1345 EP 1351 DI 10.1212/WNL.0b013e3181a0fda3 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 432AZ UT WOS:000265107200010 PM 19365056 ER PT J AU Gorgun, G Ramsay, AG Holderried, TAW Zahrieh, D Le Dieu, R Liu, F Quackenbush, J Croce, CM Gribben, JG AF Gorgun, Gullu Ramsay, Alan G. Holderried, Tobias A. W. Zahrieh, David Le Dieu, Rifca Liu, Fenglong Quackenbush, John Croce, Carlo M. Gribben, John G. TI E mu-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNOLOGICAL SYNAPSE; EXPRESSION; LENALIDOMIDE; PEPTIDES; THERAPY; MOUSE; DRUG; CD28; CD4 AB Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) E mu-TCL1 transgenic mouse model. With development of leukemia, E mu-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young E mu-TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies. C1 [Ramsay, Alan G.; Le Dieu, Rifca; Gribben, John G.] Univ London, Barts & London Sch Med, Inst Canc, London EC1M 6BQ, England. [Gorgun, Gullu; Holderried, Tobias A. W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zahrieh, David; Liu, Fenglong; Quackenbush, John] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Croce, Carlo M.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Gribben, JG (reprint author), Univ London, Barts & London Sch Med, Inst Canc, London EC1M 6BQ, England. EM john.gribben@cancer.org.uk RI Ramsay, Alan/A-8374-2015 OI Ramsay, Alan/0000-0002-0452-0420 FU CLL Research Consortium [81538]; National Cancer Institute; CLL Global Research Foundation FX We thank Peter Varney for editorial assistance, Dr. Edward Alvin Fox and the Staff of the Dana- Farber Cancer Institute Microarray Core Facility. This work was supported by the CLL Research Consortium Grant PO1 CA 81538 from the National Cancer Institute ( to J. G. G. and C. M. C.) and by grants from the CLL Global Research Foundation. NR 26 TC 68 Z9 68 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 14 PY 2009 VL 106 IS 15 BP 6250 EP 6255 DI 10.1073/pnas.0901166106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600041 PM 19332800 ER PT J AU Ford, AC Chey, WD Talley, NJ Malhotra, A Spiegel, BMR Moayyedi, P AF Ford, Alexander C. Chey, William D. Talley, Nicholas J. Malhotra, Ashish Spiegel, Brennan M. R. Moayyedi, Paul TI Yield of Diagnostic Tests for Celiac Disease in Individuals With Symptoms Suggestive of Irritable Bowel Syndrome Systematic Review and Meta-analysis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID ROME-II CRITERIA; COST-EFFECTIVENESS ANALYSIS; POPULATION-BASED COHORT; HEALTH-CARE SEEKING; GLUTEN-FREE DIET; GENERAL-POPULATION; SECONDARY CARE; PREVALENCE; DYSPEPSIA; RISK AB Background: Individuals with irritable bowel syndrome (IBS) report abdominal pain, bloating, and diarrhea, symptoms similar to those in celiac disease. Studies suggest that the prevalence of celiac disease is increased in individuals with IBS; however, evidence is conflicting, and current guidelines do not always recommend screening for celiac disease in these individuals. Methods: We conducted a systematic review and meta-analysis to estimate prevalence of celiac disease in unselected adults who met diagnostic criteria for IBS. MEDLINE (1950 to May 31, 2008) and EMBASE (1980 to May 31, 2008) were searched. Case series and case-control studies that used serologic tests for celiac disease were eligible for inclusion. Prevalence of positive serologic indications of celiac disease and biopsy-proved celiac disease were extracted and pooled for all studies and were compared between cases and controls using an odds ratio and 95% confidence interval. Results: Fourteen studies were identified comprising 4204 individuals, of whom 2278 (54%) met diagnostic criteria for IBS. Pooled prevalence of positive IgA-class antigliadin antibodies, either positive endomysial antibodies or tissue transglutaminase, and biopsy-proved celiac disease were 4.0% (95% confidence interval, 1.7-7.2), 1.63% (0.7-3.0), and 4.1% (1.9-7.0), respectively. Pooled odds ratios (95% confidence intervals) for positive IgA-class antigliadin antibodies, either positive endomysial antibodies or tissue transglutaminase, and biopsy-proved celiac disease in cases meeting diagnostic criteria for IBS compared with controls without IBS were 3.40 (1.62-7.13), 2.94 (1.36-6.35), and 4.34 (1.78-10.6). Conclusion: Prevalence of biopsy-proved celiac disease in cases meeting diagnostic criteria for IBS was more than 4-fold that in controls without IBS. C1 [Ford, Alexander C.; Moayyedi, Paul] McMaster Univ, Hlth Sci Ctr, Div Gastroenterol, Hamilton, ON L8N 3Z5, Canada. [Chey, William D.] Univ Michigan, Med Ctr, Dept Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Talley, Nicholas J.] Mayo Clin Florida, Dept Med, Jacksonville, FL USA. [Malhotra, Ashish] Mayo Clin Rochester, Div Gastroenterol & Hepatol, Rochester, MN USA. [Spiegel, Brennan M. R.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, Sch Publ Hlth, VA Ctr Outcomes Res & Educ, Los Angeles, CA 90095 USA. RP Ford, AC (reprint author), McMaster Univ, Hlth Sci Ctr, Div Gastroenterol, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM alexf12399@yahoo.com RI Ford, Alexander/K-5491-2012; Talley, nicholas/D-5399-2013 OI Ford, Alexander/0000-0001-6371-4359; Talley, nicholas/0000-0003-2537-3092 FU American College of Gastroenterology FX This study was funded by the American College of Gastroenterology (Dr Moayyedi). NR 56 TC 124 Z9 127 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 13 PY 2009 VL 169 IS 7 BP 651 EP 658 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 432AK UT WOS:000265105700002 PM 19364994 ER PT J AU Kalogeropoulos, A Georgiopoulou, V Kritchevsky, SB Psaty, BM Smith, NL Newman, AB Rodondi, N Satterfield, S Bauer, DC Bibbins-Domingo, K Smith, AL Wilson, PWF Vasan, RS Harris, TB Butler, J AF Kalogeropoulos, Andreas Georgiopoulou, Vasiliki Kritchevsky, Stephen B. Psaty, Bruce M. Smith, Nicholas L. Newman, Anne B. Rodondi, Nicolas Satterfield, Suzanne Bauer, Douglas C. Bibbins-Domingo, Kirsten Smith, Andrew L. Wilson, Peter W. F. Vasan, Ramachandran S. Harris, Tamara B. Butler, Javed TI Epidemiology of Incident Heart Failure in a Contemporary Elderly Cohort The Health, Aging, and Body Composition Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RISK-FACTORS; SURVIVAL; POPULATION; PREVALENCE; PROGNOSIS; ASSOCIATION; COMMUNITY; TRENDS; ADULTS; DEATH AB Background: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. Methods: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. Results: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P <.001). Conclusions: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts. C1 [Kalogeropoulos, Andreas; Georgiopoulou, Vasiliki; Smith, Nicholas L.; Wilson, Peter W. F.; Butler, Javed] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] VA Puget Sound Hlth Care Syst, Seattle VA Epidemiol Res & Informat Ctr, Seattle, WA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Rodondi, Nicolas] Univ Lausanne, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Satterfield, Suzanne] Univ Memphis, Dept Prevent Med, Memphis, TN 38152 USA. [Bauer, Douglas C.; Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. RP Butler, J (reprint author), Emory Univ, Emory Univ Hosp, Div Cardiol, 1365 Clifton Rd NE,Ste AT430, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Kalogeropoulos, Andreas/A-9494-2009; Newman, Anne/C-6408-2013; OI Kalogeropoulos, Andreas/0000-0002-1284-429X; Newman, Anne/0000-0002-0106-1150; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health FX This study was supported in part by the Intramural Research Program of the National Institute on Aging and by grants N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging, National Institutes of Health. NR 36 TC 78 Z9 82 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 13 PY 2009 VL 169 IS 7 BP 708 EP 715 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 432AK UT WOS:000265105700010 PM 19365001 ER PT J AU Soto-Nieves, N Puga, I Abe, BT Bandyopadhyay, S Baine, I Rao, A Macian, F AF Soto-Nieves, Noemi Puga, Irene Abe, Brian T. Bandyopadhyay, Sanmay Baine, Ian Rao, Anjana Macian, Fernando TI Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID E3 UBIQUITIN LIGASE; KAPPA-B COMPLEX; GENE-TRANSCRIPTION; HISTONE ACETYLATION; SIGNALING PROTEINS; IN-VIVO; ANERGY; ACTIVATION; DIFFERENTIATION; CALCINEURIN AB T cells, anergy can be induced after T cell receptor engagement in the absence of costimulation. Under these conditions, the expression of a specific set of anergy-associated genes is activated. Several lines of evidence suggest that nuclear factor of activated T cells (NFAT) proteins may regulate the expression of many of those genes; however, the nature of the complexes responsible for the induction of this new program of gene expression is unknown. Here, we show that transcriptional complexes formed by NFAT homodimers are directly responsible for the activation of at least two anergy-inducing genes, Grail and Caspase3. Our data shows that Grail expression is activated by direct binding of NFAT dimers to the Grail promoter at two different sites. Consequently, a mutant NFAT protein with impaired ability to dimerize is not able to induce an unresponsive state in T cells. Our results not only identify a new biological function for NFAT dimers but also reveal the different nature of NFAT-containing complexes that induce anergy versus those that are activated during a productive immune response. These data also establish a basis for the design of immunomodulatory strategies that specifically target each type of complex. C1 [Soto-Nieves, Noemi; Puga, Irene; Abe, Brian T.; Bandyopadhyay, Sanmay; Baine, Ian; Macian, Fernando] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Macian, F (reprint author), Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. EM fmacianj@aecom.yu.edu OI Baine, Ian/0000-0002-0419-0054; Puga, Irene/0000-0003-2208-3196; Macian, Fernando/0000-0003-2666-035X FU National Institutes of Health (NIH) [AI059738, CA42471, AI48213, GM007288]; Irene Diamond Foundation FX This work was supported by National Institutes of Health (NIH) grants AI059738 (F. Macian), CA42471 (A. Rao), and AI48213 (A. Rao); NIH training grants GM007288 (N. Soto-Nieves) and GM007288 (B. T. Abe and I. Baine); and the Irene Diamond Foundation (F. Macian). NR 57 TC 39 Z9 41 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 13 PY 2009 VL 206 IS 4 BP 867 EP 876 DI 10.1084/jem.20082731 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VX UT WOS:000266009600013 PM 19307325 ER PT J AU Maldonado, RA Soriano, MA Perdomo, LC Sigrist, K Irvine, DJ Decker, T Glimcher, LH AF Maldonado, Roberto A. Soriano, Michelle A. Perdomo, L. Carolina Sigrist, Kirsten Irvine, Darrell J. Decker, Thomas Glimcher, Laurie H. TI Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INTERFERON-GAMMA-RECEPTOR; STAT1 TRANSACTIVATION DOMAIN; NFAT FAMILY-MEMBERS; IFN-GAMMA; SIGNAL-TRANSDUCTION; IN-VIVO; SERINE PHOSPHORYLATION; GENE-EXPRESSION; DENDRITIC CELLS; BETA CHAIN AB The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-gamma receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-gamma ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors. C1 [Maldonado, Roberto A.; Soriano, Michelle A.; Sigrist, Kirsten; Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Perdomo, L. Carolina] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Glimcher, Laurie H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Biol Engn Div, Cambridge, MA 02139 USA. [Decker, Thomas] Univ Vienna, Dept Microbiol & Immunobiol, Max F Perutz Labs, A-1030 Vienna, Austria. RP Glimcher, LH (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM lglimche@hsph.harvard.edu FU National Institutes of Health [P01 NS038037]; Kelli and Gerald Ford Irvington Institute Postdoctoral; Austrian Science Foundation (FWF) [SFB28] FX We thank Drs. Michael Grusby, Wendy Garrett, and Marc Wein for thoughtful review of the manuscript, Drs. H. Cantor and R. Schreiber for sharing animals and antibodies and Landy Kangaloo for valuable technical help. This work was supported by National Institutes of Health grant P01 NS038037 (LHG). R. M. is a recipient of the Kelli and Gerald Ford Irvington Institute Postdoctoral Fellowship. TD is supported by the Austrian Science Foundation (FWF) through grant SFB28. LHG is a member of the Board of Directors of and holds equity in the Bristol Myers Squibb Corporation. The authors have no conflicting financial interests. NR 80 TC 31 Z9 31 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 13 PY 2009 VL 206 IS 4 BP 877 EP 892 DI 10.1084/jem.20082900 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VX UT WOS:000266009600014 PM 19349465 ER PT J AU Crawford, H Lumm, W Leslie, A Schaefer, M Boeras, D Prado, JG Tang, JM Farmer, P Ndung'u, T Lakhi, S Gilmour, J Goepfert, P Walker, BD Kaslow, R Mulenga, J Allen, S Goulder, PJR Hunter, E AF Crawford, Hayley Lumm, Wendy Leslie, Alasdair Schaefer, Malinda Boeras, Debrah Prado, Julia G. Tang, Jianming Farmer, Paul Ndung'u, Thumbi Lakhi, Shabir Gilmour, Jill Goepfert, Paul Walker, Bruce D. Kaslow, Richard Mulenga, Joseph Allen, Susan Goulder, Philip J. R. Hunter, Eric TI Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LYMPHOCYTE-BASED CONTROL; DISCORDANT COUPLES; HLA-B; RHESUS MACAQUES; VACCINE TRIAL; VIRAL LOAD; INFECTION; AIDS; GAG AB HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade-infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703 restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. In HLA-B*5703-mismatched recipients, the previously described early benefit of transmitted HLA-B*5703-associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes. C1 [Lumm, Wendy; Schaefer, Malinda; Boeras, Debrah; Farmer, Paul; Allen, Susan; Hunter, Eric] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Crawford, Hayley; Leslie, Alasdair; Prado, Julia G.; Goulder, Philip J. R.] Univ Oxford, Dept Pediat, Oxford OX1 3SY, England. [Lumm, Wendy; Schaefer, Malinda; Boeras, Debrah; Farmer, Paul; Allen, Susan; Hunter, Eric] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30329 USA. [Tang, Jianming; Kaslow, Richard] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Tang, Jianming; Kaslow, Richard] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip J. R.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4013 Durban, South Africa. [Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip J. R.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02129 USA. [Lakhi, Shabir; Mulenga, Joseph; Allen, Susan; Hunter, Eric] Zambia Emory HIV Res Project, Lusaka, Zambia. [Gilmour, Jill] Chelsea & Westminster Hosp, Core Lab, Int AIDS Vaccine Initiat, London SW10 9NH, England. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Mulenga, Joseph] Zambia Blood Transfus Serv, Lusaka, Zambia. RP Hunter, E (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30329 USA. EM eric.hunter2@emory.edu OI Tang, Jianming/0000-0003-0137-7486; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institutes of Health [AI-64060, AI-46995, AI-067073]; Bill & Melinda Gates Foundation [37874]; Wellcome Trust; Department for International Development and the Commonwealth Scholarship Commission; International AIDS Vaccine Initiative; Elizabeth Glaser Pediatric AIDS Foundation FX This work was supported by the National Institutes of Health (grant AI-64060 to E. Hunter, grant AI-46995 to P. J. R. Goulder, and grant AI-067073 B. D. Walker), the Bill & Melinda Gates Foundation Grand Challenges Program (grant 37874 to E. Hunter), the Wellcome Trust (P. J. R. Goulder and A. Leslie), the Department for International Development and the Commonwealth Scholarship Commission (H. Crawford), and the International AIDS Vaccine Initiative (S. Allen, B. D. Walker, and E. Hunter). E. Hunter is a Georgia Research Alliance Eminent Scholar, P. J. R. Goulder is an Elizabeth Glaser Pediatric AIDS Foundation Scientist, and T. Ndung'u holds the South African Research Chair in Systems Biology of HIV/AIDS. NR 41 TC 117 Z9 122 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 13 PY 2009 VL 206 IS 4 BP 909 EP 921 DI 10.1084/jem.20081984 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VX UT WOS:000266009600016 PM 19307327 ER PT J AU Wrighton, KH Lin, X Yu, PB Feng, XH AF Wrighton, Katharine H. Lin, Xia Yu, Paul B. Feng, Xin-Hua TI Transforming Growth Factor beta Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA; SIGNAL-TRANSDUCTION; FUNCTIONAL-CHARACTERIZATION; SPECIFICITY; ACTIVATION; ALK5; LOOP AB Transforming growth factor-beta (TGF beta) superfamily ligands control a diverse set of cellular processes by activating type I and type II serine-threonine receptor kinases. Canonical TGF beta signaling is mediated via the T beta RI/ALK5 type I receptor that phosphorylates Smad2 and Smad3 in their SXS motif to facilitate their activation and subsequent role in transcriptional regulation. Canonical bone morphogenic protein (BMP) signaling is mediated via the ALK1/2/3/6 type I receptors that phosphorylate Smad1, Smad5, and Smad8 in their SXS motif. However, studies in endothelial cells have shown that TGF beta can also lead to the phosphorylation of Smad1, dependent on ALK1 receptor activity. Here we present data showing that TGF beta can significantly induce Smad1 phosphorylation in several non-endothelial cell lineages. Additionally, by using chemical inhibitors specific for the TGF beta/activin/nodal (ALK4/5/7) and BMP (ALK1/2/3/6) type I receptors, we show that in some cell types TGF beta induces Smad1 phosphorylation independently of the BMP type I receptors. Thus, TGF beta-mediated Smad1 phosphorylation appears to occur via different receptor complexes in a cell type-specific manner. C1 [Wrighton, Katharine H.; Feng, Xin-Hua] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Wrighton, Katharine H.; Lin, Xia; Feng, Xin-Hua] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Yu, Paul B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr,Dept Med, Boston, MA 02114 USA. [Yu, Paul B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Boston, MA 02114 USA. RP Feng, XH (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza,Rm 137D, Houston, TX 77030 USA. EM xfeng@bcm.edu OI Yu, Paul/0000-0003-2145-4944 FU National Institutes of Health [R01DK073932, R01CA108454, R01AR053591, P50HL083794] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DK073932 ( to X. L.) and R01CA108454, R01AR053591, and P50HL083794 ( X.- H. F.). NR 20 TC 80 Z9 82 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 10 PY 2009 VL 284 IS 15 BP 9755 EP 9763 DI 10.1074/jbc.M809223200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429AJ UT WOS:000264892900015 PM 19224917 ER PT J AU Schrag, D AF Schrag, Deborah TI Evaluating the Impact of Organizational Changes in Health Care Delivery: Challenges in Study Design SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID TRIALS C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Schrag, D (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 6 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 10 PY 2009 VL 27 IS 11 BP 1744 EP 1745 DI 10.1200/JCO.2008.19.7756 PG 2 WC Oncology SC Oncology GA 447ME UT WOS:000266194400005 PM 19273700 ER PT J AU Bertagnolli, MM Niedzwiecki, D Compton, CC Hahn, HP Hall, M Damas, B Jewell, SD Mayer, RJ Goldberg, RM Saltz, LB Warren, RS Redston, M AF Bertagnolli, Monica M. Niedzwiecki, Donna Compton, Carolyn C. Hahn, Hejin P. Hall, Margaret Damas, Beatrice Jewell, Scott D. Mayer, Robert J. Goldberg, Richard M. Saltz, Leonard B. Warren, Robert S. Redston, Mark TI Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; FRAMESHIFT MUTATIONS; MUTATOR PHENOTYPE; GENE; CELLS; MECHANISM; CPT-11; HMLH1; CARCINOGENESIS; CAMPTOTHECIN AB Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) - based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono-and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV. J Clin Oncol 27: 1814-1821. (C) 2009 by American Society of Clinical Oncology C1 [Bertagnolli, Monica M.] Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Canc & Leukemia Grp Stat Ctr B, Med Ctr, Durham, NC 27706 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM mbertagnolli@partners.org RI Goldberg , Richard/M-1311-2013; OI Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [CA31946, CA33601, U10 CA031946, U10 CA033601] NR 35 TC 201 Z9 208 U1 0 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 10 PY 2009 VL 27 IS 11 BP 1814 EP 1821 DI 10.1200/JCO.2008.18.2071 PG 8 WC Oncology SC Oncology GA 447ME UT WOS:000266194400016 PM 19273709 ER PT J AU Lohoff, FW Bloch, PJ Ferraro, TN Berrettini, WH Pettinati, HM Dackis, CA O'Brien, CP Kampman, KM Oslin, DW AF Lohoff, Falk W. Bloch, Paul J. Ferraro, Thomas N. Berrettini, Wade H. Pettinati, Helen M. Dackis, Charles A. O'Brien, Charles P. Kampman, Kyle M. Oslin, David W. TI Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence SO NEUROSCIENCE LETTERS LA English DT Article DE Addiction; Association study; Cocaine; Neurotrophic factor; Genetics; Substance abuse; ARMETL1 ID POPULATION-BASED SAMPLE; RECEPTOR GENE; TYROSINE-HYDROXYLASE; LINKAGE DISEQUILIBRIUM; AFRICAN-AMERICANS; ADMIXED POPULATIONS; ADMIXTURE DYNAMICS; GENOMIC CONTROL; DRUG-ADDICTION; NO ASSOCIATION AB Cocaine-induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neurons and is expressed in brain regions that undergo cocaine-induced neuroplasticity. In this study, we hypothesize that polymorphisms in the CDNF gene (CDNF/ARMETL1) contribute to increased risk for cocaine dependence. Cocaine dependent individuals (n = 351) and unaffected controls (n = 257) of African descent were ere genotyped for four single nucleotide polymorphisms (SNPs) in the CDNF gene (rs11259365, rs7094179, rs7900873. rs2278871). We observed no significant differences in allele, genotype, or haplotype frequencies between cases and controls for any of the tested SNPs. Our study suggests that there is no association between variants in the CDNF gene and cocaine dependence. However, additional studies using larger sample sizes, comprehensive SNP coverage, and clinically homogenous populations are necessary before confidently excluding CDNF as a significant genetic risk factor for cocaine dependence. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Lohoff, Falk W.] Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav,Translat Res Labs, Philadelphia, PA 19104 USA. [Pettinati, Helen M.; Dackis, Charles A.; O'Brien, Charles P.; Kampman, Kyle M.; Oslin, David W.] Univ Penn, Sch Med, Dept Psychiat, Treatment Res Ctr, Philadelphia, PA 19104 USA. [Oslin, David W.] VISN 4 MIRECC, Vet Affairs Med Ctr, Philadelphia, PA USA. RP Lohoff, FW (reprint author), Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav,Translat Res Labs, 125 S 31st St, Philadelphia, PA 19104 USA. EM lohoff@mail.med.upenn.edu RI Lohoff, Falk/M-7951-2016 FU Center for Neurobiology and Behavior; Department of Psychiatry, University of Pennsylvania; National Institutes of Health [K08MH080372]; NIDA [P60-051186]; Veterans Affairs Administration [P50-12756]; Tzedakah Foundation; Philip and Marcia Cohen FX This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania. Financial support is gratefully acknowledged from National Institutes of Health grants K08MH080372 (F.W.L.), NIDA grants P60-051186 (C.P.O.) and P50-12756 (H.M.P), the VISN4 Mental Illness Research and Clinical Center grant from the Veterans Affairs Administration (D.W.O.), a grant from the Tzedakah Foundation (W.H.B.) and a grant from Philip and Marcia Cohen (W.H.B.). Most importantly, we thank the subjects who have participated in and contributed to these studies. NR 54 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD APR 10 PY 2009 VL 453 IS 3 BP 199 EP 203 DI 10.1016/j.neulet.2009.02.026 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 429UW UT WOS:000264946600016 PM 19429035 ER PT J AU Gekas, C Rhodes, KE Gereige, LM Helgadottir, H Ferrari, R Kurdistani, SK Montecino-Rodriguez, E Bassel-Duby, R Olson, E Krivtsov, AV Armstrong, S Orkin, SH Pellegrini, M Mikkola, HKA AF Gekas, Christos Rhodes, Katrin E. Gereige, Laurraine M. Helgadottir, Hildur Ferrari, Roberto Kurdistani, Siavash K. Montecino-Rodriguez, Encarnacion Bassel-Duby, Rhonda Olson, Eric Krivtsov, Andrei V. Armstrong, Scott Orkin, Stuart H. Pellegrini, Matteo Mikkola, Hanna K. A. TI Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR MEF2C; HEMATOPOIETIC STEM-CELLS; SKELETAL-MUSCLE DEVELOPMENT; HELIX-LOOP-HELIX; VASCULAR DEVELOPMENT; GENE-EXPRESSION; MYOGENIC BHLH; LEUKEMIA GENE; BONE-MARROW; FACTOR SCL AB The basic helix-loop-helix transcription factor stem cell leukemia gene (Scl) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Scl(fl/fl) fetal liver progenitor cell lines. Analysis of Mef2C(-/-) embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre(+)Mef2C(fl/fl) mice exhibited platelet defects similar to those observed in Scl-deficient mice. The platelet counts were reduced, whereas platelet size was increased and the platelet shape and granularity were altered. Furthermore, megakaryopoiesis was severely impaired in vitro. Chromatin immunoprecipitation microarray hybridization analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl-independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B-cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages. (Blood. 2009; 113: 3461-3471) C1 [Gekas, Christos; Rhodes, Katrin E.; Gereige, Laurraine M.; Pellegrini, Matteo; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Helgadottir, Hildur; Armstrong, Scott; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Ferrari, Roberto; Kurdistani, Siavash K.] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. [Montecino-Rodriguez, Encarnacion] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Bassel-Duby, Rhonda; Olson, Eric] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Krivtsov, Andrei V.; Armstrong, Scott; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Cambridge, MA 02138 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Stem Cell Inst, Boston, MA USA. [Pellegrini, Matteo; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Mikkola, Hanna K. A.] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Mikkola, Hanna K. A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Mikkola, HKA (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, 621 Charles E Young Dr S,LSB 2204, Los Angeles, CA 90095 USA. EM hmikkola@mcdb.ucla.edu RI Gekas, Christos/M-3209-2015; OI Gekas, Christos/0000-0002-3429-4145; Kurdistani, Siavash/0000-0003-3295-3511 FU Cancer Research Coordinating Committee (Davis, CA); Stop Cancer Foundation (Los Angeles, CA); V Foundation for Cancer Research (Cary, NC); California Institute for Regenerative Medicine (San Francisco, CA); Ruth L. Kirschstein National Research Service Award [GM07185] FX The authors thank Suvi Aivio, Mattias Magnusson, and Yanling Wang for excellent technical assistance, the staff at University of California-Los Angeles Division of Laboratory Animal Medicine laboratory for blood analysis, Marianne Cilluffo and Alicia Thompson for their expertise in electron microscopy, the University of California-Los Angeles Flow Cytometry Core for FACS sorting, and Kenneth Dorshkind for critical reading of the manuscript.; This work was supported by grants from the Cancer Research Coordinating Committee (Davis, CA), the Stop Cancer Foundation (Los Angeles, CA), the V Foundation for Cancer Research (Cary, NC) and the California Institute for Regenerative Medicine (San Francisco, CA) to H. K. A. M.), and a Ruth L. Kirschstein National Research Service Award at University of California-Los Angeles (Bethesda, MD; GM07185, to K. E. R). NR 49 TC 25 Z9 27 U1 0 U2 2 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 APR 9 PY 2009 VL 113 IS 15 BP 3461 EP 3471 DI 10.1182/blood-2008-07-167577 PG 11 WC Hematology SC Hematology GA 431HN UT WOS:000265052300011 PM 19211936 ER PT J AU Kurtz, J Raval, F Vallot, C Der, J Sykes, M AF Kurtz, Josef Raval, Forum Vallot, Casey Der, Jayden Sykes, Megan TI CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; DONOR-SPECIFIC TRANSFUSION; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; CARDIAC ALLOGRAFT-REJECTION; VERSUS-HOST-DISEASE; GROWTH-FACTOR-BETA; IN-VIVO; MIXED CHIMERISM; CUTTING EDGE; HEMATOPOIETIC CHIMERISM AB Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell-intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell-intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86(+) non-T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells. (Blood. 2009; 113: 3475-3484) C1 [Kurtz, Josef; Raval, Forum; Vallot, Casey; Der, Jayden; Sykes, Megan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bone Marrow Transplantat Sect,Transplantat Biol R, Boston, MA 02129 USA. [Kurtz, Josef; Raval, Forum; Vallot, Casey] Univ Cambridge Emmanuel Coll, Dept Biol, Boston, MA USA. RP Sykes, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bone Marrow Transplantat Sect,Transplantat Biol R, MGH E Bldg 149-5102,13th St, Boston, MA 02129 USA. EM megan.sykes@tbrc.mgh.harvard.edu FU NIH [R01HL49915] FX We thank Dr Thomas Wekerle and Dr Emmanuel Zorn for critical review of the paper, Joia Spinelli for assistance with DKO/TKO experiments, and Ms KellyWalsh for assistance in paper preparation.; This work was supported by NIH grant R01HL49915. NR 75 TC 25 Z9 25 U1 0 U2 0 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 APR 9 PY 2009 VL 113 IS 15 BP 3475 EP 3484 DI 10.1182/blood-2008-01-133736 PG 10 WC Hematology SC Hematology GA 431HN UT WOS:000265052300013 PM 19179471 ER PT J AU Wang, H Asavaroengchai, W Yeap, BY Wang, MG Wang, SM Sykes, M Yang, YG AF Wang, Hui Asavaroengchai, Wannee Yeap, Beow Yong Wang, Min-Guang Wang, Shumei Sykes, Megan Yang, Yong-Guang TI Paradoxical effects of IFN-gamma in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CD8 T-CELLS; REFRACTORY HEMATOLOGIC MALIGNANCIES; IDIOPATHIC PNEUMONIA SYNDROME; CYTOKINE GENE-EXPRESSION; ANTIGEN-PRESENTING CELLS; MURINE RENAL-CANCER; INTERFERON-GAMMA; ALPHA; MICE AB Interferon-gamma (IFN-gamma) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-gamma in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-gamma-deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-gamma plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6 -> BALB/c) chimeras. IFN-gamma promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-gamma enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-gamma-induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-gamma reduces the potential of this allo-reactivity to cause epithelial tissue GVHD. (Blood. 2009; 113: 3612-3619) C1 [Wang, Hui; Asavaroengchai, Wannee; Wang, Shumei; Sykes, Megan; Yang, Yong-Guang] Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, Boston, MA 02129 USA. [Yeap, Beow Yong] Harvard Univ, Dept Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. [Wang, Min-Guang] Lower Columbia Pathologists, Longview, WA USA. RP Yang, YG (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. EM yongguang.yang@tbrc.mgh.harvard.edu FU National Institutes of Health (Bethesda, MD) [5P01CA111519-020002]; American Cancer Society (Atlanta, GA) [RSG-03-227-01-LIB] FX The authors thank Drs Christene Huang and Giovanna Andreola for critical review of this manuscript, Mr Orlando Moreno for outstanding animal husbandry, and Ms Kelly Walsh for expert assistance with the manuscript.; This work was supported by grants from National Institutes of Health (Bethesda, MD; 5P01CA111519-020002) and American Cancer Society (Atlanta, GA; RSG-03-227-01-LIB). NR 46 TC 27 Z9 31 U1 0 U2 0 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 APR 9 PY 2009 VL 113 IS 15 BP 3612 EP 3619 DI 10.1182/blood-2008-07-168419 PG 8 WC Hematology SC Hematology GA 431HN UT WOS:000265052300030 PM 19211507 ER PT J AU Saenz, J Toner, M Risco, R AF Saenz, Jaime Toner, Mehmet Risco, Ramon TI Comparison between Ideal and Nonideal Solution Models for Single-Cell Cryopreservation Protocols SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID AQUEOUS-SOLUTIONS; STRONG ELECTROLYTES; PERMEABILITY; SPERMATOZOA; TRANSPORT; DIMETHYL; HUCKEL; VOLUME; DEBYE AB Models for cell dehydration during a cryopreservation protocol are usually based on the hypothesis of id a dilute solution. The strong electrolyte character of NaCl makes us revisit these models. The case of nonideal solution is analyzed by computing the dehydration curves without this additional hypothesis. The conclusion is that, in general, while the application of the ideal dilute solution hypothesis is convenient in many cases, for some specific cooling rates there exist important differences in the degree of dehydration predicted by these two models in the studied cases of mouse sperm and hepatocyte. It is shown how this finding has relevant implications for the design and optimization of cryopreservation protocols. C1 [Saenz, Jaime; Risco, Ramon] Univ Seville, Escuela Super Ingn, Seville 41092, Spain. [Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. RP Risco, R (reprint author), Univ Seville, Escuela Super Ingn, Seville 41092, Spain. EM ramon@us.es OI Risco Delgado, Ramon/0000-0001-5995-6590 NR 40 TC 6 Z9 6 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD APR 9 PY 2009 VL 113 IS 14 BP 4853 EP 4864 DI 10.1021/jp807274z PG 12 WC Chemistry, Physical SC Chemistry GA 427UW UT WOS:000264805600048 PM 19338369 ER PT J AU Blumenthal, D AF Blumenthal, David TI Stimulating the Adoption of Health Information Technology. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Blumenthal, David] Massachusetts Gen Hosp Partners Healthcare Syst, Inst Hlth Policy, Boston, MA 02114 USA. [Blumenthal, David] Harvard Univ, Sch Med, Boston, MA USA. RP Blumenthal, D (reprint author), Massachusetts Gen Hosp Partners Healthcare Syst, Inst Hlth Policy, Boston, MA 02114 USA. RI Tao, Youyou/D-2367-2014 NR 0 TC 316 Z9 318 U1 0 U2 18 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1477 EP 1479 DI 10.1056/NEJMp0901592 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800001 PM 19321856 ER PT J AU Campbell, EG AF Campbell, Eric G. TI The Future of Research Funding in Academic Medicine. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Campbell, Eric G.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA USA. RP Campbell, EG (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. NR 4 TC 18 Z9 19 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1482 EP 1483 DI 10.1056/NEJMp0900132 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800003 PM 19357403 ER PT J AU Cypess, AM Lehman, S Williams, G Tal, I Rodman, D Goldfine, AB Kuo, FC Palmer, EL Tseng, Y Doria, A Kolodny, GM Kahn, CR AF Cypess, Aaron M. Lehman, Sanaz Williams, Gethin Tal, Ilan Rodman, Dean Goldfine, Allison B. Kuo, Frank C. Palmer, Edwin L. Tseng, Yu-Hua Doria, Alessandro Kolodny, Gerald M. Kahn, C. Ronald TI Identification and Importance of Brown Adipose Tissue in Adult Humans. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DIET-INDUCED THERMOGENESIS; F-18-FDG PET/CT; FDG-UPTAKE; USA-FAT; OBESITY; TEMPERATURE; PATIENT; MUSCLE; SCANS AB Background: Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods: We analyzed 3640 consecutive (sup 18)F-fluorodeoxyglucose ((sup 18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (sup 18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. Results: Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (sup 18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). Conclusions: Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (sup 18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism. N Engl J Med 2009;360:1509-17. C1 [Kahn, C. Ronald] Joslin Diabet Ctr, Sect Obes & Hormone Act, Div Res, Boston, MA 02215 USA. [Lehman, Sanaz; Williams, Gethin; Tal, Ilan; Rodman, Dean; Kolodny, Gerald M.] Beth Israel Deaconess Med Ctr, Div Nucl Med, Boston, MA 02215 USA. [Kuo, Frank C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Palmer, Edwin L.] Massachusetts Gen Hosp, Div Nucl Med, Boston, MA 02114 USA. [Cypess, Aaron M.; Lehman, Sanaz; Williams, Gethin; Tal, Ilan; Rodman, Dean; Goldfine, Allison B.; Kuo, Frank C.; Palmer, Edwin L.; Tseng, Yu-Hua; Doria, Alessandro; Kolodny, Gerald M.; Kahn, C. Ronald] Harvard Univ, Sch Med, Boston, MA USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Obes & Hormone Act, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health [DK070722, P30 DK46200, DK33201, DK55545, DK046200-16]; Eli Lilly Foundation FX Supported by the Clinical Investigator Training Program, Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer and Merck; grants from the National Institutes of Health (DK070722 and P30 DK46200 [to Dr. Tseng], DK33201 and DK55545 [to Dr. Kahn], and DK046200-16 [to Dr. Cypess]); and the Eli Lilly Foundation. NR 41 TC 1391 Z9 1448 U1 32 U2 169 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1509 EP 1517 DI 10.1056/NEJMoa0810780 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800007 PM 19357406 ER PT J AU Bell, SK Rosenberg, ES AF Bell, Sigall K. Rosenberg, Eric S. TI A Man with Fever, Headache, Rash, and Vomiting Acute HIV-1 infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; T-CELL RESPONSES; UNITED-STATES; ASEPTIC-MENINGITIS; TYPE-1 INFECTION; TRANSMISSION; DISEASE; LYMPHOCYTES; RESISTANCE C1 [Bell, Sigall K.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Rosenberg, Eric S.] Massachusetts Gen Hosp, Infect Dis Unit, Dept Pathol, Boston, MA 02114 USA. [Bell, Sigall K.; Rosenberg, Eric S.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Rosenberg, Eric S.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Bell, SK (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. NR 38 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1541 EP 1549 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800012 ER PT J AU Miclea, RL Karperien, M Bosch, CA van der Horst, G van der Valk, MA Kobayashi, T Kronenberg, HM Rawadi, G Akcakaya, P Lowik, CWGM Fodde, R Wit, JM Robanus-Maandag, EC AF Miclea, Razvan L. Karperien, Marcel Bosch, Cathy A. J. van der Horst, Geertje van der Valk, Martin A. Kobayashi, Tatsuya Kronenberg, Henry M. Rawadi, Georges Akcakaya, Pinar Lowik, Clemens W. G. M. Fodde, Riccardo Wit, Jan Maarten Robanus-Maandag, Els C. TI Adenomatous polyposis coli-mediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID CHONDROCYTE DIFFERENTIATION; ENDOCHONDRAL OSSIFICATION; ARTICULAR CHONDROCYTES; BONE-FORMATION; NASAL-SEPTUM; GROWTH-PLATE; MOUSE; EXPRESSION; OSTEOBLAST; MICE AB Background: During skeletogenesis, protein levels of beta-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of beta-catenin turnover by down-regulating intracellular levels of beta-catenin. Results: To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of beta-catenin was used, our approach resulted in the accumulation of wild type beta-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells. Conclusion: Our data indicate that a tight Apc-mediated control of beta-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner. C1 [Karperien, Marcel] Univ Twente, Inst Biomed Technol, Dept Tissue Regenerat, NL-7500 AE Enschede, Netherlands. [Miclea, Razvan L.; Wit, Jan Maarten] Leiden Univ, Med Ctr, Dept Pediat, Leiden, Netherlands. [Bosch, Cathy A. J.; Akcakaya, Pinar; Robanus-Maandag, Els C.] LUMC, Dept Human Genet, Leiden, Netherlands. [van der Horst, Geertje] Leiden Univ, Med Ctr, Dept Urol, Leiden, Netherlands. [van der Valk, Martin A.] Netherlands Canc Inst, Dept Anim Pathol, Amsterdam, Netherlands. [Kobayashi, Tatsuya; Kronenberg, Henry M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit,Dept Med, Boston, MA USA. [Rawadi, Georges] Galapagos, F-93230 Romainville, France. [Lowik, Clemens W. G. M.] Leiden Univ, Med Ctr, Dept Endocrinol & Metab Dis, Leiden, Netherlands. [Fodde, Riccardo] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. RP Karperien, M (reprint author), Univ Twente, Inst Biomed Technol, Dept Tissue Regenerat, POB 217, NL-7500 AE Enschede, Netherlands. EM r.l.miclea@lumc.nl; h.b.j.karperien@tnw.utwente.nl; c.a.j.bosch@lumc.nl; g.van_der_horst@lumc.nl; ma.vd.valk@nki.ni; kobayash@HELIX.MGH.HARVARD.EDU; hkronenberg@partners.org; georges.rawadi@glpg.com; pinarakcakaya@gmail.com; c.w.g.m.lowik@lumc.nl; r.fodde@erasmusmc.nl; j.m.wit@lumc.nl; e.c.robanus@lumc.nl OI Akcakaya, Pinar/0000-0001-5868-7069; Fodde, Riccardo/0000-0001-9839-4324 FU European Society for Pediatric Endocrinology (RLM) FX This work was financially supported by a short-term research fellowship from the European Society for Pediatric Endocrinology (RLM), an unrestricted educational grant from IPSEN FARMACEUTICA BV (RLM), a research grant from The Human Growth Foundation (MK), and a research grant from the Association for International Cancer Research (CAJB). NR 50 TC 28 Z9 30 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD APR 8 PY 2009 VL 9 AR 26 DI 10.1186/1471-213X-9-26 PG 14 WC Developmental Biology SC Developmental Biology GA 454BS UT WOS:000266657200001 PM 19356224 ER PT J AU Kawamori, D Kurpad, AJ Hu, J Liew, CW Shih, JL Ford, EL Herrera, PL Polonsky, KS McGuinness, OP Kulkarni, RN AF Kawamori, Dan Kurpad, Amarnath J. Hu, Jiang Liew, Chong Wee Shih, Judy L. Ford, Eric L. Herrera, Pedro L. Polonsky, Kenneth S. McGuinness, Owen P. Kulkarni, Rohit N. TI Insulin Signaling in alpha Cells Modulates Glucagon Secretion In Vivo SO CELL METABOLISM LA English DT Article ID RECURRENTLY HYPOGLYCEMIC RATS; SENSITIVE K+ CHANNELS; SWITCH-OFF HYPOTHESIS; BETA-CELL; ENDOCRINE PANCREAS; DIABETES-MELLITUS; RECEPTOR EXPRESSION; GENE-TRANSCRIPTION; A-CELL; GLUCOSE AB Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In, this study, we created and characterized alpha cell-specific insulin receptor knockout (alpha IRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alpha IRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alpha IRKO mice. The mutants also exhibited an age-dependent increase in 0 cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions. C1 [Kawamori, Dan; Kurpad, Amarnath J.; Hu, Jiang; Liew, Chong Wee; Shih, Judy L.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Dept Cellular & Mol Physiol, Joslin Diabet Ctr, Boston, MA 02215 USA. [Kawamori, Dan; Kurpad, Amarnath J.; Hu, Jiang; Liew, Chong Wee; Shih, Judy L.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Ford, Eric L.; Polonsky, Kenneth S.] Washington Univ, Sch Med, Div Metab, Dept Internal Med, St Louis, MO 63110 USA. [Herrera, Pedro L.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [McGuinness, Owen P.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37240 USA. RP Kulkarni, RN (reprint author), Harvard Univ, Sch Med, Dept Cellular & Mol Physiol, Joslin Diabet Ctr, Boston, MA 02215 USA. EM rohit.kulkarni@joslin.harvard.edu OI /0000-0003-0771-9504 FU Research Fellowship (Manpei Suzuki Diabetes Foundation, Japan); JDRF Postdoctoral Fellowship; American Diabetes Association Research [7-04-RA-55]; NIH [DK67536, 5P30DK36836, DK31842, DK56341]; Swiss National Science Foundation; the European Union; Washington University CTSA [UL1RR024992]; (Vanderbilt MMPC) [DK59637]; (Vanderbilt DRTC) [DK20593] FX We thank Dr. C. Ronald Kahn (Joslin) for insulin receptor floxed mice; Dr. Jacques Philippe (Geneva, Switzerland) for InR1G cells; Dr. K.C. Hayes (Brandeis University, MA) for housing of mice; Drs. Pierre Lefebvre (University of Liege, Belgium), Rory McCrimmon (Yale University, CT), and Ryo Suzuki (Joslin) for discussions; Dr. Susan Bonner-Weir (Joslin) for discussions regarding phloridzin experiments; Drs. Wataru Nishimura and Arun J. Sharma (Joslin) for neonatal pancreas sections; Hui Li (Specialized Assay Core, DERC, Joslin) for assays; and Lindsay Huse for excellent assistance with manuscript preparation. We especially acknowledge the valued and continued support of Cathy and Stan Bernstein for research work in the Kulkarni lab. D.K. is the recipient of a Research Fellowship (Manpei Suzuki Diabetes Foundation, Japan) and a JDRF Postdoctoral Fellowship. This work was supported, in part, by an American Diabetes Association Research Grant 7-04-RA-55 (R.N.K.), NIH DK67536 (R.N.K.), 5P30DK36836 (Joslin DERC Specialized Assay and Advanced Microscopy Cores), the Swiss National Science Foundation (P.L.H.), the NIH/NIDDK (Beta Cell Biology Consortium) (P.L.H.), JDRF (P.L.H.), the European Union (6th F.P.) (P.L.H.), NIH DK31842 and DK56341 (Washington University DRTC) (K.S.P.), UL1RR024992 (Washington University CTSA) (K.S.P.), DK59637 (Vanderbilt MMPC) (O.P.M.), and DK20593 (Vanderbilt DRTC) (O.P.M.). K.S.P. is an advisory board member for Pfizer Inc. NR 63 TC 122 Z9 127 U1 3 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD APR 8 PY 2009 VL 9 IS 4 BP 350 EP 361 DI 10.1016/j.cmet.2009.02.007 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 430YN UT WOS:000265028600008 PM 19356716 ER PT J AU Arai, K Lo, EH AF Arai, Ken Lo, Eng H. TI An Oligovascular Niche: Cerebral Endothelial Cells Promote the Survival and Proliferation of Oligodendrocyte Precursor Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROJECTION NEURONS; TROPHIC SUPPORT; BRAIN; IDENTIFICATION; NEUROGENESIS; ANGIOGENESIS; DISEASE; CNS AB We show that cerebral endothelial cells secrete trophic factors that support the survival and proliferation of rat oligodendrocyte precursor cells (OPCs). This OPC-supportive phenomenon was mediated by Akt and Src signaling pathways. Noncytotoxic levels of oxidative stress downregulate trophic factor production and disrupt the ability of cerebral endothelial cells to support OPCs. These data suggest that a novel oligovascular niche may be important for sustaining oligodendrocyte renewal and homeostasis in mammalian brain. C1 [Arai, Ken] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, MGH E 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org; lo@helix.mgh.harvard.edu FU Deane Foundation; American Heart Association; National Institutes of Health [R37-NS37074, R01-NS48422, R01-NS53560, P50-NS10828, P01-NS55104] FX This work was supported in part by the Deane Foundation, American Heart Association, and National Institutes of Health Grants R37-NS37074, R01-NS48422, R01-NS53560, P50-NS10828, and P01-NS55104. We thank Drs. Paul Rosenberg, Xiaoying Wang, Klaus van Leyen, Shuzhen Guo, Guang Jin, Jianfeng Xu, and Josephine Lok for many helpful discussions. NR 17 TC 77 Z9 77 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 8 PY 2009 VL 29 IS 14 BP 4351 EP 4355 DI 10.1523/JNEUROSCI.0035-09.2009 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 430ST UT WOS:000265009600004 PM 19357263 ER PT J AU Kutchukian, PS Yang, JS Verdine, GL Shakhnovich, EI AF Kutchukian, Peter S. Yang, Jae Shick Verdine, Gregory L. Shakhnovich, Eugene I. TI All-Atom Model for Stabilization of alpha-Helical Structure in Peptides by Hydrocarbon Staples SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RING-CLOSING METATHESIS; FREE-ENERGY SURFACES; FOLDING PROBLEM; AMINO-ACIDS; PHOTOSWITCHABLE PEPTIDE; EMPIRICAL PARAMETERS; DISULFIDE BONDS; CROSS-LINKS; NISIN-Z; PROTEIN AB Recent work has shown that the incorporation of an all-hydrocarbon "staple" into peptides can greatly increase their alpha-helix propensity, leading to an improvement in pharmaceutical properties such as proteolytic stability, receptor affinity, and cell permeability. Stapled peptides thus show promise as a new class of drugs capable of accessing intractable targets such as those that engage in intracellular protein-protein interactions. The extent of alpha-helix stabilization provided by stapling has proven to be substantially context dependent, requiring cumbersome screening to identify the optimal site for staple incorporation. In certain cases, a staple encompassing one turn of the helix (attached at residues i and i+4) furnishes greater helix stabilization than one encompassing two turns (i,i+7 staple), which runs counter to expectation based on polymer theory. These findings highlight the need for a more thorough understanding of the forces that underlie helix stabilization by hydrocarbon staples. Here we report all-atom Monte Carlo folding simulations comparing unmodified peptides derived from RNase A and BID BH3 with various i,i+4 and i,i+7 stapled versions thereof. The results of these simulations were found to be in quantitative agreement with experimentally determined helix propensities. We also discovered that staples can stabilize quasi-stable decoy conformations, and that the removal of these states plays a major role in determining the helix stability of stapled peptides. Finally, we critically investigate why our method works, exposing the underlying physical forces that stabilize stapled peptides. C1 [Kutchukian, Peter S.; Yang, Jae Shick; Verdine, Gregory L.; Shakhnovich, Eugene I.] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [Verdine, Gregory L.; Shakhnovich, Eugene I.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Kutchukian, Peter S.; Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. RP Shakhnovich, EI (reprint author), Harvard Univ, Dept Chem & Biol Chem, 12 Oxford St, Cambridge, MA 02138 USA. EM eugene@belok.harvard.edu RI Kutchukian, Peter/A-9826-2016 OI Kutchukian, Peter/0000-0002-5684-1971 FU NSF; NIH [GM52126] FX This work was supported by an NSF fellowship (to P.S.K.) and NIH grant GM52126 (to E.I.S.). We thank Stefan Wallin for helpful discussions. NR 58 TC 60 Z9 61 U1 2 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD APR 8 PY 2009 VL 131 IS 13 BP 4622 EP 4627 DI 10.1021/ja805037p PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 427VD UT WOS:000264806300033 PM 19334772 ER PT J AU di Tomaso, E London, N Fuja, D Logie, J Tyrrell, JA Kamoun, W Munn, LL Jain, RK AF di Tomaso, Emmanuelle London, Nyall Fuja, Daniel Logie, James Tyrrell, James A. Kamoun, Walid Munn, Lance L. Jain, Rakesh K. TI PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment SO PLOS ONE LA English DT Article ID PROTEASE-ACTIVATED LIGAND; GROWTH-FACTOR; BETA-RECEPTOR; KINASE INHIBITOR; ALPHA-RECEPTOR; STROMAL CELLS; BRAIN-TUMORS; IN-VIVO; EXPRESSION; ANGIOGENESIS AB Background: Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy. Principal Findings: We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors. Conclusion: These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization. RP di Tomaso, E (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, EL Steele Lab Tumor Biol, Boston, MA 02114 USA. EM munn@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu RI Tyrrell, James/A-6359-2010; Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU NCI NIH HHS [P01 CA080124, P01-CA80124] NR 43 TC 56 Z9 57 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 8 PY 2009 VL 4 IS 4 AR e5123 DI 10.1371/journal.pone.0005123 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437RX UT WOS:000265505700019 PM 19352490 ER PT J AU Walter, LC Lindquist, K Nugent, S Schult, T Lee, SJ Casadei, MA Partin, MR AF Walter, Louise C. Lindquist, Karla Nugent, Sean Schult, Tammy Lee, Sei J. Casadei, Michele A. Partin, Melissa R. TI Impact of Age and Comorbidity on Colorectal Cancer Screening Among Older Veterans SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID FECAL-OCCULT-BLOOD; SERVICES TASK-FORCE; HEALTH-CARE-SYSTEM; PREVENTIVE SERVICES; MEDICARE BENEFICIARIES; ELDERLY-PATIENTS; UNITED-STATES; PROSTATE; AFFAIRS; QUALITY AB Background: The Veterans Health Administration, the American Cancer Society, and the American Geriatrics Society recommend colorectal cancer screening for older adults unless they are unlikely to live 5 years or have significant comorbidity that would preclude treatment. Objective: To determine whether colorectal cancer screening is targeted to healthy older patients and is avoided in older patients with severe comorbidity who have life expectancies of 5 years or less. Design: Cohort study. Setting: Veterans Affairs (VA) medical centers in Minneapolis, Minnesota; Durham, North Carolina; Portland, Oregon; and West Los Angeles, California, with linked national VA and Medicare administrative claims. Patients: 27 068 patients 70 years or older who had an outpatient visit at 1 of 4 VA medical centers in 2001 or 2002 and were due for screening. Measurements: The main outcome was receipt of fecal occult blood testing (FOBT), colonoscopy, sigmoidoscopy, or barium enema in 2001 or 2002, on the basis of national VA and Medicare claims. Charlson-Deyo comorbidity scores at the start of 2001 were used to stratify patients into 3 groups ranging from no comorbidity (score of 0) to severe comorbidity (score >= 4), and 5-year mortality was determined for each group. Results: 46% of patients were screened from 2001 through 2002. Only 47% of patients with no comorbidity were screened despite having life expectancies greater than 5 years (5-year mortality, 19%). Although the incidence of screening decreased with age and worsening comorbidity, it was still 41% for patients with severe comorbidity who had life expectancies less than 5 years (5-year mortality, 55%). The number of VA outpatient visits predicted screening independent of comorbidity, such that patients with severe comorbidity and 4 or more visits had screening rates similar to or higher than those of healthier patients with fewer visits. Limitations: Some tests may have been performed for nonscreening reasons. The generalizability of findings to persons who do not use the VA system is uncertain. Conclusion: Advancing age was inversely associated with colorectal cancer screening, whereas comorbidity was a weaker predictor. More attention to comorbidity is needed to better target screening to older patients with substantial life expectancies and avoid screening older patients with limited life expectancies. C1 San Francisco VA Med Ctr, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Minneapolis Vet Affairs Med Ctr, Minneapolis, MN USA. RP Walter, LC (reprint author), Vet Affairs Med Ctr 181G, 4150 Clement St, San Francisco, CA 94121 USA. EM louise.walter@ucsf.edu FU VA Health Services Research and Development [IIR-04-427]; Robert Wood Johnson Physician Faculty Scholar FX Grant Support: Dr. Walter is supported by VA Health Services Research and Development grant IIR-04-427 and is a Robert Wood Johnson Physician Faculty Scholar. Dr. Lee is a Hartford Geriatrics Health Outcomes Research Scholar. NR 54 TC 89 Z9 89 U1 2 U2 7 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 7 PY 2009 VL 150 IS 7 BP 465 EP + PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 432EZ UT WOS:000265117600004 PM 19349631 ER PT J AU Rigotti, NA AF Rigotti, Nancy A. TI The Future of Tobacco Treatment in the Health Care System SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID UNITED-STATES; CESSATION; SMOKING; DEPENDENCE C1 [Rigotti, Nancy A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, 50 Staniford St, Boston, MA 02114 USA. EM nrigotti@partners.org NR 14 TC 5 Z9 7 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 7 PY 2009 VL 150 IS 7 BP 496 EP 497 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 432EZ UT WOS:000265117600009 PM 19349633 ER PT J AU Spuentrup, E Ruhl, KM Botnar, RM Wiethoff, AJ Buhl, A Jacques, V Greenfield, MT Krombach, GA Gunther, RW Vangel, MG Caravan, P AF Spuentrup, Elmar Ruhl, Karl M. Botnar, Rene M. Wiethoff, Andrea J. Buhl, Alexandra Jacques, Vincent Greenfield, Matthew T. Krombach, Gabriele A. Guenther, Rolf W. Vangel, Mark G. Caravan, Peter TI Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent Initial Feasibility Study in a Swine Model SO CIRCULATION LA English DT Article DE contrast media; coronary disease; ischemia; magnetic resonance imaging; perfusion ID CORONARY-ARTERY STENOSIS; ISCHEMIC-HEART; DISEASE; STRESS; MATRIX; VOLUME; DTPA AB Background-Cardiac magnetic resonance (MR) perfusion imaging during the first pass after intravenous administration of extracellular contrast agents is hampered by the spatial and temporal resolution achievable and by the artifacts seen in ultrafast MR imaging. Furthermore, time-consuming quantitative data analysis is often added. The use of molecular MR imaging with a target-specific contrast agent with perfusion-dependent binding to myocardium may enable prolonged visualization of perfusion defects and thus may help to overcome limitations of currently used first-pass extracellular MR imaging. EP-3600 is a new gadolinium-containing molecular contrast agent that binds reversibly to myocardial collagen. Methods and Results-A significant but nonocclusive coronary artery stenosis was modeled in 7 domestic swine with an undersized MR-compatible balloon positioned in the left anterior descending artery as verified by x-ray angiography. Two animals died before contrast injection as a result of arrhythmias. In 5 swine, high-spatial-resolution gradient echo imaging (approximate to 1 x 1 mm(2) in-plane resolution) was performed before and 5, 20, 40, and 60 minutes after intravenous administration of 12.3 mu mol/kg EP-3600. Contrast was administered during stress induced by an infusion of mu 250 . mol (.) kg(-1) . min(-1) adenosine. Yb-DTPA was administered simultaneously for comparison of myocardium-to-plasma ratios. Images were assessed subjectively by 2 investigators, and signal-to-noise and contrast-to-noise ratios over time were calculated. Normal myocardium showed a significant signal-to-noise ratio increase during the entire examination time. In all animals (n = 5), the perfusion defect in the left anterior descending artery territory could be visualized with a high contrast-to-noise ratio for at least 20 minutes after contrast injection. A significantly higher myocardium-to-plasma ratio was found for EP-3600 compared with the control agent Yb-DTPA (0.85 +/- 0.26 versus 0.22 +/- 0.08, respectively; P < 0.01). Conclusion-EP-3600 is a new molecular MR imaging contrast agent that binds to the myocardium and enables prolonged, high-contrast, high-spatial-resolution visualization of myocardial perfusion defects. (Circulation. 2009; 119: 1768-1775.) C1 [Spuentrup, Elmar] Univ Cologne, Univ Hosp, Dept Radiol, D-50924 Cologne, Germany. [Spuentrup, Elmar; Ruhl, Karl M.; Buhl, Alexandra; Krombach, Gabriele A.; Guenther, Rolf W.] Rhein Westfal TH Aachen, Univ Hosp, Dept Diagnost Radiol, Aachen, Germany. [Botnar, Rene M.] Tech Univ Munich, Dept Nucl Med, Munich, Germany. [Wiethoff, Andrea J.] Philips Med Syst, Best, Netherlands. [Jacques, Vincent; Greenfield, Matthew T.] EPIX Pharmaceut, Lexington, MA USA. [Vangel, Mark G.; Caravan, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Spuentrup, E (reprint author), Univ Cologne, Univ Hosp, Dept Radiol, Kerpener Str 62, D-50924 Cologne, Germany. EM spuenti@rad.rwth-aachen.de RI Botnar, Rene/E-6875-2012 OI Botnar, Rene/0000-0003-2811-2509 FU EPIX Pharmaceuticals, Lexington Mass,; German Research Council [SP634/2-1] FX This work was supported in part by EPIX Pharmaceuticals, Lexington, Mass, and the German Research Council (SP634/2-1). NR 27 TC 28 Z9 29 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 7 PY 2009 VL 119 IS 13 BP 1768 EP 1775 DI 10.1161/CIRCULATIONAHA.108.826388 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 429OA UT WOS:000264928800011 PM 19307474 ER PT J AU Aikawa, E Aikawa, M Libby, P Figueiredo, JL Rusanescu, G Iwamoto, Y Fukuda, D Kohler, RH Shi, GP Jaffer, FA Weissleder, R AF Aikawa, Elena Aikawa, Masanori Libby, Peter Figueiredo, Jose-Luiz Rusanescu, Gabriel Iwamoto, Yoshiko Fukuda, Daiju Kohler, Rainer H. Shi, Guo-Ping Jaffer, Farouc A. Weissleder, Ralph TI Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease SO CIRCULATION LA English DT Article DE calcification; aortic valve; atherosclerosis; kidney failure, chronic; elastin ID CHRONIC KIDNEY-DISEASE; SMOOTH-MUSCLE-CELLS; VASCULAR CALCIFICATION; CYSTATIN-C; ATHEROSCLEROTIC PLAQUES; POTENTIAL MECHANISM; VULNERABLE PLAQUE; ELASTIN PEPTIDES; IN-VIVO; FAILURE AB Background-Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy. Methods and Results-Apolipoprotein- deficient (apoE(-/-))/catS(+/+) (n = 24) and apoE(-/-) / catS(+/+) (n = 24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE(-/-) / catS(+/+) cohort, whereas CRD apoE (/) / catS (/) mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE(-/-) / catS(+/+) than CRD apoE(-/-) / catS(+/+) aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium. Conclusions-The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providing new insight into the pathophysiology of cardiovascular calcification. (Circulation. 2009; 119: 1785-1794.) C1 [Aikawa, Elena; Figueiredo, Jose-Luiz; Rusanescu, Gabriel; Iwamoto, Yoshiko; Kohler, Rainer H.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. [Aikawa, Elena; Aikawa, Masanori; Libby, Peter; Jaffer, Farouc A.; Weissleder, Ralph] Harvard Univ, Sch Med, Donald W Reynolds Cardiovasc Clin Res Ctr Atheros, Boston, MA USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Aikawa, Masanori; Libby, Peter; Fukuda, Daiju; Shi, Guo-Ping] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02115 USA. RP Aikawa, E (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 13th St,Room 5420, Charlestown, MA 02129 USA. EM eaikawa@mgh.harvard.edu OI Jaffer, Farouc/0000-0001-7980-384X FU Translational Program of Excellence in Nanotechnology; Donald W. Reynolds Foundation; Leducq Foundation [07CVD04]; American Heart Association [0835460N] FX This study was supported in part by the Donald W. Reynolds Foundation (Drs Libby and Weissleder), the Translational Program of Excellence in Nanotechnology ( Drs Weissleder and Aikawa), the Leducq Foundation (07CVD04; Dr Aikawa), and the American Heart Association ( 0835460N; Dr Aikawa). NR 48 TC 135 Z9 141 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 7 PY 2009 VL 119 IS 13 BP 1785 EP U162 DI 10.1161/CIRCULATIONAHA.108.827972 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 429OA UT WOS:000264928800013 PM 19307473 ER PT J AU Kimberly, WT Gilson, A Rost, NS Rosand, J Viswanathan, A Smith, EE Greenberg, SM AF Kimberly, W. T. Gilson, A. Rost, N. S. Rosand, J. Viswanathan, A. Smith, E. E. Greenberg, S. M. TI Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; LOBAR INTRACEREBRAL HEMORRHAGE; CLINICAL-DIAGNOSIS; ALZHEIMERS-DISEASE; DEMENTIA; RISK; LEUKOARAIOSIS; VALIDATION; COGNITION; AD AB Background: Neuropathologic studies suggest an association between cerebral amyloid angiopathy (CAA) and small ischemic infarctions as well as hemorrhages. We examined the prevalence and associated risk factors for infarcts detected by diffusion-weighted imaging (DWI). Methods: We performed retrospective analysis of MR images from 78 subjects with a diagnosis of probable CAA and a similar aged group of 55 subjects with Alzheimer disease or mild cognitive impairment (AD/MCI) for comparison. DWI and apparent diffusion coefficient (ADC) maps were inspected for acute or subacute infarcts. We also examined the association between DWI lesions and demographic variables, conventional vascular risk factors, and radiographic markers of CAA severity such as number of hemorrhages on gradient-echo MRI and volume of T2-hyperintense white matter lesions. Results: Twelve of 78 subjects with CAA (15%) had a total of 17 DWI-hyperintense lesions consistent with subacute cerebral infarctions vs 0 of 55 subjects with AD/MCI (p = 0.001). The DWI lesions were located primarily in cortex and subcortical white matter. CAA subjects with DWI lesions had a higher median number of total hemorrhages ( 22 vs 4, p = 0.025) and no difference in white matter hyperintensity volume or conventional vascular risk factors compared to subjects with CAA without lesions. Conclusions: MRI evidence of small subacute infarcts is present in a substantial proportion of living patients with advanced cerebral amyloid angiopathy ( CAA). The presence of these lesions is associated with a higher burden of hemorrhages, but not with conventional vascular risk factors. This suggests that advanced CAA predisposes to ischemic infarction as well as intracerebral hemorrhage. Neurology(R) 2009; 72: 1230-1235 C1 [Greenberg, S. M.] Massachusetts Gen Hosp, JP Kistler Stroke Res Ctr, Dept Neurol, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, JP Kistler Stroke Res Ctr, Dept Neurol, Hemorrhag Stroke Res Program, 175 Cambridge St, Boston, MA 02114 USA. EM sgreenberg@partners.org OI Smith, Eric/0000-0003-3956-1668 FU NIH [RO1 AG026484, K24 NS056207] FX Supported by NIH grants RO1 AG026484 and K24 NS056207. NR 30 TC 98 Z9 102 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 7 PY 2009 VL 72 IS 14 BP 1230 EP 1235 DI 10.1212/01.wnl.0000345666.83318.03 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 429OV UT WOS:000264930900008 PM 19349602 ER PT J AU Gao, X Schwarzschild, MA Wang, H Ascherio, A AF Gao, Xiang Schwarzschild, Michael A. Wang, Hao Ascherio, Alberto TI Obesity and restless legs syndrome in men and women SO NEUROLOGY LA English DT Article ID PARKINSONS-DISEASE; GENERAL-POPULATION; RISK; PREVALENCE; SLEEP; DOPAMINE; HEALTH; RLS; PATHOPHYSIOLOGY; EPIDEMIOLOGY AB Background: Obesity and restless legs syndrome (RLS) are both associated with hypofunction of dopamine in the CNS. We therefore examined whether individuals who are obese have an increased risk of RLS in two ongoing US cohorts, the Nurses' Health Study II and the Health Professional Follow-up Study. Methods: We included 65,554 women and 23,119 men free of diabetes, arthritis, and pregnancy in the current analyses. Information on RLS was assessed using a set of standardized questions. Participants were considered to have RLS if they met four RLS diagnostic criteria recommended by the International RLS Study Group and had restless legs >= 5 times/month. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression models adjusting for age, smoking, use of antidepressant, phobic anxiety score, and other covariates. Log ORs from the two cohorts were pooled by a fixed-effects model. Results: There were 6.4% of women and 4.1% of men who were considered to have RLS. Multivariate adjusted ORs for RLS were 1.42 (95% CI: 1.3, 1.6; p trend < 0.0001) for participants with body mass index (BMI) > 30 vs < 23 kg/m(2) and 1.60 (95% CI: 1.5, 1.8; p trend < 0.0001) for highest vs lowest waist circumference quintiles. Greater BMI in early adulthood ( age 18-21 years) and weight gain were also associated with a higher prevalence of RLS (p trend < 0.01 for both). Conclusions: Both overall and abdominal adiposity are associated with increased likelihoods of having restless legs syndrome ( RLS). Further prospective studies are warranted to clarify causative association between obesity and risk of developing RLS. Neurology(R) 2009; 72: 1255-1261 C1 [Gao, Xiang; Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Gao, Xiang; Wang, Hao; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gao, X (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM xiang.gao@channing.harvard.edu FU NIH/NINDS [R01 NS048517] FX Supported by NIH/NINDS grant R01 NS048517. NR 30 TC 61 Z9 63 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 7 PY 2009 VL 72 IS 14 BP 1255 EP 1261 DI 10.1212/01.wnl.0000345673.35676.1c PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 429OV UT WOS:000264930900012 PM 19349606 ER PT J AU Costello, DJ Sims, KB AF Costello, Daniel J. Sims, Katherine B. TI EFFICACY OF LAMOTRIGINE IN DISABLING MYOCLONUS IN A PATIENT WITH AN mtDNA A3243G MUTATION SO NEUROLOGY LA English DT Editorial Material C1 [Costello, Daniel J.] Massachusetts Gen Hosp, Dept Neurol, Epilepsy Serv, Boston, MA 02114 USA. [Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Neurogenet Serv, Boston, MA 02114 USA. [Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Costello, DJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Epilepsy Serv, ACC 835,55 Fruit St, Boston, MA 02114 USA. EM djcostello@partners.org NR 3 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 7 PY 2009 VL 72 IS 14 BP 1279 EP 1280 DI 10.1212/01.wnl.0000345663.71421.1d PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 429OV UT WOS:000264930900016 PM 19349610 ER PT J AU Bassett, EK Slocum, AH Masiakos, PT Pryor, HI Farokhzad, OC Karp, JM AF Bassett, Erik K. Slocum, Alexander H. Masiakos, Peter T. Pryor, Howard I., II Farokhzad, Omid C. Karp, Jeffery M. TI Design of a mechanical clutch-based needle-insertion device SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE catheter; helical-buckling; trocar ID WELLS AB Insertion of trocars, needles, and catheters into unintended tissues or tissue compartments results in hundreds of thousands of complications annually. Current methods for blood vessel cannulation or epidural, chest tube, and initial trocar placement often involve the blind pass of a needle through several layers of tissue and generally rely on distinguishable anatomic landmarks and a high degree of clinical skill. To address this simply and without the use of electronics, a purely mechanical clutch system was developed for use in medical devices that access tissue and tissue compartments. This clutch utilizes the surface contact of a buckled filament inside an S-shaped tube to transmit force from the filament (catheter/guide wire) to the tube (needle). Upon encountering sufficient resistance at the tip, such as dense tissue, the catheter buckles and locks within the tube, causing the filament and needle to advance as one. When the needle reaches the target tissue or fluid-filled cavity, the filament unlocks and slides freely into the target region while the needle remains stationary. A similar locking phenomenon has long been observed in drill strings inside drill shafts used by the oil-drilling industry, and oil industry models were adapted to describe the motion of this clutch system. A predictive analytical model was generated and validated with empirical data and used to develop prototypes of a complete device then tested in vitro on muscle tissue and in vivo on a porcine laparoscopic model with promising results. C1 [Bassett, Erik K.; Pryor, Howard I., II] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Bassett, Erik K.; Slocum, Alexander H.] Brigham & Womens Hosp, Dept Mech Engn, Ctr Biomed Engn, Cambridge, MA 02139 USA. [Karp, Jeffery M.] Brigham & Womens Hosp, Harvard Mit Div Hlth Sci & Technol, Ctr Biomed Engn, Cambridge, MA 02139 USA. [Karp, Jeffery M.] Brigham & Womens Hosp, Ctr Biomed Engn, MIT, Cambridge, MA 02139 USA. [Masiakos, Peter T.; Pryor, Howard I., II; Farokhzad, Omid C.; Karp, Jeffery M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Farokhzad, Omid C.] Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Masiakos, Peter T.] Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. RP Bassett, EK (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 55 Fruit St, Boston, MA 02114 USA. EM ebassett1@partners.org; jkarp@rics.bwh.harvard.edu FU Deshpande Center for Technological Innovation; Center for Integration of Medicine and Innovative Technology FX We thank Terrance Norchi for providing advice regarding translational considerations, Demos Pafitis at Schlumberger for directing us to appropriate oil industry references, Dr. Denise Gee for technical laparoscopic assistance, and Dr. Douglas Shook for providing operating room access to observe catheterization procedures. This work was supported by the Deshpande Center for Technological Innovation at the Massachusetts Institute of Technology and the Center for Integration of Medicine and Innovative Technology. NR 11 TC 8 Z9 9 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 7 PY 2009 VL 106 IS 14 BP 5540 EP 5545 DI 10.1073/pnas.0808274106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500018 PM 19307560 ER PT J AU Pitroda, SP Khodarev, NN Beckett, MA Kufe, DW Weichselbaum, RR AF Pitroda, Sean P. Khodarev, Nikolai N. Beckett, Michael A. Kufe, Donald W. Weichselbaum, Ralph R. TI MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE breast cancer; expression profiling; lipid metabolism; cholesterol biosynthesis; risk factors ID CARCINOMA-ASSOCIATED ANTIGEN; 2-GENE EXPRESSION RATIO; ESTROGEN-RECEPTOR; IONIZING-RADIATION; BETA-CATENIN; MUC1 GENE; ONCOPROTEIN; CELLS; SIGNATURE; RECURRENCE AB The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in human breast cancers. Although MUC1 modulates the activity of estrogen receptor alpha (ER), there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for breast cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of genes involved in cholesterol and fatty acid metabolism. A 38-gene set of experimentally derived MUC1-induced genes associated with lipid metabolism was applied to the analysis of ER(+) breast cancer patients treated with tamoxifen. The results obtained from 2 independent databases demonstrate that patients overexpressing MUC1 and the lipid metabolic pathways are at significantly higher risk for death and recurrence/distant metastasis. By contrast, these genes were not predictive in untreated patients. Furthermore, a positive correlation was found between expression of the 38-gene set and the ER signaling pathway. These findings indicate that (i) MUC1 regulates cholesterol and fatty acid metabolism, and (ii) activation of these pathways in ER(+) breast cancers predicts failure to tamoxifen treatment. C1 [Pitroda, Sean P.; Khodarev, Nikolai N.; Beckett, Michael A.; Weichselbaum, Ralph R.] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Kufe, Donald W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. EM rrw@radonc.bsd.uchicago.edu FU Lung Cancer Foundation; National Cancer Institute [CA71933, CA78766, CA97098] FX We thank Dr. Samuel Hellman for helpful discussion of the manuscript. These studies were supported by grants from the Lung Cancer Foundation and by National Cancer Institute Grants CA71933, CA78766, and CA97098. NR 41 TC 54 Z9 54 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 7 PY 2009 VL 106 IS 14 BP 5837 EP 5841 DI 10.1073/pnas.0812029106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500069 PM 19289846 ER PT J AU Soe-Lin, S Apte, SS Andriopoulos, B Andrews, MC Schranzhofer, M Kahawita, T Garcia-Santos, D Ponka, P AF Soe-Lin, Shan Apte, Sameer S. Andriopoulos, Billy, Jr. Andrews, Marc C. Schranzhofer, Matthias Kahawita, Tanya Garcia-Santos, Daniel Ponka, Prem TI Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hemolytic anemia; iron overload; iron homeostasis; hepcidin; ferroportin ID ANTIMICROBIAL PEPTIDE HEPCIDIN; NATURAL-RESISTANCE; MOUSE-LIVER; INTRACELLULAR PARASITES; FERROPORTIN DISEASE; MICROCYTIC ANEMIA; MOLECULAR CONTROL; KNOCKOUT MICE; GENE; ERYTHROPOIESIS AB Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of (59)Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed (59)Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed (59)Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload. C1 [Schranzhofer, Matthias; Kahawita, Tanya; Ponka, Prem] McGill Univ, Dept Physiol, Montreal, PQ H3A 2T5, Canada. [Soe-Lin, Shan; Ponka, Prem] McGill Univ, Div Expt Med, Montreal, PQ H3A 2T5, Canada. [Soe-Lin, Shan; Apte, Sameer S.; Schranzhofer, Matthias; Kahawita, Tanya; Garcia-Santos, Daniel; Ponka, Prem] Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Andrews, Marc C.] Inst Rech Clin Montreal, Dept Mol Genet & Dev, Montreal, PQ H2W 1R7, Canada. [Andriopoulos, Billy, Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, Boston, MA 02114 USA. RP Ponka, P (reprint author), Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, 3755 Cote Ste Catherine Rd, Montreal, PQ H3T 1E2, Canada. EM prem.ponka@mcgill.ca RI Ponka, Prem/A-4123-2011; OI Garcia dos Santos, Daniel/0000-0003-3894-427X FU Canadian Institutes of Health Research FX The authors thank Drs. Tomas Ganz, Antonello Pietrangelo, and Mitchell Knutson for their illuminating suggestions and advice; Dr. Philippe Gros (McGill University, Montreal) for his kind gift of mice and antibodies; and Ms. Jing Zhao for her assistance with erythropoietin measurements. This research was funded by grants from the Canadian Institutes of Health Research. NR 63 TC 71 Z9 79 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 7 PY 2009 VL 106 IS 14 BP 5960 EP 5965 DI 10.1073/pnas.0900808106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500090 PM 19321419 ER PT J AU Zhu, TF Szostak, JW AF Zhu, Ting F. Szostak, Jack W. TI Preparation of Large Monodisperse Vesicles SO PLOS ONE LA English DT Article AB Preparation of monodisperse vesicles is important both for research purposes and for practical applications. While the extrusion of vesicles through small pores (similar to 100 nm in diameter) results in relatively uniform populations of vesicles, extrusion to larger sizes results in very heterogeneous populations of vesicles. Here we report a simple method for preparing large monodisperse multilamellar vesicles through a combination of extrusion and large-pore dialysis. For example, extrusion of polydisperse vesicles through 5-mu m-diameter pores eliminates vesicles larger than 5 mu m in diameter. Dialysis of extruded vesicles against 3-mu m-pore-size polycarbonate membranes eliminates vesicles smaller than 3 mu m in diameter, leaving behind a population of monodisperse vesicles with a mean diameter of 4 mu m. The simplicity of this method makes it an effective tool for laboratory vesicle preparation with potential applications in preparing large monodisperse liposomes for drug delivery. C1 [Zhu, Ting F.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Zhu, Ting F.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Zhu, Ting F.] Harvard Univ, Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA USA. RP Zhu, TF (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NASA Exobiology Program [EXB02-0031-0018]; Howard Hughes Medical Institute FX This work was supported in part by grant EXB02-0031-0018 from the NASA Exobiology Program. JWS is an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 35 Z9 35 U1 3 U2 32 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 6 PY 2009 VL 4 IS 4 AR e5009 DI 10.1371/journal.pone.0005009 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437RS UT WOS:000265505200001 PM 19347043 ER PT J AU Brocklebank, D Gayan, J Andresen, JM Roberts, SA Young, AB Snodgrass, SR Penney, JB Ramos-Arroyo, MA Cha, JJ Rosas, HD Hersch, SM Feigin, A Cherny, SS Wexler, NS Housman, DE Cardon, LR AF Brocklebank, D. Gayan, J. Andresen, J. M. Roberts, S. A. Young, A. B. Snodgrass, S. R. Penney, J. B. Ramos-Arroyo, M. A. Cha, J. J. Rosas, H. D. Hersch, S. M. Feigin, A. Cherny, S. S. Wexler, N. S. Housman, D. E. Cardon, L. R. CA Int-Venezuela Collaborative TI Repeat Instability in the 27-39 CAG Range of the HD Gene in the Venezuelan Kindreds: Counseling Implications SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE trinucleotide repeat; Huntington's disease; genetic counseling ID HUNTINGTONS-DISEASE; INTERMEDIATE ALLELES; MUTATIONS AB The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from I I to 82 years. We expect these findings to be helpful in updating genetic counseling practices. (C) 2008 Wiley-Liss, Inc. C1 [Brocklebank, D.; Gayan, J.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Gayan, J.] Neocodex, Seville, Spain. [Andresen, J. M.; Housman, D. E.] MIT, Cambridge, MA 02139 USA. [Roberts, S. A.; Wexler, N. S.] Hereditary Dis Fdn, New York, NY USA. [Roberts, S. A.; Wexler, N. S.] Columbia Univ, New York, NY USA. [Young, A. B.; Cha, J. J.; Rosas, H. D.; Hersch, S. M.] Massachusetts Gen Hosp, Charlestown, MA USA. [Snodgrass, S. R.] Childrens Hosp, Los Angeles, CA 90027 USA. [Ramos-Arroyo, M. A.] Hosp Virgen Camino, Pamplona, Iruna, Spain. [Feigin, A.] N Shore Univ Hosp, Manhasset, NY USA. [Cherny, S. S.] Univ Hong Kong, Genome Res Ctr, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Cherny, S. S.] Univ Hong Kong, Li Ka Shing Fac Med, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. [Cardon, L. R.] GlaxoSmithKline Inc, King Of Prussia, PA USA. RP Brocklebank, D (reprint author), Univ Oxford, Wellcome Trust Ctr, Roosevelt Dr, Oxford OX3 7BN, England. EM deniseb@well.ox.ac.uk RI Cherny, Stacey/B-3315-2008 OI Cherny, Stacey/0000-0002-0269-3352 FU Hereditary Disease Foundation; NINDS; NIH; W.M. Keck Foundation; Wellcome Trust; [NS22031-15]; [EY-12562] FX We are indebted to the Venezuelan families who have participated in this project throughout all these years. Their generous collaboration has been critical to the success of this project and many others. We also acknowledge support from the Hereditary Disease Foundation, NINDS, NIH, grant numbers: NS22031-15, EY-12562, W.M. Keck Foundation and the Wellcome Trust. NR 13 TC 16 Z9 16 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD APR 5 PY 2009 VL 150B IS 3 BP 425 EP 429 DI 10.1002/ajmg.b.30826 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 425YZ UT WOS:000264675500017 PM 18712713 ER PT J AU Fan, BJ Wang, DY Cheng, CY Ko, WC Lam, SC Pang, CP AF Fan, Bao Jian Wang, Dan Yi Cheng, Ching-Yu Ko, Wendy Charles Lam, Shun Chiu Pang, Chi Pui TI Different WDR36 mutation pattern in Chinese patients with primary open-angle glaucoma SO MOLECULAR VISION LA English DT Article ID DNA-SEQUENCE VARIANTS; P53 CODON-72 POLYMORPHISM; WIDE SCAN MAPS; LOXL1 GENE; INTRAOCULAR-PRESSURE; GERMAN PATIENTS; ASSOCIATION; PSEUDOEXFOLIATION; IDENTIFICATION; OPTINEURIN AB Purpose: To determine the distribution of WD repeat domain 36 (WDR36) sequence variants in Chinese patients with primary open-angle glaucoma (POAG). Methods: One hundred and thirty-five unrelated POAG patients (82 high tension glaucoma [HTG], 42 normal tension glaucoma [NTG], and 11 juvenile-onset POAG [JOAG] patients) and 77 unrelated controls were recruited. All 23 coding exons and splicing junctions of WDR36 were sequenced using BigDye(R) Terminator v3.1 cycle sequencing kit. Single nucleotide polymorphism (SNP) and haplotype associations were analyzed using PLINK (version 1.04). Results: Nineteen sequence alterations were identified, and eight of them were novel including two novel nonsynonymous SNPs (L240V and I713V). Except the common I264V polymorphism, no other previously reported disease-causing or disease-susceptibility mutations were found. The novel I713V mutation was observed in three (3.7%) patients with HTG. One intronic SNP, IVS5+30C>T (rs10038177), showed significantly higher frequency of minor allele T in HTG patients (16.5%) than in controls (1.3%; Odds ratio [OR]=15.0, p=7.9x10(-7), Bonferroni corrected p=1.5x10(-5)). Haplotype GTA, which is composed of rs13153937, rs10038177, and rs11241095, was significantly associated with HTG (OR=22.5, p=0.002, Bonferroni corrected p=0.013). Neither the individual SNPs nor haplotypes of WDR36 were associated with NTG or JOAG (Bonferroni corrected p>0.05). Conclusions: Findings in this study suggest WDR36 to be associated with sporadic HTG but not with NTG or JOAG. Our results also suggest a different mutation pattern of WDR36 in the Chinese population from other ethnic populations. C1 [Fan, Bao Jian; Wang, Dan Yi; Ko, Wendy Charles; Lam, Shun Chiu; Pang, Chi Pui] Chinese Univ Hong Kong, Dept Ophthalmol & Visual Sci, Kowloon, Hong Kong, Peoples R China. [Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Dept Ophthalmol, Taipei 112, Taiwan. [Cheng, Ching-Yu] Taipei Vet Gen Hosp, Taipei, Taiwan. [Fan, Bao Jian; Wang, Dan Yi] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Pang, CP (reprint author), Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, 147K Argyle St, Kowloon, Hong Kong, Peoples R China. EM cppang@cuhk.edu.hk RI Cheng, Ching-Yu/K-7017-2013; Pang, Chi/I-5388-2014; OI Cheng, Ching-Yu/0000-0003-0655-885X; Fan, Baojian/0000-0002-6851-2737 FU University Grants Committee, Hong Kong; Medical Panel at the Chinese University of Hong Kong [2040997] FX This work was supported in part by a block grant from the University Grants Committee, Hong Kong, and by a direct grant (2040997) from the Medical Panel at the Chinese University of Hong Kong. The authors thank Dr. Catherine C. J. Liu (Department of Ophthalmology, National Yang Ming University and Taipei Veterans General Hospital, Taiwan) for her help in collecting the clinical data of the glaucoma patients in the present study. NR 41 TC 20 Z9 20 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD APR 3 PY 2009 VL 15 IS 65-70 BP 646 EP 653 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 450OC UT WOS:000266409700002 PM 19347049 ER PT J AU Jeong, H Then, F Melia, TJ Mazzulli, JR Cui, L Savas, JN Voisine, C Paganetti, P Tanese, N Hart, AC Yamamoto, A Krainc, D AF Jeong, Hyunkyung Then, Florian Melia, Thomas J., Jr. Mazzulli, Joseph R. Cui, Libin Savas, Jeffrey N. Voisine, Cindy Paganetti, Paolo Tanese, Naoko Hart, Anne C. Yamamoto, Ai Krainc, Dimitri TI Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation SO CELL LA English DT Article ID INCLUSION-BODY FORMATION; KNOCK-IN MOUSE; CAENORHABDITIS-ELEGANS; NEURODEGENERATIVE DISEASES; TRANSCRIPTIONAL REPRESSION; POLYGLUTAMINE EXPANSIONS; CELLULAR TOXICITY; SENSORY NEURON; DYSFUNCTION; PROTEIN AB Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy. C1 [Jeong, Hyunkyung; Then, Florian; Mazzulli, Joseph R.; Cui, Libin; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Dept Neurol, Charlestown, MA 02129 USA. [Voisine, Cindy; Hart, Anne C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Ctr Canc Res, Charlestown, MA 02129 USA. [Melia, Thomas J., Jr.] Yale Univ, Dept Cell Biol, New Haven, CT 06519 USA. [Savas, Jeffrey N.; Tanese, Naoko] New York Univ, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Savas, Jeffrey N.] New York Univ, Sch Med, NYU & NIH Grad Partnership Program Struct Biol, New York, NY 10016 USA. [Paganetti, Paolo] Novartis Pharma AG, NIBR Basel, Neurosci Dis, CH-4002 Basel, Switzerland. [Yamamoto, Ai] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Dept Neurol, Charlestown, MA 02129 USA. EM krainc@helix.mgh.harvard.edu RI Yamamoto, Ai/D-1100-2011; OI Tanese, Naoko/0000-0002-1946-3211 FU DFG; [R01NS050352]; [R01 NS051303]; [R01 NS050199] FX We are grateful to Drs. K. Kegel, M. DiFiglia, C. D. Allis, A. Basu, H. Park, and A.B. Young and members of the Krainc laboratory for helpful suggestions and comments on the manuscript. We also thank Drs. D. Sarracino, B. Krastins, J. Kowalak, S. Markey, and A. Makusky for help with mass spectrometry; B. Hyman, W. Stoothoff, and C. Lill for help with live-cell imaging; E. Regulier for help with lentiviral transductions; A. Weiss and A. Roscic for help with HN10 cells; H. Ischiropoulos for use of HPLC system; N. Mizushima for Atg5-deficient cells; A. Kazantsev for CBP and CBP Delta Q constructs; Y. Yoshimori for GFP-LC3; G.A. Fitzgerald for p300 and P/CAF; P.W. Faber for osm::Htt564-150Q; and the New York Structural Biology Center for the EM facilities. This work was supported by R01NS050352 and R01 NS051303 (to D.K.) and R01 NS050199 (to A.Y.). F.T. is a fellow of the DFG. Author contributions: H.J. and F.T. contributed equally to this work. NR 48 TC 196 Z9 201 U1 5 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD APR 2 PY 2009 VL 137 IS 1 BP 60 EP 72 DI 10.1016/j.cell.2009.03.018 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 427XV UT WOS:000264813300014 PM 19345187 ER PT J AU Francis, NJ Follmer, NE Simon, MD Aghia, G Butler, JD AF Francis, Nicole J. Follmer, Nicole E. Simon, Matthew D. Aghia, George Butler, Jeffrey D. TI Polycomb Proteins Remain Bound to Chromatin and DNA during DNA Replication In Vitro SO CELL LA English DT Article ID GENOME-WIDE ANALYSIS; SIMIAN VIRUS-40 DNA; EARLY MOUSE EMBRYOS; HISTONE H3; TRANSCRIBING POLYMERASE; DROSOPHILA-MELANOGASTER; POLYTENE CHROMOSOMES; H2A UBIQUITYLATION; REPRESSIVE COMPLEX; CELLS AB The transcriptional status of a gene can be maintained through multiple rounds of cell division during development. This epigenetic effect is believed to reflect heritable changes in chromatin folding and histone modifications or variants at target genes, but little is known about how these chromatin features are inherited through cell division. A particular challenge for maintaining transcription states is DNA replication, which disrupts or dilutes chromatin-associated proteins and histone modifications. PRC1-class Polycomb group protein complexes are essential for development and are thought to heritably silence transcription by altering chromatin folding and histone modifications. It is not known whether these complexes and their effects are maintained during DNA replication or subsequently re-established. We find that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycomb complexes remain bound to replicated templates. Retention of Polycomb proteins through DNA replication may contribute to maintenance of transcriptional silencing through cell division. C1 [Francis, Nicole J.; Follmer, Nicole E.; Aghia, George; Butler, Jeffrey D.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Simon, Matthew D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Simon, Matthew D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Francis, NJ (reprint author), Harvard Univ, Dept Mol & Cellular Biol, 7 Divin Ave, Cambridge, MA 02138 USA. EM francis@mcb.harvard.edu FU National Institutes of Health [GM078456-01]; Searle Scholar award; March of Dimes Basil O'Connor Scholar award; Helen Hay Whitney fellowship FX We thank R. Kingston, T. Maniatis, W. M. Michael, N. Kleckner, A. Murray, A. Mazo, L. Kobrossy, B. Lengsfeld, and S. Lo for advice and support throughout the project and J. Muller, R. Jones, B. Stillman, and W. M. Michael for reagents. This work was supported by the National Institutes of Health (GM078456-01), a Searle Scholar award and a March of Dimes Basil O'Connor Scholar award to N.J.F., and a Helen Hay Whitney fellowship to M.D.S. NR 71 TC 103 Z9 103 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD APR 2 PY 2009 VL 137 IS 1 BP 110 EP 122 DI 10.1016/j.cell.2009.02.017 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 427XV UT WOS:000264813300018 PM 19303136 ER PT J AU Kawashima, Y Pfafferott, K Frater, J Matthews, P Payne, R Addo, M Gatanaga, H Fujiwara, M Hachiya, A Koizumi, H Kuse, N Oka, S Duda, A Prendergast, A Crawford, H Leslie, A Brumme, Z Brumme, C Allen, T Brander, C Kaslow, R Tang, J Hunter, E Allen, S Mulenga, J Branch, S Roach, T John, M Mallal, S Ogwu, A Shapiro, R Prado, JG Fidler, S Weber, J Pybus, OG Klenerman, P Ndung'u, T Phillips, R Heckerman, D Harrigan, PR Walker, BD Takiguchi, M Goulder, P AF Kawashima, Yuka Pfafferott, Katja Frater, John Matthews, Philippa Payne, Rebecca Addo, Marylyn Gatanaga, Hiroyuki Fujiwara, Mamoru Hachiya, Atsuko Koizumi, Hirokazu Kuse, Nozomi Oka, Shinichi Duda, Anna Prendergast, Andrew Crawford, Hayley Leslie, Alasdair Brumme, Zabrina Brumme, Chanson Allen, Todd Brander, Christian Kaslow, Richard Tang, James Hunter, Eric Allen, Susan Mulenga, Joseph Branch, Songee Roach, Tim John, Mina Mallal, Simon Ogwu, Anthony Shapiro, Roger Prado, Julia G. Fidler, Sarah Weber, Jonathan Pybus, Oliver G. Klenerman, Paul Ndung'u, Thumbi Phillips, Rodney Heckerman, David Harrigan, P. Richard Walker, Bruce D. Takiguchi, Masafumi Goulder, Philip TI Adaptation of HIV-1 to human leukocyte antigen class I SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE RESPONSE; MHC-CLASS-I; ESCAPE MUTATIONS; VIRAL LOAD; CELL RESPONSES; HLA-B; INFECTION; GAG; TRANSMISSION AB The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection(1). Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from. 2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P=0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n=14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV. C1 [Pfafferott, Katja; Matthews, Philippa; Payne, Rebecca; Prendergast, Andrew; Crawford, Hayley; Leslie, Alasdair; Prado, Julia G.; Goulder, Philip] Dept Paediat, Oxford OX1 3SY, England. [Frater, John; Duda, Anna; Klenerman, Paul; Phillips, Rodney] Nuffield Dept Clin Med, Oxford OX1 3SY, England. [Frater, John; Duda, Anna; Klenerman, Paul; Phillips, Rodney] James Martin 21st Century Sch, Oxford OX1 3SY, England. [Kawashima, Yuka; Fujiwara, Mamoru; Hachiya, Atsuko; Koizumi, Hirokazu; Kuse, Nozomi; Takiguchi, Masafumi] Kumamoto Univ, Div Viral Immunol, Kumamoto 8600811, Japan. [Gatanaga, Hiroyuki; Oka, Shinichi] Kumamoto Univ, Div Infect Dis, Ctr AIDS Res, Kumamoto 8600811, Japan. [Pfafferott, Katja; John, Mina; Mallal, Simon; Goulder, Philip] Royal Perth Hosp, Ctr Clin Immunol & Biomed Stat, Perth, WA 6000, Australia. [Pfafferott, Katja; John, Mina; Mallal, Simon; Goulder, Philip] Murdoch Univ, Murdoch, WA 6000, Australia. [Addo, Marylyn; Brumme, Zabrina; Brumme, Chanson; Allen, Todd; Brander, Christian; Walker, Bruce D.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02129 USA. [Gatanaga, Hiroyuki; Hachiya, Atsuko; Oka, Shinichi] Int Med Ctr Japan, AIDS Clin Ctr, Shinjuku Ku, Tokyo 1628655, Japan. [Brander, Christian] Hosp Badalona Germans Trias & Pujol, Fundacio IrsiCaixa HIVACAT, Badalona, Spain. [Brander, Christian] ICREA, Barcelona 08916, Spain. [Kaslow, Richard; Tang, James] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Hunter, Eric] Emory Univ, Vaccine Ctr, Atlanta, GA 30329 USA. [Hunter, Eric] Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Allen, Susan; Mulenga, Joseph] Zambia Emory HIV Res Project, Lusaka, Zambia. [Allen, Susan; Mulenga, Joseph] Zambia Blood Transfus Serv, Lusaka, Zambia. [Branch, Songee; Roach, Tim] Univ W Indies, Ladymeade Reference Unit, BB-11156 Bridgetown, Barbados. [Ogwu, Anthony; Shapiro, Roger] Botswana Harvard Sch Publ Hlth, AIDS Initiat Partnership, Gaborone, Botswana. [Fidler, Sarah; Weber, Jonathan] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Wright Fleming Inst, Div Med, London W2 1PG, England. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3SY, England. [Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4013 Durban, South Africa. [Harrigan, P. Richard] Miscrosoft Res, Redmond, WA USA. [Heckerman, David] BC Ctr Excellence HIV AIDS, Vancouver, BC V6Z 1Y6, Canada. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20185 USA. RP Goulder, P (reprint author), Dept Paediat, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM philip.goulder@paediatrics.ox.ac.uk RI pybus, oliver/B-2640-2012; Takiguchi, Masafumi/E-7468-2013; Kumamoto University, CAIDS/G-8446-2013; Publications, Remarkable/I-1756-2013; Allen, Todd/F-5473-2011; OI Matthews, Philippa/0000-0002-4036-4269; Pybus, Oliver/0000-0002-8797-2667; Brander, Christian/0000-0002-0548-5778; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institutes of Health [RO1AI46995, 1 R01 AI067073, R01AI64060]; Wellcome Trust; UK Medical Research Council; Mark and Lisa Schwartz Foundation; Ministry of Health, Labour and Welfare [012]; Ministry of Education, Science, Sports and Culture [18390141]; NIHR Biomedical Research Centre Programme; Elizabeth Glaser Pediatric AIDS Foundation Scientist; Marie Curie Fellow [IEF-041811] FX This work is funded by grants from the National Institutes of Health (RO1AI46995 ( P. G.), 1 R01 AI067073 ( B. D. W.), R01AI64060 ( E. H.)), the Wellcome Trust ( P. G., P. K.), the UK Medical Research Council (J.F., A. P. and P. M.), and the Mark and Lisa Schwartz Foundation, the Ministry of Health, Labour and Welfare (Health and Labour HIV/AIDS Research Grants 012), the NIHR Biomedical Research Centre Programme and the Ministry of Education, Science, Sports and Culture ( number 18390141), Japan ( M. T.). P. G. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist; J.G.P. is a Marie Curie Fellow (contract number IEF-041811). The authors are also grateful to A. McLean and H. Fryer for discussions of the manuscript. NR 30 TC 257 Z9 271 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD APR 2 PY 2009 VL 458 IS 7238 BP 641 EP U108 DI 10.1038/nature07746 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427RK UT WOS:000264796200043 PM 19242411 ER PT J AU Granziera, C Schmahmann, JD Hadjikhani, N Meyer, H Meuli, R Wedeen, V Krueger, G AF Granziera, Cristina Schmahmann, Jeremy Dan Hadjikhani, Nouchine Meyer, Heiko Meuli, Reto Wedeen, Van Krueger, Gunnar TI Diffusion Spectrum Imaging Shows the Structural Basis of Functional Cerebellar Circuits in the Human Cerebellum In Vivo SO PLOS ONE LA English DT Article AB Background: The cerebellum is a complex structure that can be affected by several congenital and acquired diseases leading to alteration of its function and neuronal circuits. Identifying the structural bases of cerebellar neuronal networks in humans in vivo may provide biomarkers for diagnosis and management of cerebellar diseases. Objectives: To define the anatomy of intrinsic and extrinsic cerebellar circuits using high-angular resolution diffusion spectrum imaging (DSI). Methods: We acquired high-resolution structural MRI and DSI of the cerebellum in four healthy female subjects at 3T. DSI tractography based on a streamline algorithm was performed to identify the circuits connecting the cerebellar cortex with the deep cerebellar nuclei, selected brainstem nuclei, and the thalamus. Results: Using in-vivo DSI in humans we were able to demonstrate the structure of the following cerebellar neuronal circuits: (1) connections of the inferior olivary nucleus with the cerebellar cortex, and with the deep cerebellar nuclei (2) connections between the cerebellar cortex and the deep cerebellar nuclei, (3) connections of the deep cerebellar nuclei conveyed in the superior (SCP), middle (MCP) and inferior (ICP) cerebellar peduncles, (4) complex intersections of fibers in the SCP, MCP and ICP, and (5) connections between the deep cerebellar nuclei and the red nucleus and the thalamus. Conclusion: For the first time, we show that DSI tractography in humans in vivo is capable of revealing the structural bases of complex cerebellar networks. DSI thus appears to be a promising imaging method for characterizing anatomical disruptions that occur in cerebellar diseases, and for monitoring response to therapeutic interventions. C1 [Granziera, Cristina] CHU Vaudois, Dept Neurol, Lausanne, Switzerland. [Schmahmann, Jeremy Dan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Hadjikhani, Nouchine; Wedeen, Van] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imag, Charlestown, MA USA. [Hadjikhani, Nouchine] Ecole Polytechn Fed, Brain Mind Inst, Lausanne, Switzerland. [Meyer, Heiko] Siemens AG, Erlangen, Germany. [Meuli, Reto] CHU Vaudois, Dept Radiol, Lausanne, Switzerland. [Krueger, Gunnar] Siemens Schweiz AG, Healthcare Sector IM&WS S, Renens, Switzerland. RP Granziera, C (reprint author), CHU Vaudois, Dept Neurol, Lausanne, Switzerland. EM Cristina.Granziera@chuv.ch RI Hadjikhani, Nouchine/C-2018-2008; Centre d'imagerie Biomedicale, CIBM/B-5740-2012; OI Hadjikhani, Nouchine/0000-0003-4075-3106; Granziera, Cristina/0000-0002-4917-8761 FU Center for Biomedical Imaging (CIBM) of Geneva - Lausanne; University of Geneva; University of Lasuanne; Ecole Polytechnique Federale de Lausanne (EPFL); Leenaards foundation; Louis-Jeantet Foundation; Siemens AG (Erlangen) Foundation; NIH [5PO1NS 35611] FX The work was supported by the Center for Biomedical Imaging (CIBM) of Geneva - Lausanne, the Universities of Geneva and Lasuanne as welll as the Ecole Polytechnique Federale de Lausanne (EPFL), the foundations Leenaards and Louis-Jeantet and Siemens AG (Erlangen). NH was also supported by NIH 5PO1NS 35611.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 57 Z9 60 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 2 PY 2009 VL 4 IS 4 AR e5101 DI 10.1371/journal.pone.0005101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PZ UT WOS:000265500700014 PM 19340289 ER PT J AU Thatte, HS He, XD Goyal, RK AF Thatte, Hemant S. He, Xue D. Goyal, Raj K. TI Imaging of Nitric Oxide in Nitrergic Neuromuscular Neurotransmission in the Gut SO PLOS ONE LA English DT Article AB Background: Numerous functional studies have shown that nitrergic neurotransmission plays a central role in peristalsis and sphincter relaxation throughout the gut and impaired nitrergic neurotransmission has been implicated in clinical disorders of all parts of the gut. However, the role of nitric oxide (NO) as a neurotransmitter continues to be controversial because: 1) the cellular site of production during neurotransmission is not well established; 2) NO may interacts with other inhibitory neurotransmitter candidates, making it difficult to understand its precise role. Methodology/Principal Findings: Imaging NO can help resolve many of the controversies regarding the role of NO in nitrergic neurotransmission. Imaging of NO and its cellular site of production is now possible. NO forms quantifiable fluorescent compound with diaminofluorescein (DAF) and allows imaging of NO with good specificity and sensitivity in living cells. In this report we describe visualization and regulation of NO and calcium (Ca(2+)) in the myenteric nerve varicosities during neurotransmission using multiphoton microscopy. Our results in mice gastric muscle strips provide visual proof that NO is produced de novo in the nitrergic nerve varicosities upon nonadrenergic noncholinergic (NANC) nerve stimulation. These studies show that NO is a neurotransmitter rather than a mediator. Changes in NO production in response to various pharmacological treatments correlated well with changes in slow inhibitory junction potential of smooth muscles. Conclusions/Significance: Dual imaging and electrophysiologic studies provide visual proof that during nitrergic neurotransmission NO is produced in the nerve terminals. Such studies may help define whether NO production or its signaling pathway is responsible for impaired nitrergic neurotransmission in pathological states. C1 [Thatte, Hemant S.] VA Boston Hlth Care Syst, Cardiothorac Div, Dept Surg, Boston, MA USA. [Thatte, Hemant S.; He, Xue D.; Goyal, Raj K.] Harvard Univ, Sch Med, Boston, MA USA. [He, Xue D.; Goyal, Raj K.] VA Boston Hlth Care Syst, Ctr Swallow & Motil Disorders, Dept Med, Boston, MA USA. RP Thatte, HS (reprint author), VA Boston Hlth Care Syst, Cardiothorac Div, Dept Surg, Boston, MA USA. EM Raj_Goyal@hms.harvard.edu FU NIDDK [DK 062867]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs [VA Merit Review Award] FX Supported in parts by a research grant DK 062867 from the NIDDK and a VA Merit Review Award from the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 7 Z9 7 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 2 PY 2009 VL 4 IS 4 AR e4990 DI 10.1371/journal.pone.0004990 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PZ UT WOS:000265500700005 PM 19340298 ER PT J AU Wingo, SN Gallardo, TD Akbay, EA Liang, MC Contreras, CM Boren, T Shimamura, T Miller, DS Sharpless, NE Bardeesy, N Kwiatkowski, DJ Schorge, JO Wong, KK Castrillon, DH AF Wingo, Shana N. Gallardo, Teresa D. Akbay, Esra A. Liang, Mei-Chi Contreras, Cristina M. Boren, Todd Shimamura, Takeshi Miller, David S. Sharpless, Norman E. Bardeesy, Nabeel Kwiatkowski, David J. Schorge, John O. Wong, Kwok-Kin Castrillon, Diego H. TI Somatic LKB1 Mutations Promote Cervical Cancer Progression SO PLOS ONE LA English DT Article AB Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but.100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence. C1 [Wingo, Shana N.; Boren, Todd] Univ Texas SW Med Ctr Dallas, Div Gynecol Oncol, Dallas, TX 75390 USA. [Gallardo, Teresa D.; Akbay, Esra A.; Contreras, Cristina M.; Miller, David S.; Castrillon, Diego H.] Univ Texas SW, Simmons Comprehensive Canc Ctr, Dept Pathol, Dallas, TX 75390 USA. [Liang, Mei-Chi; Shimamura, Takeshi; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Sharpless, Norman E.] Univ N Carolina, Sch Med, Lineberger Comprehensive Canc Ctr, Dept Med & Genet, Chapel Hill, NC USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA. [Kwiatkowski, David J.] Brigham and Womens Hosp, Dept Med, Boston, MA USA. [Schorge, John O.] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA USA. RP Wingo, SN (reprint author), Univ Texas SW Med Ctr Dallas, Div Gynecol Oncol, Dallas, TX 75390 USA. EM diego.castrillon@utsouthwestern.edu RI Miller, David/H-4604-2011; OI Miller, David/0000-0002-8215-5887; wong, kwok kin/0000-0001-6323-235X FU Sidney Kimmel Translational Science Awards; NIH NRSA [fellowship]; American Cancer Society/UT Southwestern Simmons Comprehensive Cancer Center [Young Investigator Award]; National Center for Research Resources [K26RR024196] FX This work was funded through Sidney Kimmel Translational Science Awards to D.H.C., K.K.W., N.B., and N.E.S., an NIH NRSA F31 fellowship to C.M.C., a Young Investigator Award from the American Cancer Society/UT Southwestern Simmons Comprehensive Cancer Center to D.H.C, and the National Center for Research Resources (K26RR024196) (D.H.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 130 Z9 135 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 2 PY 2009 VL 4 IS 4 AR e5137 DI 10.1371/journal.pone.0005137 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PZ UT WOS:000265500700022 PM 19340305 ER PT J AU Kabrhel, C Courtney, DM Camargo, CA Moore, CL Richman, PB Plewa, MC Nordenholtz, KE Smithline, HA Beam, DM Brown, MD Kline, JA AF Kabrhel, Christopher Courtney, D. Mark Camargo, Carlos A. Moore, Christopher L. Richman, Peter B. Plewa, Michael C. Nordenholtz, Kristen E. Smithline, Howard A. Beam, Daren M. Brown, Michael D. Kline, Jeffrey A. TI Potential Impact of Adjusting the Threshold of the Quantitative D-dimer Based on Pretest Probability of Acute Pulmonary Embolism SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Academic-Emergency-Medicine Research Forum CY JUN 02, 2008 CL Washington, DC SP Soc Acad Emergency Med DE D-dimer; emergency department; venous thromboembolism; decision-making ID VENOUS THROMBOEMBOLISM; COMPUTED-TOMOGRAPHY; CLINICAL-MODEL; DIAGNOSIS; OUTPATIENTS; MANAGEMENT; METAANALYSIS; SCORE; RULE AB The utility of D-dimer testing for suspected pulmonary embolism (PE) can be limited by test specificity. The authors tested if the threshold of the quantitative D-dimer can be varied according to pretest probability (PTP) of PE to increase specificity while maintaining a negative predictive value (NPV) of > 99%. This was a prospective, observational multicenter study of emergency department (ED) patients in the United States. Eligible patients had a diagnostic study ordered to evaluate possible PE. PTP was determined by the clinician's unstructured estimate and the Wells score. Five different D-dimer assays were used. D-dimer test performance was measured using 1) standard thresholds and 2) variable threshold values: twice (for low PTP patients), equal (intermediate PTP patients), or half (high PTP patients) of standard threshold. Venous thromboembolism (VTE) within 45 days required positive imaging plus decision to treat. The authors enrolled 7,940 patients tested for PE, and clinicians ordered a quantitative D-dimer for 4,357 (55%) patients who had PTPs distributed as follows: low (74%), moderate (21%), or high (4%). At standard cutoffs, across all PTP strata, quantitative D-dimer testing had a test sensitivity of 94% (95% confidence interval [CI] = 91% to 97%), specificity of 58% (95% CI = 56% to 60%), and NPV of 99.5% (95% CI = 99.1% to 99.7%). If variable cutoffs had been used the overall sensitivity would have been 88% (95% CI = 83% to 92%), specificity 75% (95% CI = 74% to 76%), and NPV 99.1% (95% CI = 98.7% to 99.4%). This large multicenter observational sample demonstrates that emergency medicine clinicians currently order a D-dimer in the majority of patients tested for PE, including a large proportion with intermediate PTP and high PTP. Varying the D-dimer's cutoff according to PTP can increase specificity with no measurable decrease in NPV. C1 [Kabrhel, Christopher; Camargo, Carlos A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Serv, Boston, MA 02115 USA. [Courtney, D. Mark] Northwestern Univ, Med Ctr, Dept Emergency Med, Chicago, IL 60611 USA. [Moore, Christopher L.] Yale Univ, Med Ctr, Dept Emergency Med, New Haven, CT USA. [Richman, Peter B.] Mayo Clin, Dept Emergency Med, Scottsdale, AZ USA. [Plewa, Michael C.] Med Coll Ohio, Dept Surg, St Vincent Mercy Med Ctr, Toledo, OH 43699 USA. [Nordenholtz, Kristen E.] Univ Colorado, Dept Surg, Div Emergency Med, Denver, CO 80202 USA. [Smithline, Howard A.] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Beam, Daren M.] E Carolina Univ, Sch Med, Pitt Cty Mem Hosp, Greenville, NC USA. [Brown, Michael D.] Michigan State Univ, Dept Emergency Med, Grand Rapids, MI USA. [Kline, Jeffrey A.] Carolinas Med Ctr, Dept Emergency Med, Charlotte, NC 28203 USA. RP Kline, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Serv, Boston, MA 02115 USA. EM Jeffery.kline@carolinashealthcare.org OI Kabrhel, Christopher/0000-0002-8699-7176 NR 21 TC 20 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD APR PY 2009 VL 16 IS 4 BP 325 EP 332 DI 10.1111/j.1553-2712.2009.00368.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 429XL UT WOS:000264953300007 PM 19298619 ER PT J AU Goldhamer, MEJ Cohen, AP Bates, DW Cook, EF Davis, RB Singer, DE Simon, SR AF Goldhamer, Mary Ellen J. Cohen, Amy P. Bates, David W. Cook, E. Francis Davis, Roger B. Singer, Daniel E. Simon, Steven R. TI Protecting an Endangered Species: Training Physicians to Conduct Clinical Research SO ACADEMIC MEDICINE LA English DT Article ID MEDICAL-STUDENTS; BIOMEDICAL-RESEARCH; INTERNAL-MEDICINE; PROGRAM; SCIENTISTS; CARE; INVESTIGATORS; PERSPECTIVES; CHALLENGES; OBSTACLES AB Purpose The Program in Clinical Effectiveness (PCE) at Harvard School of Public Health is a postgraduate program emphasizing clinical research. The authors sought to evaluate the research careers of physician graduates and to determine correlates of National Institutes of Health (NIH) grant funding. Method In 2006, all 1,489 graduates from 19862005 were sent a 48-item survey that collected information on demographics, program experience, chosen career path, grant awards, and research pursued postprogram. Reported NIH grants were verified on the NIH Computer Retrieval of Information on Scientific Projects Web site. Cox proportional hazard regression was used to determine participant and program features associated with NIH grant funding. Results Overall, 994 of the 1,365 located graduates (73%) responded to the survey. Graduates pursued research in the following areas: 437 respondents (44%) pursued clinical trials, 537 (54%) pursued epidemiology, and 408 (41%) pursued health services research. A total of 156 respondents (24%) were principal investigators on an NIH grant. Correlates of receiving NIH grant funding included age less than 40 years at time of program enrollment (hazard ratio [HR] 1.87, CI 1.03, 3.41), generalist status (HR 1.57, CI 1.14, 2.16), and publishing research begun as course projects (HR 1.65, CI 1.19, 2.31). Gender, academic status at enrollment, ethnicity, tuition sponsorship, and earning an advanced degree were not associated with receipt of NIH grant funding. Conclusions Physicians who enrolled in the PCE at an early age and generalist physicians were particularly successful in establishing careers as clinician-investigators. Programs such as the PCE can help to sustain the workforce of physician-investigators. C1 [Goldhamer, Mary Ellen J.; Singer, Daniel E.] Massachusetts Gen Hosp, Bulfinch Med Grp, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. [Simon, Steven R.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Cohen, Amy P.] Harvard Univ, Sch Publ Hlth, Dept Informat Technol, Boston, MA 02115 USA. [Cook, E. Francis] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bates, David W.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Davis, Roger B.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Simon, Steven R.] Harvard Pilgrim Hlth Care, Boston, MA USA. RP Goldhamer, MEJ (reprint author), Massachusetts Gen Hosp, Bulfinch Med Grp, Div Gen Med, Clin Epidemiol Unit, Wang Bldg,5th Floor,Suite 535, Boston, MA 02114 USA. EM mgoldhamer@partners.org FU institutional National Research Service Award [5 T32HP1100119] FX Dr. Goldhamer was supported on an institutional National Research Service Award 5 T32HP1100119. The Program in Clinical Effectiveness provided funds for programming the Internet survey and research assistants who assisted in locating all graduates' addresses and in verifying NIH grants on CRISP. NR 39 TC 20 Z9 21 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD APR PY 2009 VL 84 IS 4 BP 439 EP 445 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IQ UT WOS:000267655200013 PM 19318774 ER PT J AU Vogeli, C Koski, G Campbell, EG AF Vogeli, Christine Koski, Greg Campbell, Eric G. TI Policies and Management of Conflicts of Interest Within Medical Research Institutional Review Boards: Results of a National Study SO ACADEMIC MEDICINE LA English DT Article ID INDUSTRY AB Purpose To examine institutional review board (IRB) policies and practices with regard to conflicts of interest (COIs) among IRB members who review and approve research protocols and to assess IRB policies and procedures in light of federal policies and guidance. Method An anonymous survey of IRB chairs serving the most research-intensive medical institutions in the United States was conducted in fall 2005. The survey collected information about the chairs, the IRBs, and the processes IRBs had in place to manage member relationships and COIs. Results Two hundred eleven out of 296 eligible chairs responded (71.7%). One third of IRBs in the nation's medical schools and major academic medical centers did not require voting members to disclose relationships with industry. In practice, IRB member industry relationships were disclosed to the entire IRB (75.9%), the IRB chair (62.1%), and/or a group or entity separate from the IRB but within the institution it serves (52.5%). One in five chairs of IRBs did not feel confident that their IRB's policies and procedures ensured appropriate disclosure of industry relationships in every case. Finally, one in four IRBs did not have written policies defining appropriate actions when IRB member COIs were identified. Conclusions The relatively high proportion of IRBs without a requirement that voting members disclose industry relationships is inconsistent with current guidance, and likely results in lapses in awareness of when members with conflicts vote on protocols. There was no clear consensus on where oversight responsibility for member-industry relationships should lie. C1 [Vogeli, Christine; Campbell, Eric G.] Massachusetts Gen Hosp, Dept Med, Inst Hlth Policy, Boston, MA 02038 USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. RP Vogeli, C (reprint author), Massachusetts Gen Hosp, Dept Med, Inst Hlth Policy, 50 Staniford St 9th Floor, Boston, MA 02038 USA. EM cvogeli@partners.org FU NCI NIH HHS [R01 CA095400] NR 13 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD APR PY 2009 VL 84 IS 4 BP 488 EP 494 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IQ UT WOS:000267655200022 PM 19318786 ER PT J AU Eikermann, M Rasmussen, LS AF Eikermann, M. Rasmussen, L. S. TI Improving the prediction of a neuromuscular block SO ACTA ANAESTHESIOLOGICA SCANDINAVICA LA English DT Editorial Material ID MORBIDITY; IMPACT C1 [Eikermann, M.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Eikermann, M.] Univ Klinikum Essen, Essen, Germany. [Rasmussen, L. S.] Rigshosp, Copenhagen Univ Hosp, Ctr Head & Orthopaed, Dept Anaesthesia, DK-2100 Copenhagen, Denmark. [Eikermann, M.] Harvard Univ, Sch Med, Boston, MA USA. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM meikermann@partners.org NR 9 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-5172 J9 ACTA ANAESTH SCAND JI Acta Anaesthesiol. Scand. PD APR PY 2009 VL 53 IS 4 BP 423 EP 424 DI 10.1111/j.1399-6576.2009.01941.x PG 2 WC Anesthesiology SC Anesthesiology GA 418QD UT WOS:000264162400002 PM 19317860 ER PT J AU Byne, W Hazlett, EA Buchsbaum, MS Kemether, E AF Byne, William Hazlett, Erin A. Buchsbaum, Monte S. Kemether, Eileen TI The thalamus and schizophrenia: current status of research SO ACTA NEUROPATHOLOGICA LA English DT Review DE Thalamus; Schizophrenia; Mediodorsal nucleus; Pulvinar; Anterior nucleus; Centromedian nucleus ID NEVER-MEDICATED SCHIZOPHRENICS; DOPAMINE-D-2 RECEPTOR-BINDING; LATERAL GENICULATE-NUCLEUS; POOR-OUTCOME SCHIZOPHRENIA; MEDIAL PREFRONTAL CORTEX; STROOP TASK-PERFORMANCE; VOXEL-BASED MORPHOMETRY; TOTAL NEURON NUMBER; ATAXIA TYPE-3 SCA3; MEDIODORSAL NUCLEUS AB The thalamus provides a nodal link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed. C1 [Byne, William] James J Peters VA Med Ctr, Dept Psychiat, Bronx, NY 10468 USA. [Byne, William; Hazlett, Erin A.; Buchsbaum, Monte S.; Kemether, Eileen] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Byne, W (reprint author), James J Peters VA Med Ctr, Dept Psychiat, Res Bldg,Room 2F39, Bronx, NY 10468 USA. EM william.byne@mssm.edu FU veterans affairs VISN3 MI-RECC; VA merit award [MH66998, MH073911, MH60023]; Charles A. Dana Foundation ( FX Supported by the veterans affairs VISN3 MI-RECC, VA merit award (WB), MH66998 (WB), MH073911 (EAH), MH60023 (MSB) and a grant from the Charles A. Dana Foundation (MSB). NR 194 TC 83 Z9 85 U1 4 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD APR PY 2009 VL 117 IS 4 BP 347 EP 368 DI 10.1007/s00401-008-0404-0 PG 22 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 418UF UT WOS:000264174200002 PM 18604544 ER PT J AU Perlis, RH Fava, M Trivedi, MH Alpert, J Luther, JF Wisniewski, SR Rush, AJ AF Perlis, R. H. Fava, M. Trivedi, M. H. Alpert, J. Luther, J. F. Wisniewski, S. R. Rush, A. John TI Irritability is associated with anxiety and greater severity, but not bipolar spectrum features, in major depressive disorder SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE major depressive disorder; bipolar disorder; diagnosis; irritability; anger; suicide ID STAR-ASTERISK-D; SEQUENCED TREATMENT ALTERNATIVES; CORONARY-HEART-DISEASE; ILLNESS RATING-SCALE; ANGER ATTACKS; RELIEVE DEPRESSION; PSYCHIATRIC OUTPATIENTS; ATHEROSCLEROSIS RISK; SUICIDE ATTEMPTERS; CLINICAL-FEATURES AB Irritability is common during major depressive episodes, but its clinical significance and overlap with symptoms of anxiety or bipolar disorder remains unclear. We examined clinical correlates of irritability in a confirmatory cohort of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study participants with major depressive disorder (MDD). Logistic regression was used to identify features associated with presence of irritability on the clinician-rated Inventory of Depressive Symptomatology. Of 2307 study participants, 1067(46%) reported irritability at least half the time during the preceding week; they were more likely to be female, to be younger, to experience greater depression severity and anxiety, and to report poorer quality of life, prior suicide attempts and suicidal ideation. Bipolar spectrum features were not more common among those with irritability. Irritable depression is not a distinct subtype of MDD, but irritability is associated with greater overall severity, anxiety comorbidity and suicidality. C1 [Perlis, R. H.; Fava, M.; Alpert, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Trivedi, M. H.; Rush, A. John] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Luther, J. F.; Wisniewski, S. R.] Univ Pittsburgh, Pittsburgh, PA USA. [Perlis, R. H.; Fava, M.; Alpert, J.] Harvard Univ, Sch Med, Boston, MA USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM rperlis@partners.org OI Wisniewski, Stephen/0000-0002-3877-9860; Alpert, Jonathan/0000-0002-4332-908X; Rush, Augustus/0000-0003-2004-2382 FU NIMH [N01 MH-90003, K23MH67060]; Bowman Family Foundation award; NARSAD Young Investigator/Sidney R. Baer, Jr. Foundation award. FX We would like to thank all the STAR*D investigators for all the help in making this large and complex multicenter study possible and for generating the data for this report, and acknowledge the editorial support of Jon Kilner, MS, MA, and the secretarial support of Fast Word Information Processing Inc. (Dallas, Texas). NR 47 TC 33 Z9 33 U1 3 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD APR PY 2009 VL 119 IS 4 BP 282 EP 289 DI 10.1111/j.1600-0447.2008.01298.x PG 8 WC Psychiatry SC Psychiatry GA 414HW UT WOS:000263855500005 PM 19207123 ER PT J AU Bech, P Wilson, P Wessel, T Lunde, M Fava, M AF Bech, P. Wilson, P. Wessel, T. Lunde, M. Fava, M. TI A validation analysis of two self-reported HAM-D-6 versions SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE HAM-D17; paper-and-pencil self-reported HAM-D6; interactive-voice-recording HAM-D6; Mokken's item response theory-model; unidimensionality; validation analysis ID DEPRESSION RATING-SCALE; MAJOR DEPRESSION; SENSITIVITY; CITALOPRAM; INVENTORY; SEVERITY; DISORDER AB The six items of the clinician-administrated Hamilton Depression Scale (HAM-D-6) cover the core items of depressive states reflecting the antidepressive effect of medication. In this study, the two self-reported versions of the HAM-D-6 have been psychometrically validated to ensure the unidimensionality of this administration form in patients with mild-to-moderate depression. The item response theory analysis of Mokken was used to test the unidimensionality of both the Interactive Voice Recording System (IVRS) version of the HAM-D-6 and a paper-and-pencil self-reported version (S-HAM-D-6). Patients with typical major depression and with seasonal affective disorder were included. The Mokken analysis showed that the two self-reported versions of the HAM-D-6 obtained coefficients of homogeneity above 0.40, similar to the clinician-rated HAM-D-6 and thus implying unidimensionality. By contrast, the full HAM-D-17 versions (self-reported as well as clinician-rated) obtained coefficients of homogeneity below 0.40, implying that the HAM-D-17 is a multidimensional scale. The analysis show that both the IVRS version and the S-HAM-D-6 version are unidimensional self-rating scales for the measurement of depressive states. C1 [Bech, P.; Lunde, M.] Copenhagen Univ Hosp, Frederiksborg Gen Hosp, Psychiat Res Unit, DK-3400 Hillerod, Denmark. [Wilson, P.; Wessel, T.] Sepracor Inc, Clin Res, Marlborough, MA USA. [Fava, M.] Massachusetts Gen Hosp, Depress Clin, Boston, MA 02114 USA. [Fava, M.] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. RP Bech, P (reprint author), Copenhagen Univ Hosp, Frederiksborg Gen Hosp, Psychiat Res Unit, Dyrehavevej 48, DK-3400 Hillerod, Denmark. EM pebe@noh.regionh.dk NR 37 TC 14 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD APR PY 2009 VL 119 IS 4 BP 298 EP 303 DI 10.1111/j.1600-0447.2008.01289.x PG 6 WC Psychiatry SC Psychiatry GA 414HW UT WOS:000263855500007 PM 19032701 ER PT J AU James, S Akerblom, A Cannon, CP Emanuelsson, H Husted, S Katus, H Skene, A Steg, PG Storey, RF Harrington, R Becker, R Wallentin, L AF James, Stefan Akerblom, Axel Cannon, Christopher P. Emanuelsson, Hakan Husted, Steen Katus, Hugo Skene, Allan Steg, Philippe Gabriel Storey, Robert F. Harrington, Robert Becker, Richard Wallentin, Lars TI Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial SO AMERICAN HEART JOURNAL LA English DT Article ID ST-SEGMENT ELEVATION; PRASUGREL ACHIEVES GREATER; ASPIRIN-TREATED PATIENTS; MYOCARDIAL-INFARCTION; EUROPEAN-SOCIETY; ARTERY-DISEASE; TASK-FORCE; AZD6140; PHARMACOKINETICS; PHARMACODYNAMICS AB Background Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y(12) receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate-receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. Methods PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutoneous coronary intervention or for non-ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. Conclusion The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population. (Am Heart J 2009; 157:599-605.) C1 [Wallentin, Lars] Univ Uppsala Hosp, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Emanuelsson, Hakan] AstraZeneca R&D, Molndal, Sweden. [Husted, Steen] Arhus Univ Hosp, Dept Cardiol, Aarhus, Denmark. [Katus, Hugo] Univ Klinikum Heidelberg, Med Klin, Heidelberg, Germany. [Skene, Allan] Nottingham Clin Res Ltd, Nottingham, England. [Steg, Philippe Gabriel] Univ Paris, F-75252 Paris, France. [Steg, Philippe Gabriel] AP HP, INSERM, U 698, F-75252 Paris, France. [Storey, Robert F.] Univ Sheffield, Cardiovasc Res Unit, Sheffield, S Yorkshire, England. [Harrington, Robert; Becker, Richard] Duke Clin Res Inst, Durham, NC USA. RP Wallentin, L (reprint author), Univ Uppsala Hosp, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. EM lars.wallentin@ucr.uu.se RI Katus, Hugo/P-1712-2016 NR 20 TC 174 Z9 190 U1 4 U2 23 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD APR PY 2009 VL 157 IS 4 BP 599 EP 605 DI 10.1016/j.ahj.2009.01.003 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432CC UT WOS:000265110100002 PM 19332184 ER PT J AU Mak, KH Bhatt, DL Shao, MY Hankey, GJ Easton, JD Fox, KAA Topol, EJ AF Mak, Koon-Hou Bhatt, Deepak L. Shao, Mingyuan Hankey, Graeme J. Easton, J. Donald Fox, Keith A. A. Topol, Eric J. TI Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; THROMBOLYTIC THERAPY; MORTALITY; DISEASE; TRIAL; CALCIFICATION; METAANALYSIS; OUTPATIENTS; DISPARITIES; STROKE AB Background Atherothrombosis is a common condition affecting individuals worldwide. Its impact on different ethnic groups receiving evidence-based therapy is unclear. We aimed to determine if ethnicity is an independent predictor for cardiovascular events and bleeding complications in a contemporary clinical trial on antiplatelet therapy. Methods This was a prospective observational study of 15,603 patients enrolled in the CHARISMA trial followed up every 6 months for a median of 28 months. The primary efficacy end point was the first occurrence of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was bleeding. Results The cohort comprised 12,502 (80.1%) white, 486 (3.1%) black, 775 (5.0%) Asian, and 1,613(10.3%) Hispanic patients. There was no difference in the occurrence of the primary composite end point among the 4 ethnic groups. Compared with Asians, cardiovascular and all-cause mortality occurred more frequently among black (adjusted hazard 2.19 and 2.04) and Hispanic (adjusted hazard, 1.83 and 1.69) patients. Although the occurrence of severe bleeding was similarly low among the 4 ethnic groups, Asian (adjusted hazard, 2.21) and black (adjusted hazard, 3.06) patients were more likely to have moderate bleeding complications than Hispanic patients.. Conclusion In this trial of individuals at risk of vascular events, ethnicity was not a significant, independent predictor of the primary composite cardiovascular event. However, ethnicity was a significant, independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics), and moderate bleeding complications (blacks and Asians). (Am Heart J 2009;157:658-65.) C1 [Mak, Koon-Hou] Gleneagles Med Ctr, Singapore 258499, Singapore. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Shao, Mingyuan] Cleveland Clin, Cleveland, OH 44106 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Hankey, Graeme J.] Univ Western Australia, Royal Perth Hosp, Dept Neurol, Perth, WA 6009, Australia. [Easton, J. Donald] Brown Univ, Providence, RI 02912 USA. [Easton, J. Donald] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Fox, Keith A. A.] Univ & Royal Infirm Edinburgh, Edinburgh, Midlothian, Scotland. [Topol, Eric J.] Scripps Translat Res Inst, La Jolla, CA USA. RP Mak, KH (reprint author), Gleneagles Med Ctr, 6 Napier Rd 08-13, Singapore 258499, Singapore. EM makheart@gmail.com RI Hankey, Graeme /H-4968-2014; OI Hankey, Graeme /0000-0002-6044-7328; Topol, Eric/0000-0002-1478-4729 NR 22 TC 46 Z9 46 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD APR PY 2009 VL 157 IS 4 BP 658 EP 665 DI 10.1016/j.ahj.2008.08.031 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432CC UT WOS:000265110100011 PM 19332192 ER PT J AU Truong, QA Cannon, CP Zakai, NA Rogers, IS Giugliano, RP Wiviott, SD McCabe, CH Morrow, DA Braunwald, E AF Truong, Quynh A. Cannon, Christopher P. Zakai, Neil A. Rogers, Ian S. Giugliano, Robert P. Wiviott, Stephen D. McCabe, Carolyn H. Morrow, David A. Braunwald, Eugene TI Thrombolysis in Myocardial Infarction (TIMI) Risk Index predicts long-term mortality and heart failure in patients with ST-elevation myocardial infarction in the TIMI 2 clinical trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROME; NATIONAL REGISTRY; II TRIAL; THERAPY; SCORE AB Background TIMI (Thrombolysis in Myocardial Infarction) Risk Index (TRI) is a simple bedside score that predicts 30-day mortality in patients with ST-elevation myocardial infarction (MI). We sought to evaluate whether TRI was predictive of long-term mortality and clinical events. Methods In the TIMI 2 trial, 3,153 patients (Mean age 57 10 years, 82% men) were randomized to invasive (n = 1,583) versus conservative In = 1,570) strategy postfibrinolysis with median follow-up of 3 years. TIMI Risk Index was divided into 5 groups. The primary end point was all-cause mortality. Secondary analyses included recurrent MI, congestive heart failure (CHF), and combined end points. Results When compared with group 1, mortality in group 5 was more than 5-fold higher (hazard ratio [HR] 5.83, P < .0001) and was also increased in group 4 (HR 2.80, P < .0001) and group 3 (HR 1.96, P = .002) (c statistic 0.69). No difference was seen between groups 1 and 2 (P = .74). A similar increasing gradient effect was seen across TRI strata with group 5 having the highest risk for CHF (HR 4.13, P < .0001) and the highest risk for composite death/CHF (HR 4.35, P < .0001) over group 1. There was no difference in recurrent MI between the groups (P = .22). After controlling for other risk indicators, the relationship between TRI and mortality remained significant: group 5, HR 4.11, P < .0001; group 4, HR 2.14, P = .0009; group 3, HR 1.69, P = .02. When stratified by TRI groups, no differences in mortality or composite death/MI were found between treatment strategies. Conclusions The simple TRI can predict increased long-term mortality, CHF, and composite death/CHF. (Am Heart J 2009; 157:673-79.) C1 [Cannon, Christopher P.; Giugliano, Robert P.; Wiviott, Stephen D.; McCabe, Carolyn H.; Morrow, David A.; Braunwald, Eugene] Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Div Cardiovasc, Boston, MA 02115 USA. [Truong, Quynh A.; Rogers, Ian S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Truong, Quynh A.; Rogers, Ian S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. RP Cannon, CP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Div Cardiovasc, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org FU National Heart, Lung, and Blood Institute (Bethesda, MD); National Institutes of Health (Bethesda, MD) [L30HL093896, T32HL076136] FX The TIMI 2 trial was supported by research contracts from the National Heart, Lung, and Blood Institute (Bethesda, MD). Drs Truong and Rogers received support from National Institutes of Health (Bethesda, MD) grant L30HL093896 and T32HL076136. NR 19 TC 9 Z9 11 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD APR PY 2009 VL 157 IS 4 BP 673 EP 679 DI 10.1016/j.ahj.2008.12.010 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432CC UT WOS:000265110100013 PM 19332194 ER PT J AU Gilon, D Mehta, RH Oh, JK Januzzi, JL Bossone, E Cooper, JV Smith, DE Fang, JM Nienaber, CA Eagle, KA Isselbacher, EM AF Gilon, Dan Mehta, Rajendra H. Oh, Jae K. Januzzi, James L., Jr. Bossone, Eduardo Cooper, Jeanna V. Smith, Dean E. Fang, Jianming Nienaber, Christoph A. Eagle, Kim A. Isselbacher, Eric M. CA Int Registry Acute Aortic Dissecti TI Characteristics and In-Hospital Outcomes of Patients With Cardiac Tamponade Complicating Type A Acute Aortic Dissection SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HEMODYNAMIC COLLAPSE; RELIEF AB Cardiac tamponade (TMP) is a life-threatening complication of acute type A aortic dissection (AAD). The purpose of this study was to assess the clinical characteristics and in-hospital outcomes of TMP in the setting of AAD on the basis of the findings in the large cohort of the International Registry of Acute Aortic Dissection (IRAD). Six hundred seventy-four patients (mean age 61.8 +/- 14.2 years) with AAD in IRAD were studied. TMP was suspected on clinical grounds and confirmed by diagnostic imaging. Univariate testing was followed by multivariate logistic regression analysis to determine the association of TMP. TMP was detected in 126 patients with AAD (18.7%). Age did not differ between patients with and without TMP. Those with TMP less often had previous cardiac surgery (7.0% vs 17.1%, p = 0.007). Syncope (37.8% vs 13.7%, p <0.0001) and altered mental status (31.2% vs 10.6%, p <0.0001) were more common in patients with AAD with TMP than without TMP. Patients with TMP were more likely to have widened mediastina on chest x-ray (72.6% vs 60.3%, p = 0.02) and to have periaortic hematomas (44.7% vs 21.2%, p <0.0001). In-hospital outcomes were significantly worse in patients with TMP. The mortality of patients with TMP remained significantly higher, even after adjustment for baseline clinical characteristics (p <0.001). On logistic regression, altered mental status, hypotension, and early mortality were identified as independent correlates of TMP. In conclusion, TMP is not uncommon in patients with AAD. Syncope, altered mental status, and a widened mediastinum on chest x-ray on presentation suggest TMP, the presence of which warrants urgent operative therapy to improve outcome. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;103:1029-1031) C1 [Gilon, Dan] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Mehta, Rajendra H.; Cooper, Jeanna V.; Smith, Dean E.; Eagle, Kim A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Oh, Jae K.] Mayo Clin, Rochester, MN USA. [Januzzi, James L., Jr.; Fang, Jianming; Isselbacher, Eric M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bossone, Eduardo] CNR, Lecce, Italy. [Nienaber, Christoph A.] Univ Klinikum Rostock, Rostock, Germany. RP Gilon, D (reprint author), Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. EM gilond@cc.huji.ac.il FU University of Michigan Health System, Ann Arbor, Michigan; Varbedian Fund for Aortic Research, Ann Arbor, Michigan FX The International Registry of Acute Aortic Dissection is supported by grants from the University of Michigan Health System, Ann Arbor, Michigan, and the Varbedian Fund for Aortic Research, Ann Arbor, Michigan. NR 12 TC 34 Z9 37 U1 2 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 1 PY 2009 VL 103 IS 7 BP 1029 EP 1031 DI 10.1016/j.amjcard.2008.12.013 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 428AA UT WOS:000264819000025 PM 19327436 ER PT J AU Smith, SM Gardner, KK Locke, J Zwart, SR AF Smith, Scott M. Gardner, Keri K. Locke, James Zwart, Sara R. TI Vitamin D supplementation during Antarctic winter SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CELL-MEDIATED-IMMUNITY; SERUM-LEVELS; OLDER-ADULTS; D DEFICIENCY; 25-HYDROXYVITAMIN-D; DISEASE; OSTEOPOROSIS; POPULATION; PREVALENCE; WOMEN AB Background: Persons with limited exposure to ultraviolet B light, including space travelers, may not receive enough vitamin D. Recent studies indicate that optimal serum 25-hydroxyvitamin D [25(OH) D] should be >= 80 nmol/L. Objective: This study was designed to evaluate the effectiveness of 3 doses of vitamin D to raise and maintain 25(OH) D to a concentration.80 nmol/L in persons with limited ultraviolet B light exposure. Design: This was a 5-mo, prospective, randomized, double-blind study of vitamin D supplementation. It was conducted during winter in Antarctica at the McMurdo Station, when ultraviolet B radiation levels are essentially zero. The 55 subjects were randomly divided into 3 groups for vitamin D supplementation: 2000 IU/d (n = 18), 1000 IU/d (n = 19), and 400 IU/d (n = 18). An additional 7 subjects did not take supplements or took supplements of their own choosing. Blood samples were collected about every 2 mo during the winter. Results: About 5 mo after supplementation started, 25(OH)D increased to 71 +/- 23 nmol/L in the 2000-IU/d group, 63 +/- 25 nmol/L in the 1000-IU/d group, and 57 +/- 15 nmol/L in the 400-IU/d group and decreased to 34 +/- 12 nmol/L in the group not taking supplements. Conclusions: These data will enable us to provide space crews with evidence-based recommendations for vitamin D supplementation. The findings also have implications for other persons with limited ultraviolet light exposure, including polar workers and the elderly. Am J Clin Nutr 2009; 89:1092-8. C1 [Smith, Scott M.; Locke, James] NASA, Lyndon B Johnson Space Ctr, Space Life Sci Directorate, Houston, TX 77058 USA. [Gardner, Keri K.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Gardner, Keri K.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Zwart, Sara R.] Univ Space Res Assoc, Houston, TX USA. RP Smith, SM (reprint author), NASA, Lyndon B Johnson Space Ctr, Space Life Sci Directorate, Mail Code SK3,2101 NASA Pkwy, Houston, TX 77058 USA. EM scott.m.smith@nasa.gov FU NASA; National Science Foundation FX Supported by the NASA Human Research Program and made possible by the National Science Foundation. NR 46 TC 43 Z9 44 U1 0 U2 6 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR 1 PY 2009 VL 89 IS 4 BP 1092 EP 1098 DI 10.3945/ajcn.2008.27189 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 420WF UT WOS:000264319200016 PM 19225122 ER PT J AU Schnur, J Nguyen, S Divino, C Heimann, T Vidal, C AF Schnur, Jessica Nguyen, Scott Divino, Celia Heimann, Tomas Vidal, Claudia TI Coexisting Rectal and Urachal Carcinoma: A Case Report SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE adenocarcinoma; rectal carcinoma; urachal carcinoma; urachus C1 [Schnur, Jessica; Nguyen, Scott; Divino, Celia; Heimann, Tomas; Vidal, Claudia] Mt Sinai Hosp, Dept Surg, New York, NY 10029 USA. [Schnur, Jessica; Nguyen, Scott; Divino, Celia; Heimann, Tomas; Vidal, Claudia] Mt Sinai Hosp, Dept Pathol, New York, NY 10029 USA. [Schnur, Jessica; Nguyen, Scott; Divino, Celia; Heimann, Tomas; Vidal, Claudia] Bronx Vet Affairs Med Ctr, Bronx, NY USA. RP Schnur, J (reprint author), Mt Sinai Hosp, Dept Surg, New York, NY 10029 USA. EM jessica.schnur@mssm.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD APR PY 2009 VL 32 IS 2 BP 220 EP 221 DI 10.1097/01.coc.0000230170.25322.cd PG 2 WC Oncology SC Oncology GA 431JF UT WOS:000265056900020 PM 19346817 ER PT J AU Shen, J Pinkus, GS Deshpande, V Cibas, ES AF Shen, Jian Pinkus, Geraldine S. Deshpande, Vikram Cibas, Edmund S. TI Usefulness of EMA, GLUT-1, and XIAP for the Cytologic Diagnosis of Malignant Mesothelioma in Body Cavity Fluids SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Malignant mesothelioma; Cytology; Benign effusion; Epithelial membrane antigen; EMA; Glucose transporter-1; GLUT-1; X-linked inhibitor of apoptosis; XIAP ID EPITHELIAL MEMBRANE ANTIGEN; NEEDLE-ASPIRATION DIAGNOSIS; CYSTIC SQUAMOUS LESIONS; GROWTH-FACTOR-RECEPTOR; CELL BLOCKS; NONNEOPLASTIC MESOTHELIUM; GLUCOSE TRANSPORTERS; SEROUS EFFUSIONS; BENIGN; EXPRESSION AB We compared the effectiveness of epithelial membrane antigen (EAM)with 2 newly described markers, X-linked inhibitor of apoptosis protein (XIAP) and an isoform of glucose transporter (GLUT-1), in the distinction between malignant mesothelioma (MM) and benign effusion (BE) in body cavity fluids. Immunohistochemical studies were performed on cell block sections from, 35 cases of histologically confirmed MM and 38 BEs, using antibodies to EMA, XIAP, GLUT-1 (GLUT-1m, monoclonal; GLUT-1p, polyclonal). Results were graded based on the percentage of cells staining: negative (0016), 1+ (<25%), 2+ (25%-49%), 3+ (50%-74%), and4+ (75%-100%). The performance of each marker was compared using receiver operating characteristic curve analysis. EMA demonstrated the best accuracy, with an area under the curve of 0.91 as compared with XIAP (0.6 7), GLUT-1 in (0.74), and GLUT-1p (0.80). Based on these findings, EMA is a better marker than XIAP or GLUT-1 for the diagnosis of MM. C1 [Shen, Jian; Deshpande, Vikram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Serv,James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Shen, Jian; Pinkus, Geraldine S.; Cibas, Edmund S.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02114 USA. RP Shen, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Serv,James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. NR 39 TC 38 Z9 38 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD APR PY 2009 VL 131 IS 4 BP 516 EP 523 DI 10.1309/AJCPWFW7O1FVFLKT PG 8 WC Pathology SC Pathology GA 421TO UT WOS:000264381400008 PM 19289587 ER PT J AU Peerschke, EIB Castellone, DD Ledford-Kraemer, M Van Cott, EM Meijer, P AF Peerschke, Ellinor I. B. Castellone, Donna D. Ledford-Kraemer, Marlies Van Cott, Elizabeth M. Meijer, Piet CA NASCOLA Proficiency Testing Comm TI Laboratory Assessment of Factor VIII Inhibitor Titer The North American Specialized Coagulation Laboratory Association Experience SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Coagulation; Factor VIII inhibitor titer; Hemophilia; Proficiency testing; North American Specialized Coagulation Laboratory Association; NASCOLA; ECAT ID PREVIOUSLY UNTREATED PATIENTS; IMMUNE TOLERANCE INDUCTION; HEMOPHILIA-A; BETHESDA ASSAY; NIJMEGEN MODIFICATION; C INHIBITORS; FACTOR-IX; ANTIBODIES; ELISA; SPECIFICITY AB Quantification of inhibitory antibodies against infused factor VIII (FVIII) has an important role in the management of patients with hemophilia A. This article summarizes results from the largest North American FVIII inhibitor proficiency testing challenge conducted to date. Test samples, 4 negative and 4 positive (1-3 Bethesda units [BU]/mL), were distributed by the ECAT Foundation in conjunction with the North American Specialized Coagulation Laboratory Association and analyzed by 38 to 42 laboratories in 2006 and 2007. Whereas laboratories were able to distinguish between the absence and presence of low-titer FVIII inhibitors, the intralaboratory coefficient of variation was high (30%-42%) for inhibitor positive samples, and the definition of lower detection limits of the assay was variable (0-1 BU/mL). Most laboratories performed the Bethesda assay with commercially supplied buffered normal pooled plasma in a 1:1 mix patient plasma. These data provide information for the development of consensus guidelines to improve FVIII inhibitor quantification. C1 [Peerschke, Ellinor I. B.; Castellone, Donna D.] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ledford-Kraemer, Marlies] CLOT ED, Islamorada, FL USA. [Meijer, Piet] ECAT Fdn, Leiden, Netherlands. RP Peerschke, EIB (reprint author), Mt Sinai Sch Med, Dept Pathol, Leahn Bldg,1425 Madison Ave,Room 8-02 A, New York, NY 10029 USA. NR 21 TC 25 Z9 25 U1 2 U2 3 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD APR PY 2009 VL 131 IS 4 BP 552 EP 558 DI 10.1309/AJCPMKP94CODILWS PG 7 WC Pathology SC Pathology GA 421TO UT WOS:000264381400012 PM 19289591 ER PT J AU Kane, B Karren, J Garcia-Godoy, C Garcia-Godoy, F AF Kane, Barbara Karren, Jordan Garcia-Godoy, Cristina Garcia-Godoy, Franklin TI Sealant adaptation and penetration into occlusal fissures SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID PERFORMANCE; CARIES; PIT AB Purpose: To evaluate the adaptation and penetration into occlusal fissures of two different types of fissure sealants. Methods: Extracted third molars (n=10) with evident occlusal fissures were cleaned with a pumice/water Slurry and randomly divided into two groups and sealed following the manufacturers' directions as follows: Group 1 - Embrace fissure sealant (Pulpdent). Surfaces were cleaned and dried, then etched for 15 seconds. Excess water was removed leaving C, the surface slightly moist. Sealant was applied from cusp to cusp without covering marginal ridges and light cured for 20 seconds using a halogen light at 500 mW/cm(2). Group 2 - ClinPro (3M Espe). Surfaces were cleaned and dried then etched for 15 seconds. The etched surface was rinsed and thoroughly dried. Dried surfaces appeared frosty white. Sealant was placed making sure not to go beyond etched area, and light cured for 20 seconds. Teeth were thermocycled (500x) and sectioned with an Isomet in a mesio-distal direction (4 slices per tooth). The sections were examined under the SEM. The marginal adaptation of the sealants was evaluated under the SEM using the following criteria: 1 = Smooth adaptation. Sealant flows with enamel. No ledges 2 = Sealant is not well adapted. Ledge may be present. The penetration ability of the sealants was evaluated under the SEM using the following criteria: 1 = Sealant penetrated 1/3 the total length of the fissure: 2 = Sealant penetrated 1/2 the total length of the fissure; 3 = Sealant penetrated the total length of the fissure. The results were statistically analyzed using a t-test. Results: Embrace showed consistently more intimate marginal adaptation than ClinPro in fissures of the same approximate width and depth (P < 0.05). (Am J Dent 2009-,22:89-91). C1 [Kane, Barbara; Karren, Jordan; Garcia-Godoy, Cristina; Garcia-Godoy, Franklin] Nova SE Univ, Coll Dent Med, Biosci Res Ctr, Ft Lauderdale, FL 33328 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Garcia-Godoy, F (reprint author), Nova SE Univ, Coll Dent Med, Biosci Res Ctr, 3200 S Univ Dr, Ft Lauderdale, FL 33328 USA. EM fgarciagodoy@gmail.com NR 29 TC 3 Z9 4 U1 1 U2 5 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD APR PY 2009 VL 22 IS 2 BP 89 EP 91 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 475FL UT WOS:000268343900005 PM 19626971 ER PT J AU Satia, JA Littman, A Slatore, CG Galanko, JA White, E AF Satia, Jessie A. Littman, Alyson Slatore, Christopher G. Galanko, Joseph A. White, Emily TI Long-term Use of beta-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE beta carotene; carotenoids; cohort studies; dietary supplements; lung neoplasms; randomized controlled trials as topic; vitamins ID DIETARY CAROTENOIDS; WOMENS HEALTH; CARDIOVASCULAR-DISEASE; ALPHA-TOCOPHEROL; POOLED ANALYSIS; UNITED-STATES; COHORT; CONSUMPTION; NUTRITION; FRUIT AB High-dose beta-carotene supplementation in high-risk persons has been linked to increased lung cancer risk in clinical trials; whether effects are similar in the general population is unclear. The authors examined associations of supplemental beta-carotene, retinol, vitamin A, lutein, and lycopene with lung cancer risk among participants, aged 50-76 years, in the VITamins And Lifestyle (VITAL) cohort Study in Washington State. In 2000-2002, eligible persons (n = 77,126) completed a 24-page baseline questionnaire, including detailed questions about supplement use (duration, frequency, dose) during the previous 10 years from multivitamins and individual supplements/mixtures. Incident lung cancers (n = 521) through December 2005 were identified by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Longer duration of use of individual beta-carotene, retinol, and lutein supplements (but not total 10-year average dose) was associated with statistically significantly elevated risk of total lung cancer and histologic cell types; for example, hazard ratio = 2.02, 95% confidence interval: 1.28, 3.17 for individual supplemental lutein with total lung cancer and hazard ratio = 3.22, 95% confidence interval: 1.29, 8.07 for individual beta-carotene with small-cell lung cancer for > 4 years versus no use. There was little evidence for effect modification by gender or smoking status. Long-term use of individual beta-carotene, retinol, and lutein supplements should not be recommended for lung cancer prevention, particularly among smokers. C1 [Satia, Jessie A.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Satia, Jessie A.; Galanko, Joseph A.] Univ N Carolina, Div Digest Dis & Nutr, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. [Littman, Alyson; White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Littman, Alyson] VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Slatore, Christopher G.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. RP Satia, JA (reprint author), Univ N Carolina, Dept Nutr, 2209 McGavran Greenberg Hall,CB 7461, Chapel Hill, NC 27599 USA. EM jsatia@unc.edu FU NCI NIH HHS [R03 CA119683-02, R03 CA119683] NR 41 TC 50 Z9 56 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 815 EP 828 DI 10.1093/aje/kwn409 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500004 PM 19208726 ER PT J AU Fang, SC Cavallari, JM Eisen, EA Chen, JC Mittleman, MA Christiani, DC AF Fang, Shona C. Cavallari, Jennifer M. Eisen, Ellen A. Chen, Jiu-Chiuan Mittleman, Murray A. Christiani, David C. TI Vascular Function, Inflammation, and Variations in Cardiac Autonomic Responses to Particulate Matter Among Welders SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE augmentation; C-reactive protein; disease susceptibility; heart rate; inflammation; particulate matter; vascular diseases; welding ID HEART-RATE-VARIABILITY; CORONARY-ARTERY-DISEASE; C-REACTIVE PROTEIN; HEALTHY-YOUNG MEN; AIR-POLLUTION; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; PULSE PRESSURE; FINE PARTICLES; RISK AB Patients with health conditions associated with impaired vascular function and inflammation may be more susceptible to the adverse health effects of fine particulate (particulate matter with a mass median aerodynamic diameter of <= 2.5 mu m (PM(2.5))) exposure. In 2006, the authors conducted a panel study to investigate directly whether vascular function and inflammation (assessed by C-reactive protein) modify PM(2.5)-associated reductions in heart rate variability among 23 young male workers (mean age, 40 years) from Massachusetts. Concurrent 24-hour ambulatory electrocardiogram and personal PM(2.5) exposure information was collected over a total of 36 person-days, including either or both welding and nonwelding days. Linear mixed models were used to examine the 5-minute standard deviation of normal-to-normal intervals (SDNN) in relation to the moving PM(2.5) averages in the preceding 1-4 hours. C-reactive protein levels and 3 measures of vascular function (augmentation index, mean arterial pressure, and pulse pressure) were determined at baseline. The authors observed an inverse association between the 1-hour PM(2.5) and 5-minute SDNN. Greater SDNN declines were observed among those with C-reactive protein (P(interaction) < 0.001) and augmentation index (P = 0.06) values at or above the 75th percentile and pulse pressure values below the 75th percentile (P < 0.001). Systemic inflammation and poorer vascular function appear to aggravate particle-related declines in heart rate variability among workers. C1 [Fang, Shona C.; Cavallari, Jennifer M.; Eisen, Ellen A.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Chen, Jiu-Chiuan; Mittleman, Murray A.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mittleman, Murray A.] Beth Israel Deaconess Med Ctr, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Fang, SC (reprint author), 665 Huntington Ave,Bldg 1,Room 1402, Boston, MA 02115 USA. EM sfang@hsph.harvard.edu RI Chen, JC/I-2261-2016 FU National Institute of Environmental Health Sciences [ES009860, ES00002]; Education and Research Center of the Harvard-National Institute for Occupational Safety and Health [T42 OH008416]; [T32 ES 07069] FX Conflict of interest: none declared. NR 56 TC 29 Z9 30 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 848 EP 856 DI 10.1093/aje/kwn405 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500007 PM 19153215 ER PT J AU Liu, W Hahn, H Odze, RD Goyal, RK AF Liu, Weitian Hahn, Hejin Odze, Robert D. Goyal, Raj K. TI Metaplastic Esophageal Columnar Epithelium Without Goblet Cells Shows DNA Content Abnormalities Similar to Goblet Cell-Containing Epithelium SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Ultrastructural-Pathology CY 2008 CL San Diego, CA SP Soc Ultrastructural Pathol ID BARRETTS-ESOPHAGUS; INTESTINAL METAPLASIA; GASTROESOPHAGEAL JUNCTION; NEOPLASTIC PROGRESSION; DISTAL ESOPHAGUS; ADENOCARCINOMA; CANCER; INSTABILITY; DYSPLASIA; DIAGNOSIS AB OBJECTIVES: The mucosa of patients with columnar-lined esophagus recognized on endoscopy usually shows epithelium with and without goblet cells. Columnar epithelium with goblet cells ("Barrett's esophagus") is generally believed to represent a premalignant lesion and has been shown to contain DNA abnormalities. However, the biological properties of non-goblet columnar epithelium remain unknown. The purpose of this study was to determine the DNA content properties of non-goblet epithelium in patients with metaplastic columnar epithelium of the esophagus. METHODS: Mucosal biopsies of the esophagus from 68 patients with columnar metaplasia of the esophagus (22 without goblet cells and 46 with goblet cells) and 19 patients with normal gastric mucosa (controls) were histologically evaluated for the density of goblet cells. The latter group was divided into low-density, high-density, and very high-density goblet cell subgroups. Tissue sections of non-goblet epithelium and goblet cell epithelium (where present) were evaluated by image cytometry, and high-fidelity DNA histograms were created to indicate the G0/G1 peak DNA index (DI), DNA content heterogeneity index (HI), and the percentage of cells with DNA exceeding 5N (5N-EC). G0/G1 peaks with DI >1.1 were considered aneuploid. RESULTS: Normal gastric controls showed a mean peak DI of 1.02 +/- 0.03 and an HI of 11.6 +/- 0.7. None of the controls revealed aneuploidy or 5 N-EC. Patients with metaplastic columnar epithelium with goblet cells showed a DI of 1.15 +/- 0.12, HI of 18.2 +/- 2.1, mild aneuploidy in 54 % of the cases, and 5 N-EC in 15% of the cases, all of which were significantly higher than in controls. Patients with metaplastic columnar epithelium without goblet cells showed DNA content results statistically similar to those of patients with metaplastic columnar epithelium with goblet cells, and also revealed significantly higher values compared with those of controls. Furthermore, there were no significant differences in any of the key DNA content abnormalities between non-goblet and goblet cell-containing epithelium in patients with metaplastic columnar epithelium with goblet cells, or between these two types of epithelium according to the density of goblet cells. CONCLUSIONS: DNA content abnormalities occur with equal frequency and extent in metaplastic columnar epithelium of the esophagus without goblet cells compared with metaplastic columnar epithelium with goblet cells. These findings suggest that metaplastic non-goblet columnar epithelium of the esophagus may have neoplastic potential. C1 [Odze, Robert D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Liu, Weitian; Goyal, Raj K.] Harvard Univ, Sch Med, Div Gastroenterol, Dept Med,VA Boston Healthcare Syst, W Roxbury, MA USA. RP Odze, RD (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM rodze@partners.org FU NCI NIH HHS [R01 CA125711]; NIDDK NIH HHS [R01 DK062867, R01 DK062867-05]; PHS HHS [62867] NR 35 TC 99 Z9 102 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD APR PY 2009 VL 104 IS 4 BP 816 EP 824 DI 10.1038/ajg.2009.85 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 431AR UT WOS:000265034200004 PM 19293780 ER PT J AU Passos, MCF Lembo, AJ Conboy, LA Kaptchuk, TJ Kelly, JM Quilty, MT Kerr, CE Jacobson, EE Hu, R Friedlander, E Drossman, DA AF Passos, Maria C. F. Lembo, Anthony J. Conboy, Lisa A. Kaptchuk, Ted J. Kelly, John M. Quilty, Mary T. Kerr, Catherine E. Jacobson, Eric E. Hu, Rong Friedlander, Elizabeth Drossman, Douglas A. TI Adequate Relief in a Treatment Trial With IBS Patients: A Prospective Assessment SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; QUALITY-OF-LIFE; SYMPTOM IMPROVEMENT; RECEPTOR ANTAGONIST; DOUBLE-BLIND; END-POINT; EFFICACY; SAFETY; WOMEN; ALOSETRON AB OBJECTIVES: Adequate relief (AR) of irritable bowel syndrome (IBS) symptoms (IBS-AR) has been used as a primary end point in many randomized controlled trials of IBS and is considered by the Rome III committee to be an acceptable primary end point. However, controversy exists on whether baseline severity confounds the effect of the treatment outcome. The aim is (1) to compare a subjective report of IBS-AR with global assessment of improvement (IBS-GAI), change in IBS symptom severity scale (IBS-SSS), and IBS quality of life (IBS-QOL); (2) to explore whether initial IBS symptom severity influences the ability of these outcome measures to detect differences post treatment; and (3) to determine whether psychological symptoms influence the sensitivity of these measures, in a randomized controlled treatment trial. METHODS: A total of 289 adult IBS patients were recruited to a treatment trial. Baseline IBS-SSS scores were used to classify IBS severity as mild (<175), moderate (175-300), or severe (>300). Questionnaires were completed at baseline and after 3 weeks of treatment with sham acupuncture or wait-list control. RESULTS: IBS baseline severity (IBS-SSS) significantly affected the proportion of patients who reported IBS-AR at 3 weeks (mild, 70%; moderate, 49.7%; severe, 38.8%) (P<0.05). However, once the patients who reported IBS-AR at baseline (28.0%) were excluded from the analysis, baseline severity no longer affected the proportion of patients reporting IBS-AR. Baseline severity did not have a significant effect on patients reporting moderate or significant improvement on the IBS-GAI (mild, 30%; moderate, 25.3%; severe, 18.8%) (P = NS). Psychological symptoms had no significant correlations with responders after adjusting for baseline severity. CONCLUSIONS: These data suggest that IBS-AR as an end point is inversely related to baseline symptom severity. However, if patients who report AR at screening were excluded from study participation, baseline symptom severity was no longer confounded with a report of AR at the study end point. C1 [Passos, Maria C. F.; Lembo, Anthony J.; Friedlander, Elizabeth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Conboy, Lisa A.; Kaptchuk, Ted J.; Quilty, Mary T.; Kerr, Catherine E.; Hu, Rong] Harvard Univ, Sch Med, Osher Inst, Boston, MA USA. [Kelly, John M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kelly, John M.] Endicott Coll, Beverly, MA USA. [Jacobson, Eric E.] Harvard Univ, Sch Med, Dept Social Med, Boston, MA 02115 USA. [Drossman, Douglas A.] Univ N Carolina, Chapel Hill, NC USA. RP Lembo, AJ (reprint author), 330 Brookline Ave Rabb Rose 1, Boston, MA 02215 USA. EM alembo@bidmc.harvard.edu RI Kerr, Catherine/D-3299-2009 FU NIH [1R01 AT01414-01]; National Center for Complementary and Alternative Medicine (NCCAM); National Institutes of Digestive, Diabetes and Kidney Disease (NIDDK); NCCAM [1R21 AT002860-01, 1 R21 AT002564, 1K24 AT004095]; Office of Behavioral and Social Science Research (OBSSR) FX This research was made possible by NIH Grant Numbers 1R01 AT01414-01 from the National Center for Complementary and Alternative Medicine (NCCAM) and the National Institutes of Digestive, Diabetes and Kidney Disease (NIDDK), Grant Number 1R21 AT002860-01 from NCCAM and the Office of Behavioral and Social Science Research (OBSSR), and Grant Numbers 1 R21 AT002564 and 1K24 AT004095 from NCCAM. e contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Maria Passos was supported by a grant from National Council for Scientific and Technological Development (CNPq) from Brazil. NR 31 TC 17 Z9 18 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD APR PY 2009 VL 104 IS 4 BP 912 EP 919 DI 10.1038/ajg.2009.13 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 431AR UT WOS:000265034200018 PM 19293784 ER PT J AU Singh, H Kadiyala, H Bhagwath, G Shethia, A El-Serag, H Walder, A Velez, ME Petersen, LA AF Singh, Hardeep Kadiyala, Himabindu Bhagwath, Gayathri Shethia, Anila El-Serag, Hashem Walder, Annette Velez, Maria E. Petersen, Laura A. TI Using a Multifaceted Approach to Improve the Follow-Up of Positive Fecal Occult Blood Test Results SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID COMPLETE DIAGNOSTIC EVALUATION; PRIMARY-CARE PHYSICIANS; ABNORMAL PAP-SMEARS; COLORECTAL-CANCER; PATIENT NAVIGATION; COLON EVALUATION; CONTROLLED-TRIAL; NATIONAL-SURVEY; TASK-FORCE; HEALTH AB OBJECTIVES : Inadequate follow-up of abnormal fecal occult blood test (FOBT) results occurs in several types of practice settings. Our institution implemented multifaceted quality improvement (QI) activities in 2004-2005 to improve follow-up of FOBT-positive results. Activities addressed precolonoscopy referral processes and system-level factors such as electronic communication, provider education, and feedback. We evaluated their effects on timeliness and appropriateness of positive-FOBT follow-up and identified factors that affect colonoscopy performance. METHODS: Retrospective electronic medical record review was used to determine outcomes before and after QI activities in a multispecialty ambulatory clinic of a tertiary care Veterans Affairs facility and its affiliated satellite clinics. From 1869 FOBT-positive cases, 800 were randomly selected from time periods before and after QI activities. Two reviewers used a pretested standardized data collection form to determine whether colonoscopy was appropriate or indicated based on predetermined criteria and if so, the timeliness of colonoscopy referral and performance before and after QI activities. RESULTS: In cases where a colonoscopy was indicated, the proportion of patients who received a timely colonoscopy referral and performance were significantly higher post-implementation (60.5% vs. 31.7%, P < 0.0001 and 11.4% vs. 3.4%, P = 0.0005). A significant decrease also resulted in median times to referral and performance (6 vs. 19 days, P < 0.0001 and 96.5 vs. 190 days, P < 0.0001) and in the proportion of positive-FOBT test results that had received no follow-up by the time of chart review (24.3% vs. 35.9%, P = 0.0045). Significant predictors of absence of the performance of an indicated colonoscopy included performance of a non-colonoscopy procedure such as barium enema or flexible sigmoidoscopy (OR = 16.9; 95% CI, 1.9-145.1), patient non-adherence (OR = 33.9; 95% CI, 17.3-66.6), not providing an appropriate provisional diagnosis on the consultation (OR = 17.9; 95% CI, 11.3-28.1), and gastroenterology service not rescheduling colonoscopies after an initial cancellation (OR = 11.0; 95% CI, 5.1-23.7). CONCLUSIONS: Multifaceted QI activities improved rates of timely colonoscopy referral and performance in an electronic medical record system. However, colonoscopy was not indicated in over one third of patients with positive FOBTs, raising concerns about current screening practices and the appropriate denominator used for performance measurement standards related to colon cancer screening. C1 [Singh, Hardeep; Petersen, Laura A.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Hlth Policy & Qual Program, Houston VA HSR&D Ctr Excellence, Houston, TX 77030 USA. [Singh, Hardeep; Shethia, Anila; El-Serag, Hashem; Walder, Annette; Petersen, Laura A.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Singh, Hardeep; Petersen, Laura A.] Baylor Coll Med, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Kadiyala, Himabindu; Bhagwath, Gayathri] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Gen Med, Dept Med, Houston, TX 77030 USA. [El-Serag, Hashem; Velez, Maria E.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Gastroenterol Sect, Houston, TX 77030 USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu FU NIH K23 career development award [K23CA125585]; Houston VA HSR&D Center of Excellence [HFP90-020]; Michael E. DeBakey Veterans Affairs Medical Center FX The study was supported by an NIH K23 career development award (K23CA125585) to Dr Singh, and in part by the Houston VA HSR&D Center of Excellence (HFP90-020) and the Michael E. DeBakey Veterans Affairs Medical Center. These sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manusc ript. NR 62 TC 31 Z9 31 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD APR PY 2009 VL 104 IS 4 BP 942 EP 952 DI 10.1038/ajg.2009.55 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 431AR UT WOS:000265034200023 PM 19293786 ER PT J AU Donohue, JM Huskamp, HA Wilson, IB Weissman, J AF Donohue, Julie M. Huskamp, Haiden A. Wilson, Ira B. Weissman, Joel TI Whom Do Older Adults Trust Most to Provide Information About Prescription Drugs? SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article DE prescription drug costs; patient-provider communication; trust in physicians; cost-related nonadherence ID MEDICATION NONADHERENCE; PHYSICIAN COMMUNICATION; COMMON MEDICATIONS; PATIENT TRUST; COST; CARE; KNOWLEDGE; QUALITY; BENEFIT; RELIABILITY AB Background: Cost-related nonadherence to medications is common among older adults, yet physician-patient communication about medication cost concerns is infrequent. One factor affecting communication and adherence may be older adults' confidence in the information about prescription drugs provided by physicians and other sources. Objectives: This study was conducted to identify which source older adults most trust to provide information on drugs and to examine the relationship between older patients' trust in physicians to provide price information and the Occurrence of cost-related nonadherence. Methods: We conducted a cross-sectional national telephone survey of individuals aged >= 50 years who were taking at least I prescription medication. Respondents were asked how Much they would trust various Sources (physician, pharmacist, nurse, insurance plan, the Internet, Consumer groups, friends and family) to provide helpful information on "the price of the prescription medicine compared to others like it" and on "how well the prescription medicine will work for you compared to other medicines like it." The response options were a lot, somewhat, and not at all. Other measures of interest were respondents' beliefs concerning physicians' ability to lower drug costs and patient activation. We also evaluated the potential association between trust in physicians to deliver drug price information and cost-related medication nonadherence. Results: Compared with the other Sources of information Studied, doctors and pharmacists were the sources that respondents were most likely to trust "a lot" to provide information on drug prices (55.6% and 61.7%, respectively) and to provide information on drug effectiveness (79.9% and 66.4%). Less than half (42.3%) of respondents who said that they trusted their doctor to provide drug price information "somewhat" or "not at all" agreed that there are ways doctors could lower drug Costs (P = 0.01 vs those who trusted their doctor "a lot"). Adults aged >= 65 years were more likely than those aged 50 to 64 years to trust their doctors "a lot" to provide information on drug prices (odds ratio [OR] = 1.44; 95% CI, 1.08-1.92); the same was true of members of minority groups compared with white respondents (OR = 1.72; 95% CI, 1.13-2.61). Among individuals with high drug spending, those who placed "a lot" of trust in their doctors to provide price information were less likely than those who trusted their doctor "somewhat" or "not at all" to have cost-related nonadherence (OR = 0.40; 95% Cl, 0.20-0.78). Conclusions: In this survey, older adults trusted physicians and pharmacists more than the other Sources Studied to provide information on prescription drugs. Trust in physicians to provide price information was an important moderator of the effect of high drug spending on cost-related nonadherence. Efforts to provide patients and their providers with comparative data on drug prices and effectiveness may reduce cost-related nonadherence. (Am J Geriatr Pharmacother. 2009;7:105-116) (C) 2009 Excerpta Medica Inc. C1 [Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15261 USA. [Huskamp, Haiden A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Wilson, Ira B.] Tufts Univ New England Med Ctr, Boston, MA USA. [Weissman, Joel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, Boston, MA USA. RP Donohue, JM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, 130 DeSoto St,Crabtree Hall A613, Pittsburgh, PA 15261 USA. EM jdonohue@pitt.edu RI Wilson, Ira/F-9190-2016; OI Wilson, Ira/0000-0002-0246-738X; Donohue, Julie/0000-0003-2418-6017 FU Consumers Union's Consumer Reports Best Buy Drugs program; Engelberg Foundation; National Library of Medicine; National Center for Research Resources (NCRR) [KL2-RR024154-01, K24 RR020300]; National Institutes of Health Roadmap for Medical Research FX The survey described in this article was funded by a grant from the Consumers Union's Consumer Reports Best Buy Drugs program, which is Supported by grants from the Engelberg Foundation and the National Library of Medicine. Dr. Donohue has received support from grant KL2-RR024154-01 from the National Center for Rescarch Resources (NCRR), a component of the National Institutes of Health Roadmap for Medical Research. Dr. Wilson was funded by a grant from the NCRR, (K24 RR020300).; The authors thank Aiju Men, MS (Department of Health Policy & Management, University of Pittsburgh Graduate School Of Public Health), for assistance with programming. Ill addition, they acknowledge the contributions of the Consumer Reports National Research Center and Richard Grant, MD, MPH (Harvard Medical School), as well as the helpful comments of Judith Lave, PhD (Department of Health Policy & Management, University of Pittsburgh Graduate School of Public Health). NR 47 TC 37 Z9 37 U1 3 U2 7 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD APR PY 2009 VL 7 IS 2 BP 105 EP 116 DI 10.1016/j.amjopharm.2009.04.005 PG 12 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 440XY UT WOS:000265734200005 PM 19447363 ER PT J AU Federman, AD Safran, DG Keyhani, S Cole, H Halm, EA Siu, AL AF Federman, Alex D. Safran, Dana Gelb Keyhani, Salomeh Cole, Helen Halm, Ethan A. Siu, Albert L. TI Awareness of Pharmaceutical Cost-Assistance Programs Among Inner-City Seniors SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article DE seniors; low income; pharmaceutical cost-assistance programs ID HEALTH LITERACY; MEDICARE; CARE; ASSOCIATION; OUTCOMES; BENEFIT; DISEASE; ACCESS; IMPACT AB Background: Lack of awareness may be a significant barrier to participation by low- and middle-income seniors in pharmaceutical cost-assistance programs. Objective: The goal Of this study was to determine whether older adults' awareness of 2 major state and federal pharmaceutical cost-assistance programs was associated with the seniors' ability to access and process information about assistance programs. Methods: Data were gathered from a cross-sectional study of independently living, English- or Spanish-speaking adults aged >= 60 years. Participants were interviewed in 30 community-based settings (19 apartment complexes and 11 senior centers) in New York, New York. The analysis focused on adults aged >= 65 years who lacked Medicaid coverage. multivariable logistic regression was used to model program awareness as a function of information access (family/social support, attendance at senior or community centers and places of worship, viewing of live health insurance presentations, instrumental activities of daily living, site of medical care, computer use, and having a proxy decision maker for health insurance matters) and information-processing ability (education level, English proficiency, health literacy, and cognitive function). The main outcome measure was awareness of New York's state pharmaceutical assistance program (Elderly Pharmaceutical Insurance Coverage [EPIC]) and the federal Medicare Part D low-income subsidy program (Extra Help). Results: A total of 269 patients were enrolled (mean [SD] age, 76.9 [7.5] years; 32.0% male; 39.9% white). Awareness of the programs differed widely: 77.3% knew of EPIC and 22.3% knew of Extra Help. In multivariable analysis, study participants were more likely to have heard of the EPIC program if they had attended a live presentation about health Insurance issues (adjusted odds ratio [AOR], 3.40; 95% CI, 1.20-9.61) and less likely if they received care in a clinic (AOR, 0.45; 95% CI, 0.23-0.92). Awareness of Extra Help in the multivariable models was more likely among Study participants who had viewed a live health insurance presentation (AOR, 3.35; 95% CI, 1.55-7.24) and less likely for those with inadequate health literacy (AOR, 0.15; 95% CI, 0.03-0.74). Conclusions: Viewing of live health insurance presentations and adequate health literacy were associated with greater awareness of important pharmaceutical cost-assistance programs in this study, in low-income, elderly individuals. The findings Suggest that use of live presentations, in addition to health literacy materials and messages, may be important strategies in promoting knowledge of and enrollment in state and federal pharmaceutical cost-assistance programs for low-income seniors. (Am J Geriatr Pharmacother. 2009;7:117-129) (C) 2009 Excerpta Medica Inc. C1 [Federman, Alex D.; Cole, Helen] Mt Sinai Sch Med, Div Gen Internal Med, New York, NY 10029 USA. [Safran, Dana Gelb] Tufts Univ New England Med Ctr, Hlth Inst, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Safran, Dana Gelb] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. [Keyhani, Salomeh] Mt Sinai Sch Med, Dept Hlth Policy, New York, NY 10029 USA. [Keyhani, Salomeh; Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Div Gen Internal Med, Dallas, TX 75390 USA. [Siu, Albert L.] Bronx Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Siu, Albert L.] Mt Sinai Sch Med, Brookdale Dept Geriatr & Adult Dev, New York, NY 10029 USA. RP Federman, AD (reprint author), Mt Sinai Sch Med, Div Gen Internal Med, 1 Gustave L Levy Pl,Box 1087, New York, NY 10029 USA. EM alex.federman@mssm.edu FU National Institute on Aging [1K23AG028955-01]; VA Health Services Research and Development Service; Mount Sinai School of Medicine Alzheimer's Disease Research Center [NIH AG0051318] FX The authors thank Paul Hebert, PhD, for technical assistance with statistical procedures. NR 45 TC 2 Z9 2 U1 2 U2 8 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD APR PY 2009 VL 7 IS 2 BP 117 EP 129 DI 10.1016/j.amjopharm.2009.04.003 PG 13 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 440XY UT WOS:000265734200006 PM 19447364 ER PT J AU Ettenhofer, ML Hinkin, CH Castellon, SA Durvasula, R Ullman, J Lam, M Myers, H Wright, MJ Foley, J AF Ettenhofer, Mark L. Hinkin, Charles H. Castellon, Steven A. Durvasula, Ramani Ullman, Jodi Lam, Mona Myers, Hector Wright, Matthew J. Foley, Jessica TI Aging, Neurocognition, and Medication Adherence in HIV Infection SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the International-Neuropsychological-Society CY FEB 06-09, 2008 CL Waikoloa, HI SP Int Neuropsychol Soc DE HIV; AIDS; aging; cognition; medication adherence; executive functions ID ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; NEUROPSYCHOLOGICAL PERFORMANCE; AGE; DEMENTIA; DISEASE; ADULTS; METAANALYSIS; ZIDOVUDINE; DISORDERS AB Objective: To evaluate the hypothesis that poor adherence to highly active antiretroviral treatment (HAART) would be more strongly related to cognitive impairment among older than among younger HIV-seropositive adults. Setting and Participants: A volunteer sample of 431 HIV-infected adult patients prescribed self-administered HAART was recruited from community agencies and university-affiliated infectious disease clinics in the Los Angeles area. Measurements: Neurocognitive measures included tests of attention, information processing speed, learning/memory, verbal fluency, motor functioning, and executive functioning. Medication adherence was measured using microchip-embedded pill bottle caps (Medication Event Monitoring System) and se report. Latent/structural analysis techniques were used to evaluate factor models of cognition and adherence. Results: Mean adherence rates were higher among older (>= 50 years) than younger (<50 years) HIV-positive adults. However, latent/structural modeling demonstrated that neurocognitive impairment was associated with poorer medication adherence among older participants only. When cognitive subdomains were examined individually, executive functioning, motor functioning, and processing speed were most strongly related to adherence in this age group. CD4 count and drug problems were also more strongly associated with adherence among older than younger adults. Conclusions: Older HIV-positive individuals with neurocognitive impairment or drug problems are at increased risk of suboptimal adherence to medication. Likewise, older adults may be especially vulnerable to immunological and neurocognitive dysfunction under conditions of suboptimal LOART adherence. These findings highlight the importance of optimizing medication adherence rates and evaluating neurocognition in the growing population of older HIV-infected patients. (Am J Geriatr Psychiatry 2009; 17:281-290) C1 [Ettenhofer, Mark L.] Univ Calif Los Angeles, Semel Inst, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Hinkin, Charles H.; Castellon, Steven A.; Lam, Mona] VA Greater Los Angeles Hlth Care Syst, Psychol Serv, Los Angeles, CA USA. [Durvasula, Ramani] Calif State Univ Los Angeles, Dept Psychol, Los Angeles, CA 90032 USA. [Ullman, Jodi] Calif State Univ San Bernardino, Dept Psychol & Human Dev, Los Angeles, CA USA. [Myers, Hector] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Ettenhofer, ML (reprint author), Univ Calif Los Angeles, Semel Inst, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza, Los Angeles, CA 90095 USA. EM MEttenhofer@mednct.ucla.edu FU NIDA NIH HHS [R01 DA013799, R01 DA013799-01A1, R01 DA013799-02, R01 DA013799-02S1, R01 DA013799-03, R01 DA013799-04, R01 DA13799]; NIMH NIH HHS [T32 MH019535-14, R01 MH058552, R01 MH058552-02, R01 MH058552-03, R01 MH058552-04, R01 MH058552-05, R01 MH58552, T32 MH019535, T32 MH019535-12, T32 MH019535-13, T32 MH019535-15, T32 MH019535-16, T32 MH019535-17, T32 MH19535] NR 40 TC 50 Z9 51 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD APR PY 2009 VL 17 IS 4 BP 281 EP 290 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 432QG UT WOS:000265148600004 PM 19307857 ER PT J AU Driscoll, DF Thoma, A Franke, R Klotsch, K Nehne, J Bistrian, BR AF Driscoll, David F. Thoma, Andrea Franke, Rolf Klotsch, Karsten Nehne, Jorg Bistrian, Bruce R. TI Lipid globule size in total nutrient admixtures prepared in three-chamber plastic bags SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Additives; Control, quality; Electrolytes; Emulsions; Injections; Osmolarity; Particle size; Soybean oil; Stability; Storage; Triglycerides; Vehicles; Vitamins ID INJECTABLE EMULSIONS; STABILITY; STANDARDS; INFUSION; GLASS; RATS AB Purpose. The stability of injectable lipid emulsions in three-chamber plastic (3CP) bags, applying the globule-size limits established by United States Phormacopeia (USP) chapter 729, was studied. Methods. A total of five premixed total nutrient admixture (TNA) products packaged in 3CP bags from two different lipid manufacturers containing either 20% soybean oil or a mixture of soybean oil and medium-chain-triglyceride oil as injectable lipid emulsions were tested. Two low-osmolarity 3CP bags and three high-osmolarity 3CP bags were studied. All products were tested with the addition of trace elements and multivitamins. All additive conditions (with and without electrolytes) were tested in triplicate at time 0 (immediately after mixing) and at 6, 24, 30, and 48 hours after mixing; the bags were stored at 24-26 degrees C. All additives were equally distributed in each bag for comparative testing, applying both globule sizing methods outlined in USP chapter 729, Results. Of the bags tested, all bags from one manufacturer were coarse emulsions, showing signs of significant growth in the large-diameter tail when mixed as a TNA formulation and failing the limits set by method II of USP chapter 729 from the outset and throughout the study, while the bags from the other manufacturer were fine emulsions and met these limits. Of the bags that failed, significant instability was noted in one series containing additional electrolytes. Conclusion. Injectable lipid emulsions provided in 3CP bags that did not meet the globule-size limits of USP chapter 729 produced coarser TNA formulations than emulsions that met the USP limits. C1 [Driscoll, David F.] Stable Solut LLC, Goleta, CA 93117 USA. [Driscoll, David F.] BIDMC, Nutr Infect Lab, Boston, MA USA. [Driscoll, David F.] Harvard Univ, Sch Med, Boston, MA USA. [Nehne, Jorg] Hosp Care Pilot Plant Pharma, Melsungen, Germany. RP Driscoll, DF (reprint author), Stable Solut LLC, 551 Mills Way, Goleta, CA 93117 USA. EM d.driscoll.ssi@gmail.com FU B. Braun, Melsungen, Germany FX Supported by a grant from B. Braun, Melsungen, Germany NR 20 TC 14 Z9 16 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD APR 1 PY 2009 VL 66 IS 7 BP 649 EP 656 DI 10.2146/ajhp080164 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 423KA UT WOS:000264494000013 PM 19299372 ER PT J AU Boulev, R Nunes, P Brown, D AF Boulev, Richard Nunes, Paula Brown, Dennis TI TRANSFERRIN INDUCES VASOPRESSIN RECEPTOR TYPE 2 (V2R) INTERNALIZATION AND EFFECTS WATER OSMEOSTASIS IN VIVO SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meeting of the National-Kidney-Foundation CY MAR 25-29, 2009 CL Nashville, TN SP Natl Kidney Fdn C1 Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2009 VL 53 IS 4 MA 31 BP A30 EP A30 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 425JI UT WOS:000264632400056 ER PT J AU Ramirez, P Al-Shahrouri, H Fanti, P Abboud, H Lorenzo, C Haffner, S AF Ramirez, Peter Al-Shahrouri, Hania Fanti, Paolo Abboud, Hanna Lorenzo, Carlos Haffner, Steven TI NMR IDENTIFIES ATHEROGENIC LIPOPROTEIN ABNORMALITIES IN EARLY DIABETIC NEPHROPATHY THAT ARE UNRECOGNIZED BY CONVENTIONAL ANALYSIS SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meeting of the National-Kidney-Foundation CY MAR 25-29, 2009 CL Nashville, TN SP Natl Kidney Fdn C1 Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. S Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2009 VL 53 IS 4 MA 168 BP A64 EP A64 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 425JI UT WOS:000264632400193 ER PT J AU Gold, J Buonopane, RJ Caggiano, RA Picciotto, M Vogeli, C Kanner, NT Babcock, RL Li, ZH Jellinek, M Drubner, SJ Sklar, KJ Murphy, JM AF Gold, Joseph Buonopane, Ralph J. Caggiano, Robert A. Picciotto, Mark Vogeli, Christine Kanner, Natalie T. Babcock, Rebecca L. Li, Zhonghe Jellinek, Michael Drubner, Stacey J. Sklar, Kenneth J. Murphy, J. Michael TI Assessing Outcomes in Child Psychiatry SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID GLOBAL ASSESSMENT SCALE; RATING-SCALE; ANCHORED VERSION; OPEN-LABEL; BPRS-C; RELIABILITY; CGAS; SCHIZOPHRENIA; ADOLESCENTS; TRIAL AB Objective: To report on the first year of a program using standardized rating scales within a large, multisite mental health system of care for children and to assess the validity, reliability, and feasibility of these scales. Study Design: Naturalistic follow-up of clinicians' ratings. Methods: Clinicians filled out the Brief Psychiatric Rating Scale for Children (BPRS-C) and the Children's Global Assessment Scale (CGAS) at intake and discharge/90-day follow-up for all new patients. Results: Data were collected on 2396 patients from all 20 sites serving children in the Partners HealthCare network. Mean scores for both BPRS-C and CGAS showed worst functioning at inpatient sites, followed by Acute Residential Treatment, then partial hospital, then outpatient sites. All patients re-rated at discharge or 90-day follow-up showed a significant improvement in scores. Inter-item reliability on the BPRS-C was acceptable, with Cronbach alphas of .78 and .81. Feasibility at intake was demonstrated in that 66% of all patients had a completed form at intake. Reassessment at discharge also appeared to be feasible in more restrictive levels of care, but less feasible in outpatient sites, where fewer than 25% of all patients had a follow-up form. Conclusions: This evaluation suggested that the 2 standardized measures appeared to be valid and reliable as part of routine intake and discharge/follow-up in a large child psychiatry system of care. Whether these measures are truly clinically useful remains to be demonstrated because there is at present no gold standard for assessing the quality of treatment or change caused by it. C1 [Gold, Joseph; Buonopane, Ralph J.; Picciotto, Mark; Babcock, Rebecca L.] McLean Hosp, Belmont, MA 02178 USA. [Gold, Joseph; Buonopane, Ralph J.; Picciotto, Mark; Vogeli, Christine; Jellinek, Michael; Murphy, J. Michael] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Caggiano, Robert A.] N Shore Med Ctr, Dept Psychiat, Salem, MA USA. [Vogeli, Christine; Li, Zhonghe] MGH Inst Hlth Policy, Boston, MA USA. [Drubner, Stacey J.; Sklar, Kenneth J.] Partners Psychiat & Mental Hlth, Boston, MA USA. [Jellinek, Michael] Newton Wellesley Hosp, Dept Psychiat, Newton, MA USA. [Kanner, Natalie T.; Babcock, Rebecca L.; Jellinek, Michael; Murphy, J. Michael] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Murphy, JM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,YAW 6A, Boston, MA 02114 USA. EM mmurphy6@partners.org NR 20 TC 11 Z9 11 U1 1 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD APR PY 2009 VL 15 IS 4 BP 210 EP 216 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 433WS UT WOS:000265237100001 PM 19355793 ER PT J AU Rose, AJ Hermos, JA Frayne, SM Pogach, LM Berlowitz, DR Miller, DR AF Rose, Adam J. Hermos, John A. Frayne, Susan M. Pogach, Leonard M. Berlowitz, Dan R. Miller, Donald R. TI Does Opioid Therapy Affect Quality of Care for Diabetes Mellitus? SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID OPTIMAL GLYCEMIC CONTROL; WOOD-JOHNSON-FOUNDATION; CHRONIC NONCANCER PAIN; SELF-MANAGEMENT; IMPACT; PERSPECTIVES; PERFORMANCE; PREVALENCE; DISORDERS; BARRIERS AB Objective: To examine whether veterans who received chronic opioid therapy had worse diabetes performance measures than patients who did not receive opioids. Study Design: Retrospective cohort study. Methods: We identified all patients with diabetes mellitus receiving care in US Department of Veterans Affairs facilities during 2004. Cases received at least 6 prescriptions for chronic opioids during 2004, while controls were randomly selected from among patients with diabetes who received no opioids. We compared process measures (glycosylated hemoglobin and low-density lipoprotein cholesterol levels tested and an eye examination performed) and outcome measures (glycosylated hemoglobin level <= 9.0% and low-density lipoprotein cholesterol level <= 130 mg/dL) between groups. Results: Cases (n = 47,756) had slightly worse diabetes performance measures than controls (n = 220,912) after adjustment for covariates. For example, 86.4% of cases and 89.0% of controls had a glycosylated hemoglobin test during fiscal year 2004 (adjusted odds ratio, 0.69; P <.001). Among cases, receipt of higher-dose opioids was associated with additional decrement in diabetes performance measures, with a dose-response relationship. Conclusions: Chronic opioid therapy among patients within the Veterans Affairs system is associated with slightly worse diabetes performance measures compared with patients who do not receive opioids. However, patients receiving higher dosages of opioids had additional decrements in diabetes performance measures; these patients may be appropriate targets for interventions to improve their care for pain and diabetes. C1 [Rose, Adam J.; Berlowitz, Dan R.; Miller, Donald R.] Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. [Rose, Adam J.; Hermos, John A.; Berlowitz, Dan R.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Hermos, John A.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Frayne, Susan M.] VA Palo Alto Healthcare Syst, Ctr Hlth Care Evaluat, Palo Alto, CA USA. [Frayne, Susan M.] Stanford Univ, Div Gen Internal Med, Stanford, CA 94305 USA. [Pogach, Leonard M.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Pogach, Leonard M.] New Jersey Vet Healthcare Syst, Ctr Healthcare Knowledge Management, E Orange, NJ USA. [Berlowitz, Dan R.; Miller, Donald R.] Boston Univ, Dept Hlth Policy & Management, Sch Publ Hlth, Boston, MA USA. RP Rose, AJ (reprint author), Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, 200 Springs Rd,Bldg 70, Bedford, MA 01730 USA. EM adamrose@bu.edu FU US Department of Veterans Affairs Clinical Sciences Research and Development Service; US Department of Veterans Affairs Health Services Research and Development Service FX This study was supported by a grant from the US Department of Veterans Affairs Clinical Sciences Research and Development Service (principal investigator DRM and coprincipal investigator LMP). Dr Rose is supported by a career development grant from the US Department of Veterans Affairs Health Services Research and Development Service. The views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. NR 44 TC 9 Z9 9 U1 1 U2 3 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD APR PY 2009 VL 15 IS 4 BP 217 EP 224 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 433WS UT WOS:000265237100002 PM 19355794 ER PT J AU Naik, AD Woofter, AL Skinner, JM Abraham, NS AF Naik, Aanand D. Woofter, Aaron L. Skinner, Jessica M. Abraham, Neena S. TI Pharmaceutical Company Influence on Nonsteroidal Anti-Inflammatory Drug Prescribing Behaviors SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID CONSENSUS PANEL; PHYSICIANS; QUALITY; OSTEOARTHRITIS; PRESCRIPTION; IMPROVEMENT; STRATEGIES; GUIDELINES; INHIBITORS; ADHERENCE AB Objectives: To describe the taxonomy of methods used by pharmaceutical companies to influence physicians' nonsteroidal anti-inflammatory drug (NSAID) prescribing behaviors and to elicit physicians' perceptions of and counterbalances to these influences. Study Design: In-depth interviews analyzed using the constant comparative method of qualitative data analysis. Methods: Qualitative interviews were conducted with physicians representing various clinical specialties. Interviews were transcribed and coded inductively using grounded theory. Recruitment was stopped at 25 participants after the attainment of thematic saturation, when no new concepts emerged from ongoing analysis of consecutive interviews. Results: Physicians described a variety of influences that shaped their NSAID prescribing behaviors, including detailing and direct contact with pharmaceutical representatives, requests from patients inspired by direct-to-consumer advertisements, and marketing during medical school and residency training. Physicians described practice guidelines, peer-reviewed evidence, and opinions of local physician experts as important counterweights to pharmaceutical company influence. Local physician experts interpreted and provided context for new clinical evidence, practice guidelines, and NSAID-related marketing. Conclusions: The social and communicative strategies used by pharmaceutical companies can be adapted to improve physicians' adoption of guidelines for safer NSAID prescribing. Communicative interactions between local experts and other physicians who prescribe NSAIDs may be the critical target for future interventions to promote safer NSAID prescribing. C1 [Naik, Aanand D.; Woofter, Aaron L.; Abraham, Neena S.] Michael E DeBakey Vet Affairs Med Ctr, Res & Dev Ctr Excellence, Gastroenterol Outcomes Geriatr Unit Hlth Serv, Houston, TX USA. [Woofter, Aaron L.] Duke Univ, Div Gastroenterol, Raleigh, NC USA. [Naik, Aanand D.; Skinner, Jessica M.; Abraham, Neena S.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Naik, AD (reprint author), Houston Ctr Qual Care & Utilizat Studies, Michael E DeBakey VA Med Ctr, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM anaik@bcm.tmc.edu FU Houston Center for Quality of Care & Utilization Studies; Houston Veterans Affairs Health Sciences Research and Development Center of Excellence [HFP90-020]; National Institute on Aging Career Development Award [5K23AG027144]; American Gastroenterological Association Foundation-Sucampo-Association of Specialty Professors Designated Research Award in Geriatric Gastroenterology; Department of Veterans Affairs [VA IIR 115-05] FX This study was supported by resources and use of facilities at the Houston Center for Quality of Care & Utilization Studies, Houston Veterans Affairs Health Sciences Research and Development Center of Excellence (HFP90-020). Dr Naik is supported by a National Institute on Aging Career Development Award (5K23AG027144). Dr Abraham is supported by an American Gastroenterological Association Foundation-Sucampo-Association of Specialty Professors Designated Research Award in Geriatric Gastroenterology and by a Merit Review Award from the Department of Veterans Affairs (VA IIR 115-05). No funding agencies had a role in the design and conduct of the study, analysis and interpretation of data, or preparation and approval of the manuscript. The views expressed herein are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs or Baylor College of Medicine. NR 31 TC 4 Z9 4 U1 1 U2 4 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD APR PY 2009 VL 15 IS 4 BP E9 EP E15 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 433WS UT WOS:000265237100007 PM 19341315 ER PT J AU Munshi, MN Hayes, M Sternthal, A Ayres, D AF Munshi, Medha N. Hayes, Mellody Sternthal, Adrianne Ayres, Darlene TI Use of Serum c-Peptide Level to Simplify Diabetes Treatment Regimens in Older Adults SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Peptide; Diabetes; Older adults; Simplification; Treatment ID ORAL ANTIDIABETIC AGENTS; ELDERLY-PATIENTS; MELLITUS AB BACKGROUND: Diabetes management in older adults is challenging. Poor glycemic control and high risk of hypoglycemia are common in older patients on a complicated insulin regimen. Newer oral hypoglycemic agents have provided an opportunity to simplify regimens in patients with type-2 diabetes on insulin. Serum c-peptide is a test to assess endogenous production of insulin. We analyze the use of serum c-peptide level in simplifying diabetes regimen by decreasing or stopping insulin injection and adding oral hypoglycemic agents in older adults. METHODS: One hundred patients aged over 65 years with either poor glycemic control or difficulty coping with insulin regimen seen at a geriatric diabetes clinic were analyzed for this study. The data on serum c-peptide levels and A1c, along with demographic information, were obtained from medical charts. RESULTS: Sixty-five of 100 patients (aged 79 +/- 14 years, duration of diabetes 21 +/- 13 years) had detectable serum c-peptide levels. Forty-six of 65 patients were available for simplification of regimen. Eleven of 46 patients had other co-morbidities preventing use of oral hypoglycemic agents. In 35/65 patients, simplification was completed successfully. Nineteen of 35 patients were converted to all-oral regimens (off insulin), while 16/35 had simplification of regimen by addition of oral hypoglycemic agents and lowering the number of insulin injections from an average of 2.7 to 1.5 injections/day (P = .001). Glycemic control improved significantly in patients with a simplified regimen (8.0% +/- 1.5% vs 7.4% +/- 1.5%; P < .002), and patients reported fewer hypoglycemia episodes. CONCLUSIONS: Serum c-peptide level can be used to simplify insulin regimen in older adults with diabetes. (C) 2009 Elsevier Inc. All rights reserved. . The American Journal of Medicine (2009) 122, 395-397 C1 [Munshi, Medha N.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Munshi, Medha N.; Hayes, Mellody; Sternthal, Adrianne; Ayres, Darlene] Joslin Diabet Ctr, Boston, MA 02215 USA. [Munshi, Medha N.] Harvard Univ, Sch Med, Boston, MA USA. RP Munshi, MN (reprint author), Beth Israel Deaconess Med Ctr, 110 Frances St,LMOB 1B, Boston, MA 02215 USA. EM medha.munshi@joslin.harvard.edu FU DERC; NIH [5P30 DK36836-19 (MM)]; ADA [1-07-CR-40 (MM)]; Office of the Congressionally Directed Medical Research Programs [W81XWH-07-1-0282(MM)] FX The study was partly supported by a grant from the DERC; NIH 5P30 DK36836-19 (MM), a clinical research award from ADA 1-07-CR-40 (MM), and Department of Defense PRMRP of the Office of the Congressionally Directed Medical Research Programs, W81XWH-07-1-0282(MM). NR 9 TC 4 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD APR PY 2009 VL 122 IS 4 BP 395 EP 397 DI 10.1016/j.amjmed.2008.12.008 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 432OA UT WOS:000265142400018 PM 19332236 ER PT J AU Nogueira, RG Schwamm, LH Hirsch, JA AF Nogueira, R. G. Schwamm, L. H. Hirsch, J. A. TI Endovascular Approaches to Acute Stroke, Part 1: Drugs, Devices, and Data SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN-ACTIVATOR; MIDDLE CEREBRAL-ARTERY; SELF-EXPANDING STENT; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; RANDOMIZED CONTROLLED-TRIAL; MECHANICAL CLOT DISRUPTION; AMERICAN-HEART-ASSOCIATION; INTERNAL CAROTID-ARTERY; INTRAARTERIAL THROMBOLYSIS AB Despite years of research and pioneering clinical work, stroke remains a massive public health concern. Since 1996, we have lived in the era of US Food and Drug Administration-approved intravenous (IV) recombinant tissue plasminogen activator (rtPA). This treatment, despite its promise, continues to exhibit its limitations. Encovascular therapy has several theoretic advantages over IV rtPA, including site specificity, longer treatment windows, and higher recanalization rates. In this article, we will review the various pharmacologic strategies for acute stroke treatment, providing both a historic context and the state of the art. The drugs will be classified on the basis of their theoretic rationale for therapy. Next, we will review the various devices and strategies for mechanical revascularization with an aim toward comprehensiveness. These range from wire disruption of thrombus to preclinical trials for novel mechanical solutions. This first installment of this 2-part series will end with an analysis of retrograde reperfusion techniques. C1 [Nogueira, R. G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Endovasc Neurosurg Interve, Dept Intervent Neuroradiol & Endovasc Neurosurg, Boston, MA 02114 USA. [Nogueira, R. G.; Schwamm, L. H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nogueira, R. G.; Schwamm, L. H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Nogueira, R. G.; Schwamm, L. H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurocrit Care & Vasc Neurol Sect, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Nogueira, RG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Endovasc Neurosurg Interve, Dept Intervent Neuroradiol & Endovasc Neurosurg, 55 Fruit St,GRB-2-241, Boston, MA 02114 USA. EM rnogueira@partners.org OI Schwamm, Lee/0000-0003-0592-9145 NR 99 TC 75 Z9 79 U1 0 U2 4 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2009 VL 30 IS 4 BP 649 EP 661 DI 10.3174/ajnr.A1486 PG 13 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 438VL UT WOS:000265583700003 PM 19279271 ER PT J AU Konstas, AA Goldmakher, GV Lee, TY Lev, MH AF Konstas, A. A. Goldmakher, G. V. Lee, T. -Y. Lev, M. H. TI Theoretic Basis and Technical Implementations of CT Perfusion in Acute Ischemic Stroke, Part 1: Theoretic Basis SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; TISSUE-PLASMINOGEN-ACTIVATOR; HIGH-RESOLUTION MEASUREMENT; SUSCEPTIBILITY CONTRAST MRI; 3-DIMENSIONAL FUNCTIONAL CT; INITIAL CLINICAL-EXPERIENCE; TRACER BOLUS PASSAGES; COMPUTED-TOMOGRAPHY; SUBARACHNOID HEMORRHAGE AB CT perfusion (CTP) is a functional imaging technique that provides important information about capillary-level hemodynamics of the brain parenchyma and is a natural complement to the strengths of unenhanced CT and CT angiography in the evaluation of acute stroke, vasospasm, and other neurovascular disorders. CTP is critical in determining the extent of irreversibly infarcted brain tissue (infarct "core") and the severely ischemic but potentially salvageable tissue ("penumbra"). This is achieved by generating parametric maps of cerebral blood flow, cerebral blood volume, and mean transit time. C1 [Konstas, A. A.; Goldmakher, G. V.; Lev, M. H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lee, T. -Y.] Robarts Res Inst, Imaging Res Labs, London, ON N6A 5C1, Canada. RP Konstas, AA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM akonstas@partners.org RI Lee, Ting-Yim/M-1721-2013 NR 73 TC 101 Z9 108 U1 0 U2 8 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2009 VL 30 IS 4 BP 662 EP 668 DI 10.3174/ajnr.A1487 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 438VL UT WOS:000265583700004 PM 19270105 ER PT J AU Cipriano, LE Steinberg, ML Gazelle, GS Gonzalez, RG AF Cipriano, L. E. Steinberg, M. L. Gazelle, G. S. Gonzalez, R. G. TI Comparing and Predicting the Costs and Outcomes of Patients with Major and Minor Stroke Using the Boston Acute Stroke Imaging Scale Neuroimaging Classification System SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-of-Neuroradiology CY MAY 31-JUN 05, 2008 CL New Orleans, LA SP Amer Soc Neuroradiol ID ACUTE ISCHEMIC-STROKE; ACUTE MYOCARDIAL-INFARCTION; CEREBROVASCULAR EVENTS; INPATIENT COSTS; RESOURCE USE; CENTERS; TRIAL; RECOMMENDATIONS; ANGIOGRAPHY; VALIDATION AB BACKGROUND AND PURPOSE: A neuroimaging-based ischemic stroke classification system that predicts costs and outcomes would be useful for clinical prognostication and hospital resource planning. The Boston Acute Stroke Imaging Scale (BASIS), a neuroimaging-based ischemic stroke classification system, was tested to determine whether it was able to predict the costs and clinical outcomes of patients with stroke at an urban academic medical center. MATERIALS AND METHODS: Patients with ischemic stroke who presented in the emergency department in 2000 (230 patients) and 2005 (250 patients) were classified by using BASIS as having either a major or minor stroke. Compared outcomes included death, length of hospitalization, discharge disposition, use of imaging and intensive care unit (ICU) resources, and total in-hospital cost. Continuous variables were compared by univariate analysis by using the Student t test or the Satterthwaite test adjusted for unequal variances. Categoric variables were tested with the chi(2) test. Multiple regression analyses related total hospital cost (dependent variable) to stroke severity (major versus minor), sex, age, presence of comorbidities, and death during hospitalization. Logistic regression analysis was applied to identify the significant predictive variables indicating a greater likelihood of discharge home. RESULTS: In both years, individuals with strokes classified as major had a significantly longer length of stay, spent more days in the ICU, and had a higher cost of hospitalization than patients with minor strokes (all outcomes, P < .0001). All deaths (8 in 2000, 26 in 2005) occurred in patients with major stroke. Whereas 73% of patients with minor stroke were discharged home, only 12.2% of patients with major stroke were discharged home (P < .0001); 61% of patients with major stroke were discharged to a rehabilitation or skilled nursing facility. Patients with major stroke cost 4.4 times and 3.0 times that of patients with minor stroke in 2000 and 2005, respectively. Making up less than one third of all patients, patients with major stroke accounted for 60% of the total in-hospital cost of acute stroke care. CONCLUSIONS: BASIS, a neuroimaging-based stroke classification system, is highly effective at predicting in-hospital resource use, acute-hospitalization cost, and outcome, Predictive ability was maintained across the years Studied. C1 [Gonzalez, R. G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroradiol Div, Boston, MA 02114 USA. [Cipriano, L. E.; Gazelle, G. S.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Steinberg, M. L.] Harvard Univ, Harvard Design Sch, Cambridge, MA 02138 USA. [Gazelle, G. S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Gazelle, G. S.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02114 USA. RP Gonzalez, RG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroradiol Div, GRB 285,55 Fruit St, Boston, MA 02114 USA. EM rggonzalez@partners.org RI Cipriano, Lauren/C-3521-2017 OI Cipriano, Lauren/0000-0001-5568-4516 FU NINDS NIH HHS [NS50041] NR 34 TC 21 Z9 21 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2009 VL 30 IS 4 BP 703 EP 709 DI 10.3174/ajnr.A1441 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 438VL UT WOS:000265583700011 PM 19164436 ER PT J AU Babiarz, LS Romero, JM Murphy, EK Brobeck, B Schaefer, PW Gonzalez, RG Lev, MH AF Babiarz, L. S. Romero, J. M. Murphy, E. K. Brobeck, B. Schaefer, P. W. Gonzalez, R. G. Lev, M. H. TI Contrast-Enhanced MR Angiography Is Not More Accurate Than Unenhanced 2D Time-of-Flight MR Angiography for Determining >= 70% Internal Carotid Artery Stenosis SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID DIGITAL-SUBTRACTION-ANGIOGRAPHY; MAGNETIC-RESONANCE ANGIOGRAPHY; COMPUTED TOMOGRAPHIC ANGIOGRAPHY; ROW CT ANGIOGRAPHY; SYMPTOMATIC PATIENTS; IMAGING MODALITY; DECISION-MAKING; IN-VITRO; ENDARTERECTOMY; OCCLUSION AB BACKGROUND AND PURPOSE: Internal carotid artery (ICA) atheromatous disease is an important cause of ischemic stroke, and endarterectomy or stent placement is typically indicated for symptomatic patients with >= 70% stenosis. Our purpose was to compare contrast-enhanced MR angiography (CE-MRA) with unenhanced 2D time-of-flight MR angiography (2D TOF MRA) in detecting hemodynamically significant ICA stenosis, by using CT angiography (CTA) as the reference standard. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study. We identified 177 consecutive patients (354 ICAs) who received correlative CE-MRA, 2D TOF MRA, and CTA. Two neuroradiologists blinded to the CTA data graded the degree of ICA stenosis according to a 5-point scale. Additionally, luminal signal-intersity characteristics including 1) signal intensity dropout, 2) distal-vessel narrowing, and 3) distal-vessel signal-intensity reduction were recorded, MRA results were correlated with those of CTA, and receiver-operating-characteristic (ROC) curves were constructed. RESULTS: On CTA, there were 55 ICAs with and 299 without >= 70% stenosis. CE-MRA was 84% sensitive and 96% specific for detecting >= 70% stenosis, 2D TOF MRA was 80% sensitive and 95% specific. The area under the ROC curve was 0.97 for CE-MRA and 0.95 for 2D TOF MRA (P = .51, riot significant). For both MRA studies, each of the luminal signal-intensity characteristics had high specificity (>98%) but poor-to-mild sensitivity (35%-66%) in detecting >= 70% stenosis. CONCLUSIONS: Although it is established that CF-MRA more accurately delineates neurovascular anatomy than does unenhanced 2D TOF MRA, the administration of gadolinium did not offer a significant advantage in distinguishing surgically treatable ICA stenosis. This conclusion may be important in patients with contraindications to gadolinium. C1 [Babiarz, L. S.; Romero, J. M.; Murphy, E. K.; Brobeck, B.; Schaefer, P. W.; Gonzalez, R. G.; Lev, M. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Romero, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM jmromero@partners.org NR 59 TC 17 Z9 19 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2009 VL 30 IS 4 BP 761 EP 768 DI 10.3174/ajnr.A1464 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 438VL UT WOS:000265583700021 PM 19164440 ER PT J AU Stefancyk, AL AF Stefancyk, Amanda L. TI Postponing Medication Administration SO AMERICAN JOURNAL OF NURSING LA English DT Editorial Material C1 Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Stefancyk, AL (reprint author), Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. EM astefancyk@partners.org NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD APR PY 2009 VL 109 IS 4 BP 21 EP 23 PG 3 WC Nursing SC Nursing GA 427ZV UT WOS:000264818500014 PM 19325302 ER PT J AU Savar, A Andreoli, MT Kloek, CE Andreoli, CM AF Savar, Aaron Andreoli, Michael T. Kloek, Carolyn E. Andreoli, Christopher M. TI Enucleation for Open Globe Injury SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID SYMPATHETIC OPHTHALMIA; OCULAR TRAUMA; EYE INJURIES; EPIDEMIOLOGY; CLASSIFICATION AB PURPOSE: To report the experience of enucleation after open globe at an ophthalmic trauma referral center. DESIGN: Retrospective, observational study. METHODS: In an ophthalmic trauma referral center the charts of all patients having Suffered an open globe injury between January 1, 2000 and June 30, 2007 were reviewed. Variables assessed were age, gender, type of injury (rupture or laceration [penetrating, intraocular foreign body, or perforating]), ocular trauma score, visual acuity, subsequent enucleation, indication for and timing of enucleation, presence of sympathetic ophthalmia, and length of follow,up. RESULTS: Among 660 open globe injuries, 55 have undergone enucleation (including 4 eviscerations), 11 primarily and 44 secondarily. Eyes with ruptures were significantly more likely to be enucleated than those with injuries attributable to lacerations (P < .001). The most common reason for secondary enucleation was a blind, painful eye. Two patients (0.3%) developed sympathetic ophthalmia and have maintained good vision in the sympathizing eye. CONCLUSIONS: The vast majority of open globes can be repaired without requiring primary enucleation. Secondary enucleation is most commonly carried out for pain. Eyes with no light perception can be closely observed if the patient chooses. (Am J Ophthalmol 2009; 147:595-600. (C) 2009 by Elsevier Inc. All rights reserved.) C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Andreoli, CM (reprint author), 133 Brookline Ave, Boston, MA 02215 USA. EM christopher.andreoli@meei.harvard.edu NR 33 TC 34 Z9 38 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2009 VL 147 IS 4 BP 595 EP 600 DI 10.1016/j.ajo.2008.10.017 PG 6 WC Ophthalmology SC Ophthalmology GA 424KW UT WOS:000264566600007 PM 19181305 ER PT J AU Andreoli, CM Andreoli, MT Kloek, CE Ahuero, AE Vavvas, D Durand, ML AF Andreoli, Christopher M. Andreoli, Michael T. Kloek, Carolyn E. Ahuero, Audrey E. Vavvas, Demetrios Durand, Marlene L. TI Low Rate of Endophthalmitis in a Large Series of Open Globe Injuries SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID INTRAOCULAR FOREIGN-BODIES; PENETRATING EYE INJURIES; POSTTRAUMATIC ENDOPHTHALMITIS; ANTIBIOTIC-PROPHYLAXIS; OCULAR INJURIES; RISK-FACTORS; TRAUMA; TRIAL; OUTCOMES; REMOVAL AB PURPOSE: To determine the percentage of patients in whom endophthalmitis developed after open globe injury. DESIGN: Retrospective, noncomparative, consecutive case series. METHODS: Charts of all patients (675 in total) treated surgically for open globe injury at the Massachusetts Eye and Ear Infirmary (MEEI) between January 1, 2000 and July 31, 2007 were reviewed. Cases with at least 30 days of follow,up were included in statistical analyses (558 in total). A standardized treatment protocol was used in all cases. Intravenous vancomycin and ceftazidime were started on admission and were stopped after 48 hours. Patients were discharged on topical antibiotics, corticosteroids, and cycloplegia. Surgical repairs were performed by the chief of trauma, a full-time position rotating yearly, who is on call for all open globe trauma. Data collection variables included timing of injury and repair, mechanism of injury, details of surgical repair, and details of follow-up such as duration, presence of complications, and vision. A primary outcome measure of endophthalmitis and secondary outcome measure of risk factors for endophthalmitis were studied. RESULTS: During 7.5 years, 675 open globe injuries were treated at MEEI. Of these, 558 had at least 30 days of follow,up (mean, 11 months) and were used in statistical analyses. The overall percentage of endophthalmitis was 0.9% (3 culture-positive cases and 2 culture-negative cases). Four of the 5 cases achieved final acuity of 20/80 or better. Risk factors for endophthalmitis included intraocular foreign body (P = .03; odds ratio, 7.52) and primary intraocular lens placement (P = .05). CONCLUSIONS: A standardized protocol including surgical repair by a dedicated eye trauma service and 48 hours of intravenous antibiotics was associated with a posttraumatic endophthalmitis percentage of less than 1%. (Am J Ophthalmol 2009; 147:601-608. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Andreoli, Christopher M.; Andreoli, Michael T.; Kloek, Carolyn E.; Ahuero, Audrey E.; Vavvas, Demetrios] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Andreoli, Christopher M.; Andreoli, Michael T.; Kloek, Carolyn E.; Ahuero, Audrey E.; Vavvas, Demetrios; Durand, Marlene L.] Harvard Univ, Sch Med, Boston, MA USA. [Durand, Marlene L.] Massachusetts Eye & Ear Infirm, Infect Dis Serv, Boston, MA 02114 USA. [Durand, Marlene L.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Andreoli, Christopher M.] Harvard Vanguard Med Associates, Dept Ophthalmol, Boston, MA USA. RP Andreoli, CM (reprint author), 113 Brookline Ave, Boston, MA 02215 USA. EM christopher_andreoli@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 29 TC 44 Z9 51 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2009 VL 147 IS 4 BP 601 EP 608 DI 10.1016/j.ajo.2008.10.023 PG 8 WC Ophthalmology SC Ophthalmology GA 424KW UT WOS:000264566600008 PM 19181306 ER PT J AU Ngo, L Latham, NK Jette, AM Soukup, J Iezzoni, LI AF Ngo, Long Latham, Nancy K. Jette, Alan M. Soukup, Jane Iezzoni, Lisa I. TI Use of Physical and Occupational Therapy by Medicare Beneficiaries Within Five Conditions 1994-2001 SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Physical Therapy; Occupational Therapy; Medicare; Prospective Payment ID OBSTRUCTIVE PULMONARY-DISEASE; CARDIAC REHABILITATION; PROSPECTIVE-PAYMENT; POSTSTROKE REHABILITATION; RANDOMIZED-TRIAL; OLDER-ADULTS; STROKE REHABILITATION; MYOCARDIAL-INFARCTION; HEALTH OUTCOMES; CLINICAL-TRIAL AB Objective: To examine the use of physical therapy and occupational therapy among Medicare beneficiaries nationwide before and after the 1997 Balanced Budget Act, which introduced prospective payment for rehabilitation services. Design: We analyzed responses from the longitudinal Medicare Current Beneficiary Survey, merged with Medicare claims, to track physical therapy and occupational therapy rates and intensity (units of service) from 1994 through 2001. This observational study focused on elderly and disabled Medicare beneficiaries within five conditions: stroke, acute myocardial infarction, chronic obstructive pulmonary disease, arthritis, and lower-limb mobility problems. We used cubic smoothing spline functions to describe trends in service intensity over time and generalized estimating equations to assess changes in service intensity. Results: Controlling for demographic characteristics, adjusted mean level of physical therapy and occupational therapy intensity rose significantly between 1994 and 2001 for all five conditions. Service intensity leveled off in 1999 for occupational therapy and 2000 for physical therapy. With few exceptions, physical therapy and occupational therapy intensity was not significantly associated with patients' demographic characteristics. Conclusions: Medicare beneficiaries with conditions that can potentially benefit from physical therapy or occupational therapy or both continued to get these services at similar-and sometimes increasing-intensity during years after passage of the Balanced Budget Act. C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Soukup, Jane] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Latham, Nancy K.; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. RI Latham, Nancy/K-3405-2012; OI Jette, Alan/0000-0002-2117-9973 FU NICHD NIH HHS [HD043913-02, R01 HD043913, R01 HD043913-02] NR 79 TC 3 Z9 3 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD APR PY 2009 VL 88 IS 4 BP 308 EP 321 DI 10.1097/PHM.0b013e318198a791 PG 14 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 422TY UT WOS:000264451800010 PM 19190486 ER EF