FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Cadogan, MP Edelen, MO Lorenz, KA Jones, M Yosef, J Hascall, T Simon, B Harker, JO Ferrell, B Saliba, D AF Cadogan, Mary P. Edelen, Maria Orlando Lorenz, Karl A. Jones, Malia Yosef, Julia Hascall, Thomas Simon, Barbara Harker, Judith O. Ferrell, Bruce Saliba, Debra TI The Relationship of Reported Pain Severity to Perceived Effect on Function of Nursing Home Residents SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Pain; Nursing home; Activity limitation ID MINIMUM DATA SET; SYMPTOM ASSESSMENT SCALE; RECEIVING PRIMARY-CARE; QUALITY INDICATOR; NONMALIGNANT PAIN; OLDER-ADULTS; PREVALENCE; INTENSITY; RELIABILITY; PERSPECTIVE AB Background. We examined whether questions addressing the effect of pain on day-to-day function add unique information to the standardized verbal descriptor scale for pain severity in nursing homes (NHs). Methods. Interviews were conducted with 123 residents in two Veterans Affairs NHs. All participants were asked about pain presence. Residents reporting pain were asked about severity of worst pain (mild, moderate, severe, very severe/horrible), degree of bother (not at all, a little, a moderate amount, a great deal), and the effect of pain on daily function (whether pain made it hard to "sleep," "get out of bed," or "spend time with other people" and whether activities were limited because of pain). Results. Fifty-one percent of participants reported pain. The correlation between pain severity report and overall count of activity interference was significant (Spearman's rho = .449, p = .001). In general, for each activity, the proportion reporting interference increased as severity increased. Fischer's exact test showed significant association only for "hard to get out of bed" (p = .0175) and "hard to sleep" (p = .0211). As expected, residents reporting "mild" pain reported less activity interference than those reporting "very severe" pain. The association between pain and activity interference was more variable and less predictable among residents with "moderate" or "severe" pain. Conclusion. Questions addressing the effect of pain on day-to-day functions are an important addition to standardized pain assessments, particularly for persons who report intermediate levels of pain severity because the perceived effect on daily function may vary most among individuals at these levels. C1 [Cadogan, Mary P.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90095 USA. [Lorenz, Karl A.; Ferrell, Bruce] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. [Edelen, Maria Orlando; Lorenz, Karl A.; Jones, Malia; Saliba, Debra] RAND Corp, Santa Monica, CA USA. [Cadogan, Mary P.; Lorenz, Karl A.; Yosef, Julia; Hascall, Thomas; Simon, Barbara; Harker, Judith O.; Saliba, Debra] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Saliba, Debra] Univ Calif Los Angeles, Borun Ctr Gerontol Res, Los Angeles, CA 90095 USA. RP Cadogan, MP (reprint author), Univ Calif Los Angeles, Sch Nursing, Factor 5-952,Box 956919, Los Angeles, CA 90095 USA. EM mcadogan@sonnet.ucla.edu FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service [SDR 03-217] FX This research was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service SDR 03-217.; The views expressed in this research are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 31 TC 20 Z9 20 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2008 VL 63 IS 9 BP 969 EP 973 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 360RI UT WOS:000260074800010 PM 18840802 ER PT J AU Scherer, RK Scarmeas, N Brandt, J Blacker, D Albert, MS Stern, Y AF Scherer, Rachel K. Scarmeas, Nikolaos Brandt, Jason Blacker, Deborah Albert, Marilyn S. Stern, Yaakov TI The Relation of Patient Dependence to Home Health Aide Use in Alzheimer's Disease SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Alzheimer's disease; Home health care; Dependence Scale ID NURSING-HOME; PSYCHOPATHOLOGICAL FEATURES; FAMILY CAREGIVERS; MOTOR SIGNS; DEMENTIA; CARE; PLACEMENT; PREDICTORS; INSTITUTIONALIZATION; EXPERIENCE AB Background. Although there has been much research devoted to understanding the predictors of nursing home placement (NHP) in Alzheimer's disease (AD) patients, there is currently a lack of research concerning the predictors of home health care. The objective of this study was to examine whether the Dependence Scale can predict home health aide (HHA) use. Methods. The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States. Markov analyses (n = 75) were used to calculate annual transition probabilities for the "new onset" of HHA use (instances where an HHA was absent at the previous visit, but present at the next visit) as a function of HHA presence at the preceding year's visit and dependence level at that preceding year's visit. Results. The dependence level at the previous year's visit was a significant predictor of HHA use at the next year's visit. Three specific items of the Dependence Scale (needing household chores done for oneself, needing to be watched or kept company when awake, and needing to be escorted when outside) were significant predictors of the presence of an HHA. Conclusion. The Dependence Scale is a valuable tool for predicting HHA use in AD patients. Obtaining a better understanding of home health care in AD patients may help delay NHP and have a positive impact on the health and wellbeing of both the caregiver and the patient. C1 [Scherer, Rachel K.; Scarmeas, Nikolaos; Stern, Yaakov] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Cognit Neurosci Div,Gertrude H Sergievsky Ctr, New York, NY USA. [Scherer, Rachel K.; Scarmeas, Nikolaos; Stern, Yaakov] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Scherer, Rachel K.; Scarmeas, Nikolaos; Stern, Yaakov] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA. [Brandt, Jason; Albert, Marilyn S.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Brandt, Jason; Albert, Marilyn S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Boston, MA USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Stern, Y (reprint author), Sergievsky Ctr, 630 West 168th St,P&S Box 16, New York, NY 10032 USA. EM ys11@columbia.edu OI Brandt, Jason/0000-0001-7381-6244 FU National Institute on Aging [AG07370]; National Center for Research Resources [RR0064] FX The Predictors Study is supported by grants AG07370 (from the National Institute on Aging) and RR0064 (from the National Center for Research Resources).; Author contributions are as follows: Rachel K. Scherer: conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript for important intellectual content; Yaakov Stem and Nikolaos Scanneas : conception and design, acquisition of data, analysis and interpretation of data, critical revision of manuscript for important intellectual content; Jason Brandt, Deborah Blacker, and Marilyn Albert: acquisition of data, critical revision of manuscript for important intellectual content. NR 39 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2008 VL 63 IS 9 BP 1005 EP 1009 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 360RI UT WOS:000260074800016 PM 18840808 ER PT J AU Fried, LF AF Fried, Linda F. TI Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease SO KIDNEY INTERNATIONAL LA English DT Review DE proteinuria; chronic kidney disease; statin; lipids; progression ID CHRONIC RENAL-INSUFFICIENCY; CORONARY-HEART-DISEASE; DIABETIC-NEPHROPATHY; MESANGIAL CELLS; DENSITY LIPOPROTEINS; NEPHROTIC PATIENTS; RAT MODEL; PROTEINURIA; SIMVASTATIN; INJURY AB Chronic kidney disease, especially in the setting of proteinuria, is characterized by hyperlipidemia. In animal models, hyperlipidemia causes glomerular foam cells and glomerulosclerosis. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) ameliorates kidney disease in these models. The data of the role of hyperlipidemia in progression of human kidney disease are less clear. Data from small studies in glomerular disease suggest that statins decrease proteinuria. Data mainly from cardiovascular studies suggest that statins decrease the loss of glomerular filtration. The benefit of statins may derive from their lipid lowering effects. More recently, data suggest that the benefit of statins is greater than lipid lowering alone. The pleiotropic effects of statins may derive from inhibition of other downstream targets (isoprenoids) of the mevalonic acid pathway that are separate from cholesterol synthesis. Statins inhibits isoprenylation of Ras and Rho GTPases. These effects may lead to decreased monocyte/macrophage infiltration in the glomerulus, decreased mesangial proliferation and decreased accumulation of extracellular matrix and fibrosis. In addition, inhibition of RhoA and Ras may decrease inflammation and increase eNOS activity. These effects could lead to improvement in the progression of kidney disease. C1 Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. RP Fried, LF (reprint author), Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Renal Sect, Univ Dr,Mailstop 111F-U, Pittsburgh, PA 15240 USA. EM Linda.Fried@va.gov NR 60 TC 41 Z9 47 U1 0 U2 1 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 SEP PY 2008 VL 74 IS 5 BP 571 EP 576 DI 10.1038/ki.2008.231 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 338TM UT WOS:000258531800009 PM 18528321 ER PT J AU Lannfelt, L Blennow, K Zetterberg, H Batsman, S Ames, D Hrrison, J Masters, CL Targum, S Bush, AI Murdoch, R Wilson, J Ritchie, CW AF Lannfelt, Lars Blennow, Kaj Zetterberg, Henrik Batsman, Stellan Ames, David Hrrison, John Masters, Colin L. Targum, Steve Bush, Ashley I. Murdoch, Ross Wilson, Janet Ritchie, Craig W. CA PBT2 201 EURO Study Grp TI Safety, efficacy, and biomarker findings of PBT2 in targeting A beta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial SO LANCET NEUROLOGY LA English DT Article ID TRANSGENIC MICE; CEREBROSPINAL-FLUID; AMYLOID-BETA; PROTEIN; ZINC; RECEPTOR; BATTERY; CSF AB Background PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu(2+)-mediated and Zn(2+)-mediated toxic oligomerisation of A beta seen in Alzheimer's disease (AD). Strong preclinical efficacy data and the completion of early, clinical safety studies have preceded this phase IIa study, the aim of which was to assess the effects of PBT2 on safety, efficacy, and biomarkers of AD. Methods Between December 6, 2006, and September 21, 2007, community-dwelling patients over age 55 years were recruited to this 12-week, double-blind, randomised trial of PBT2. Patients were randomly allocated to receive 50 mg PBT2, 250 mg PBT2, or placebo. Inclusion criteria were early AD (mini-mental state examination [MMSE] score between 20 and 26 points or Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) score between 10 and 25 points), taking a stable dose of acetylcholinesterase inhibitor (donepezil, galantamine, or rivastigmine) for at least 4 months, a modified Hachinski score of 4 points or less, and CT or MRI results that were consistent with AD. The principal outcomes were safety and tolerability. Secondary outcomes were plasma and CSF biomarkers and cognition. Analysis was intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00471211. Findings 78 patients were randomly assigned (29 to placebo, 20 to PBT2 50 mg, and 29 to PBT2 250 mg) and 74 (95%) completed the study. 42 (54%) patients had at least one treatment emergent adverse event (10 [50%] on PBT2 50 mg, 18 [62%] on PBT2 250 mg, and 14 [48%] on placebo). No serious adverse events were reported by patients on PBT2. Patients treated with PBT2 250 mg had a dose-dependent (p=0.023) and significant reduction in CSF A beta(42) concentration compared with those treated with placebo (difference in least squares mean change from baseline was -56.0 pg/mL, 95% Cl -101.5 to -11.0; p=0.006). PBT2 had no effect on plasma biomarkers of AD or serum Zn(2+) and Cu(2+) concentrations. Cognition testing included ADAS-cog, MMSE, and a neuropsychological test battery (NTB). Of these tests, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group: category fluency test (2.8 words, 0.1 to 5.4; p=0.041) and trail making part B (-48.0 s, -83.0 to -13.0; p=0.009). Interpretation The safety profile is favourable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma is suggestive of a central effect of the drug on A beta metabolism. Cognitive efficacy was restricted to two measures of executive function. Future trials that are larger and longer will establish if the effects of PBT2 on biomarkers and cognition that are reported here translate into clinical effectiveness. C1 [Ritchie, Craig W.] Univ London Imperial Coll Sci Technol & Med, Dept Psychol, London W6 8LN, England. [Lannfelt, Lars] Univ Uppsala Hosp, Dept Publ Hlth & Geriatr, Uppsala, Sweden. [Blennow, Kaj; Zetterberg, Henrik] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden. [Batsman, Stellan] Vardcentralen Kalix, Kalix, Sweden. [Ames, David] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia. [Ames, David] Natl Ageing Res Inst, Melbourne, Vic, Australia. [Hrrison, John] Cogstate Ltd, Warminister, England. [Masters, Colin L.; Bush, Ashley I.] Univ Melbourne, Mental Hlth Res Inst, Melbourne, Vic, Australia. [Targum, Steve] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Murdoch, Ross; Wilson, Janet] Prana Biotechnol, Melbourne, Vic, Australia. RP Ritchie, CW (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Psychol, 37 Claybrook Rd, London W6 8LN, England. EM c.ritchie@imperial.ac.uk RI Brodaty, Henry/E-2753-2010; Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 NR 31 TC 360 Z9 370 U1 7 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD SEP PY 2008 VL 7 IS 9 BP 779 EP 786 DI 10.1016/S1474-4422(08)70167-4 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 345HZ UT WOS:000258988400013 PM 18672400 ER PT J AU Harisinghani, M AF Harisinghani, Mukesh TI Nanoparticle-enhanced MRI: are we there yet? SO LANCET ONCOLOGY LA English DT Editorial Material ID LYMPH-NODE DISSECTION; PROSTATE-CANCER; METASTASES C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Harisinghani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM mharisinghani@partners.org NR 6 TC 6 Z9 6 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2008 VL 9 IS 9 BP 814 EP 815 DI 10.1016/S1470-2045(08)70215-8 PG 2 WC Oncology SC Oncology GA 346HT UT WOS:000259060100004 PM 18760237 ER PT J AU Emerick, KS Hadlock, TA Cheney, ML AF Emerick, Kevin S. Hadlock, Tessa A. Cheney, Mack L. TI Nasofacial Reconstruction with Calvarial Bone Grafts in Compromised Defects SO LARYNGOSCOPE LA English DT Article DE Nasofacial; reconstruction; calvarial bone graft; autogenous graft ID NASAL RECONSTRUCTION; HARVEST; MORBIDITY AB Objectives/Hypothesis: To determine the utility of calvarial bone grafting in multiple reconstructive settings. In particular to examine the success of calvarial bone grafting of the nasofacial skeleton in a compromised wound bed. Study Design: Case series. Methods: A retrospective review was performed to identify patients undergoing calvarial bone graft reconstruction of the nasofacial skeleton. Patients were identified from operative records and the medical record was reviewed to identify age, gender, site of defect, indication for the operation, size of bone graft harvested, postoperative and delayed complications, radiation exposure, need for additional soft tissue, and graft loss. Results: Eighty-seven patients who underwent split calvarial bone grafts were identified and had a complete medical record available for review. Ninety grafts were harvested. Five subsites in the nasofacial skeleton were identified as sites for reconstruction. Forty cases were performed for revision of a previous complication, including 13 who had a previous alloplastic implant. Twenty-four additional cases were performed in a compromised wound bed and 64% of all cases were performed in either a revision or compromised setting. There was an 11% incidence of early postoperative complications, but there were no major complications at the donor site and only two major complications at the recipient site. Conclusion: Calvarial bone is a very useful material in the primary, revision, and compromised settings. This series suggests that split calvarial bone grafts is an adaptable, durable, and reliable material. It can be reliably used in the setting of radiation, infection, and inflammation. C1 [Emerick, Kevin S.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Emerick, KS (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Kevin_Emerick@meei.harvard.edu NR 14 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2008 VL 118 IS 9 BP 1534 EP 1538 DI 10.1097/MLG.0b013e318178273e PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 368ZQ UT WOS:000260662700003 PM 18545214 ER PT J AU Feldman, EJ Cortes, J DeAngelo, DJ Holyoake, T Simonsson, B O'Brien, SG Reiffers, J Turner, AR Roboz, GJ Lipton, JH Maloisel, F Colombat, P Martinelli, G Nielsen, JL Petersdorf, S Guilhot, F Barker, J Kirschmeier, P Frank, E Statkevich, P Zhu, Y Loechner, S List, A AF Feldman, E. J. Cortes, J. DeAngelo, D. J. Holyoake, T. Simonsson, B. O'Brien, S. G. Reiffers, J. Turner, A. R. Roboz, G. J. Lipton, J. H. Maloisel, F. Colombat, P. Martinelli, G. Nielsen, J. L. Petersdorf, S. Guilhot, F. Barker, J. Kirschmeier, P. Frank, E. Statkevich, P. Zhu, Y. Loechner, S. List, A. TI On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia SO LEUKEMIA LA English DT Article DE lonafarnib; MDS; CMML ID FARNESYLTRANSFERASE INHIBITOR R115777; FARNESYL TRANSFERASE INHIBITOR; PHASE-I; RAS MUTATIONS; SOLID TUMORS; PROTEIN; TIPIFARNIB; TRIAL; RISK AB Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200 -300mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44 -86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML. C1 [Feldman, E. J.] Cornell Univ, Div Hematol & Med Oncol, Weill Med Coll, New York Presbyterian Hosp, New York, NY 10021 USA. [Cortes, J.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [DeAngelo, D. J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Holyoake, T.] Glasgow Royal Infirm, Div Canc & Mol Pathol, Glasgow G4 0SF, Lanark, Scotland. [Simonsson, B.] Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden. [O'Brien, S. G.] Univ Newcastle, Dept Hematol, Newcastle Upon Tyne, Tyne & Wear, England. [Reiffers, J.] Univ Victor Segalen, Bordeaux, France. [Reiffers, J.] Inst Bergonie, Bordeaux, France. [Turner, A. R.] Cross Canc Inst, Div Med Oncol, Edmonton, AB T6G 1Z2, Canada. [Lipton, J. H.] Princess Margaret Hosp, Div Med Oncol & Hematol & Oncol, Toronto, ON M4X 1K9, Canada. [Maloisel, F.] Hop Univ Strasbourg, Dept Hematol Oncol, Strasbourg, France. [Colombat, P.] CHU Tours, Dept Hematol, Tours, France. [Martinelli, G.] Univ Bologna, Dept Hematol Oncol, Bologna, Italy. [Nielsen, J. L.] Univ Hosp, Dept Hematol, Aarhus, Denmark. [Petersdorf, S.] Seattle Canc Care Alliance, Div Med Oncol, Seattle, WA USA. [Guilhot, F.] CHU Poitiers, INSERM, CIC 802, Dept Oncol Haematol & Cell Therapeut, Poitiers, France. [Barker, J.] Univ Minnesota, Dept Hematol, Minneapolis, MN USA. [Kirschmeier, P.; Frank, E.; Statkevich, P.; Zhu, Y.; Loechner, S.] Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA. [List, A.] H Lee Moffitt Canc Ctr & Res Inst, Malignant Hematol Div, Tampa, FL USA. RP Feldman, EJ (reprint author), Cornell Univ, Div Hematol & Med Oncol, Weill Med Coll, New York Presbyterian Hosp, 525 E 68th St, New York, NY 10021 USA. EM ejf2001@med.cornell.edu OI holyoake, tessa/0000-0002-0608-6066 FU NCI NIH HHS [P30 CA016672] NR 23 TC 35 Z9 37 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2008 VL 22 IS 9 BP 1707 EP 1711 DI 10.1038/leu.2008.156 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 346KH UT WOS:000259066900008 PM 18548095 ER PT J AU Hill, KS Freeman, LC Yucel, RM Kuhlthau, KA AF Hill, Kristen S. Freeman, Linda C. Yucel, Recai M. Kuhlthau, Karen A. TI Unmet Need among Children with Special Health Care Needs in Massachusetts SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Children with special health care needs; Unmet need; Access to care; Participatory Action Research; Family participation ID NATIONAL-SURVEY; ACCESS; EMPLOYMENT; PROFILE; MODEL AB Objectives We partnered with a Massachusetts family workgroup to analyze state level data that would be most useful to consumers and advocates in Massachusetts. Methods Massachusetts' and US data from the 2001 National Survey of Children with Special Health Care Needs (NSCSHCN) were analyzed. We examined types of need and prevalence of unmet need for all CSHCN and for more severely affected CSHCN. We also correlated unmet need to child and family characteristics using multivariate logistic regression. Results In Massachusetts, 17% of CSHCN and 37% of children more severely affected did not receive needed care. CSHCN who were uninsured anytime during the previous year were nearly 5 times more likely to experience an unmet need (OR = 4.95, CI: 1.69-14.51). Children with more functional limitations (OR = 3.15; CI: 1.59-6.24) and unstable health care needs (OR = 3.26; CI: 1.33-8.00) were also more likely to experience an unmet need. Receiving coordinated care in a medical home (OR = 0.46; CI: 0.23-0.90) was associated with reduced reports of unmet need. Conclusions With input from families of CSHCN, researchers can direct their analyses to answering the questions and concerns most meaningful to families. We estimate that 1 in 6 CSHCN in Massachusetts did not receive needed care, with more than 1 in 3 CSHCN with a more severe condition experiencing an unmet need. Enabling factors were predictors of unmet need suggesting solutions such as expanding insurance coverage and improving services systems for CSHCN. C1 [Hill, Kristen S.; Kuhlthau, Karen A.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Freeman, Linda C.] New England SERVE, Massachusetts Consortium Children Special Hlth Ca, Boston, MA USA. [Yucel, Recai M.] Univ Massachusetts, Dept Biostat & Epidemiol, Sch Publ Hlth, Amherst, MA 01003 USA. RP Hill, KS (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM kristenshill@yahoo.com NR 46 TC 13 Z9 13 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD SEP PY 2008 VL 12 IS 5 BP 650 EP 661 DI 10.1007/s10995-007-0283-3 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 361AB UT WOS:000260098800013 PM 17899342 ER PT J AU Morgan, SC Lee, HY Relaix, F Sandell, LL Levorse, JM Loeken, MR AF Morgan, Sarah C. Lee, Hyung-Yul Relaix, Frederic Sandell, Lisa L. Levorse, John M. Loeken, Mary R. TI Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Cardiac neural crest; Cardiac outflow tract; Pax3; p53; Apoptosis; Congenital defect ID PERSISTENT TRUNCUS ARTERIOSUS; CONGENITAL HEART-DISEASE; SPLOTCH SP(2H) MUTANT; TUMOR-SUPPRESSOR; MOUSE MUTANT; PAX-3 GENE; CARDIOVASCULAR DEVELOPMENT; WAARDENBURG SYNDROME; TUBE DEFECTS; P53 AB During neural tube closure, Pax3 is required to inhibit p53-dependent apoptosis. Pax3 is also required for migration of cardiac neural crest (CNC) from the neural tube to the heart and septation of the primitive single cardiac outflow tract into the aorta and pulmonary arteries. Whether Pax3 is required for CNC migration and outflow tract septation by inhibiting p53-dependent apoptosis is not known. in this study, mouse strains carrying reporters linked to Pax3 alleles were used to map the fate of CNC cells in embryos which were either Pax3-sufficient (expressing one or two functional Pax3 alleles) or Pax3-deficient (expressing two null Pax3 alleles), and in which p53 had been inactivated or not. Migrating CNC cells were observed in both Pax3-sufficient and -deficient embryos, but CNC cells were sparse and disorganized in Pax3-deficient embryos as migration progressed. The defective migration was associated with increased cell death. Suppression of p53, either by null mutation of the p53 gene, or administration of a p53 inhibitor, pifithrin-cc, prevented the defective CNC migration and apoptosis in Pax3-deficient embryos, and also restored proper development of cardiac outflow tracts. These results indicate that Pax3 is required for cardiac outflow tract septation because it blocks p53-dependent processes during CNC migration. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Morgan, Sarah C.; Lee, Hyung-Yul; Loeken, Mary R.] Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02215 USA. [Relaix, Frederic] Univ Paris 06, Fac Med Pitie Salpetriere, INSERM, UMR S 787, F-75634 Paris 13, France. [Sandell, Lisa L.] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Levorse, John M.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Loeken, MR (reprint author), Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM mary.loeken@joslin.harvard.edu RI Sandell, Lisa/M-4238-2013; OI Sandell, Lisa/0000-0002-1735-8223; Loeken, Mary/0000-0002-8056-9816 FU American Diabetes Association [1-04-RA-65]; National Institutes of Health [RO1 DK52865] FX We are appreciative of Dr. Shoba Thirumangalathu for assistance with preliminary experiments. Michelle Ocana, Mark Chafel, and Daniel Tom of the optical Imaging Facility at the Harvard Center for Neurodegeneration and Repair provided assistance with confocal microscopy LLS and JML acknowledge the contributions of Dr. Shirley Tilghman to the generation of the Pax3GFP/+ mice, and FR acknowledges the contributions of Dr. Margaret Buckingham to the generation of the Pax3IRESnLacZ/+ mice. We are extremely grateful to Dr. Sean Wu for providing expert advice in interpreting cardiac histological sections. This work was supported by grants from the American Diabetes Association (1-04-RA-65) and the National Institutes of Health (RO1 DK52865) to M.R.L. NR 57 TC 33 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP-OCT PY 2008 VL 125 IS 9-10 BP 757 EP 767 DI 10.1016/j.mod.2008.07.003 PG 11 WC Developmental Biology SC Developmental Biology GA 358OO UT WOS:000259927600001 PM 18672055 ER PT J AU Hausmann, LRM Jeong, K Bost, JE Ibrahim, SA AF Hausmann, Leslie R. M. Jeong, Kwonho Bost, James E. Ibrahim, Said A. TI Perceived discrimination in health care and health status in a racially diverse sample SO MEDICAL CARE LA English DT Article DE discrimination; health inequality; health status; national surveys; race and ethnicity ID SELF-REPORTED DISCRIMINATION; AFRICAN-AMERICAN WOMEN; US BLACK-WOMEN; MENTAL-HEALTH; INTERVIEW SURVEY; BLOOD-PRESSURE; NEW-HAMPSHIRE; RACISM; PERCEPTIONS; EXPERIENCES AB Background: Despite the surge of recent research on the association between perceived discrimination and health-related outcomes, few studies have focused on race-based discrimination encountered in health care settings. This study examined the prevalence of such discrimination, and its association with health status, for the 3 largest race/ethnic groups in the United States. Methods: Data were drawn from the 2004 Behavioral Risk Factor Surveillance System survey. The primary variables were perceived racial discrimination in health care and self-reported health status. Multivariable logistic regression was used to compare the prevalence of perceived discrimination for whites, African Americans, and Hispanics, and to examine the association between perceived discrimination and health status, controlling for sex, age, income, education, health care coverage, affordability of medical care, racial salience, and state. Results: Perceived discrimination was reported by 2%, 5.2%, and 10.9% of whites, Hispanics, and African Americans, respectively. Only the difference between African Americans and whites remained significant in adjusted analyses [odds ratio (OR) = 3.22, 95% confidence interval (CI) = 2.46-4.21]. Racial/ethnic differences in perceived discrimination depended on income, education, health care coverage, and affordability of medical care. Perceived discrimination was associated with worse health status for the overall sample (OR = 1.71, 95% CI = 1.35-2.16). Stratified analyses revealed that this relationship was significant for whites (OR = 2.00, 95% CI = 1.45-2.77) and African Americans (OR = 1.95, 95% CI = 1.39-2.73), but not for Hispanics (OR = 0.55, 95% CI = 0.24-1.22). Conclusions: Perceived racial discrimination in health care is much more prevalent for African Americans than for whites or Hispanics. Furthermore, such discrimination is associated with worse health both for African Americans and for whites. C1 [Hausmann, Leslie R. M.; Ibrahim, Said A.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Jeong, Kwonho; Bost, James E.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Bost, James E.] Univ Pittsburgh, Res Ctr, Hlth Care Data Ctr, Pittsburgh, PA USA. [Ibrahim, Said A.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. RP Hausmann, LRM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr 151C-H, Pittsburgh, PA 15206 USA. EM leslie.hausmann@gmail.com FU VA Health Services Research and Development Career Development Award [RCD 06-287]; National Center for Research Resources (NCRR); National Institutes of Health (NIH); NIH Roadmap for Medical Research [ULI RR024153]; National Institutes of Musculoskeletal and Skin Disorders K24 Award [1K24AR055259-01]; VA Health Services Research and Development Award; Harold Amos Robert Wood Johnson Scholar Award FX Supported by VA Health Services Research and Development Career Development Award #RCD 06-287 (to L.R.M.H.). Supported by the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research grant #ULI RR024153. Supported by the National Institutes of Musculoskeletal and Skin Disorders K24 Award #1K24AR055259-01 (to S.A.I., also the recipient of a VA Health Services Research and Development Award and the Harold Amos Robert Wood Johnson Scholar Award). NR 52 TC 76 Z9 77 U1 5 U2 15 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 SEP PY 2008 VL 46 IS 9 BP 905 EP 914 DI 10.1097/MLR.0b013e3181792562 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 344RQ UT WOS:000258945400004 PM 18725844 ER PT J AU Sales, A Sharp, N Li, YF Lowy, E Greiner, G Liu, CF Alt-White, A Rick, C Sochalski, J Mitchell, PH Rosenthal, G Stetler, C Cournoyer, P Needleman, J AF Sales, Anne Sharp, Nancy Li, Yu-Fang Lowy, Elliott Greiner, Gwendolyn Liu, Chuan-Fen Alt-White, Anna Rick, Cathy Sochalski, Julie Mitchell, Pamela H. Rosenthal, Gary Stetler, Cheryl Cournoyer, Paulette Needleman, Jack TI The association between nursing factors and patient mortality in the Veterans Health Administration - The view from the nursing unit level SO MEDICAL CARE LA English DT Article ID COMORBIDITY INDEX; HOSPITALS; CARE; DATABASES; OUTCOMES; QUALITY; VALIDATION; ICD-9-CM; AFFAIRS AB Context: Nurse staffing is not the same across an entire hospital. Nursing care is delivered in geographically-based units, with wide variation in staffing levels. In particular, staffing in intensive care is much richer than in nonintensive care acute units. Objective: To evaluate the association of in-hospital patient mortality with registered nurse staffing and skill mix comparing hospital and unit level analysis using data from the Veterans Health Administration (VHA). Design, Settings, and Patients: A retrospective observational study using administrative data from 129,579 patients from 453 nursing units (171 ICU and 282 non-ICU) in 123 VHA hospitals. Methods: We used hierarchical multilevel regression models to adjust for patient, unit, and hospital characteristics, stratifying by whether or not patients had an ICU stay during admission. Main Outcome Measure: In-hospital mortality. Results: Of the 129,579 patients, mortality was 2.9% overall: 6.7% for patients with an ICU stay compared with 1.6% for those without. Whether the analysis was done at the hospital or unit level affected findings. RN staffing was not significantly associated with in-hospital mortality for patients with ail ICU stay (OR, 1.02; 95% Cl, 0.99-1.03). For non-ICU patients, increased RN staffing was significantly associated with decreased mortality risk (OR, 0.91; 95% CI, 0.86-0.96). RN education was not significantly associated with mortality. Conclusions: Our findings suggest that the association between RN staffing and skill mix and in-hospital patient mortality depends on whether the analysis is conducted at the hospital or unit level. Variable staffing on non-ICU units may significantly contribute to in-hospital mortality risk. C1 [Sales, Anne] Univ Alberta, Fac Nursing, Edmonton, AB T6G 2G3, Canada. [Sales, Anne; Sharp, Nancy; Li, Yu-Fang; Lowy, Elliott; Greiner, Gwendolyn; Liu, Chuan-Fen] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Sales, Anne; Liu, Chuan-Fen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Alt-White, Anna; Rick, Cathy] VA Cent Off, Off Nursing Serv, Washington, DC USA. [Sochalski, Julie] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Mitchell, Pamela H.] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Rosenthal, Gary] Univ Iowa, Iowa City, IA 52242 USA. [Rosenthal, Gary] Iowa City VA Med Ctr, Iowa City, IA USA. [Stetler, Cheryl; Cournoyer, Paulette; Needleman, Jack] Univ Calif Los Angeles, Los Angeles, CA USA. RP Sales, A (reprint author), Univ Alberta, Fac Nursing, 3-114 Clin Sci Bldg, Edmonton, AB T6G 2G3, Canada. EM anne.sales@ualberta.ca RI Sales, Anne/D-9678-2012; Needleman, Jack/I-5461-2013; OI Needleman, Jack/0000-0002-2875-0589; Sales, Anne/0000-0001-9360-3334 FU Office of Research and Development; Health Services RD Service; Department of Veterans Affairs [IIR 01-160] FX Supported by the Office of Research and Development, Health Services R&D Service, Department of Veterans Affairs, project number IIR 01-160. NR 23 TC 50 Z9 53 U1 0 U2 2 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 SEP PY 2008 VL 46 IS 9 BP 938 EP 945 DI 10.1097/MLR.0b013e3181791a0a PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 344RQ UT WOS:000258945400008 PM 18725848 ER PT J AU Ling, BS Trauth, JM Fine, MJ Mor, MK Resnick, A Braddock, CH Bereknyei, S Weissfeld, JL Schoen, RE Ricci, EM Whittle, J AF Ling, Bruce S. Trauth, Jeanette M. Fine, Michael J. Mor, Maria K. Resnick, Abby Braddock, Clarence H. Bereknyei, Sylvia Weissfeld, Joel L. Schoen, Robert E. Ricci, Edmund M. Whittle, Jeffrey TI Informed decision-making and colorectal cancer screening - Is it occurring in primary care? SO MEDICAL CARE LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 25-28, 2007 CL Toronto, CANADA SP Soc Gen Internal Med DE informed choice; decision-making; patient preference; colorectal cancer screening; communication ID RECOMMENDATIONS; PREFERENCES; GUIDELINES; RATIONALE; RISK AB Background: Current recommendations advise patients to participate in the decision-making for selecting a colorectal cancer (CRC) screening option. The degree to which providers communicate the information necessary to prepare patients for participation in this process is not known. Objective: To assess the level of informed decision-making occurring during actual patient-provider communications on CRC screening and test for the association between informed decision-making and screening behavior. Research Design: Observational study of audiotaped clinic visits between patients and their providers in the primary care clinic at a Veterans Administration Medical Center. Subjects: Male patients, age 50-74 years, presenting to a primary care visit at the study site. Measures: The Informed Decision-Making (IDM) Model was used to code the audiotapes for 9 elements of communication that should occur to prepare patients for participation in decision-making. The primary outcome is completion of CRC screening during the study period. Results: The analytic cohort consisted of 91 patients due for CRC screening who had a test ordered at the visit. Six of the 9 IDM elements occurred in <= 20% of the visits with none addressed in >= 50%. CRC screening occurred less frequently for those discussing "pros and cons" (12% vs. 46%, P = 0.01) and "patient preferences" (6% vs. 47%, P = 0.001) compared with those who did not. Conclusions: We found that a lack of informed decision-making occurred during CRC screening discussions and that particular elements of the process were negatively associated with screening. Further research is needed to better understand the effects of informed decision-making on screening behavior. C1 [Ling, Bruce S.; Fine, Michael J.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Ling, Bruce S.; Fine, Michael J.; Mor, Maria K.; Resnick, Abby] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Ling, Bruce S.; Fine, Michael J.; Weissfeld, Joel L.; Schoen, Robert E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Trauth, Jeanette M.; Ricci, Edmund M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Braddock, Clarence H.; Bereknyei, Sylvia] Stanford Univ, Div Gen Internal Med, Sch Med, Palo Alto, CA 94304 USA. [Whittle, Jeffrey] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Ling, BS (reprint author), Univ Pittsburgh, Ctr Res Hlth Care, 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM lingbs@upmc.edu FU AHRQ HHS [5P01 HS10864]; NCI NIH HHS [5K07 CA090359] NR 23 TC 48 Z9 49 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 SEP PY 2008 VL 46 IS 9 SU 1 BP S23 EP S29 DI 10.1097/MLR.0b013e31817dc496 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 344RR UT WOS:000258945500005 PM 18725829 ER PT J AU McMahon, R Berbeco, R Nishioka, S Ishikawa, M Papiez, L AF McMahon, Ryan Berbeco, Ross Nishioka, Seiko Ishikawa, Masayori Papiez, Lech TI A real-time dynamic-MLC control algorithm for delivering IMRT to targets undergoing 2D rigid motion in the beam's eye view SO MEDICAL PHYSICS LA English DT Article DE MLC; organ motion; IMRT; tracking ID MODULATED RADIATION-THERAPY; BREATHING MULTILEAF COLLIMATOR; TUMOR RESPIRATORY MOTION; PAIR OPTIMAL-CONTROL; INTRAFRACTION MOTION; GATED RADIOTHERAPY; TRACKING SYSTEM; MOVING TARGET; ORGAN MOTION; PREDICTION AB An MLC control algorithm for delivering intensity modulated radiation therapy (IMRT) to targets that are undergoing two-dimensional (2D) rigid motion in the beam's eye view (BEV) is presented. The goal of this method is to deliver 3D-derived fluence maps over a moving patient anatomy. Target motion measured prior to delivery is first used to design a set of planned dynamic-MLC (DMLC) sliding-window leaf trajectories. During actual delivery, the algorithm relies on real-time feedback to compensate for target motion that does not agree with the motion measured during planning. The methodology is based on an existing one-dimensional (1D) algorithm that uses on-the-fly intensity calculations to appropriately adjust the DMLC leaf trajectories in real-time during exposure delivery [McMahon , Med. Phys. 34, 3211-3223 (2007)]. To extend the 1D algorithm's application to 2D target motion, a real-time leaf-pair shifting mechanism has been developed. Target motion that is orthogonal to leaf travel is tracked by appropriately shifting the positions of all MLC leaves. The performance of the tracking algorithm was tested for a single beam of a fractionated IMRT treatment, using a clinically derived intensity profile and a 2D target trajectory based on measured patient data. Comparisons were made between 2D tracking, 1D tracking, and no tracking. The impact of the tracking lag time and the frequency of real-time imaging were investigated. A study of the dependence of the algorithm's performance on the level of agreement between the motion measured during planning and delivery was also included. Results demonstrated that tracking both components of the 2D motion (i.e., parallel and orthogonal to leaf travel) results in delivered fluence profiles that are superior to those that track the component of motion that is parallel to leaf travel alone. Tracking lag time effects may lead to relatively large intensity delivery errors compared to the other sources of error investigated. However, the algorithm presented is robust in the sense that it does not rely on a high level of agreement between the target motion measured during treatment planning and delivery. (C) 2008 American Association of Physicists in Medicine. C1 [McMahon, Ryan] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Berbeco, Ross] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Div Med Phys, Boston, MA 02115 USA. [Berbeco, Ross] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nishioka, Seiko] NTT E Japan Sapporo Hosp, Sapporo, Hokkaido, Japan. [Ishikawa, Masayori] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Papiez, Lech] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. RP McMahon, R (reprint author), Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. EM ryanmcmahon@purdue.edu RI Ishikawa, Masayori/D-9878-2012 NR 35 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 SEP PY 2008 VL 35 IS 9 BP 3875 EP 3888 DI 10.1118/1.2963987 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 342GQ UT WOS:000258773000007 PM 18841838 ER PT J AU Chan, HP Wei, J Zhang, YH Helvie, MA Moore, RH Sahiner, B Hadjiiski, L Kopans, DB AF Chan, Heang-Ping Wei, Jun Zhang, Yiheng Helvie, Mark A. Moore, Richard H. Sahiner, Berkman Hadjiiski, Lubomir Kopans, Daniel B. TI Computer-aided detection of masses in digital tomosynthesis mammography: Comparison of three approaches SO MEDICAL PHYSICS LA English DT Article DE digital breast tomosynthesis; computer-aided detection; masses; SART ID BREAST TOMOSYNTHESIS; SCREENING MAMMOGRAPHY; TEXTURE ANALYSIS; DETECTION SYSTEM; DIAGNOSIS; IMAGES; CLASSIFICATION; PERFORMANCE; EXPERIENCE AB The authors are developing a computer-aided detection (CAD) system for masses on digital breast tomosynthesis mammograms (DBT). Three approaches were evaluated in this study. In the first approach, mass candidate identification and feature analysis are performed in the reconstructed three-dimensional (3D) DBT volume. A mass likelihood score is estimated for each mass candidate using a linear discriminant analysis (LDA) classifier. Mass detection is determined by a decision threshold applied to the mass likelihood score. A free response receiver operating characteristic (FROC) curve that describes the detection sensitivity as a function of the number of false positives (FPs) per breast is generated by varying the decision threshold over a range. In the second approach, prescreening of mass candidate and feature analysis are first performed on the individual two-dimensional (2D) projection view (PV) images. A mass likelihood score is estimated for each mass candidate using an LDA classifier trained for the 2D features. The mass likelihood images derived from the PVs are backprojected to the breast volume to estimate the 3D spatial distribution of the mass likelihood scores. The FROC curve for mass detection can again be generated by varying the decision threshold on the 3D mass likelihood scores merged by backprojection. In the third approach, the mass likelihood scores estimated by the 3D and 2D approaches, described above, at the corresponding 3D location are combined and evaluated using FROC analysis. A data set of 100 DBT cases acquired with a GE prototype system at the Breast Imaging Laboratory in the Massachusetts General Hospital was used for comparison of the three approaches. The LDA classifiers with stepwise feature selection were designed with leave-one-case-out resampling. In FROC analysis, the CAD system for detection in the DBT volume alone achieved test sensitivities of 80% and 90% at average FP rates of 1.94 and 3.40 per breast, respectively. With the 2D detection approach, the FP rates were 2.86 and 4.05 per breast, respectively, at the corresponding sensitivities. In comparison, the average FP rates of the system combining the 3D and 2D information were 1.23 and 2.04 per breast, respectively, at 80% and 90% sensitivities. The difference in the detection performances between the 2D and the 3D approach, and that between the 3D and the combined approach were both statistically significant (p=0.02 and 0.01, respectively) as estimated by alternative FROC analysis. The combined system is a promising approach to improving automated mass detection on DBTs. (C) 2008 American Association of Physicists in Medicine. C1 [Wei, Jun; Zhang, Yiheng; Helvie, Mark A.; Sahiner, Berkman; Hadjiiski, Lubomir] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Moore, Richard H.; Kopans, Daniel B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Chan, HP (reprint author), Univ Michigan, Dept Radiol, 1500 E Med Ctr Dr,Med Inn Bldg C477, Ann Arbor, MI 48109 USA. EM chanhp@umich.edu FU USPHS [CA120234, CA95153]; U. S. Army Medical Research and Materiel Command [DAMD 17-02-1-0214] FX This work is supported by USPHS Grant Nos. CA120234 and CA95153, and U. S. Army Medical Research and Materiel Command Grant No. DAMD 17-02-1-0214. NR 28 TC 50 Z9 50 U1 0 U2 8 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 SEP PY 2008 VL 35 IS 9 BP 4087 EP 4095 DI 10.1118/1.2968098 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 342GQ UT WOS:000258773000030 PM 18841861 ER PT J AU Solomon, VR Haq, W Smilkstein, M Srivastava, K Rajakumar, S Puri, SK Katti, SB AF Solomon, V. Raja Haq, W. Smilkstein, M. Srivastava, Kumkum Rajakumar, S. Puri, Sunil K. Katti, S. B. TI Synthesis and antimalarial activity of novel side chain modified antimalarial agents derived from 4-aminoquinoline SO MEDICINAL CHEMISTRY LA English DT Article DE 4-aminoquinoline; amino acid conjugates; antimalarial agents ID BETA-HEMATIN FORMATION; PLASMODIUM-FALCIPARUM; ANTIPLASMODIAL ACTIVITY; RETAIN ACTIVITY; CHLOROQUINE; INHIBITION; RESISTANCE; PROTEIN; POLYMERIZATION; MECHANISM AB Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decade's emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified. C1 [Solomon, V. Raja; Haq, W.; Katti, S. B.] Cent Drug Res Inst, Div Med & Proc Chem, Lucknow 226001, Uttar Pradesh, India. [Smilkstein, M.] Portland VA Med Ctr, Portland, OR 97239 USA. [Srivastava, Kumkum; Rajakumar, S.; Puri, Sunil K.] Cent Drug Res Inst, Div Parasitol, Lucknow 226001, Uttar Pradesh, India. RP Katti, SB (reprint author), Cent Drug Res Inst, Div Med & Proc Chem, Lucknow 226001, Uttar Pradesh, India. EM setu_katti@yahoo.com FU CDRI [7213]; CSIR, New Delhi FX The authors thank the Director, CDRI for the support and the SAIF for the spectral data. The authors are thankful to Michael Riscoe, Ph. D., for careful reading the manuscript. One of the authors (V. R. Solomon) thanks the CSIR, New Delhi for Senior Research Fellowship. CDRI communication no. 7213. NR 25 TC 6 Z9 6 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4064 J9 MED CHEM JI Med. Chem. PD SEP PY 2008 VL 4 IS 5 BP 446 EP 456 DI 10.2174/157340608785700207 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 352OH UT WOS:000259506100004 PM 18782041 ER PT J AU Berin, I Teixeira, J AF Berin, Inna Teixeira, Jose TI Utility of serum antimullerian hormone/Mullerian-Inhibiting Substance for predicting ovarian reserve in older women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID ANTI-MULLERIAN HORMONE; ASSISTED REPRODUCTIVE TECHNOLOGY; MOUSE OVARY; IMMUNOASSAY; CYCLES; INFERTILITY; EXPRESSION; OBESITY; MALES; TESTS C1 [Berin, Inna; Teixeira, Jose] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Berin, I (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. OI Teixeira, Jose/0000-0002-6438-5064 FU NICHD NIH HHS [R01 HD052701] NR 33 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP-OCT PY 2008 VL 15 IS 5 BP 824 EP 826 DI 10.1097/gme.0b013e31817c42f4 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 347BJ UT WOS:000259113500004 PM 18600185 ER PT J AU Connolly, T AF Connolly, Thomas TI Documenting clinical encounters: a recipe for success SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Connolly, T (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. NR 4 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 SEP-OCT PY 2008 VL 15 IS 5 BP 830 EP 831 DI 10.1097/gme.0b013e318182d377 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 347BJ UT WOS:000259113500006 PM 18779675 ER PT J AU Thurston, RC Bromberger, JT Joffe, H Avis, NE Hess, R Crandall, CJ Chang, YF Green, R Matthews, KA AF Thurston, Rebecca C. Bromberger, Joyce T. Joffe, Hadine Avis, Nancy E. Hess, Rachel Crandall, Carolyn J. Chang, Yuefang Green, Robin Matthews, Karen A. TI Beyond frequency: who is most bothered by vasomotor symptoms? SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE vasomotor symptoms; hot flashes; hot flushes; night sweats; mood; sleep ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL HORMONE-THERAPY; MENOPAUSAL HOT FLASHES; WOMENS HEALTH; SLEEP DISTURBANCE; NEGATIVE AFFECT; ASSOCIATION; ESTROGEN; PERIMENOPAUSAL; POPULATION AB Objective: Most menopausal women report vasomotor symptoms (hot flashes, night sweats). However, not all women with vasomotor symptoms, including frequent symptoms, are bothered by them. The primary aim was to identify correlates of vasomotor symptom bother beyond symptom frequency. Design: The Study of Women's Health Across the Nation participants reporting vasomotor symptoms at annual visit 7 comprised the sample (N = 1,042). Assessments included hot flash and night sweats frequency (number per week) and bother (1, not at all-4, very much). Negative affect (index of depressive symptoms, anxiety, perceived stress, negative mood), symptom sensitivity, sleep problems, and vasomotor symptom duration (number of years) were examined cross-sectionally in relation to bother in ordinal logistic regression models with symptom frequency and covariates. Hot flashes and night sweats were considered separately. Results: In multivariable models controlling for hot flash frequency, negative affect (odds ratio [OR] = 1.27, 95% CI: 1.08-1.51), symptom sensitivity (OR = 1.18, 95% CI: 1.03-1.37), sleep problems (OR = 1.38, 95% CI: 1.04-1.85), poorer health (OR = 1.24, 95% CI: 1.03-1.48), duration of hot flashes (OR = 1.14, 95% CI: 1.06-1.23), younger age (OR = 0.94,95% CI: 0.89-0.99), and African American race (vs white, OR = 1.59, 95% CI: 1.12-2.26) were associated with hot flash bother. After controlling for night sweats frequency and covariates, sleep problems (OR = 1.84, 95% CI: 1.33-2.55) and night sweats duration (OR = 1.10, 95% CI: 1.02-1.20) were associated with night sweats bother. Conclusions: Beyond frequency, factors associated with bothersome hot flashes include mood, symptom sensitivity, symptom duration, sleep problems, age, and race. Correlates of bothersome night sweats include sleep problems and symptom duration. In addition to reducing frequency, interventions for vasomotor symptoms might consider addressing modifiable factors related to symptom bother. C1 [Thurston, Rebecca C.; Matthews, Karen A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Hess, Rachel; Green, Robin] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Chang, Yuefang] Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15213 USA. [Thurston, Rebecca C.; Bromberger, Joyce T.; Matthews, Karen A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Joffe, Hadine; Hess, Rachel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Avis, Nancy E.] Wake Forest Univ, Sch Med, Dept Social Sci & Hlth Policy, Div Publ Hlth Sci, Winston Salem, NC USA. [Crandall, Carolyn J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Green, Robin] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. RP Thurston, RC (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM thurstonrc@upmc.edu FU National Institutes of Health (NIH); Department of Health and Human Services; National Institute on Aging (NIA); National Institute of Nursing Research; NIH Office [NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495]; NIH [K23 AG029216, K12 AG01004, K23 AG024254] FX The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging (NIA), the National Institute of Nursing Research and the NIH Office of Research on Women's Health (grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, and AG012495). Dr. Thurston (K23 AG029216). Dr. Crandall (K12 AG01004), and Dr. Hess (K23 AG024254) received grant support from the NIH through the NIA. NR 42 TC 71 Z9 72 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP-OCT PY 2008 VL 15 IS 5 BP 841 EP 847 DI 10.1097/gme.0b013e318168f09b PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 347BJ UT WOS:000259113500008 PM 18521049 ER PT J AU Rothberg, BEG Moeder, CB Kluger, H Halaban, R Elder, DE Murphy, GF Lazar, A Prieto, V Duncan, LM Rimm, DL AF Rothberg, Bonnie E. Gould Moeder, Christopher B. Kluger, Harriet Halaban, Ruth Elder, David E. Murphy, George F. Lazar, Alexander Prieto, Victor Duncan, Lynn McDivitt Rimm, David L. TI Nuclear to non-nuclear Pmel17/gp100 expression (HMB45 staining) as a discriminator between benign and malignant melanocytic lesions SO MODERN PATHOLOGY LA English DT Article DE immunohistochemistry; immunofluorescence; nevus; melanoma; diagnostic; cutaneous ID SPITZ NEVI; PARAFFIN SECTIONS; BLUE NEVI; MELANOMA; TUMORS; CELLS; LOCALIZATION; COMPOUND; PROTEINS AB HMB45 is a mouse monoclonal antibody raised against Pmel17/gp100, a melanoma-specific marker, which is routinely used in the diagnosis of primary cutaneous malignant melanoma. The standard expression pattern for a positive HMB45 staining result on immunohistochemistry is based upon the results of chromogenic-based methods. We re-evaluated the patterns of HMB45 staining across the 480-core 'SPORE melanoma progression array' containing lesions representing the spectrum of melanocytic lesions ranging from thin nevus to visceral metastasis using the fluorescence-based staining technique and automated quantitative analysis ( AQUA) of the obtained digital images. The methods validated the expected cytoplasmic HMB45 staining pattern in 70/108 malignant lesions and in the epithelial components of nevus specimens. However, the fluorescence- based approach revealed a nuclear gp100 localization present in the dermal component of all nevi that was not seen before. This nuclear localization could not be observed on routine chromogenic stains, because the standard hematoxylin nuclear counterstain overwhelms the weak nuclear HMB45 stain. The thin (0.450 +/- 0.253) and thick (0.513 +/- 0.227) nevi had strongly positive mean In(nuclear/non-nuclear AQUA score ratios), which are significantly higher than those from the group of malignant lesions (P < 0.0001). This finding was reproduced on a smaller but independent progression array composed of nevi and melanomas from the Yale Pathology archives (P < 0.01). The odds ratio associated with a sample being a nevus was 2.24 (95% CI: 1.87-2.69, P < 0.0001) for each 0.1 unit increase of the In(nuclear/non-nuclear AQUA score ratio) to yield an ROC curve with 0.93 units of area and a simultaneously maximized sensitivity of 0.92 and specificity of 0.80 for distinguishing benign nevi from malignant melanomas. On the basis of this preliminary study, we propose that the ratio of nuclear to non-nuclear HMB45 staining may be useful for diagnostic challenges in melanocytic lesions. C1 [Rothberg, Bonnie E. Gould; Moeder, Christopher B.; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Kluger, Harriet] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA. [Halaban, Ruth] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. [Elder, David E.] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lazar, Alexander; Prieto, Victor] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Duncan, Lynn McDivitt] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Rimm, DL (reprint author), Yale Univ, Sch Med, Dept Pathol, 310 Cedar St,POB 208023, New Haven, CT 06520 USA. EM david.rimm@yale.edu RI Lazar, Alexander/A-3416-2008 OI Lazar, Alexander/0000-0002-6395-4499 FU NIH [RO-1 CA 114277]; Yale SPORE in Skin Cancer [1P50 CA121974] FX This work was funded by NIH RO-1 CA 114277 to Dr Rimm and Yale SPORE in Skin Cancer Grants 1P50 CA121974 to Dr R Halaban. NR 27 TC 11 Z9 12 U1 0 U2 1 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 SEP PY 2008 VL 21 IS 9 BP 1121 EP 1129 DI 10.1038/modpathol.2008.100 PG 9 WC Pathology SC Pathology GA 341LR UT WOS:000258716500008 PM 18552823 ER PT J AU Ijuin, T Yu, YE Mizutani, K Pao, A Tateya, S Tamori, Y Bradley, A Takenawa, T AF Ijuin, Takeshi Yu, Y. Eugene Mizutani, Kiyohito Pao, Annie Tateya, Sanshiro Tamori, Yoshikazu Bradley, Allan Takenawa, Tadaomi TI Increased insulin action in SKIP heterozygous knockout mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID 3T3-L1 ADIPOCYTES; GLUT4 TRANSLOCATION; ADIPOSE-TISSUE; PTEN; RESISTANCE; SHIP2; GENE; OBESITY; MUSCLE; IDENTIFICATION AB Insulin controls glucose homeostasis and lipid metabolism, and insulin impairment plays a critical role in the pathogenesis of diabetes mellitus. Human skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) is a member of the phosphatidylinositol 3,4,5-trisphosphate phosphatase family (T. Ijuin et al. J. Biol. Chem. 275: 10870-10875, 2000; T. Ijuin and T. Takenawa, Mol. Cell. Biol. 23: 1209-1220, 2003). Previous studies showed that SKIP negatively regulates insulin-induced phosphatidylinositol 3-kinase signaling (Ijuin and Takenawa, Mol. Cell. Biol. 23: 1209-1220, 2003). We now have generated mice with a targeted mutation of the mouse ortholog of the human SKIP gene, Pps. Adult heterozygous Pps mutant mice show increased insulin sensitivity and reduced diet-induced obesity with increased Akt/protein kinase B (PKB) phosphorylation in skeletal muscle but not in adipose tissue. The insulin-induced uptake of 2-deoxyglucose into the isolated soleus muscle was significantly enhanced in Pps mutant mice. A hyperinsulinemic-euglycemic clamp study also revealed a significant increase in the rate of systemic glucose disposal in Pps mutant mice without any abnormalities in hepatic glucose production. Furthermore, in vitro knockdown studies in L6 myoblast cells revealed that reduction of SKIP expression level increased insulin-stimulated Akt/PKB phosphorylation and 2-deoxyglucose uptake. These results imply that SKIP regulates insulin signaling in skeletal muscle. Thus, SKIP may be a promising pharmacologic target for the treatment of insulin resistance and diabetes. C1 [Ijuin, Takeshi; Takenawa, Tadaomi] Kobe Univ, Grad Sch Med, Div Lipid Biochem, Kobe, Hyogo 6500017, Japan. [Yu, Y. Eugene; Pao, Annie] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Yu, Y. Eugene; Pao, Annie] Roswell Pk Canc Inst, Genet Program, Buffalo, NY 14263 USA. [Yu, Y. Eugene] New York State Ctr Excellence Bioinformat & Life, Buffalo, NY USA. [Tateya, Sanshiro; Tamori, Yoshikazu] Kobe Univ, Grad Sch Med, Div Endocrinol Diabet & Metab, Kobe, Hyogo 6500017, Japan. [Bradley, Allan] Wellcome Trust Sanger Inst, Cambridge, England. [Mizutani, Kiyohito] Harvard Univ, Massachusetts Gen Hosp, Neurobiol Dis Lab, Genet & Aging Res Unit,Med Sch, Charlestown, MA USA. RP Takenawa, T (reprint author), Kobe Univ, Grad Sch Med, Div Lipid Biochem, Kobe, Hyogo 6500017, Japan. EM takenawa@med.kobe-u.ac.jp OI Ijuin, Takeshi/0000-0002-0618-1776 FU MEXT/JST; NIH/National Cancer Institute; NIH [R01HL91519]; Roswell Park Cancer Institute; National Cancer Institute FX We thank H. F. Lodish for the Glut4 cDNA; H. Sakoda and T. Asano for instructions regarding animal experiments; and K. Kawanaka, K. Koshinaka, Z. Li, and T. Kwong for the technical assistance. We are also grateful to A. Suzuki, Y. Horie, and T. Sasaki for helpful discussions and to M. Kamiya for assistance with animal experiments.; This work was supported by grants-in-aid from the MEXT/JST to T. Takenawa, from the NIH/National Cancer Institute to A. Bradley, NIH grant R01HL91519 to Y. E. Yu, and in part by a Roswell Park Cancer Institute Cancer Center Support Grant from the National Cancer Institute. NR 32 TC 30 Z9 30 U1 0 U2 13 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 SEP PY 2008 VL 28 IS 17 BP 5184 EP 5195 DI 10.1128/MCB.01990-06 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 341DY UT WOS:000258695600005 PM 18573875 ER PT J AU Gwack, Y Srikanth, S Oh-hora, M Hogan, PG Lamperti, ED Yamashita, M Gelinas, C Neems, DS Sasaki, Y Feske, S Prakriya, M Rajewsky, K Rao, A AF Gwack, Yousang Srikanth, Sonal Oh-hora, Masatsugu Hogan, Patrick G. Lamperti, Edward D. Yamashita, Megumi Gelinas, Curtis Neems, Daniel S. Sasaki, Yoshiteru Feske, Stefan Prakriya, Murali Rajewsky, Klaus Rao, Anjana TI Hair loss and defective T- and B-Cell function in mice lacking ORAI1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED CALCIUM-CHANNELS; CA2+ STORE DEPLETION; PLASMA-MEMBRANE; CRAC CHANNELS; MAST-CELLS; PORE SUBUNIT; I-CRAC; STIM1; ENTRY; LYMPHOCYTES AB ORAI1 is a pore subunit of the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel. To examine the physiological consequences of ORAI1 deficiency, we generated mice with targeted disruption of the Orai1 gene. The results of immunohistochemical analysis showed that ORAI1 is expressed in lymphocytes, skin, and muscle of wild-type mice and is not expressed in Orai1(-/-) mice. Orai1(-/-) mice with the inbred C57BL/6 background showed perinatal lethality, which was overcome by crossing them to outbred ICR mice. Orai1(-/-) mice were small in size, with eyelid irritation and sporadic hair loss resembling the cyclical alopecia observed in mice with keratinocyte-specific deletion of the Cnb1 gene. T and B cells developed normally in Orai1(-/-) mice, but B cells showed a substantial decrease in Ca(2+) influx and cell proliferation in response to B-cell receptor stimulation. Naive and differentiated Orai1(-/-) T cells showed substantial reductions in store-operated Ca(2+) entry, CRAC currents, and cytokine production. These features are consistent with the severe combined immunodeficiency and mild extraimmunological symptoms observed in a patient with a missense mutation in human ORAI1 and distinguish the ORAI1-null mice described here from a previously reported Orai1 gene-trap mutant mouse which may be a hypomorph rather than a true null. C1 [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Yamashita, Megumi; Prakriya, Murali] Northwestern Univ, Dept Biol Chem & Mol Pharmacol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Rm 152,Warren Alpert Bldg, Boston, MA 02115 USA. EM arao@idi.harvard.edu OI Feske, Stefan/0000-0001-5431-8178 FU NIH; JDRF; March of Dimes Foundation; Uehara Memorial Foundation FX We thank Hui Hu, Mark Sundrud, and Christine Patterson (Rajewsky lab) for help with experiments involving the generation of fetal liver chimeras, analysis of Tregs, and analysis of B-cell development, respectively. We also thank Jeffery L. Kutok from the specialized histopathology core at the Dana Farber/Harvard Cancer Center for his help with optimizing conditions for immunohistochemistry.; This work was supported by NIH and JDRF grants to A. R., an NIH grant and a March of Dimes Foundation grant to S. F., and NIH grants to M.P. and K.R. M.O. and Y.S. were supported by research fellowships from the Uehara Memorial Foundation.; P.G.H., S.F. and A.R. declare that they have competing financial interests. NR 56 TC 156 Z9 157 U1 1 U2 5 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 SEP PY 2008 VL 28 IS 17 BP 5209 EP 5222 DI 10.1128/MCB.00360-08 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 341DY UT WOS:000258695600007 PM 18591248 ER PT J AU Gabriely, G Wurdinger, T Kesari, S Esau, CC Burchard, J Linsley, PS Krichevsky, AM AF Gabriely, Galina Wurdinger, Thomas Kesari, Santosh Esau, Christine C. Burchard, Julja Linsley, Peter S. Krichevsky, Anna M. TI MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENES; BREAST-CANCER; IN-VIVO; TISSUE INHIBITOR; CELL LINES; EXPRESSION; METASTASIS; RECK; ANGIOGENESIS; ACTIVATION AB Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer. C1 [Krichevsky, Anna M.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med,Ctr Neurol Dis, Boston, MA 02115 USA. [Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wurdinger, Thomas] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Wurdinger, Thomas] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res,Med Sch, Boston, MA 02115 USA. [Wurdinger, Thomas] VU Med Ctr, Neurooncol Res Grp, Canc Ctr Amsterdam, Amsterdam, Netherlands. [Kesari, Santosh] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Esau, Christine C.] Regulus Therapeut, Carlsbad, CA USA. [Burchard, Julja; Linsley, Peter S.] Rosetta Inpharmat LLC, Seattle, WA USA. RP Krichevsky, AM (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med,Ctr Neurol Dis, 4 Blackfan Circle,HIM 758, Boston, MA 02115 USA. EM akrichevsky@rics.bwh.harvard.edu RI leng, xianwei/F-9073-2011; Kesari, Santosh/E-8461-2013 FU Brain Tumor Society; Paul Brazen American Brain Tumor; Steve Kaplan American Brain Tumor Association Fellowship; [NCI R21CA116141] FX We thank Xandra O. Breakefield for helpful discussions and use of her laboratory facilities (GTBT CA6924) and Ralph Weissleder for providing the MMP probe and access to the Imaging Facility (NIH-NCI P50 CA86355-04). We thank John Pham for significant intellectual and experimental contribution to this work. A plasmid coding for the luciferase reporter of miR-21 activity was a kind gift from Ambion.; This study was supported by NCI R21CA116141 and Brain Tumor Society grants (to A.M.K.), a Paul Brazen American Brain Tumor Association Fellowship (to G.G.), and a Steve Kaplan American Brain Tumor Association Fellowship (to T.W.). NR 60 TC 495 Z9 547 U1 3 U2 49 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 SEP PY 2008 VL 28 IS 17 BP 5369 EP 5380 DI 10.1128/MCB.00479-08 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 341DY UT WOS:000258695600020 PM 18591254 ER PT J AU Lu, TC Wang, ZH Feng, XB Chuang, P Fang, W Chen, YB Neves, S Maayan, A Xiong, HB Liu, YS Iyengar, R Klotman, PE He, JC AF Lu, Ting-Chi Wang, Zhaohui Feng, Xiaobei Chuang, Peter Fang, Wei Chen, Yibang Neves, Susana Maayan, Avi Xiong, Huabao Liu, Yusen Iyengar, Ravi Klotman, Paul E. He, John Cijiang TI Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-KINASE PHOSPHATASE-1; HIV-ASSOCIATED NEPHROPATHY; MAP KINASE; GENE-TRANSCRIPTION; NEPHROTIC SYNDROME; PROXIMAL PROMOTER; RENAL DEVELOPMENT; NPHS2 PROMOTER; MESSENGER-RNA; ACTIVATION AB Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. atRA stimulated CREB and USF1 binding to the MKP1 gene promoter, as shown by gel shifting and chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by a reporter gene assay using the MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1). C1 [Lu, Ting-Chi; Chuang, Peter; Fang, Wei; Klotman, Paul E.; He, John Cijiang] Mt Sinai Sch Med, Div Nephrol, Dept Med, New York, NY 10029 USA. [Chen, Yibang; Neves, Susana; Maayan, Avi; Iyengar, Ravi; He, John Cijiang] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Xiong, Huabao] Mt Sinai Sch Med, Immunobiol Ctr, New York, NY 10029 USA. [He, John Cijiang] James J Peters VA Med Ctr, Bronx, NY USA. [Wang, Zhaohui; Feng, Xiaobei] Shanghai Jiao Tong Univ, Sch Med, Dept Nephrol, Rui Jin Hosp, Shanghai 200030, Peoples R China. [Liu, Yusen] Ohio State Univ, Childrens Res Inst, Columbus, OH 43210 USA. RP He, JC (reprint author), Mt Sinai Sch Med, Div Nephrol, Dept Med, Box 1243,1 Gustave L Levy Pl, New York, NY 10029 USA. EM Cijiang.he@mssm.edu RI Liu, Yusen/E-3527-2011 FU NIH [K08 DK079781, K08 DK065495, R01 DK078897, P01 DK056492, R01 DK38761] FX Ting-Chi Lu is a recipient of an NIH career development award (K08 DK079781). John Cijiang He is a recipient of an NIH career development award (K08 DK065495) and is supported by NIH R01 DK078897. This work was also supported by NIH grants P01 DK056492 to Paul E. Klotman and R01 DK38761 to Ravi Iyengar. NR 48 TC 25 Z9 28 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 SEP PY 2008 VL 28 IS 18 BP 5785 EP 5794 DI 10.1128/MCB.00245-08 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 344TU UT WOS:000258951000019 PM 18625721 ER PT J AU McEwen, JM Kaplan, JM AF McEwen, Jason M. Kaplan, Joshua M. TI UNC-18 promotes both the anterograde trafficking and synaptic function of Syntaxin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CAENORHABDITIS-ELEGANS; ENDOPLASMIC-RETICULUM; SNARE COMPLEX; C-ELEGANS; SEC1/MUNC18 PROTEINS; VESICLE TRAFFICKING; MEMBRANE-FUSION; GENE ENCODES; ACTIVE ZONE; SM-PROTEIN AB The SM protein UNC-18 has been proposed to regulate several aspects of secretion, including synaptic vesicle docking, priming, and fusion. Here, we show that UNC-18 has a chaperone function in neurons, promoting anterograde transport of the plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein Syntaxin-1. In unc-18 mutants, UNC-64 (Caenorhabditis elegans Syntaxin-1) accumulates in neuronal cell bodies. Colocalization studies and analysis of carbohydrate modifications both suggest that this accumulation occurs in the endoplasmic reticulum. This trafficking defect is specific for UNC-64 Syntaxin-1, because 14 other SNARE proteins and two active zone markers were unaffected. UNC-18 binds to Syntaxin through at least two mechanisms: binding to closed Syntaxin, or to the N terminus of Syntaxin. It is unclear which of these binding modes mediates UNC-18 function in neurons. The chaperone function of UNC-18 was eliminated in double mutants predicted to disrupt both modes of Syntaxin binding, but it was unaffected in single mutants. By contrast, mutations predicted to disrupt UNC-18 binding to the N terminus of Syntaxin caused significant defects in locomotion behavior and responsiveness to cholinesterase inhibitors. Collectively, these results demonstrate the UNC-18 acts as a molecular chaperone for Syntaxin transport in neurons and that the two modes of UNC-18 binding to Syntaxin are involved in different aspects of UNC-18 function. C1 [McEwen, Jason M.; Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Genet, Massachusetts Gen Hosp,Dept Mol Biol, Boston, MA 02114 USA. RP Kaplan, JM (reprint author), Harvard Univ, Sch Med, Dept Genet, Massachusetts Gen Hosp,Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu FU National Institutes of Health [GM-54728] FX We thank the following for strains, reagents, and advice: M. Nonet, E. Jorgensen (University of Utah, Salt Lake City, UT), L. Dreier (University of California, Los Angeles, CA), and the C. elegans Genetics Stock Center. We also thank members of the Kaplan laboratory for critical comments on this manuscript and T. Cherry for initial observations. This work was supported by National Institutes of Health grant GM-54728 (to J.M.K.). NR 54 TC 42 Z9 44 U1 2 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP PY 2008 VL 19 IS 9 BP 3836 EP 3846 DI 10.1091/mbc.E08-02-0160 PG 11 WC Cell Biology SC Cell Biology GA 348AM UT WOS:000259183200020 PM 18596236 ER PT J AU Rettig, MB Heber, D An, JB Seeram, NP Rao, JY Liu, HR Klatte, T Belldegrun, A Moro, A Henning, SM Mo, DQ Aronson, WJ Pantuck, A AF Rettig, Matthew B. Heber, David An, Jiabin Seeram, Navindra P. Rao, Jian Y. Liu, Huiren Klatte, Tobias Belldegrun, Arie Moro, Aune Henning, Susanne M. Mo, Deqiong Aronson, William J. Pantuck, Allan TI Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappa B-dependent mechanism SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTOR; CARCINOMA-CELLS; MOUSE MODEL; IN-VITRO; PROGRESSION; INFLAMMATION; CARCINOGENESIS; ANGIOGENESIS; METABOLITES AB Constitutive nuclear factor-kappa B (NF-kappa B) activation is ob served in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-kappa B and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-kappa B blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-kappa B activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-kappa B activity. C1 [Rettig, Matthew B.; An, Jiabin; Mo, Deqiong] VA Greater Los Angeles Healthcare Syst W Los Ange, Dept Med, Los Angeles, CA 90073 USA. [Rettig, Matthew B.; Liu, Huiren] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90024 USA. [Rettig, Matthew B.; Klatte, Tobias; Belldegrun, Arie; Aronson, William J.; Pantuck, Allan] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. [Rao, Jian Y.] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. [Seeram, Navindra P.; Moro, Aune; Henning, Susanne M.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Human Nutr, Los Angeles, CA 90095 USA. [Aronson, William J.] VA Greater Los Angeles Healthcare Syst W Los Ange, Dept Urol, Los Angeles, CA 90073 USA. RP Rettig, MB (reprint author), VA Greater Los Angeles Healthcare Syst W Los Ange, Dept Med, Bldg 304,Room E1-113,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM mrettig@mednet.ucla.edu FU Sence Foundation and POM Wonderful; University of California-Los Angeles Prostate Specialized Program of Research Excellence [P50 CA92131]; Department of Defense [W81XWH-04-1-0529]; Department of Veterans Affairs Merit Review Program FX Sence Foundation and POM Wonderful (A. Pantuck), University of California-Los Angeles Prostate Specialized Program of Research Excellence grant P50 CA92131, and Department of Defense award W81XWH-04-1-0529 and Department of Veterans Affairs Merit Review Program (M.B. Rettig). NR 36 TC 58 Z9 61 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2008 VL 7 IS 9 BP 2662 EP 2671 DI 10.1158/1535-7163.MCT-08-0136 PG 10 WC Oncology SC Oncology GA 350XP UT WOS:000259387300008 PM 18790748 ER PT J AU Zhang, M Alicot, EM Carroll, MC AF Zhang, Ming Alicot, Elisabeth M. Carroll, Michael C. TI Human natural IgM can induce ischemia/reperfusion injury in a murine intestinal model SO MOLECULAR IMMUNOLOGY LA English DT Article DE Human; Natural antibody; IgM; Ischemia; Reperfusion injury; Intestinal model ID ISCHEMIA-REPERFUSION INJURY; ACUTE MYOCARDIAL-INFARCTION; MEMBRANE ATTACK COMPLEX; MANNOSE-BINDING LECTIN; LOW-FLOW STATES; MUCOSAL LESION; ANTIBODY; PATHWAY; IDENTIFICATION; ACTIVATION AB A new mechanism of ischemia/reperfusion (I/R) injury is discovered recently operating through innate autoimmunity. Studies of different animal I/R models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving complement system which is activated by autoreactive natural IgM. Whether similar mechanism operating in human is still unknown. We investigated this important question by testing if human natural IgM could induce I/R injury in an established murine intestinal model. RAG-1(-/-) mice (immunoglobulin deficient), which are protected from I/R injury, were reconstituted with purified normal human IgM and subjected in an intestinal injury model. Reconstituted RAG-1(-/-) mice that were underwent sham treatment did not show tissue injury in intestine. In contrast, reconstituted RAG-1(-/-) mice that underwent 40 min intestinal ischemia and 3 h reperfusion showed significant injury in the local tissues. In addition, immunohistochemistry showed that complement C4 were deposited in intestinal villi of I/R but not sham treated mice. Therefore, our study is the first report describing that human natural IgM is capable to induce I/R injury in the intestinal model, and further suggests that innate autoimmunity may operate under pathogenic conditions in human. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Zhang, Ming] Suny Downstate Med Ctr, Dept Anesthesiol, Brooklyn, NY 11203 USA. [Alicot, Elisabeth M.] DecImmune Therapeut, Boston, MA 02115 USA. [Alicot, Elisabeth M.; Carroll, Michael C.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Zhang, M (reprint author), Suny Downstate Med Ctr, Dept Anesthesiol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. EM ming.zhang@downstate.edu; carroll@cbr.med.harvard.edu FU NHLBI NIH HHS [R21 HL088527, R21 HL088527-01A1] NR 22 TC 26 Z9 29 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2008 VL 45 IS 15 BP 4036 EP 4039 DI 10.1016/j.molimm.2008.06.013 PG 4 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 363CZ UT WOS:000260244800021 PM 18672288 ER PT J AU Finnerty, CC Jeschke, MG Herndon, DN Gamelli, R Gibran, N Klein, M Silver, G Arnoldo, B Remick, D Tompkins, RG AF Finnerty, Celeste C. Jeschke, Marc G. Herndon, David N. Gamelli, Richard Gibran, Nicole Klein, Matthew Silver, Geoff Arnoldo, Brett Remick, Daniel Tompkins, Ronald G. CA Investigators Inflammation TI Temporal cytokine profiles in severely burned patients: A comparison of adults and children SO MOLECULAR MEDICINE LA English DT Article ID PEDIATRIC-PATIENTS; INJURY; POSTBURN; SIZE; TIME; INTERLEUKIN-6; INFLAMMATION; MORTALITY; PLASMA AB A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structural changes of essential organs. The release of cytokines has been implicated in this hypermetabolic response. The severity of the hypermetabolic response following burn injury increases with age, as does the mortality rate. Due to the relationship between the hypermetabolic and inflammatory responses, we sought to compare the plasma cytokine profiles following a severe burn in adults and in children. We enrolled 25 adults and 24 children who survived a flame burn covering more than 20% of total body surface area (TBSA), The concentrations of 22 cytokines were measured using the Linco multiplex array system (St. Charles, MO, USA). Large perturbations in the expression of pro- and anti-inflammatory cytokines were seen following thermal injury. During the first week following burn injury, IFN-gamma, IL-10, IL-17, IL-4, IL-6, and IL-8 were detected at significantly higher levels in adults compared with children, P < 0.05. Significant differences were measured during the second week post-burn for IL-1 beta (higher in children) and IL-5 (higher in adults), P < 0.05. IL-18 was more abundant in children compared with adults during the third week post-burn, P < 0.05. Between post-burn d 21 and d 66, IL-1 alpha was detected at higher concentrations in pediatric compared with adult patients, P < 0.05. Only GM-CSF expression was significantly different at all time points; it was detected at lower levels in pediatric patients, P < 0.05. Eotaxin, G-CSF IL-13, IL-15, IP-10, MCP-1, and MIP-1 alpha were detected at significantly different concentrations in adult compared with pediatric patients at multiple time points, P < 0.05. There were no differences in IL-12, IL-2, IL-7, or TNF levels in adult compared with pediatric burn patients at any of these time points. Following severe flame burns, the cytokine profiles in pediatric patients differ compared with those in adult patients, which may provide insight with respect to the higher morbidity rate in adults. Furthermore, the dramatic discrepancies observed in plasma cytokine detection between children and adults suggest that these two patient populations may benefit from different therapeutic interventions to achieve attenuation of the post-burn inflammatory response. C1 [Finnerty, Celeste C.; Jeschke, Marc G.; Herndon, David N.] Univ Texas Med Branch, Shriners Hosp Children, Galveston, TX 77550 USA. [Finnerty, Celeste C.; Jeschke, Marc G.; Herndon, David N.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA. [Arnoldo, Brett] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA. [Gamelli, Richard; Silver, Geoff] Loyola Univ, Stritch Sch Med, Dept Surg, Maywood, IL 60153 USA. [Gibran, Nicole; Klein, Matthew] Univ Washington, Harborview Med Ctr, Sch Med, Dept Surg, Seattle, WA 98104 USA. [Remick, Daniel] Boston Univ, Sch Med, Boston, MA 02118 USA. [Tompkins, Ronald G.] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Tompkins, Ronald G.] Harvard Univ, Sch Med, Boston, MA USA. RP Finnerty, CC (reprint author), Univ Texas Med Branch, Shriners Hosp Children, 815 Market St, Galveston, TX 77550 USA. EM ccfinner@utmb.edu OI Remick, Daniel/0000-0002-2615-3713 FU National Institute of General Medical Sciences [U54 GM-62119-04, P50 GM-60338, R01 GM-56687, T32 GM-008256]; Shriners Hospitals for Children [8660] FX This study was supported in part by a Large Scale Collaborative Research Grant from the National Institute of General Medical Sciences (U54 GM-62119-04) awarded to Ronald G Tompkins at the Massachusetts General Hospital, Boston, MA, USA, and in part by research grants awarded to David N Herndon at the University of Texas Medical Branch, Galveston, TX, USA, by the National Institute of General Medical Sciences (P50 GM-60338, R01 GM-56687, T32 GM-008256) and by the Shriners Hospitals for Children (8660). NR 24 TC 70 Z9 75 U1 0 U2 3 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD SEP-OCT PY 2008 VL 14 IS 9-10 BP 553 EP 560 DI 10.2119/2007-00132.Finnerty PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 352YJ UT WOS:000259533000003 PM 18548133 ER PT J AU Gorman, MP Healy, B Polgar-Turcsanyi, M Chitnis, T AF Gorman, Mark P. Healy, Brian Polgar-Turcsanyi, Mariann Chitnis, Tanuja TI Relapses are more frequent in pediatric-onset than adult-onset multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 13th Annual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis CY SEP 17-20, 2008 CL Montreal, CANADA SP Amer Comm Treatment & Res Multiple Scleros, European Comm Treatment & Res Multiple Scleros, Latin Amer Comm Treatment & Res Multiple Scleros C1 [Gorman, Mark P.; Chitnis, Tanuja] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Healy, Brian; Polgar-Turcsanyi, Mariann] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2008 VL 14 BP S66 EP S66 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 354YL UT WOS:000259675700205 ER PT J AU Hawker, KS O'Connor, P Freedman, MS Calabresi, PA Antel, JP Simon, J Hauser, SL Waubant, E Vollmer, T Panitch, H Zhang, J Chin, P Smith, C AF Hawker, Kathleen S. O'Connor, Paul Freedman, Mark S. Calabresi, Peter A. Antel, Jack P. Simon, Jack Hauser, Stephen L. Waubant, Emmanuelle Vollmer, Timothy Panitch, Hillel Zhang, Jiameng Chin, Peter Smith, Craig TI Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 13th Annual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis CY SEP 17-20, 2008 CL Montreal, CANADA SP Amer Comm Treatment & Res Multiple Scleros, European Comm Treatment & Res Multiple Scleros, Latin Amer Comm Treatment & Res Multiple Scleros C1 [Hawker, Kathleen S.] Ohio State Univ, Columbus, OH 43210 USA. [O'Connor, Paul] Univ Toronto, Toronto, ON, Canada. [Freedman, Mark S.] Ottawa Hosp, Ottawa, ON, Canada. [Calabresi, Peter A.] Johns Hopkins Univ, Baltimore, MD USA. [Antel, Jack P.] McGill Univ, Montreal, PQ, Canada. [Simon, Jack] Portland VA Med Ctr, Portland, OR USA. [Hauser, Stephen L.; Waubant, Emmanuelle] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Vollmer, Timothy] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Panitch, Hillel] Univ Vermont, Burlington, VT USA. [Zhang, Jiameng; Chin, Peter; Smith, Craig] Genentech Inc, San Francisco, CA 94080 USA. RI Hauser, Stephen/J-2978-2016 NR 0 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2008 VL 14 BP S299 EP S299 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 354YL UT WOS:000259675700978 ER PT J AU Kinkel, RP O'Connor, P Simon, J Carulli, J Castrillo, MD Goelz, S Hyde, R Lanker, S Pace, A Sandrock, A Zhang, H AF Kinkel, R. P. O'Connor, Paul Simon, Jack Carulli, John Castrillo, Maria del Carmen Goelz, Susan Hyde, Robert Lanker, Stefan Pace, Amy Sandrock, Alfred Zhang, Hao TI Magnetic resonance imaging activity predicts multiple sclerosis patients' response to treatment with interferon beta-1a SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 13th Annual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis CY SEP 17-20, 2008 CL Montreal, CANADA SP Amer Comm Treatment & Res Multiple Scleros, European Comm Treatment & Res Multiple Scleros, Latin Amer Comm Treatment & Res Multiple Scleros C1 [Kinkel, R. P.] Beth Israel Deaconess Med Ctr, Multiple Sclerosis Ctr, Boston, MA 02215 USA. [O'Connor, Paul] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Simon, Jack] Portland VA Med Ctr, Portland, OR USA. [Carulli, John; Castrillo, Maria del Carmen; Goelz, Susan; Hyde, Robert; Lanker, Stefan; Pace, Amy; Sandrock, Alfred; Zhang, Hao] Biogen Idec Inc, Cambridge, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2008 VL 14 BP S51 EP S51 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 354YL UT WOS:000259675700153 ER PT J AU Vandenbark, AA Burrows, GG Ravey, EP Offner, H AF Vandenbark, Arthur A. Burrows, Gregory G. Ravey, Edward P. Offner, Halina TI Phase I safety study of RTL1000, a recombinant T-cell receptor ligand specific for MOG peptide, in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 13th Annual Meeting of the Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/24th Congress of the European-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis/5th Congress of the Latin-Amer-Comm-for-Treatment-and-Res-in-Multiple-Sclerosis CY SEP 17-20, 2008 CL Montreal, CANADA SP Amer Comm Treatment & Res Multiple Scleros, European Comm Treatment & Res Multiple Scleros, Latin Amer Comm Treatment & Res Multiple Scleros C1 [Vandenbark, Arthur A.] Portland VA Med Ctr, Portland, OR USA. [Burrows, Gregory G.; Ravey, Edward P.; Offner, Halina] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2008 VL 14 BP S247 EP S247 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 354YL UT WOS:000259675700811 ER PT J AU Muller, FL Liu, Y Jernigan, A Borchelt, D Richardson, A van Remmen, H AF Muller, Florian L. Liu, Yuhong Jernigan, Amanda Borchelt, David Richardson, Arlan van Remmen, Holly TI MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models SO MUSCLE & NERVE LA English DT Article DE ALS; MnSOD; oxidative stress; G93A; H46R/H48Q ID AMYOTROPHIC-LATERAL-SCLEROSIS; MANGANESE SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; NEURODEGENERATIVE DISEASES; OXIDATIVE STRESS; MICE; MINOCYCLINE; DAMAGE; ONSET; INCLUSIONS AB Mitochondrial dysfunction and oxidative stress are thought to participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). The purpose of this study was to determine the effect of reduced mitochondrial antioxidant defense on lifespan and disease progression in two mouse models of familial ALS (G93A and H46R/H48Q mutant lines) that represent pseudo-wildtype and metal-deficient AILS mutants, respectively. The metal-deficient H46R/H48Q mutant differs from the G93A mutant in that it cannot bind copper in the active site and thus lacks SOD activity. We crossed each of these mutant lines with mice deficient in the mitochondrial matrix antioxidant enzyme MnSOD (Sod2(+/-) mice). In both high (G93A(1) (Gur)) and low (G93A(DL)) copy G93A strains, MnSOD deficiency caused a decrease in lifespan that was associated with a reduced disease duration rather than earlier disease onset. In contrast, MnSOD deficiency had no effect on lifespan or disease parameters of H46R/H48Q mutant mice. MnSOD deficiency thus has a differential effect on disease progression in different mutant SOD1 ALS mouse models, suggesting that different ALS-causing mutations in SOD1 result in disease progression by at least proximally different mechanisms/pathways. C1 [Richardson, Arlan; van Remmen, Holly] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Muller, Florian L.; Richardson, Arlan; van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Liu, Yuhong; Jernigan, Amanda; Richardson, Arlan; van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Borchelt, David] Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. RP van Remmen, H (reprint author), S Texas Vet Hlth Care Syst, San Antonio, TX USA. EM vanremmen@uthscsa.edu FU Department of Veteran Affairs (HVR); Muscular Dystrophy Association [MDA 3879]; NIA [5T3-AG021890-02] FX Supported by a VA Merit grant from the Department of Veteran Affairs (HVR), a grant from the Muscular Dystrophy Association (#MDA 3879), and NIA training grant #5T3-AG021890-02 (FLM). We thank Jay Cox and Marian Sabia for excellent animal care and husbandary and Morgen Hickey for assistance with the tables. NR 38 TC 13 Z9 14 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD SEP PY 2008 VL 38 IS 3 BP 1173 EP 1183 DI 10.1002/mus.21049 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 346ES UT WOS:000259052000011 PM 18720509 ER PT J AU Napoli, C Williams-Ignarro, S Byrns, R Balestrieri, ML Crilmi, E Farzati, B Mancini, FP de Nigris, F Matarazzo, A D'Amora, M Abbondanza, C Fiorito, C Giovane, A Florio, A Varricchio, E Palagiano, A Minucci, PB Tecce, MF Giordanoo, A Pavan, A Ignarro, LJ AF Napoli, Claudio Williams-Ignarro, Sharon Byrns, Russell Balestrieri, Maria Luisa Crilmi, Ettore Farzati, Bartolomeo Mancini, Francesco P. de Nigris, Filomena Matarazzo, Angelo D'Amora, Maurizio Abbondanza, Ciro Fiorito, Carmela Giovane, Alfonso Florio, Anna Varricchio, Ettore Palagiano, Antonio Minucci, Pellegrino Biagio Tecce, Mario Felice Giordanoo, Antonio Pavan, Antonio Ignarro, Louis J. TI Therapeutic targeting of the stem cell niche in experimental hindlimb ischemia SO NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE LA English DT Article DE bone marrow; ischemic vascular diseases; neoangiogenesis; vascular niche ID BONE-MARROW-CELL; COLONY-STIMULATING FACTOR; HORMONE-RELATED PROTEIN; HEMATOPOIETIC GROWTH-FACTORS; PARATHYROID-HORMONE; METABOLIC INTERVENTION; ENDOTHELIAL-CELLS; HUMAN OSTEOBLASTS; INDUCED ANGIOGENESIS; PROGENITOR CELLS AB Background The custom microenvironment 'vascular niche' is a potential therapeutic target for several pathophysiological conditions. Osteoblasts regulate the hematopoietic stein cell niche, and activation of the parathyroid hormone (PTH) receptor can increase the number of cells mobilized into the bloodstream. Methods C57B1/6 mice were randomly assigned treatment with granulocyte-colony stimulating factor (G-CSF), PTH, G-CSF Plus PTH or saline. An mice underwent hindlimb ischemia. Blood flow was measured by laser Doppler imaging. Indices of capillary activity were determined 1)), electron microscopy in muscle tissue. CD34(+) and Ki67(+) cells were detected and evaluated by immunofluorescence, apoptosis by TUNEL, surface antigen and endothelial progenitor cells by fluorescence-activated cell sorting analysis, and vascular endothelial growth factor-164 and angiopoietin-1 expression by reverse-transcriptase polymerase chain reaction. Frozen bone marrow sections were stained for antigen-specific B cells and fibronectin and analyzed by confocal laser scanning microscopy. Results Following mobilization induced by G-CSF treatment, mice also treated with PTH showed increases in blood flow, capillary density, nitrite/nitrate release, angiogenic factors and circulating progenitor cells, as well as reduced apoptosis, fibrosis, oxidative stress and inflammation in ischemic muscles. Furthermore, hematopoietic antigen-specific B cells in the bone marrov were also increased by G-CSF alone and in combination with PTH. Conclusions PTH might increase the efficiency of hematopoietic stem-cell-based therapy in a recognized model of peripheral ischemia. Our translational experimental therapeutic targeting of the vascular niche points to novel clinical targets for the hematopoictic stem-cell treatment of ischemic vascular diseases. C1 [Napoli, Claudio; Balestrieri, Maria Luisa; Farzati, Bartolomeo; de Nigris, Filomena; Matarazzo, Angelo; Abbondanza, Ciro; Giovane, Alfonso; Florio, Anna; Palagiano, Antonio; Minucci, Pellegrino Biagio] Univ Naples 2, Dept Gen Pathol, Excellence Res Ctr Cardiovasc Dis, Dept Biochem, I-80138 Naples, Italy. [Napoli, Claudio; Balestrieri, Maria Luisa; Farzati, Bartolomeo; de Nigris, Filomena; Matarazzo, Angelo; Abbondanza, Ciro; Giovane, Alfonso; Florio, Anna; Palagiano, Antonio; Minucci, Pellegrino Biagio] Univ Naples 2, Div Vasc Surg, Sch Med 1, I-80138 Naples, Italy. [Williams-Ignarro, Sharon] Univ Calif Los Angeles, Div Anesthesiol, Los Angeles, CA 90095 USA. [Byrns, Russell; Ignarro, Louis J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Crilmi, Ettore] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Mancini, Francesco P.; Varricchio, Ettore] Univ Sannio, Dept Biol & Environm Sci, Benevento, Italy. [D'Amora, Maurizio] ASLNA1, Hosp Incurabili, Div Clin Pathol, Naples, Italy. [Fiorito, Carmela] IRCCS Multimed, Milan, Italy. [Tecce, Mario Felice] Univ Salerno, Sch Pharm, Dept Pharmacol, Salerno, Italy. [Giordanoo, Antonio] Temple Univ, Sbarro Inst Canc Res & Mol Med, Coll Sci & Technol, Philadelphia, PA 19122 USA. [Giordanoo, Antonio] Univ Siena, Dept Human Pathol & Oncol, I-53100 Siena, Italy. [Pavan, Antonio] Univ Roma La Sapienza, Sch Med 2, Div Clin Pathol, Rome, Italy. [Byrns, Russell; Ignarro, Louis J.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA. RP Napoli, C (reprint author), Univ Naples 2, Dept Gen Pathol, Excellence Res Ctr Cardiovasc Dis, Dept Biochem, Via De Crecchio 7, I-80138 Naples, Italy. EM claudio.napoli@unina2.it RI Tecce, Mario /L-7295-2013; OI FLORIO, Anna/0000-0002-0879-5640; Napoli, Claudio/0000-0002-5455-555X; VARRICCHIO, Ettore/0000-0001-6241-7096; de nigris, filomena/0000-0002-2322-1557; Giovane, Alfonso/0000-0002-2508-2597; TECCE, Mario Felice/0000-0003-2355-6047 FU Ministero, dell'Universita e Ricerca Scientifica PRIN 2006; PRIN 2005; Fondation Jerome Lejeune; NIH; Regione Campania 2007; Sbarro Research Institute; Ricerca di Ateneo 2006; Camera di Commercio to the University of Sannio; University of Salerno FX These studies were supported by grants from the following institutions: Ministero, dell'Universita e Ricerca Scientifica PRIN 2006 to C Napoli and PRIN 2005 to A Giovane; Fondation Jerome Lejeune to C Napoli; NIH to S Williams-Ignarro, A Giordano, LJ Ignarro and C Napoli; Regione Campania 2007 to ML Balestrieri and C Napoli; Sbarro Research Institute to A Giordano; Ricerca di Ateneo 2006 and Camera di Commercio to the University of Sannio for FP Mancini and E Varricchio; and research funds of the University of Salerno to MF Tecce. NR 39 TC 26 Z9 28 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1743-4297 J9 NAT CLIN PRACT CARD JI Nat. Clin. Pract. Cardiovasc. Med. PD SEP PY 2008 VL 5 IS 9 BP 571 EP 579 DI 10.1038/ncpcardio1214 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339MF UT WOS:000258581000014 PM 18414452 ER PT J AU Weinger, K AF Weinger, Katie TI Diabetes education at diagnosis: sooner rather than later? SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material DE diagnosis; patient education; smoking; type 2 diabetes mellitus; weight loss ID SELF-MANAGEMENT; MORTALITY; TRIAL AB Few well-designed, randomized, controlled trials have examined the clinical consequences of diabetes education at diagnosis. As a result, relatively few patients with type 2 diabetes mellitus have access to such programs. In this Practice Point commentary, I discuss the study of Davies et al., which examined the effect of a structured diabetes education intervention at diagnosis on glycemic control, weight loss, and smoking cessation during a 12-month follow-up period. A control group that received standard diabetes education and guideline-based care was also enrolled. Although glycemic control did not differ between the two groups, patients in the intervention group lost more weight and were more likely to have stopped smoking by 12 months than those in the control group. These findings suggest potential long-term benefits of early patient education. Future studies that examine long-term follow-up data from this cohort would be useful to determine whether early diabetes education has any effect on glycemia later in the disease course. C1 [Weinger, Katie] Joslin Diabet Ctr, Boston, MA 02215 USA. [Weinger, Katie] Harvard Univ, Sch Med, Boston, MA USA. RP Weinger, K (reprint author), Joslin Diabet Ctr, Suite 350,1 Joslin Pl, Boston, MA 02215 USA. EM katie.weinger@joslin.harvard.edu NR 7 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD SEP PY 2008 VL 4 IS 9 BP 482 EP 483 DI 10.1038/ncpendmet0899 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 338HV UT WOS:000258498800003 PM 18594487 ER PT J AU Bogaert, YE Chonchol, M AF Bogaert, Yolanda E. Chonchol, Michel TI Assessing the benefits and harms of statin treatment in patients with chronic kidney disease SO NATURE CLINICAL PRACTICE NEPHROLOGY LA English DT Editorial Material DE cardiovascular risk; chronic kidney disease; meta-analysis; mortality; statins ID RENAL-FUNCTION; PEOPLE; ATORVASTATIN; METAANALYSIS; PRAVASTATIN AB This Practice Point commentary discusses a meta-analysis by Strippoli et al. that included 50 randomized and quasi-randomized trials of statins in patients with different stages of kidney disease (predialysis, dialysis and transplantation; n = 30,144). The authors found that statins safely reduced lipid concentrations and the risk of cardiovascular events and cardiovascular mortality, but that the agents had no effect on all-cause mortality overall and had uncertain renoprotective effects. The analysis was comprehensive and well executed. A decreased risk of all-cause mortality with statins was found in studies of predialysis patients but not in studies of renal transplant recipients or patients on chronic dialysis. Statin doses used in the trials were well tolerated and safe in all subgroups of patients with chronic kidney disease; therefore, we feel that statin use to maintain LDL cholesterol below 100 mg/dl (2.6 mmol/l) should be initiated to potentially decrease cardiovascular risk in such patients. The benefits of statin therapy on all-cause mortality and the clinically significant benefits of this treatment on progression of kidney disease are still unclear, and additional trial evidence in patients with chronic kidney disease is needed. C1 [Bogaert, Yolanda E.] Denver Vet Affairs Med Ctr, Div Renal Dis & Hypertens, Denver, CO 80262 USA. [Chonchol, Michel] Univ Colorado Hlth Sci, Div Renal Dis & Hypertens, Denver, CO USA. RP Bogaert, YE (reprint author), Denver Vet Affairs Med Ctr, Div Renal Dis & Hypertens, Denver, CO 80262 USA. EM yolanda.bogaert@uchsc.edu NR 7 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1745-8323 J9 NAT CLIN PRACT NEPHR JI Nat. Clin. Pract. Nephrol. PD SEP PY 2008 VL 4 IS 9 BP 470 EP 471 DI 10.1038/ncpneph0892 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 339JK UT WOS:000258573700002 PM 18628740 ER PT J AU Hertig, A Watnick, S Strevens, H Boulanger, H Berkane, N Rondeau, E AF Hertig, Alexandre Watnick, Suzanne Strevens, Helena Boulanger, Henri Berkane, Nadia Rondeau, Eric TI How should women with pre-eclampsia be followed up? New insights from mechanistic studies SO NATURE CLINICAL PRACTICE NEPHROLOGY LA English DT Review DE gestational hypertension; glomerular endotheliosis; pre-eclampsia; pregnancy; sFlt-1 ID URINARY ALBUMIN EXCRETION; GROWTH-FACTOR RECEPTOR-1; NORMAL-PREGNANCY; TYROSINE KINASE-1; ANTIANGIOGENIC FACTORS; RETROSPECTIVE COHORT; ANGIOGENIC FACTORS; REMOTE PROGNOSIS; SOLUBLE ENDOGLIN; BLOOD-PRESSURE AB Understanding of the maternal syndrome of pre-eclampsia has greatly improved over the past 5 years. Specifically, the notion has emerged that the placenta is a source of antiangiogenic factors, such as soluble fms-like tyrosine kinase 1, that can progressively impair the mother's vascular and glomerular function throughout pregnancy. This impairment can be harmless during normal pregnancy, but in cases of defective placentation, concentrations of antiangiogenic factors increase to a level that compromises vital vascular functions in the short term and jeopardizes long-term maternal and fetal outcomes. In both pre-eclamptic and healthy pregnancies, the transient imbalance between angiogenic and antiangiogenic factors elicited by pregnancy acts as a 'stress test' for the endothelium, particularly in the glomerular capillary bed. Women who do not pass this test (i.e. those who develop pre-eclampsia or gestational hypertension) should be screened for glomerular disease, and their cardiovascular risk should be carefully monitored throughout life. C1 [Hertig, Alexandre; Rondeau, Eric] Hop Tenon, Dept Nephrol & Renal Transplantat, F-75020 Paris, France. [Watnick, Suzanne] Portland VA Med Ctr, Portland, OR USA. [Strevens, Helena] Lund Univ, Dept Obstet & Gynecol, Lund, Sweden. [Boulanger, Henri] Clin Estree, Dept Nephrol & Dialysis, Stains, France. [Berkane, Nadia] Hop Tenon, Dept Obstet & Gynecol, F-75020 Paris, France. RP Hertig, A (reprint author), Hop Tenon, Dept Nephrol & Renal Transplantat, 4 Rue Chine, F-75020 Paris, France. EM alexandre.hertig@tnn.aphp.fr RI Strevens, Helena/B-4976-2009; OI Boulanger, Henri/0000-0001-8017-1640 NR 59 TC 9 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1745-8323 J9 NAT CLIN PRACT NEPHR JI Nat. Clin. Pract. Nephrol. PD SEP PY 2008 VL 4 IS 9 BP 503 EP 509 DI 10.1038/ncpneph0880 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 339JK UT WOS:000258573700013 PM 18628742 ER PT J AU Kahle, KT Staley, KJ Nahed, BV Gamba, G Hebert, SC Lifton, RP Mount, DB AF Kahle, Kristopher T. Staley, Kevin J. Nahed, Brian V. Gamba, Gerardo Hebert, Steven C. Lifton, Richard P. Mount, David B. TI Roles of the cation-chloride cotransporters in neurological disease SO NATURE CLINICAL PRACTICE NEUROLOGY LA English DT Review DE cation-chloride cotransporters; cell volume homeostasis; gamma-aminobutyric acid; KCC2; NKCC1 ID K-CL COTRANSPORTER; TEMPORAL-LOBE EPILEPSY; CEREBRAL-ARTERY OCCLUSION; ROOT GANGLION NEURONS; LAMINA-I NEURONS; NEONATAL SEIZURES; DOWN-REGULATION; CELL-VOLUME; INTRACELLULAR CHLORIDE; NA-K-2CL COTRANSPORTER AB In the nervous system, the intracellular chloride concentration ([Cl(-)](i)) determines the strength and polarity of gamma-aminobutyric acid (GABA)-mediated neurotransmission. [Cl(-)](i) is determined, in part, by the activities of the SLC12 cation-chloride cotransporters (CCCs). These transporters include the Na-K-2Cl cotransporter NKCC1, which mediates chloride influx, and various K-Cl cotransporters-such as KCC2 and KCCB-that extrude chloride. A precise balance between NKCC1 and KCC2 activity is necessary for inhibitory GABAergic signaling in the adult CNS, and for excitatory GABAergic signaling in the developing CNS and the adult PNS. Altered chloride homeostasis, resulting from mutation or dysfunction of NKCC1 and/or KCC2, causes neuronal hypoexcitability or hyperexcitability; such derangements have been implicated in the pathogenesis of seizures and neuropathic pain. [Cl(-)](i) is also regulated to maintain normal cell volume. Dysfunction of NKCC1 or of swelling-activated K-Cl cotransporters has been implicated in the damaging secondary effects of cerebral edema after ischemic and traumatic brain injury, as well as in swelling-related neurodegeneration. CCCs represent attractive therapeutic targets in neurological disorders the pathogenesis of which involves deranged cellular chloride homoestasis. C1 [Kahle, Kristopher T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Gamba, Gerardo] Univ Nacl Autonoma Mexico, Biomed Res Inst, Inst Nacl Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Hebert, Steven C.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT USA. [Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, New Haven, CT USA. RP Kahle, KT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. EM kkahle@partners.org NR 121 TC 173 Z9 180 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1745-834X J9 NAT CLIN PRACT NEURO JI Nat. Clin. Pract. Neurol. PD SEP PY 2008 VL 4 IS 9 BP 490 EP 503 DI 10.1038/ncpneuro0883 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA 343LF UT WOS:000258854500009 PM 18769373 ER PT J AU Schurko, B Oh, WK AF Schurko, Brian Oh, William K. TI Docetaxel chemotherapy remains the standard of care in castration-resistant prostate cancer SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Editorial Material DE castration; chemotherapy; docetaxel; prostate cancer; survival ID MITOXANTRONE PLUS PREDNISONE AB This Practice Point commentary discusses the findings of a randomized, multicenter, report published by Berthold et al, in which the results of the pivotal TAX 327 study are updated. The original TAX 327 study, published in 2004, randomly allocated men with castration-resistant prostate cancer to one of three chemotherapy regimens: docetaxel 75 mg/m(2) administered every 3 weeks, docetaxel 30 mg/m(2) administered weekly for 5 of every 6 weeks, or mitoxantrone 12 mg/m(2) every 3 weeks. All patients received prednisone 5 mg twice daily. The original trial showed a significant survival benefit for those patients receiving docetaxel every 3 weeks compared with those receiving mitoxantrone. The updated analysis demonstrates that docetaxel remains the standard first-line chemotherapy for patients with castration-resistant prostate cancer. This commentary highlights the key results that were updated from the original TAX 327 study and also discusses several unresolved issues, including the optimum timing of chemotherapy initiation and its duration. C1 [Schurko, Brian; Oh, William K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Oh, WK (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 44 Binney St, Boston, MA 02115 USA. EM william_oh@dfci.harvard.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 7 TC 16 Z9 18 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD SEP PY 2008 VL 5 IS 9 BP 506 EP 507 DI 10.1038/ncponc1201 PG 2 WC Oncology SC Oncology GA 340CG UT WOS:000258623100004 PM 18648352 ER PT J AU Hodi, FS Oble, DA Drappatz, J Velazquez, EF Ramaiya, N Ramakrishna, N Day, AL Kruse, A Mac Rae, S Hoos, A Mihm, M AF Hodi, F. Stephen Oble, Darryl A. Drappatz, Jan Velazquez, Elsa F. Ramaiya, Nikhil Ramakrishna, Naren Day, Arthur L. Kruse, Andrea Mac Rae, Suzanne Hoos, Axel Mihm, Martin TI CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Article DE advanced melanoma; central nervous system; CTLA-4 blockade; immune regulation; immunotherapy ID BRAIN METASTASES; IN-VIVO; ANTIGEN-4; REGRESSION; THERAPY; GLIOMAS; TRIAL AB Background A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. MRI of the spine and brain revealed multiple metastases. The patient received ipilimumab and after 3 months experienced intermittent confusion and focal seizures. Investigations Electroencephalogram and MRI scans of the spine and brain, followed by surgical removal of a left frontal cortical brain metastasis and subsequent histological and pathological analyses. Diagnosis Metastatic melanoma from an unknown primary tumor. Management The patient was treated with ipilimumab on a compassionate-use program and dexamethasone, celecoxib, and levetiracetam to treat the symptoms and seizures. Postoperative stereotactic radiosurgery was initiated. C1 [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Melanoma Program, Boston, MA 02115 USA. [Velazquez, Elsa F.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. [Ramakrishna, Naren] Brigham & Womens Hosp, Div CNS Radiat Oncol, Boston, MA 02115 USA. [Day, Arthur L.] Brigham & Womens Childrens Hosp, Dept Neurosurg, Boston, MA USA. [Mihm, Martin] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Melanoma Program, 44 Binney St, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu NR 17 TC 73 Z9 73 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD SEP PY 2008 VL 5 IS 9 BP 557 EP 561 DI 10.1038/ncponc1183 PG 5 WC Oncology SC Oncology GA 340CG UT WOS:000258623100010 PM 18665147 ER PT J AU Ferreira, MAR O'Donovan, MC Meng, YA Jones, IR Ruderfer, DM Jones, L Fan, J Kirov, G Perlis, RH Green, EK Smoller, JW Grozeva, D Stone, J Nikolov, I Chambert, K Hamshere, ML Nimgaonkar, VL Moskvina, V Thase, ME Caesar, S Sachs, GS Franklin, J Gordon-Smith, K Ardlie, KG Gabriel, SB Fraser, C Blumenstiel, B Defelice, M Breen, G Gill, M Morris, DW Elkin, A Muir, WJ McGhee, KA Williamson, R MacIntyre, DJ MacLean, AW Clair, DS Robinson, M Van Beck, M Pereira, ACP Kandaswamy, R McQuillin, A Collier, DA Bass, NJ Young, AH Lawrence, J Ferrier, IN Anjorin, A Farmer, A Curtis, D Scolnick, EM McGuffin, P Daly, MJ Corvin, AP Holmans, PA Blackwood, DH Gurling, HM Owen, MJ Purcell, SM Sklar, P Craddock, N AF Ferreira, Manuel A. R. O'Donovan, Michael C. Meng, Yan A. Jones, Ian R. Ruderfer, Douglas M. Jones, Lisa Fan, Jinbo Kirov, George Perlis, Roy H. Green, Elaine K. Smoller, Jordan W. Grozeva, Detelina Stone, Jennifer Nikolov, Ivan Chambert, Kimberly Hamshere, Marian L. Nimgaonkar, Vishwajit L. Moskvina, Valentina Thase, Michael E. Caesar, Sian Sachs, Gary S. Franklin, Jennifer Gordon-Smith, Katherine Ardlie, Kristin G. Gabriel, Stacey B. Fraser, Christine Blumenstiel, Brendan Defelice, Matthew Breen, Gerome Gill, Michael Morris, Derek W. Elkin, Amanda Muir, Walter J. McGhee, Kevin A. Williamson, Richard MacIntyre, Donald J. MacLean, Alan W. Clair, David St Robinson, Michelle Van Beck, Margaret Pereira, Ana C. P. Kandaswamy, Radhika McQuillin, Andrew Collier, David A. Bass, Nicholas J. Young, Allan H. Lawrence, Jacob Ferrier, I. Nicol Anjorin, Adebayo Farmer, Anne Curtis, David Scolnick, Edward M. McGuffin, Peter Daly, Mark J. Corvin, Aiden P. Holmans, Peter A. Blackwood, Douglas H. Gurling, Hugh M. Owen, Michael J. Purcell, Shaun M. Sklar, Pamela Craddock, Nick CA Wellcome Trust Case Control Consor TI Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder SO NATURE GENETICS LA English DT Article ID LOCI; DISEASES; RANVIER; GENES AB To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder. C1 [Ferreira, Manuel A. R.; Meng, Yan A.; Ruderfer, Douglas M.; Fan, Jinbo; Perlis, Roy H.; Stone, Jennifer; Sachs, Gary S.; Purcell, Shaun M.; Sklar, Pamela] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Meng, Yan A.; Smoller, Jordan W.; Stone, Jennifer; Sachs, Gary S.; Purcell, Shaun M.; Sklar, Pamela] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Ferreira, Manuel A. R.; Meng, Yan A.; Ruderfer, Douglas M.; Fan, Jinbo; Perlis, Roy H.; Stone, Jennifer; Purcell, Shaun M.; Sklar, Pamela] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Ferreira, Manuel A. R.; Meng, Yan A.; Ruderfer, Douglas M.; Fan, Jinbo; Perlis, Roy H.; Smoller, Jordan W.; Stone, Jennifer; Chambert, Kimberly; Ardlie, Kristin G.; Gabriel, Stacey B.; Blumenstiel, Brendan; Defelice, Matthew; Scolnick, Edward M.; Daly, Mark J.; Purcell, Shaun M.; Sklar, Pamela] Harvard Univ, Stanley Ctr Psychiat Res, Broad Inst, Cambridge, MA 02142 USA. [Ferreira, Manuel A. R.; Meng, Yan A.; Ruderfer, Douglas M.; Fan, Jinbo; Perlis, Roy H.; Smoller, Jordan W.; Stone, Jennifer; Chambert, Kimberly; Ardlie, Kristin G.; Gabriel, Stacey B.; Blumenstiel, Brendan; Defelice, Matthew; Scolnick, Edward M.; Daly, Mark J.; Purcell, Shaun M.; Sklar, Pamela] MIT, Cambridge, MA 02142 USA. [Ferreira, Manuel A. R.] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [O'Donovan, Michael C.; Jones, Ian R.; Kirov, George; Green, Elaine K.; Grozeva, Detelina; Nikolov, Ivan; Hamshere, Marian L.; Moskvina, Valentina; Fraser, Christine; Holmans, Peter A.; Owen, Michael J.; Craddock, Nick] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff CF14 4XN, England. [Jones, Lisa; Caesar, Sian; Gordon-Smith, Katherine] Univ Birmingham, Div Neurosci, Dept Psychiat, Birmingham B15 2QZ, England. [Nikolov, Ivan; Hamshere, Marian L.; Moskvina, Valentina; Holmans, Peter A.] Cardiff Univ, Sch Med, Biostat & Bioinformat Unit, Cardiff CF14 4XN, England. [Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Thase, Michael E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Breen, Gerome; Clair, David St] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Breen, Gerome; Elkin, Amanda; Williamson, Richard; Collier, David A.; McGuffin, Peter] Kings Coll London, Inst Psychiat, SGDP, London SE5 8AF, England. [Gill, Michael; Morris, Derek W.; Corvin, Aiden P.] St James Hosp, Trinity Coll, Trinity Ctr hlth Sci, Dublin 8, Ireland. [Muir, Walter J.; McGhee, Kevin A.; MacIntyre, Donald J.; MacLean, Alan W.; Van Beck, Margaret; Blackwood, Douglas H.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. [Robinson, Michelle; Pereira, Ana C. P.; Kandaswamy, Radhika; McQuillin, Andrew; Bass, Nicholas J.; Lawrence, Jacob; Anjorin, Adebayo; Curtis, David; Gurling, Hugh M.] UCL, Windeyer Inst Med Sci, Dept Mental Hlth Sci, Mol Psychiat Lab, London W1T 4JF, England. [Young, Allan H.; Ferrier, I. Nicol] Royal Victoria Infirm, Sch Neurol Neurolbiol & Psychiat, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Young, Allan H.] UBC, Inst Mental Hlth, Vancouver, BC V6T 2A1, Canada. [Scolnick, Edward M.; Sklar, Pamela] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Sklar, P (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM sklar@chgr.mgh.harvard.edu; craddockn@Cardiff.ac.uk RI Breen, Gerome/A-5540-2010; Holmans, Peter/F-4518-2015; Ruderfer, Douglas/M-5795-2016; McQuillin, Andrew/C-1623-2008; Jones, Ian/B-4925-2009; turton, miranda/F-4682-2011; Ferreira, Manuel/D-3609-2013; Gurling, Hugh/A-5029-2010; McGuffin, Peter/A-1565-2012; OI Breen, Gerome/0000-0003-2053-1792; Holmans, Peter/0000-0003-0870-9412; Ruderfer, Douglas/0000-0002-2365-386X; McQuillin, Andrew/0000-0003-1567-2240; MacIntyre, Donald J/0000-0001-6963-1335; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; McGuffin, Peter/0000-0002-9888-2907; Morris, Derek/0000-0002-3413-570X; Gill, Michael/0000-0003-0206-5337; Escott-Price, Valentina/0000-0003-1784-5483 FU US National Institute of Mental Health [MH062137, MH067288, MH063445, MH63420, N01MH80001]; Johnson & Johnson Pharmaceutical Research & Development, Sylvan C. Herman Foundation, Stanley Medical Research Institute, Dauten Family, Merck Genome Research Institute; National Health Medical Research Council; National Center for Research Resources [U54 RR020278]; MDF - The Bipolar Organization; Neuroscience Research Charitable Trust; central London NHS Blood Transfusion Service; Priory Hospitals; UK MRC [G9623693N, G0500791]; Health Research Board and Science Foundation Ireland; Trinity College Biobank; Wellcome Trust, London; Chief Scientist Office of the Scottish Executive; MRC, London FX Study supported by US National Institute of Mental Health (MH062137, MH067288, P. S.; MH063445, J. W. S.; MH63420, V. L. N.; N01MH80001, G. S. S., M. E. T. and M. S. Bauer), NARSAD (R. H. P., S. P., J. F., P. S.); Johnson & Johnson Pharmaceutical Research & Development, Sylvan C. Herman Foundation, Stanley Medical Research Institute, Dauten Family, Merck Genome Research Institute (E. M. S.); and National Health Medical Research Council (MRC), Australia (M. A. R. F.). Broad Institute Center for Genotyping and Analysis supported by U54 RR020278, National Center for Research Resources. UCL sample collection supported by MDF - The Bipolar Organization, Neuroscience Research Charitable Trust, central London NHS Blood Transfusion Service, Priory Hospitals and UK MRC (G9623693N, G0500791). Dublin sample collection supported by the Health Research Board and Science Foundation Ireland; controls supplied by J. McPartlin, Trinity College Biobank. Edinburgh cohort collection supported by the Wellcome Trust, London, Chief Scientist Office of the Scottish Executive and MRC, London. WTCCC genotype analyses were funded by the Wellcome Trust and undertaken within the context of the WTCCC. WTCCC members are listed in Supplementary Note. NR 15 TC 632 Z9 640 U1 5 U2 57 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 SEP PY 2008 VL 40 IS 9 BP 1056 EP 1058 DI 10.1038/ng.209 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 342CC UT WOS:000258761200015 PM 18711365 ER PT J AU Graham, RR Cotsapas, C Davies, L Hackett, R Lessard, CJ Leon, JM Burtt, NP Guiducci, C Parkin, M Gates, C Plenge, RM Behrens, TW Wither, JE Rioux, JD Fortin, PR Graham, DC Wong, AK Vyse, TJ Daly, MJ Altshuler, D Moser, KL Gaffney, PM AF Graham, Robert R. Cotsapas, Chris Davies, Leela Hackett, Rachel Lessard, Christopher J. Leon, Joanlise M. Burtt, Noel P. Guiducci, Candace Parkin, Melissa Gates, Casey Plenge, Robert M. Behrens, Timothy W. Wither, Joan E. Rioux, John D. Fortin, Paul R. Graham, Deborah Cunninghame Wong, Andrew K. Vyse, Timothy J. Daly, Mark J. Altshuler, David Moser, Kathy L. Gaffney, Patrick M. TI Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus SO NATURE GENETICS LA English DT Article ID RHEUMATOID-ARTHRITIS; UNITED-STATES; A20; ITGAM; RISK AB Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors. We carried out a genome-wide association scan and replication study and found an association between SLE and a variant in TNFAIP3 (rs5029939, meta-analysis P = 2.89 x 10-(12), OR = 2.29). We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis ( RA). These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA. C1 [Lessard, Christopher J.; Moser, Kathy L.; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthritis & Immunol Res Program, Oklahoma City, OK 73104 USA. [Graham, Robert R.; Cotsapas, Chris; Davies, Leela; Hackett, Rachel; Burtt, Noel P.; Guiducci, Candace; Parkin, Melissa; Gates, Casey; Plenge, Robert M.; Daly, Mark J.; Altshuler, David] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Cotsapas, Chris; Daly, Mark J.] Harvard Univ, Sch Med, Mass Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotsapas, Chris; Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Lessard, Christopher J.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Leon, Joanlise M.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Behrens, Timothy W.] Genentech Inc, San Francisco, CA 94080 USA. [Wither, Joan E.] Arthritis Ctr Excellence, Toronto, ON, Canada. [Wither, Joan E.] Univ Hlth Network, Toronto Western Hosp, Res Inst, Div Genet & Dev, Toronto, ON, Canada. [Wither, Joan E.; Fortin, Paul R.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Wither, Joan E.] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Rioux, John D.] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Fortin, Paul R.] Univ Hlth Network, Univ Toronto Lupus Clin, Ctr Prognosis Studies Rheumat Dis, Toronto Western Hosp, Toronto, ON, Canada. [Graham, Deborah Cunninghame; Wong, Andrew K.; Vyse, Timothy J.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Fac Med, Mol Genet & Rheumatol Sect, London, England. RP Gaffney, PM (reprint author), Oklahoma Med Res Fdn, Arthritis & Immunol Res Program, Oklahoma City, OK 73104 USA. EM gaffneyp@lupus.omrf.org RI Altshuler, David/A-4476-2009; Rioux, John/A-9599-2015; Wong, Andrew/M-8899-2016 OI Cotsapas, Chris/0000-0002-7772-5910; Altshuler, David/0000-0002-7250-4107; Rioux, John/0000-0001-7560-8326; Wong, Andrew/0000-0003-2079-4779 FU US National Institutes of Health [AI063274, AR052125, AR043247]; NIH NSRA award [5F32AR50927-RRG]; Lupus Foundation of Minnesota; Arthritis Foundation; Wellcome Trust [076113]; ENH/Northwestern University [MH059571]; Emory University School of Medicine [MH59587]; Louisiana State University Health Sciences Center, New Orleans, Louisiana [MH067257]; University of California-Irvine [MH60870]; Washington University, St. Louis [U01, MH060879]; University of Iowa, Iowa [MH59566]; University of Colorado [MH059565]; University of Pennsylvania [MH061675]; University of Queensland [MH059588]; Mt. Sinai School of Medicine [MH59586]; Massachusetts General Hospital [63420]; Canadian Institute of Health Research [CIHR 62840] FX Support for this work was obtained from the US National Institutes of Health (grants AI063274 (P. M. G.), AR052125 (P. M. G.) and AR043247 (K. L. M.)), NIH NSRA award (5F32AR50927-RRG), Lupus Foundation of Minnesota (P. M. G., K. L. M.) and the Arthritis Foundation (K. L. M.).; This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. Permission for use of these data was obtained from the oversight committees of the respective cohorts. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the "Molecular Genetics of Schizophrenia II'' (MGS-2) collaboration. The investigators and co-investigators are as follows: ENH/Northwestern University, MH059571, P. V. Gejman (Collaboration Coordinator; PI), A. R. Sanders; Emory University School of Medicine, MH59587, F. Amin (PI); Louisiana State University Health Sciences Center, New Orleans, Louisiana, MH067257, N. Buccola (PI); University of California-Irvine, MH60870, W. Byerley (PI); Washington University, St. Louis, U01, MH060879, C. R. Cloninger (PI); University of Iowa, Iowa, MH59566, R. Crowe (PI), D. Black; University of Colorado, MH059565, R. Freedman (PI); University of Pennsylvania, MH061675, D. Levinson (PI); University of Queensland, MH059588, B. Mowry (PI); Mt. Sinai School of Medicine, MH59586, J. Silverman (PI). The samples were collected by V. L. Nimgaonkar's group at the University of Pittsburgh, as part of a multi-institutional collaborative research project with J. Smoller and P. Sklar (Massachusetts General Hospital) (grant MH 63420). We thank T. Hudson for helpful discussions, T. McKenzie for coordinating the GenES study, J.O. Claudio for ensuring ethics approval of DNA sample sharing, J. Su for assistance with management of the GenES database and all the CaNIOS investigators that have contributed to GenES. GenES is funded by the Canadian Institute of Health Research (CIHR# 62840).; We thank S. Gabriel and the entire Affymetrix genotyping team at the Broad Institute of Harvard and MIT. We thank F. Kuruvilla, J. Korn and S. McCarroll for assistance with the Birdseed genotype-calling algorithm.; We would also like to acknowledge the research assistants and coordinators that recruited the individuals in the study. Most importantly, we thank the individuals who have participated in and contributed to these studies. NR 12 TC 337 Z9 342 U1 0 U2 15 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 SEP PY 2008 VL 40 IS 9 BP 1059 EP 1061 DI 10.1038/ng.200 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 342CC UT WOS:000258761200016 PM 19165918 ER PT J AU McCarroll, SA Huett, A Kuballa, P Chilewski, SD Landry, A Goyette, P Zody, MC Hall, JL Brant, SR Cho, JH Duerr, RH Silverberg, MS Taylor, KD Rioux, JD Altshuler, D Daly, MJ Xavier, RJ AF McCarroll, Steven A. Huett, Alan Kuballa, Petric Chilewski, Shannon D. Landry, Aimee Goyette, Philippe Zody, Michael C. Hall, Jennifer L. Brant, Steven R. Cho, Judy H. Duerr, Richard H. Silverberg, Mark S. Taylor, Kent D. Rioux, John D. Altshuler, David Daly, Mark J. Xavier, Ramnik J. TI Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COPY-NUMBER VARIATION; AUTOPHAGY; GENE; SUSCEPTIBILITY; ENHANCER; RETROPOSON; SELECTION; LOCI; SNPS AB Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM(1,2), but coding-sequence variation has been excluded as a source of this association(2). We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r(2) = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant. C1 [McCarroll, Steven A.; Altshuler, David; Daly, Mark J.] Harvard Univ, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [McCarroll, Steven A.; Altshuler, David] Harvard Univ, Sch Med, Dept Mol Biol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [McCarroll, Steven A.; Chilewski, Shannon D.; Zody, Michael C.; Rioux, John D.; Altshuler, David; Daly, Mark J.] MIT, Broad Inst, Cambridge, MA 02142 USA. [McCarroll, Steven A.; Chilewski, Shannon D.; Zody, Michael C.; Rioux, John D.; Altshuler, David; Daly, Mark J.] Harvard Univ, Cambridge, MA 02142 USA. [Huett, Alan; Kuballa, Petric; Landry, Aimee; Xavier, Ramnik J.] Harvard Univ, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Huett, Alan; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Goyette, Philippe] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Goyette, Philippe] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Zody, Michael C.] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75124 Uppsala, Sweden. [Hall, Jennifer L.] Univ Minnesota, Sch Med, Div Cardiol, Dept Med, Minneapolis, MN 55455 USA. [Brant, Steven R.] Johns Hopkins Univ, Dept Med, Harvey M & Lyn P Meyerhoff Inflammatory Bowel Dis, Baltimore, MD 21231 USA. [Cho, Judy H.] Yale Univ, Div Gastroenterol, Dept Med, Ctr Inflammatory Bowel Dis, New Haven, CT 06519 USA. [Duerr, Richard H.] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Dept Med,Med Ctr, Pittsburgh, PA 15213 USA. [Duerr, Richard H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Silverberg, Mark S.] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada. [Taylor, Kent D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Taylor, Kent D.] Cedars Sinai Med Ctr, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90048 USA. RP Daly, MJ (reprint author), Harvard Univ, Sch Med, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM mjdaly@chgr.mgh.harvard.edu; xavier@molbio.mgh.harvard.edu RI McCarroll, Steven/A-8433-2009; Altshuler, David/A-4476-2009; Silverberg, Mark/B-4183-2008; Rioux, John/A-9599-2015; OI Altshuler, David/0000-0002-7250-4107; Rioux, John/0000-0001-7560-8326; Duerr, Richard/0000-0001-6586-3905 FU US National Institute of Allergy and Infection Diseases [AI062773, HL088297, DK43351]; CCIB developmental funds; Lilly Life Sciences Research Fellowship; Burroughs Wellcome Foundation; Crohn's and Colitis Foundation of America; NIDDK [DK064869]; [DK62431]; [DK62422]; [DK62420]; [DK62432]; [DK62423]; [DK62413]; [DK62429] FX The current work was funded by a US National Institute of Allergy and Infection Diseases grant, AI062773, HL088297, DK43351, and CCIB developmental funds to R.J.X. and by a Lilly Life Sciences Research Fellowship to S. A. M. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium is funded by the following grants: DK62431 (S. R. B.), DK62422 (J.H.C.), DK62420 (R.H.D.), DK62432 and DK064869 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.), and DK62429 (J.H.C.). Additional support was provided by the Burroughs Wellcome Foundation (J.H.C.), the Crohn's and Colitis Foundation of America (S.R.B., J.H.C., J.D.R.), and the NIDDK, DK064869 (J.D.R.). M. Garber and C. Bekpen provided helpful discussion; C. Patil and J. Korn provided thoughtful comments on the manuscript. LC3-GFP lentiviral vector was a gift from C. Munz (The Rockefeller University). NR 28 TC 372 Z9 382 U1 3 U2 14 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 SEP PY 2008 VL 40 IS 9 BP 1107 EP 1112 DI 10.1038/ng.215 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 342CC UT WOS:000258761200025 PM 19165925 ER PT J AU Bromley, SK Mempel, TR Luster, AD AF Bromley, Shannon K. Mempel, Thorsten R. Luster, Andrew D. TI Orchestrating the orchestrators: chemokines in control of T cell traffic SO NATURE IMMUNOLOGY LA English DT Review ID HIGH ENDOTHELIAL VENULES; LYMPH-NODE CORTEX; CD1D-RESTRICTED NKT CELLS; LYMPHOCYTES IN-VIVO; HUMAN TH17 CELLS; DENDRITIC CELLS; CUTTING EDGE; LEUKOCYTE MIGRATION; RECEPTOR EXPRESSION; REGULATORY-CELLS AB The understanding of how chemokines orchestrate the trafficking and activity of immune cells has increased considerably. So far, over 50 chemokines and 20 chemokine receptors have been identified. Detailed analyses have demonstrated the function of chemokine receptors on T cell subsets, the temporal and spatial expression patterns of chemokines in vivo and the phenotypes of animals genetically deficient in one component or several components of the chemokine-chemokine receptor system. New microscopy modalities for studying the influence of chemokines on the migratory activity of T cells in the lymph node have also brought new insights. Here we review such advances with particular emphasis on control of the migration of T cell subsets in lymph nodes and in peripheral tissues in homeostasis and inflammation. C1 [Bromley, Shannon K.; Mempel, Thorsten R.; Luster, Andrew D.] Harvard Univ, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Sch Med, Charlestown, MA 02129 USA. RP Luster, AD (reprint author), Harvard Univ, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Sch Med, Charlestown, MA 02129 USA. EM aluster@mgh.harvard.edu NR 111 TC 312 Z9 317 U1 3 U2 30 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 SEP PY 2008 VL 9 IS 9 BP 970 EP 980 DI 10.1038/ni.f.213 PG 11 WC Immunology SC Immunology GA 339DZ UT WOS:000258559600005 PM 18711434 ER PT J AU Kim, C Sano, Y Todorova, K Carlson, BA Arpa, L Celada, A Lawrence, T Otsu, K Brissette, JL Arthur, JSC Park, JM AF Kim, Chun Sano, Yasuyo Todorova, Kristina Carlson, Bradley A. Arpa, Luis Celada, Antonio Lawrence, Toby Otsu, Kinya Brissette, Janice L. Arthur, J. Simon C. Park, Jin Mo TI The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression SO NATURE IMMUNOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; INNATE IMMUNE-RESPONSES; P38 MAP KINASE; NF-KAPPA-B; SUBSTRATE-SPECIFICITY; MACROPHAGE APOPTOSIS; INHIBITION; STRESS; INTERLEUKIN-10; PHOSPHATASE-1 AB The mitogen-activated protein kinase p38 mediates cellular responses to injurious stress and immune signaling. Among the many p38 isoforms, p38 alpha is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38 alpha activation is linked to cell type-specific outputs in mouse models of cutaneous inflammation. We found that both myeloid and epithelial p38 alpha elicit inflammatory responses, yet p38 alpha signaling in each cell type served distinct inflammatory functions and varied depending on the mode of skin irritation. In addition, myeloid p38 alpha limited acute inflammation via activation of anti-inflammatory gene expression dependent on mitogen -and stress-activated kinases. Our results suggest a dual function for p38 alpha in the regulation of inflammation and show mixed potential for its inhibition as a therapeutic strategy. C1 [Kim, Chun; Sano, Yasuyo; Todorova, Kristina; Brissette, Janice L.; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Kim, Chun; Sano, Yasuyo; Todorova, Kristina; Brissette, Janice L.; Park, Jin Mo] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Carlson, Bradley A.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,Natl Inst Hlth, Bethesda, MD 20892 USA. [Arpa, Luis; Celada, Antonio] Univ Barcelona, E-08028 Barcelona, Spain. [Arpa, Luis; Celada, Antonio] Inst Biomed Res, Macrophage Biol Grp, Barcelona 08028, Spain. [Lawrence, Toby] Barts & London Queen Marys Sch Med & Dent, Ctr Translat Oncol, Inst Canc, London EC1M 6BQ, England. [Lawrence, Toby] Barts & London Queen Marys Sch Med & Dent, Ctr Translat Oncol, CR UK Clin Ctr, London EC1M 6BQ, England. [Otsu, Kinya] Osaka Univ, Grad Sch Med, Dept Cardiovasc Med, Suita, Osaka 5650871, Japan. [Arthur, J. Simon C.] Univ Dundee, MRC, Prot Phosphorylat Unit, Sir James Black Ctr, Dundee DD1 5EH, Scotland. RP Park, JM (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM jmpark@cbrc2.mgh.harvard.edu RI Arthur, J. Simon/B-8058-2010; Lawrence, Toby/F-4461-2015 OI Arthur, J. Simon/0000-0002-8135-1958; FU Cutaneous Biology Research Center; US National Institutes of Health [DK043351]; Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital FX We thank S. Krane (Massachusetts General Hospital) for the MMP-13-specific antibody and advice on its use; D. Ginsburg (University of Michigan School of Medicine) for the PAI-2-specific antibody; R. Bravo (Bristol-Myers Squibb Pharmaceutical Research Institute) and C. Caelles (Institute for Research in Biomedicine, Barcelona) for Dusp1-KO mice; and M. Karin for discussion about Jnk-activation mechanisms in p38 alpha-deficient cells. Supported by the Cutaneous Biology Research Center through the Massachusetts General Hospital-Shiseido Agreement (J. M. P.), the US National Institutes of Health (DK043351 to D. Podolsky) and the Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital (J. M. P.). NR 50 TC 126 Z9 128 U1 2 U2 6 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 SEP PY 2008 VL 9 IS 9 BP 1019 EP 1027 DI 10.1038/ni.1640 PG 9 WC Immunology SC Immunology GA 339DZ UT WOS:000258559600014 PM 18677317 ER PT J AU Ananieva, O Darragh, J Johansen, C Carr, JM McIlrath, J Park, JM Wingate, A Monk, CE Toth, R Santos, SG Iversen, L Arthur, JSC AF Ananieva, Olga Darragh, Joanne Johansen, Claus Carr, Julia M. McIlrath, Joanne Park, Jin Mo Wingate, Andrew Monk, Claire E. Toth, Rachel Santos, Susana G. Iversen, Lars Arthur, J. Simon C. TI The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling SO NATURE IMMUNOLOGY LA English DT Article ID INNATE IMMUNE-RESPONSES; STRESS-INDUCED PHOSPHORYLATION; ACTIVATED PROTEIN-KINASE; POLYMICROBIAL SEPSIS; SEPTIC PERITONITIS; ENDOGENOUS IL-10; CECAL LIGATION; SHOCK; MICE; PHOSPHATASE-1 AB The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation. C1 [Ananieva, Olga; Darragh, Joanne; Carr, Julia M.; McIlrath, Joanne; Wingate, Andrew; Monk, Claire E.; Toth, Rachel; Santos, Susana G.; Arthur, J. Simon C.] Univ Dundee, Sch Life Sci, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland. [Johansen, Claus; Iversen, Lars] Aarhus Univ Hosp, Dept Dermatol, DK-8000 Aarhus C, Denmark. [Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Arthur, JSC (reprint author), Univ Dundee, Sch Life Sci, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland. EM j.s.c.arthur@dundee.ac.uk RI Arthur, J. Simon/B-8058-2010; Santos, Susana/L-9351-2013 OI Arthur, J. Simon/0000-0002-8135-1958; Santos, Susana/0000-0002-8604-2978 FU UK Medical Research Council; Arthritis Research Campaign; Novo Nordic Foundation; Danish Research Agency; Astra-Zeneca; Boehringer-Ingelheim; GlaxoSmithKline; Merck; Pfizer FX We thank A. O'Garra (National Institute of Medical Research, London) for the IL-10-neutralizing antibody. Supported by the UK Medical Research Council, Arthritis Research Campaign, Novo Nordic Foundation, Danish Research Agency, Astra-Zeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, and Pfizer. NR 50 TC 155 Z9 163 U1 0 U2 8 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 SEP PY 2008 VL 9 IS 9 BP 1028 EP 1036 DI 10.1038/ni.1644 PG 9 WC Immunology SC Immunology GA 339DZ UT WOS:000258559600015 PM 18690222 ER PT J AU Faul, C Donnelly, M Merscher-Gomez, S Chang, YH Franz, S Delfgaauw, J Chang, JM Choi, HY Campbell, KN Kim, K Reiser, J Mundel, P AF Faul, Christian Donnelly, Mary Merscher-Gomez, Sandra Chang, Yoon Hee Franz, Stefan Delfgaauw, Jacqueline Chang, Jer-Ming Choi, Hoon Young Campbell, Kirk N. Kim, Kwanghee Reiser, Jochen Mundel, Peter TI The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A SO NATURE MEDICINE LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR SLIT DIAPHRAGM; CATHEPSIN-L; NEPHROTIC-SYNDROME; 14-3-3 PROTEINS; ALPORT-SYNDROME; SYNAPTOPODIN; CALCINEURIN; DISEASE; BINDING AB The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells ( NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment. C1 [Faul, Christian; Donnelly, Mary; Merscher-Gomez, Sandra; Campbell, Kirk N.; Reiser, Jochen; Mundel, Peter] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Faul, Christian; Donnelly, Mary; Merscher-Gomez, Sandra; Chang, Yoon Hee; Franz, Stefan; Delfgaauw, Jacqueline; Choi, Hoon Young; Campbell, Kirk N.; Kim, Kwanghee; Mundel, Peter] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Chang, Jer-Ming] Kaohsiung Med Univ, Hsiao Kang Municipal Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Reiser, Jochen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Nephrol Div, Boston, MA 02129 USA. [Reiser, Jochen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Program Glomerular Dis, Boston, MA 02129 USA. RP Mundel, P (reprint author), Univ Miami, Miller Sch Med, Dept Med, 1600 NW 10th Ave, Miami, FL 33136 USA. EM pmundel@med.miami.edu RI Faul, Christian/D-1549-2011; OI Chang, Yoon Hee/0000-0003-1600-4842 FU Albert Einstein College of Medicine; Deutsche Forschungsgemeinschaft; US National Institutes of Health [DA18886, DK57683, DK062472]; George M.O'Brien Kidney Center [DK064236, DK073495] FX We thank C. Chiu and S. Ratner for excellent technical assistance and T. Reinheckel for the analysis of CatL cleavage sites. We thank the Mount Sinai School of Medicine Mouse Genetics Research Facility for performing pronuclear injections. We also thank J.B. Kopp (US National Institutes of Health) for providing the podocin-rtTA mice, H. Fu (Emory University) for yellow fluorescence protein-tagged difopein and E.N. Olson (The University of Texas Southwestern Medical Center at Dallas) for wild-type and constitutively active calcineurin cDNA constructs. Y.H.C. was supported by a research fellowship from the Albert Einstein College of Medicine, S. F. was supported by Karger Stiftung and J.D. was supported by the Deutsche Forschungsgemeinschaft. This work was supported by US National Institutes of Health grants DA18886, DK57683 and DK062472 and the George M.O'Brien Kidney Center grants DK064236 (to P. M.) and DK073495 (to J.R.). NR 43 TC 417 Z9 457 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2008 VL 14 IS 9 BP 931 EP 938 DI 10.1038/nm.1857 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 345IB UT WOS:000258988600025 PM 18724379 ER PT J AU Hemler, ME AF Hemler, Martin E. TI Targeting of tetraspanin proteins - potential benefits and strategies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID HEPATITIS-C-VIRUS; TRANSMEMBRANE 4 SUPERFAMILY; CANINE-DISTEMPER VIRUS; DIPHTHERIA-TOXIN RECEPTOR; TUMOR-CELL MOTILITY; MICE LACKING CD81; SPERM-EGG FUSION; ENRICHED MICRODOMAINS; EXTRACELLULAR DOMAIN; PLASMA-MEMBRANE AB The tetraspanin transmembrane proteins have emerged as key players in malignancy, the immune system, during fertilization and infectious disease processes. Tetraspanins engage in a wide range of specific molecular interactions, occurring through the formation of tetraspanin-enriched microdomains (TEMs). TEMs therefore serve as a starting point for understanding how tetraspanins affect cell signalling, adhesion, morphology, motility, fusion and virus infection. An abundance of recent evidence suggests that targeting tetraspanins, for example, by monoclonal antibodies, soluble large-loop proteins or RNAi technology, should be therapeutically beneficial. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Martin_Hemler@dfci.harvard.edu FU National Institutes of Health grants [GM38903, CA42368] FX The author gratefully acknowledges support from the National Institutes of Health grants GM38903 and CA42368. NR 190 TC 141 Z9 145 U1 4 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2008 VL 7 IS 9 BP 747 EP 758 DI 10.1038/nrd2659 PG 12 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 344GV UT WOS:000258915800017 PM 18758472 ER PT J AU Mora, JR Iwata, M von Andrian, UH AF Mora, J. Rodrigo Iwata, Makoto von Andrian, Ulrich H. TI Vitamin effects on the immune system: vitamins A and D take centre stage SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; TRANS-RETINOIC ACID; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BLOOD MONONUCLEAR-CELLS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; BONE-MARROW TRANSPLANTATION; INTESTINAL DENDRITIC CELLS; DRAINING LYMPH-NODES; VERSUS-HOST DISEASE; ENDOTHELIUM IN-VIVO AB Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity. C1 [Mora, J. Rodrigo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Iwata, Makoto] Tokushima Bunri Univ, Lab Biodef Res, Fac Pharmaceut Sci, Kagawa 7692193, Japan. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Mora, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. EM j_rodrigo_mora@harvard.hms.edu; uva@harvard.hms.edu RI von Andrian, Ulrich/A-5775-2008 FU Crohn's & Colitis Foundation of America; Cancer Research Institute; Howard M. Goodman; Center for the Study of IBD [DK 43351]; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology; Naito Foundation; Uehara Memorial Foundation; National Institutes of Health [AI061663, AI069259, AI072252, HL56949, AR42689] FX We thank S. Davis for editorial assistance and E. Villablanca for critical reading of this manuscript. J.R.M. is grateful to I. Ramos for constant support. J.R.M. is supported by grants from the Crohn's & Colitis Foundation of America, the Cancer Research Institute, the Howard M. Goodman Fellowship and the Center for the Study of IBD (DK 43351). M. I. is supported by the Grants-in-Aid from Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, the Naito Foundation and the Uehara Memorial Foundation. U. H. V. A. is supported by National Institutes of Health grants AI061663, AI069259, AI072252, HL56949 and AR42689. NR 162 TC 521 Z9 540 U1 12 U2 59 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2008 VL 8 IS 9 BP 685 EP 698 DI 10.1038/nri2378 PG 14 WC Immunology SC Immunology GA 341LS UT WOS:000258716600013 PM 19172691 ER PT J AU van den Heuvel, S Dyson, NJ AF van den Heuvel, Sander Dyson, Nicholas J. TI Conserved functions of the pRB and E2F families SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID CELL-CYCLE CONTROL; NEMATODE CAENORHABDITIS-ELEGANS; SYNTHETIC MULTIVULVA GENES; DROSOPHILA FOLLICLE CELLS; ENHANCED RNA INTERFERENCE; MYB-MUVB/DREAM COMPLEX; ZINC-FINGER PROTEIN; S-PHASE ENTRY; C-ELEGANS; DNA-REPLICATION AB Proteins that are related to the retinoblastoma tumour suppressor pRB and the E2F transcription factor are conserved in many species of plants and animals. The mammalian orthologues of pRB and E2F are best known for their roles in cell proliferation, but it has become clear that they affect many biological processes. Here we describe the functions of pRB-related proteins and E2F proteins that have emerged from genetic and biochemical experiments in Caenorhabditis elegans and Drosophila melanogaster. The similarities that have been observed between worms, flies and mammals provide insight into the core activities of pRB and E2F proteins and show how a common regulatory module can control various biological functions in different organisms. C1 [van den Heuvel, Sander] Univ Utrecht, NL-3584 CH Utrecht, Netherlands. [Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP van den Heuvel, S (reprint author), Univ Utrecht, Padualaan 8, NL-3584 CH Utrecht, Netherlands. EM S.J.L.vandenHeuvel@uu.nl; dyson@helix.mgh.harvard.edu RI van den Heuvel, Sander/B-8892-2011 FU National Institutes of Health FX We thank D. Fay, B. Duronio, M. Frolov and members of our laboratories for their comments and I. The for help with the figures. Because of the length restrictions we were unable to cover several important topics and we apologize to colleagues for studies that could not be described in full detail. The research in our laboratories was funded by grants from the National Institutes of Health. NR 170 TC 247 Z9 250 U1 5 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD SEP PY 2008 VL 9 IS 9 BP 713 EP 724 DI 10.1038/nrm2469 PG 12 WC Cell Biology SC Cell Biology GA 340HO UT WOS:000258636900016 PM 18719710 ER PT J AU Dwyer, K Lu, B Crikis, S Robson, S Rajakumar, S D'Apice, A Cowan, P AF Dwyer, K. Lu, B. Crikis, S. Robson, S. Rajakumar, S. D'Apice, A. Cowan, P. TI THE IMPACT OF PURINERGIC SIGNALLING IN RENAL ISCHAEMIA-REPERFUSION INJURY SO NEPHROLOGY LA English DT Meeting Abstract C1 [Dwyer, K.; Lu, B.; Crikis, S.; Rajakumar, S.; D'Apice, A.; Cowan, P.] St Vincents Hosp, Melbourne, Vic, Australia. [Dwyer, K.; Rajakumar, S.; D'Apice, A.; Cowan, P.] Univ Melbourne, Dept Med, Melbourne, Vic 3010, Australia. [Robson, S.] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1320-5358 J9 NEPHROLOGY JI Nephrology PD SEP PY 2008 VL 13 SU 3 SI SI MA 073 BP A118 EP A118 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V28AB UT WOS:000208652600074 ER PT J AU Molins, A Stufflebeam, SM Brown, EN Hamalainen, MS AF Molins, A. Stufflebeam, S. M. Brown, E. N. Hamalainen, M. S. TI Quantification of the benefit from integrating MEG and EEG data in minimum l(2)-norm estimation SO NEUROIMAGE LA English DT Article DE EEG; MEG; MNE; dSPM; multimodal imaging; resolution ID SINGULAR-VALUE ANALYSIS; SURFACE-BASED ANALYSIS; COMBINING MEG; LOCALIZATION; ELECTROENCEPHALOGRAPHY; MAGNETOENCEPHALOGRAPHY; OPTIMIZATION; TOMOGRAPHY; SIMULATION; ACCURACY AB Source current estimation from electromagnetic (MEG and EEG) signals is an ill-posed problem that often produces blurry or inaccurately positioned estimates. The two modalities have distinct factors limiting the resolution, e.g., MEG cannot detect radially oriented sources, while EEG is sensitive to accuracy of the head model. This makes combined EEG+MEG estimation techniques desirable, but different acquisition noise statistics, complexity of the head models, and lack of pertinent metrics all Complicate the assessment of the resulting improvements. We investigated analytically the effect of including EEG recordings in MEG studies versus the addition of new MEG channels when computing noise-normalized minimum l(2)-norm estimates. Three-compartment boundary-element forward models were constructed using structural MRI scans for four subjects. Singular value analysis of the resulting forward models predicted better performance of the EEG+MEG case in the form of higher matrix rank. MNE inverse operators for EEG, MEG and EEG + MEG were constructed using the sensor noise covariance estimated from data. Metrics derived from the resolution matrices predicted higher spatial resolution in EEG+ MEG as compared to MEG due to decreased spread (lower spatial dispersion, higher resolution index) with no reduction in dipole localization error. The effect was apparent in all source locations, with increased magnitude for deep areas such as the cingulate cortex. We were also able to corroborate the results for the somatosensory cortex using median nerve responses. (c) 2008 Elsevier Inc. All rights reserved. C1 [Molins, A.; Stufflebeam, S. M.; Brown, E. N.; Hamalainen, M. S.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Stufflebeam, S. M.; Brown, E. N.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Stufflebeam, S. M.; Brown, E. N.; Hamalainen, M. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stufflebeam, S. M.; Brown, E. N.; Hamalainen, M. S.] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. RP Molins, A (reprint author), Harvard Univ, MIT, Div Hlth Sci & Technol, MIT Bldg 46,Room 46-6057A 46 Vassar St, Cambridge, MA 02139 USA. EM amolins@mit.edu RI Hamalainen, Matti/C-8507-2013 FU NCRR NIH HHS [P41RR14075]; NIBIB NIH HHS [R01 EB006385, R01 EB006385-02, R01 EB06385]; NIDA NIH HHS [R01 DA015644]; NIH HHS [DP1 OD003646]; NIMH NIH HHS [K08MH067966] NR 28 TC 70 Z9 70 U1 0 U2 6 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 SEP PY 2008 VL 42 IS 3 BP 1069 EP 1077 DI 10.1016/j.neuroimage.2008.05.064 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 343PA UT WOS:000258864800003 PM 18602485 ER PT J AU Hazlett, EA Buchsbaum, MS Zhang, J Newmark, RE Glanton, CF Zelmanova, Y Haznedar, MM Chu, KW Nenadic, I Kemether, EM Tang, CY New, AS Siever, LJ AF Hazlett, Erin A. Buchsbaum, Monte S. Zhang, Jing Newmark, Randall E. Glanton, Cathryn F. Zelmanova, Yuliya Haznedar, M. Mehmet Chu, King-Wai Nenadic, Igor Kemether, Eileen M. Tang, Cheuk Y. New, Antonia S. Siever, Larry J. TI Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating SO NEUROIMAGE LA English DT Article DE dorsolateral prefrontal cortex; caudate nucleus; putamen; thalamus; mediodorsal nucleus; fMRI; schizophrenia; schizotypal personality disorder; startle; prepulse inhibition; attention; sensorimotor gating ID SCHIZOTYPAL PERSONALITY-DISORDER; DEFICIENT ATTENTIONAL MODULATION; STARTLE EYEBLINK MODIFICATION; POSITRON-EMISSION-TOMOGRAPHY; PREPULSE INHIBITION; ACOUSTIC STARTLE; CAUDATE-NUCLEUS; METABOLIC RATES; FUNCTIONAL MRI; BASAL GANGLIA AB Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eyeblink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human Work demonstrates that frontal-striatal-thalamic (FST) circuitry modulates PPI, This study used functional magnetic resonance imaging (fMRI) to investigate FST circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder(SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high-and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions-dorsolateral prefrontal cortex (Brodmann areas 46, 9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus. In contrast, schizophrenia patients failed to show differential BOLD responses in FST circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST Circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients. (c) 2008 Elsevier Inc. All rights reserved. C1 [Hazlett, Erin A.; Buchsbaum, Monte S.; Zhang, Jing; Newmark, Randall E.; Glanton, Cathryn F.; Zelmanova, Yuliya; Haznedar, M. Mehmet; Chu, King-Wai; Kemether, Eileen M.; New, Antonia S.; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Tang, Cheuk Y.] Mt Sinai Sch Med, Dept Radiol, New York, NY 10029 USA. [New, Antonia S.; Siever, Larry J.] Bronx Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY USA. [Nenadic, Igor] Univ Jena, Dept Psychiat & Psychotherapy, D-6900 Jena, Germany. RP Hazlett, EA (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1505, New York, NY 10029 USA. EM erin.hazlett@mssm.edu FU National Alliance for Research on Schizophrenia and Depression (NARSAD) [MH073911] FX This research was supported by an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) and MH073911 to E.A.H. NR 64 TC 44 Z9 47 U1 2 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 SEP PY 2008 VL 42 IS 3 BP 1164 EP 1177 DI 10.1016/j.neuroimage.2008.05.039 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 343PA UT WOS:000258864800011 PM 18588988 ER PT J AU Martella, G Platania, R Vita, D Madeo, G Tscherter, A Tassone, A Bonsi, R Kitada, T Shen, J Pisani, A AF Martella, G. Platania, R. Vita, D. Madeo, G. Tscherter, A. Tassone, A. Bonsi, R. Kitada, T. Shen, J. Pisani, A. TI Selective increase in sensitivity to group II mGluR activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin SO NEUROPHARMACOLOGY LA English DT Meeting Abstract CT 6th International mGluR Meeting CY SEP 14-19, 2008 CL Taormina, ITALY C1 [Martella, G.; Platania, R.; Madeo, G.; Tscherter, A.; Pisani, A.] Univ Roma Tor Vergata, Dept Neurosci, Rome, Italy. [Vita, D.; Tassone, A.; Kitada, T.; Pisani, A.] Fondaz Santa Lucia IRCCS, Rome, Italy. [Kitada, T.; Shen, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2008 VL 55 IS 4 MA 82 BP 609 EP 609 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 353CX UT WOS:000259544800112 ER PT J AU Kahle, KT Staley, KJ AF Kahle, Kristopher T. Staley, Kevin J. TI The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures SO NEUROSURGICAL FOCUS LA English DT Article DE cation-chloride cotransporter; chloride transport; gamma-aminobutyric acid; KCC2; NKCC1; neonatal seizures ID K-CL COTRANSPORTER; CATION-CHLORIDE COTRANSPORTERS; POSTNATAL RAT BRAINS; INTRACELLULAR CHLORIDE; EXCITATORY ACTIONS; CORTICAL-NEURONS; IN-VITRO; DEVELOPMENTAL-CHANGES; MOLECULAR PHYSIOLOGY; ANTIEPILEPTIC DRUGS AB Seizures that occur during the neonatal period do so with a greater frequency than at any other age, have profound consequences for cognitive and motor development, and are difficult to treat with the existing series of antiepileptic drugs. During development, gamma-aminobutyric acid (GABA)ergic neurotransmission undergoes a switch from excitatory to inhibitory due to a reversal of neuronal chloride (Cl(-)) gradients. The intracellular level of chloride ([Cl(-)](i)) in immature neonatal neurons, compared with mature adult neurons, is about 20-40 mM higher due to robust activity of the chloride-importing Na-K-2Cl cotransporter NKCC1, such that the binding of GABA to ligand-gated GABA(A) receptor-associated Cl(-) channels triggers Cl(-) efflux and depolarizing excitation. In adults, NKCC1 expression decreases and the expression of the genetically related chloride-extruding K-Cl cotransporter KCC2 increases, lowering [Cl(-)](i) to a level such that activation of GABA(A) receptors triggers Cl(-) influx and inhibitory hyperpolarization. The excitatory action of GABA in neonates, while playing an important role in neuronal development and synaptogenesis, accounts for the decreased seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants in this age group. Bumetanide, a furosemide-related diuretic already used to treat volume overload in neonates, is a specific inhibitor of NKCC1 at low doses, can switch the GABA equilibrium potential of immature neurons from depolarizing to hyperpolarizing, and has recently been shown to inhibit epileptic activity in vitro and in vivo in animal models of neonatal seizures. The fundamental role of NKCC1 in establishing excitatory GABAergic neurotransmission in the neonate makes it a tempting target of a novel mechanism-based anticonvulsant strategy that could utilize the well-known pharmacology of bumetanide to help treat neonatal seizures. C1 [Kahle, Kristopher T.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, Boston, MA 02114 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Div Pediat Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kahle, KT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM kkahle@partners.org NR 80 TC 40 Z9 41 U1 1 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD SEP PY 2008 VL 25 IS 3 AR E22 DI 10.3171/FOC/2008/25/9/E22 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 343AA UT WOS:000258823500022 PM 18759624 ER PT J AU Sisterson, JM AF Sisterson, J. M. TI Measurement of recoil nuclei losses for proton-induced reactions in Al, Si, Mg and Fe at 200 and 500 MeV SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION B-BEAM INTERACTIONS WITH MATERIALS AND ATOMS LA English DT Article DE Proton beams; Spallation reactions; Recoil losses; Mean recoil forward ranges ID CROSS-SECTION MEASUREMENTS; SHORT-LIVED RADIONUCLIDES; NEUTRON-INDUCED REACTIONS; ENERGIES; BE-10; AL-27; C-14; NI AB The recoil losses of product nuclei in proton-induced reactions at 200 and 500 MeV in Al, Si, Mg and Fe targets were measured using carbon catcher foils or stacks of Mylar foils. In all cases, the recoil losses were less than 1% for the target thicknesses used and so in the ongoing systematic study to measure cross sections for proton- and neutron-induced reactions, these losses are not important. For Fe targets irradiated at 200 MeV, the recoil losses in the forward direction for several product nuclei measured in both a carbon catcher foil and a Mylar stack were in good agreement. From the recoil losses, the mean forward recoil ranges for several product nuclei were calculated. (c) 2008 Published by Elsevier B.V. C1 [Sisterson, J. M.] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Sisterson, J. M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sisterson, JM (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. EM jsisterson@partners.org FU National Aeronautics and Space Administration [NAG5-4302, NAG5-7987, NAG5-10538, COS03-0018-000] FX The results presented here are based on work supported by the National Aeronautics and Space Administration under Grants NAG5-4302, NAG5-7987, NAG5-10538 and COS03-0018-000 issued through the Office of Space Science. We thank the following for their invaluable help in the experiments at TRIUMF: Dr. J. Vincent, Dr. A.Y. Zyuzin; and the cyclotron operators and technical staff at TRIUMF. We thank, R.J. Schneider IV for his help with the gamma ray spectroscopy measurements at HCL. NR 16 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-583X J9 NUCL INSTRUM METH B JI Nucl. Instrum. Methods Phys. Res. Sect. B-Beam Interact. Mater. Atoms PD SEP PY 2008 VL 266 IS 18 BP 3913 EP 3918 DI 10.1016/j.nimb.2008.06.022 PG 6 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Atomic, Molecular & Chemical; Physics, Nuclear SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA 361WE UT WOS:000260157400003 ER PT J AU Goebel, M Stengel, A Tache, Y AF Goebel, Miriam Stengel, Andreas Tache, Yvette TI Continued controversy on obestatin as a gut hormone influencing food intake and gastrointestinal motility SO OBESITY AND METABOLISM-MILAN LA English DT Editorial Material DE Food intake; gastrointestinal motility; ghrelin; GPR39; obestatin ID PROTEIN-COUPLED RECEPTOR; GHRELIN-ASSOCIATED PEPTIDE; DES-ACYL GHRELIN; PERIPHERAL OBESTATIN; SPLICE VARIANTS; WEIGHT-GAIN; BODY-WEIGHT; RODENTS; RATS; SECRETION AB Obestatin is still trying to keep up with its bigger brother ghrelin and looking for reproducible biological actions on food intake regulation and gastrointestinal motility. Obestatin was initially described to arise from post-translational processing of preproghrelin and to oppose ghrelin-stimulated feeding, gastrointestinal motility and body weight gain and to reduce food intake upon acute or chronic peripheral injection via activation oil the, until then, orphan G-protein-coupled receptor 39 (GPR39). However; all these original findings have been challenged by the inability of the vast majority of subsequent studies to reproduce these new findings. Several groups tried to overcome differences in the experimental settings accounting for varying study outcomes. Unfortunately, the the majority of laboratories failed even after exact application of the original study design to establish reproducible influence of obestatin on food intake, body weight or gut motility while a minority of reports found that obestatin induces a small reduction of food intake in rodents under specific conditions. Controversy also arises regarding the processing of preproghrelin to generate obestatin in the stomach and the circulation along with. its regulation 411 nutrient status. Evidence that obestatin is not the endogenous ligand for GPR39 is compelling. Therefore, existing knowledge curtails the enthusiasm for obestatin as a new player able to control appetite and body weight opposing the well established orexigenic effect of ghrelin. Puzzling questions remain to be solved regarding discrepant results and whether new biological actions wait for the peptide or more likely, other ghrelin gene-derived peptides issued from the recent revised ghrelin genomic structure will prove to be of greater biological significance. Obesity and Metabolism 2008; 4: 143-148. C1 Univ Calif Los Angeles, Div Digest Dis, Ctr Neurobiol Stress, CURE Digest Res Ctr,Dept Med, Los Angeles, CA USA. RP Tache, Y (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Neurovisceral Sci & Womens Hlth, CURE Bldg 115,Room 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ytache@mednet.ucla.edu NR 59 TC 3 Z9 4 U1 0 U2 2 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1825-3865 J9 OBES METAB-MILAN JI Obes. Metab.-Milan PD SEP PY 2008 VL 4 IS 3 BP 143 EP 148 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 358GW UT WOS:000259906100001 ER PT J AU Tarnoff, M Kaplan, LM Shikora, S AF Tarnoff, Michael Kaplan, Lee M. Shikora, Scott TI An evidenced-based assessment of preoperative weight loss in bariatric surgery SO OBESITY SURGERY LA English DT Editorial Material ID Y GASTRIC BYPASS; CARDIOVASCULAR RISK-FACTORS; MORBIDLY OBESE-PATIENTS; KNEE ARTHROPLASTY; VENTRAL HERNIAS; REPAIR; DIET; MASS C1 [Tarnoff, Michael; Shikora, Scott] Tufts Med Ctr, Ctr Minimally Invas Obes Surg, Boston, MA 02067 USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Div Gastroenterol & Obes Med, Boston, MA 02114 USA. RP Tarnoff, M (reprint author), Tufts Med Ctr, Ctr Minimally Invas Obes Surg, 800 Washington St,Box 900, Boston, MA 02067 USA. EM mtarnoff@tuftsmedicalcenter.org NR 22 TC 34 Z9 35 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD SEP PY 2008 VL 18 IS 9 BP 1059 EP 1061 DI 10.1007/s11695-008-9603-y PG 3 WC Surgery SC Surgery GA 337SS UT WOS:000258456400001 PM 18587621 ER PT J AU Zhang, S Metelev, V Tabatadze, D Zamecnik, P Bogdanov, A AF Zhang, Surong Metelev, Valeri Tabatadze, David Zamecnik, Paul Bogdanov, Alexei, Jr. TI Near-infrared fluorescent oligodeoxyribonucleotide reporters for sensing NF-kappa B DNA interactions in vitro SO OLIGONUCLEOTIDES LA English DT Article ID MOLECULAR BEACONS; BINDING PROTEINS; INTRAMOLECULAR DIMERS; PROBES; ACTIVATION; OLIGONUCLEOTIDES; HYBRIDIZATION; TUMORS; CELLS AB Two types of reporters for optical sensing of NF-kappa B p50 protein-oligodeoxyribonucleotide (ODN) duplex interactions were designed and compared in vitro. The reporters were based on the effect of fluorescence resonance energy transfer (FRET) between the pair donor Cy5.5 near-infrared (NIR) fluorochrome and either 800CW emitting fluorescence dye acceptor (800CW-Cy), or a nonemitting QSY 21 dye quencher (QSY-Cy). The donor and the acceptor dyes were covalently linked to the complementary oligonucleotides, respectively: Cy dye was conjugated to 3'-thiol, whereas 800CW or QSY21 were conjugated to a hydrophilic internucleoside phosphate amino linker. The reporters were tested initially using recombinant NF-kappa B p50 protein binding assays. Both reporters were binding p50 protein, which protected oligonucleotide duplex from degradation in the presence of exonuclease. The incubation of 800CW-Cy reporter in the presence of control or IL-1 beta treated human endothelial cells showed the uptake of the reporter in the cytoplasm and the nucleus. The measurement of NIR fluorescence ratio (i.e. Cy5.5/ 800CW) showed a partial loss of FRET and the increased Cy5.5 fluorescence in nontreated, control cells. Thus, the specific p50 binding to ODN duplex reporters affected the donor -acceptor fluorochrome pair. NF-kappa B p50 exhibited the protective effect on FRET between NIR fluorochromes linked to the complementary strands of the reporter duplex. C1 [Zhang, Surong; Metelev, Valeri; Bogdanov, Alexei, Jr.] Univ Massachusetts, Sch Med, Dept Radiol, Lab Mol Imaging Probes, Worcester, MA 01610 USA. [Bogdanov, Alexei, Jr.] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. [Tabatadze, David; Zamecnik, Paul] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. RP Bogdanov, A (reprint author), Univ Massachusetts, Sch Med, Dept Radiol, Lab Mol Imaging Probes, S2-804,55 Lake Ave, Worcester, MA 01610 USA. EM Alexei.Bogdanov@umassmed.edu RI Metelev, Valeri/I-3238-2012 FU Mathers Foundation; National Institutes of Health [5 R01 AI060872-02]; National Institutes of Health Exploratory [R21 CA116144] FX This work was supported in part by grants from The G. Harold and Leila V. Mathers Foundation and National Institutes of Health Grant 5 R01 AI060872-02. S. Z., V. M., and A. B. were supported in part by National Institutes of Health Exploratory Grant R21 CA116144 to A. B. The authors thank Mrs. Karen Pierson for technical assistance. NR 31 TC 8 Z9 9 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-4576 J9 OLIGONUCLEOTIDES JI Oligonucleotides PD SEP PY 2008 VL 18 IS 3 BP 235 EP 243 DI 10.1089/oli.2008.0135 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 360JU UT WOS:000260054600004 PM 18699740 ER PT J AU Dotto, GP AF Dotto, G. P. TI Notch tumor suppressor function SO ONCOGENE LA English DT Review DE cancer stem cells; p53; p63; Rho signaling; epigenetics; keratinocytes ID NF-KAPPA-B; CERVICAL-CANCER CELLS; NEGATIVE TRANSCRIPTIONAL REGULATOR; KERATINOCYTE STEM-CELLS; RBP-J-KAPPA; SIGNALING PATHWAYS; BETA-CATENIN; GROWTH ARREST; HAIR FOLLICLE; P53 HOMOLOG AB Cancer development results from deregulated control of stem cell populations and alterations in their surrounding environment. Notch signaling is an important form of direct cell-cell communication involved in cell fate determination, stem cell potential and lineage commitment. The biological function of this pathway is critically context dependent. Here we review the pro-differentiation role and tumor suppressing function of this pathway, as revealed by loss-of-function in keratinocytes and skin, downstream of p53 and in cross-connection with other determinants of stem cell potential and/or tumor formation, such as p63 and Rho/CDC42 effectors. The possibility that Notch signaling elicits a duality of signals, involved in growth/differentiation control and cell survival will be discussed, in the context of novel approaches for cancer therapy. C1 Univ Lausanne, Inst Biochem, CH-1066 Epalinges, Switzerland. [Dotto, G. P.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Dotto, GP (reprint author), Univ Lausanne, Inst Biochem, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland. EM gian-paolo.dotto@unil.ch FU NIH [AR39190, AR054856]; Swiss National Foundation; European Union [LSHB-CT-2005-019067] FX I thank Dr Cathrin Brisken for careful reading of the paper. This study was supported by NIH Grants AR39190, AR054856, the Swiss National Foundation, a grant from the European Union (Epistem, Sixth Framework Program, LSHB-CT-2005-019067). NR 117 TC 145 Z9 156 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2008 VL 27 IS 38 BP 5115 EP 5123 DI 10.1038/onc.2008.225 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 344GM UT WOS:000258914900005 PM 18758480 ER PT J AU Vorobeychik, Y Chen, L Bush, MC Mao, JR AF Vorobeychik, Yakov Chen, Lucy Bush, Mary Chasko Mao, Jianren TI Improved opioid analgesic effect following opioid dose reduction SO PAIN MEDICINE LA English DT Article DE opioid-induced hyperalgesia; cancer pain; methadone; chronic pain; NMDA receptor antagonist ID ROSTRAL VENTROMEDIAL MEDULLA; ABNORMAL PAIN SENSITIVITY; INDUCED HYPERALGESIA; ANTINOCICEPTIVE TOLERANCE; MORPHINE-TOLERANCE; EXPOSURE; MANAGEMENT; TOXICITY; KETAMINE; THERAPY AB Introduction. Traditionally, opioids have been the cornerstone of therapy for patients suffering from cancer pain, regardless of the potential to develop opioid tolerance. In chronic pain patients who experience worsening pain despite increasing doses of opioids, the clinical role of opioid-induced hyperalgesia is gaining more recognition. Case. Presented here is the case of a 56-year-old man with recurrent squamous cell lung carcinoma and spinal metastases, suffering with intractable 8/10 pain on the visual analog scale in his chest, lower thoracic spine, and upper lumbar spine. He was admitted five times for pain control. In spite of escalating doses of oxycodone, morphine, and hydromorphone, the patient continued to experience severe pain. Also, he endured undesirable sedation, fatigue, and generalized weakness. The clinical picture suggested the possibility of opioid-induced hyperalgesia. We decreased the hydromorphone dose by 40-50% and started methadone. The patient's pain level dropped to a more acceptable 3/10. He was more alert, and his pain was tolerable until his death. Discussion. Opioid-induced hyperalgesia might be considered in a patient who has no evidence of disease progression, who is on clinically reasonable doses of opioids, and whose pain escalates as opioid doses are increased. A reduction of opioids and the addition of a low-dose N-methyl-D-aspartate receptor antagonist may provide a favorable clinical outcome in those patients who have failed to benefit from opioid rotation and other adjunctive pain treatments. C1 [Vorobeychik, Yakov; Bush, Mary Chasko] Penn State Coll Med, Dept Anesthesiol, Pain Med Div, Penn State Milton S Hershey Med Ctr, Hershey, PA 17033 USA. [Chen, Lucy; Mao, Jianren] Massachusetts Gen Hosp, MGH Pain Ctr, Boston, MA 02114 USA. RP Vorobeychik, Y (reprint author), Penn State Coll Med, Dept Anesthesiol, Pain Med Div, Penn State Milton S Hershey Med Ctr, HU32,500 Univ Dr,POB 850, Hershey, PA 17033 USA. EM yvorobeychik@psu.edu NR 19 TC 30 Z9 32 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD SEP PY 2008 VL 9 IS 6 BP 724 EP 727 DI 10.1111/j.1526-4637.2008.00501.x PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 339SM UT WOS:000258597600011 PM 18816332 ER PT J AU Goldenbaum, DM Christopher, M Gallagher, RM Fishman, S Payne, R Joranson, D Edmondson, D Mckee, J Thexton, A AF Goldenbaum, Donald M. Christopher, Myra Gallagher, Rollin M. Fishman, Scott Payne, Richard Joranson, David Edmondson, Drew McKee, Judith Thexton, Arthur TI Physicians charged with opioid analgesic-prescribing offenses SO PAIN MEDICINE LA English DT Article DE physicians; opioids; prescribing; prosecution; criminal; charges ID PAIN; PROSECUTION AB Objective. To provide a "big picture" overview of the characteristics and outcomes of recent criminal and administrative cases in which physicians have been criminally prosecuted or charged by medical boards with offenses related to inappropriate prescribing of opioid analgesics. Design. We identified as many criminal and administrative cases of these types as possible that occurred between 1998 and 2006. Cases were identified using a wide variety of sources, including organizational and government agency databases, published news accounts, and Web sites. Factual characteristics of these cases and their outcomes, and of the physicians involved, were then further researched using additional sources and methods. Setting. Study findings are intended to apply to practicing U.S. patient care physicians as a whole. Patients or Other Participants. There were no patients or participants in this study. Outcome Measures. We analyzed the numbers and types of cases and physicians involved, criminal and administrative charges brought, case outcomes and sanctions, specialties, and other characteristics of the physicians involved. Results. The study identified 725 doctors, representing an estimated 0.1% of practicing patient care physicians, who were charged between 1998 and 2006 with criminal and/or administrative offenses related to prescribing opioid analgesics. A plurality of these (39.3%) were General Practice/Family Medicine physicians, compared with 3.5% who were self-identified or board-certified pain specialists. Physicians in this sample were more likely to be male, older, and not board certified (P < 0.001). Drug Enforcement Administration (DEA) criminal and complaint investigations averaged 658 per year (2003-2006) and "for cause" surrenders of DEA registrations averaged 369.7 (2000-2006). Conclusions. Criminal or administrative charges and sanctions for prescribing opioid analgesics are rare. In addition, there appears to be little objective basis for concern that pain specialists have been "singled out" for prosecution or administrative sanctioning for such offenses. C1 [Goldenbaum, Donald M.; Christopher, Myra] Ctr Pract Bioeth, Res Evaluat & Publicat Program, Kansas City, MO 64105 USA. [Gallagher, Rollin M.] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Fishman, Scott] Univ Calif Davis, Davis, CA 95616 USA. [Joranson, David] Univ Wisconsin, Madison, WI USA. [Payne, Richard] Duke Univ, Sch Divin, Durham, NC USA. [Edmondson, Drew] Attorney Gen, Oklahoma City, OK USA. [McKee, Judith] Natl Assoc Attorneys Gen, Washington, DC USA. [Thexton, Arthur] Wisconsin Dept Regulat & Licensing, Madison, WI USA. RP Goldenbaum, DM (reprint author), Ctr Pract Bioeth, Res Evaluat & Publicat Program, 1111 Main,Suite 500, Kansas City, MO 64105 USA. EM dgoldenbaum@practicalbioethics.org NR 24 TC 20 Z9 20 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD SEP PY 2008 VL 9 IS 6 BP 737 EP 747 DI 10.1111/j.1526-4637.2008.00482.x PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 339SM UT WOS:000258597600013 PM 18657218 ER PT J AU Visser, A Rehman, S Makoul, G AF Visser, Adriaan Rehman, Shakaib Makoul, Gregory TI Special issue: International Conference on Communication in Healthcare - Charleston 2007 SO PATIENT EDUCATION AND COUNSELING LA English DT Editorial Material C1 [Visser, Adriaan; Rehman, Shakaib] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Makoul, Gregory] St Francis Hosp & Med Ctr, Hartford, CT USA. RP Visser, A (reprint author), Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. EM adriaan.visser@planet.nl NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2008 VL 72 IS 3 SI SI BP 357 EP 358 DI 10.1016/j.pec.2008.06.002 PG 2 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 353QE UT WOS:000259582400001 PM 18684583 ER PT J AU Haidet, P Hatem, DS Fecile, ML Stein, HF Haley, HLA Kimmel, B Mossbarger, DL Inui, TS AF Haidet, Paul Hatem, David S. Fecile, Mary Lynn Stein, Howard F. Haley, Heather-Lyn A. Kimmel, Barbara Mossbarger, David L. Inui, Thomas S. TI The role of relationships in the professional formation of physicians: Case report and illustration of an elicitation technique SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT International Conference on Communication in Healthcare (ICCH) CY OCT 09-12, 2007 CL Charleston, SC SP Amer Acad Commun Healthcare DE physician-patient relations; patient-centered care; organizational culture; education; medical; qualitative research ID RELATIONSHIP-CENTERED CARE; HIDDEN CURRICULUM; MEDICINE AB Objective: Studies of physicians' professional development highlight the important effect that the learning environment has in shaping student attitudes, behaviors, and values. The objective of this study was to better understand the interplay among relationships and experiences in mediating the effects of the learning environment. Methods: We randomly recruited 2nd- and 4th-year students from among volunteers at each of five medical schools. One interviewer at each school conducted a face-to-face, open-ended, semi-structured interview with each student. The interviewers used a method called 'life-circle diagramming' to direct the student to draw a picture of all of the relationships in his/her life that had an influence on the sort of doctor that each student saw him/herself becoming. Interviews lasted between 60 and 120 min. Using a narrative framework that focuses on elements of students' stories (e.g., setting, characters, plot), we analyzed transcripts through an iterative process of individual reading and group discussion to derive themes and relationships among themes. Results: Twenty students completed interviews. These students are embedded in complex webs of relationships with colleagues, friends, family, role models, patients, and others. Most students entered medical school with formed notions of what they wanted to 'be like' as physicians. While students generally gravitated toward relationships with like-minded people, their experiences varied, and some students could sense themselves changing as they moved through school. Such changes were often related to important events or issues. The relationships that students found themselves in during the context of these events had an important effect on students' beliefs about what kinds of behaviors and attitudes were possible and desirable in their future practice. Conclusions: Students proceed through medical school embedded in complex webs of relationships that exert a powerful influence (both positive and negative) on their formation as physicians. Practice Implications: Educational interventions that foster adoption of professional values need to acknowledge the influence of relationships, and assist students to harness and shape relational effects on their growth and development. The life-circle diagramming activity holds potential to promote reflection and self-knowledge, and to provide a foundation for professional growth, Published by Elsevier Ireland Ltd. C1 [Haidet, Paul; Kimmel, Barbara] DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. [Haidet, Paul; Kimmel, Barbara] Baylor Coll Med, Houston, TX 77030 USA. [Hatem, David S.; Haley, Heather-Lyn A.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Fecile, Mary Lynn] Univ Texas Med Branch, Galveston, TX USA. [Stein, Howard F.] Univ Oklahoma, Coll Med, Oklahoma City, OK 73190 USA. [Mossbarger, David L.; Inui, Thomas S.] Regenstrief Inst Inc, Indianapolis, IN USA. [Mossbarger, David L.; Inui, Thomas S.] Indiana Univ, Sch Med, Bloomington, IN 47405 USA. RP Haidet, P (reprint author), DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM phaidet@bcm.tmc.edu OI Haley, Heather-Lyn/0000-0002-4064-9547 NR 23 TC 22 Z9 22 U1 1 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 SEP PY 2008 VL 72 IS 3 SI SI BP 382 EP 387 DI 10.1016/j.pec.2008.05.016 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 353QE UT WOS:000259582400005 PM 18619760 ER PT J AU Chang, JC Dado, D Frankel, RM Rodriguez, KL Zickmund, S Ling, BS Arnold, RM AF Chang, Judy C. Dado, Diane Frankel, Richard M. Rodriguez, Keri L. Zickmund, Susan Ling, Bruce S. Arnold, Robert M. TI When pregnant patients disclose substance use: Missed opportunities for behavioral change counseling SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT International Conference on Communication in Healthcare (ICCH) CY OCT 09-12, 2007 CL Charleston, SC SP Amer Acad Commun Healthcare DE prenatal care; obstetrics; substance-use; practitioner-patient interaction; risk communication; qualitative research ID PRENATAL ALCOHOL EXPOSURE; FAMILY-PRACTICE RESIDENTS; SMOKING-CESSATION; OBSTETRICIAN-GYNECOLOGISTS; PHYSICIAN ATTITUDES; MOTIVATIONAL INTERVENTION; MEDICAL-SCHOOLS; LEGAL COERCION; UNITED-STATES; RISK-FACTORS AB Objective: The first obstetric visit is an opportunity to provide counseling to women with substance abuse risks, including smoking, drug use, and alcohol use. Little is known about how obstetric care providers and patients discuss these issues. Our objective was to examine patient-provider communication about substance use behaviors during these visits. Methods: We audio-taped and transcribed verbatim first prenatal visits in an outpatient hospital clinic, then qualitatively analyzed them for content and process of communication using modified grounded theory methods. Results: Twenty-nine providers (21 residents, 5 midwives, 3 nurse practitioners) and 51 patients participated. Twenty-five patients were smokers, 4 used alcohol, and I I used drugs. Provider responses to smoking disclosures included discussions of risks, encouragement to quit-cut down, affirmation of attempts to quit-cut down, and referral to smoking cessation programs. Responses to alcohol or drug disclosures included only a general statement regarding risks and referral to genetics. Conclusion: Providers were less attentive to alcohol and drugs than smoking where they had pre-established patterns of response. Practice implications: Providers should discuss behavioral change strategies and motivations with pregnant patients who use drugs and/or alcohol as well as those who smoke. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Chang, Judy C.; Dado, Diane] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci & Med, UPMC, Pittsburgh, PA 15213 USA. [Frankel, Richard M.] Indiana Univ, Sch Med, Inst Hlth Care, Indianapolis, IN USA. [Rodriguez, Keri L.; Zickmund, Susan; Ling, Bruce S.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Rodriguez, Keri L.; Zickmund, Susan; Ling, Bruce S.; Arnold, Robert M.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Chang, JC (reprint author), Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci & Med, UPMC, 300 Halket St, Pittsburgh, PA 15213 USA. EM jchang@mail.magee.edu FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [L30 RR019716, L30 RR019716-02, L30 RR019716-01]; NICHD NIH HHS [K12 HD043441-03, 5 K12 HD43441-04, K12 HD043441, K12 HD043441-01, K12 HD043441-02] NR 74 TC 16 Z9 16 U1 1 U2 12 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 SEP PY 2008 VL 72 IS 3 SI SI BP 394 EP 401 DI 10.1016/j.pec.2008.06.001 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 353QE UT WOS:000259582400007 PM 18620835 ER PT J AU Verma, S Tavare, CJ Gilles, FH AF Verma, Shalini Tavare, C. Jane Gilles, Floyd H. TI Histologic Features and Prognosis in Pediatric Medulloblastoma SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE anaplastic medulloblastoma; desmoplastic/nodular medulloblastoma; large cell medulloblastoma; medulloblastoma; medulloblastoma with extensive nodularity ID CHILDRENS CANCER GROUP; ONCOLOGY-GROUP; BRAIN-TUMORS; CHILDHOOD; BEHAVIOR; VARIANT; REPRODUCIBILITY; STRATIFICATION; ANAPLASIA; SYSTEM AB Because individual histologic features in childhood medulloblastoma alter survival likelihood, the recent 4th edition of file World Health Organization (WHO) Classification of Brain Tumors recognizes desmoplastic/nodular medulloblastoma. medulloblastoma with extensive nodularity, large cell medulloblastoma, and anaplastic medulloblastoma, in addition to medulloblastoma with no other distinguishing features. To identify features affecting Survival likelihood, we investigated 33 histologic features in 556 childhood tumors diagnosed as medulloblastoma in the Childhood Brain Turner Consortium (CBTC) database; all features have CBTC verified read-reread reliability and those features important in the classification of medulloblastoma and its WHO variants regardless of their measured reliability. Nineteen features had no effect oil Survival likelihood, and 8 features were too prevalent or too rare to measure their effect oil survival. Nodules, balls, high cell density. and fine fibrillary stroma improved Survival likelihood; necrosis and prominent nucleoli worsened survival likelihood. Of note, the presence of desmoplasia, currently a defining feature (along with nodules) for desmoplastic/nodular medulloblastoma, had no effect oil survival likelihood. We conclude that the presence of nodularity in medulloblastoma is important to improved survival likelihood., particularly when combined with balls and fine fibrillary stroma. Given the "overlap" of desmoplastic/nodular medulloblastoma and nodular medulloblastoma, we Suggest they be combined into a diagnosis of nodular medulloblastoma. with nodules, balls, and fine fibrillary stroma as defining criteria. We also suggest that because of the considerable overlap of anaplastic medulloblastoma and large cell medulloblastoma they be combined into 1 diagnosis of anaplastic/large cell medulloblastoma, with necrosis and prominent nucleoli among file defining criteria. C1 [Tavare, C. Jane; Gilles, Floyd H.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Verma, Shalini] Vet Affairs Greater Los Angeles Med Ctr, LAC USC Med Ctr, Dept Pathol, Los Angeles, CA USA. RP Gilles, FH (reprint author), Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. EM fgilles@chla.usc.edu NR 36 TC 10 Z9 10 U1 0 U2 6 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD SEP-OCT PY 2008 VL 11 IS 5 BP 337 EP 343 DI 10.2350/07-09-0353.1 PG 7 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 373KD UT WOS:000260969600001 PM 18201118 ER PT J AU Leavey, PJ Mascarenhas, L Marina, N Chen, ZJ Krailo, M Miser, J Brown, K Tarbell, N Bernstein, ML Granowetter, L Gebhardt, M Grier, HE AF Leavey, Patrick J. Mascarenhas, Leo Marina, Neyssa Chen, Zhengjia Krailo, Mark Miser, James Brown, Ken Tarbell, Nancy Bernstein, Mark L. Granowetter, Linda Gebhardt, Mark Grier, Holcombe E. TI Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE children; Ewing sarcoma; multi-modality therapy; prognostic factors for patients ID PRIMITIVE NEUROECTODERMAL TUMOR; NEOADJUVANT CHEMOTHERAPY; BONE; EXPERIENCE; SURVIVAL AB Background. The prognosis for patients with recurrent Ewing sarcoma(EWS) is very poor with 5-year survival of 13%. Methods. To evaluate prognostic factors for these patients we studied patients initially treated on the multi-institutional study INT0091. Results. Two hundred sixty-two patients experienced disease recurrence. The median time to first recurrence was 1.3 years (0-7.4 years), 1.4 years (0-7.4 years) for patients with initially localized disease and I year (0-6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (P<0.0001). Twenty-one percent of patients, with recurrent or progressive disease >= 2 years from initial diagnosis, had an estimated 5-year survival of 30% (vs. 7% estimated 5-year survival with an earlier recurrence). No statistical difference was detected between patients whose disease recurred <1 year and between 1 and 2 years from initial diagnosis. A stepwise relative risk model and backwards stepwise regression was used to explore factors significantly associated with risk for post-recurrence death. Significant risk factors for death after recurrence included recurrence at combined local and distant sites, elevated LDH at initial diagnosis and initial recurrence less than 2 years after diagnosis. isolated pulmonary recurrence was not predictive of survival after recurrence. Conclusion. Patients with a longer disease control interval represent the subset of patients most likely to survive following recurrence of EWS. All patients with recurrence would benefit from collaborative trials to investigate new therapeutic options. C1 [Leavey, Patrick J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Mascarenhas, Leo; Krailo, Mark] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Mascarenhas, Leo] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Marina, Neyssa] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Marina, Neyssa] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Chen, Zhengjia; Krailo, Mark] Operat Ctr, Childrens Oncol Grp, Arcadia, CA USA. [Miser, James] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Brown, Ken] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Tarbell, Nancy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bernstein, Mark L.] Dalhousie Univ, IWK Hlth Ctr, Halifax, NS, Canada. [Granowetter, Linda] Columbia Presbyterian Coll Phys & Surg, New York, NY USA. [Gebhardt, Mark; Grier, Holcombe E.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Leavey, PJ (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM patrick.leavey@utsouthwestern.edu OI Granowetter MD, Linda/0000-0002-2399-9107 FU NCI NIH HHS [U10 CA098543-06, U10 CA098543, CA 98543, U10 CA098413-05, CA 30969, CA 13539] NR 12 TC 60 Z9 68 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2008 VL 51 IS 3 BP 334 EP 338 DI 10.1002/pbc.21618 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 329YU UT WOS:000257907300005 PM 18506764 ER PT J AU Trachtenberg, F Maserejian, NN Tavares, M Soncini, JA Hayes, C AF Trachtenberg, Felicia Maserejian, Nancy Nairi Tavares, Mary Soncini, Jennifer Ann Hayes, Catherine TI Extent of Tooth Decay in the Mouth and Increased Need for Replacement of Dental Restorations: The New England Children's Amalgam Trial SO PEDIATRIC DENTISTRY LA English DT Article DE DENTAL RESTORATION FAILURE; LONGEVITY; DENTAL CARIES; PEDIATRIC DENTISTRY; CLINICAL TRIAL AB Purpose: The purpose of this study was to assess the relationship between baseline caries experience and the restoration replacement rate in children. Methods: The 5-year New England Children's Amalgam Trial recruited 534 6- to 10-year-old children with 2 or more carious posterior teeth. The association between decay and longevity of restorations was assessed. Restorations with no follow-up (N=391) were excluded from analysis. Results: The overage follow-up was 3.0+/-1.6 years in 489 children. Restorations with follow-up (N=3,604) were placed in mouths with a median of 15 dfs/DFS and 8 dft/DFT. The need for replacement increased significantly (Ps <= 001) with increasing numbers of dfs/DFS and dft/DFT. After 5 years of follow-up, at least 15% of restorations in a mouth with >= 14 dfs/DFS needed replacement, compared to 9% for 2 to 5 dfs/DFS. Comparing dft/DFT after 5 years of follow-up, there was a 23% replacement rate for >= 12 dft/DFT compared to 10% for 2 to 3 dft/DFT. Decay in the mouth had a greater association with the need for replacement due to new caries compared to replacement due to recurrent caries. Conclusion: Children with more decay at the time of restoration placement were at higher risk for replacement of restorations. (Pediatr Dent 2008;30:388-92) Received March 28, 2007 / Last Revision August 73, 2007 / Revision Accepted August 28, 2007 C1 [Trachtenberg, Felicia; Maserejian, Nancy Nairi] New England Res Inst, Watertown, MA 02172 USA. [Tavares, Mary; Soncini, Jennifer Ann] Forsyth Inst, Boston, MA USA. [Soncini, Jennifer Ann] Boston Univ, Sch Dent Med, Dept Pediat Dent, Boston, MA 02215 USA. [Hayes, Catherine] Tufts Univ, Sch Dent Med, Dept Publ Hlth & Community Serv, Boston, MA 02111 USA. RP Trachtenberg, F (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. EM ftrachtenberg@neriscience.com FU National Institute of Dental and Craniofacial Research [U01 DE11886] FX The study was supported by the National Institute of Dental and Craniofacial Research (Grant No. U01 DE11886), which also participated in the design and conduct of the study. NR 19 TC 3 Z9 3 U1 0 U2 1 PU AMER ACAD PEDIATRIC DENTISTRY PI CHICAGO PA 211 E CHICAGO AVENUE SUITE 1036, CHICAGO, IL 60611-2616 USA SN 0164-1263 J9 PEDIATR DENT JI Pediatr. Dent. PD SEP-OCT PY 2008 VL 30 IS 5 BP 388 EP 392 PG 5 WC Dentistry, Oral Surgery & Medicine; Pediatrics SC Dentistry, Oral Surgery & Medicine; Pediatrics GA V13JR UT WOS:000207663600003 PM 18942597 ER PT J AU Zhang, SL Chen, YW Tran, S Chenier, I Chan, JSD Inagami, T Ingelfinger, JR AF Zhang, S. L. Chen, Y. W. Tran, S. Chenier, I. Chan, J. S. D. Inagami, T. Ingelfinger, J. R. TI Deficiency of intrarenal AT2R impairs Pax-2 and N-myc expression during nephrogenesis SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Chen, Y. W.; Tran, S.; Chenier, I.] Univ Montreal, Chum Hotel Dieu, Ctr Hosp, Res Ctr, Montreal, PQ, Canada. [Inagami, T.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ingelfinger, J. R.] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2008 VL 23 IS 9 BP 1669 EP 1669 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 325NC UT WOS:000257594600369 ER PT J AU O'Shea, TM Kuban, KCK Allred, EN Paneth, N Pagano, M Dammann, O Bostic, L Brooklier, K Butler, S Goldstein, DJ Hounshell, G Keller, C McQuiston, S Miller, A Pasternak, S Plesha-Troyke, S Price, J Romano, E Solomon, KM Jacobson, A Westra, S Leviton, A AF O'Shea, T. Michael Kuban, Karl C. K. Allred, Elizabeth N. Paneth, Nigel Pagano, Marcello Dammann, Olaf Bostic, Lisa Brooklier, Kara Butler, Samantha Goldstein, Donald J. Hounshell, Gail Keller, Cecelia McQuiston, Susan Miller, Alice Pasternak, Steve Plesha-Troyke, Susan Price, Joan Romano, Elaine Solomon, Katherine M. Jacobson, Amanda Westra, Sjirk Leviton, Alan CA Extremely Low Gestational Age Newb TI Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children SO PEDIATRICS LA English DT Article DE prematurity; cognitive development; intraventricular hemorrhage; periventricular leukomalacia; neonatal follow-up; Bayley Scales of Infant Development ID LOW-BIRTH-WEIGHT; WHITE-MATTER INJURY; PRETERM INFANTS; CEREBRAL-PALSY; NEURODEVELOPMENTAL OUTCOMES; INTRAVENTRICULAR HEMORRHAGE; CEREBELLAR INJURY; PREMATURE-INFANT; HEAD ULTRASOUND; RISK AB BACKGROUND. Studies of the relationship between ultrasound images from preterm newborns and developmental delay most often are based on small samples defined by birth weight and exclude infants not testable with standardized assessments. METHODS. We evaluated associations between ultrasound-defined lesions of the brain and developmental delays at 24 months' corrected age in 1017 children born before the 28th postmenstrual week. Brain ultrasound scans were read for concordance on 4 lesions: intraventricular hemorrhage, moderate/severe ventriculomegaly, white matter echodense/hyperechoic lesions, and white matter echodense/hypoechoic lesions and 2 diagnoses-periventricular leukomalacia and periventricular hemorrhagic infarction. Certified examiners, who were not aware of the infants' ultrasound findings, administered the Bayley Scales of Infant Development-Second Edition. Children with an impairment (eg., blindness) that precluded testing with the Bayley Scales and those for whom >2 test items were omitted were classified using the Vineland Adaptive Behavior Scales Motor Skills Domain instead of the Psychomotor Development Index and the Adaptive Behavior Composite instead of the Mental Development Index. RESULTS. Fully 26% of all of the children had delayed mental development (ie, Mental Development Index < 70), and 31% had delayed psychomotor development (ie, Psychomotor Development Index < 70). Ultrasound abnormalities were more strongly associated with low Psychomotor Development Index than with low Mental Development Index. Children without cranial ultrasound abnormality had the lowest probability (23% and 26%) of delayed mental or psychomotor development. Moderate/severe ventriculomegaly was associated with a more than fourfold increase in the risk of psychomotor delay and an almost threefold increase in the risk of mental delay. Echolucency was the next best predictor of delayed mental and psychomotor development. The probability of low scores varied with the number of zones involved and with the location of echolucency. At particularly high risk were infants with bilateral cerebellar hemorrhage, co- occurring ventriculomegaly and echolucency bilateral echolucency, or echolucency located posteriorly. CONCLUSIONS. Focal white matter damage, as characterized by echolucent/hypoechoic lesion, and diffuse damage, as suggested by late ventriculomegaly, are associated with delayed mental and psychomotor development. C1 [O'Shea, T. Michael; Goldstein, Donald J.; Hounshell, Gail] Wake Forest Univ, Dept Pediat, Winston Salem, NC 27109 USA. [Kuban, Karl C. K.] Boston Univ, Div Pediat Neurol, Dept Pediat, Boston Med Ctr, Boston, MA 02215 USA. [Allred, Elizabeth N.; Leviton, Alan] Harvard Univ, Neuroepidemiol Unit, Dept Neurol, Childrens Hosp Boston, Boston, MA 02115 USA. [Allred, Elizabeth N.; Pagano, Marcello] Harvard Univ, Dept Biostat, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Dammann, Olaf; Keller, Cecelia] Floating Hosp Children, Tufts Med Ctr, Div Newborn Med, Boston, MA USA. [Bostic, Lisa; Jacobson, Amanda] Univ N Carolina, Dept Occupat Therapy, Chapel Hill, NC USA. [Brooklier, Kara; Solomon, Katherine M.] William Beaumont Hosp, Ctr Human Dev, Royal Oak, MI 48072 USA. [Butler, Samantha] Childrens Hosp, Dept Psychiat, Boston, MA 02115 USA. [McQuiston, Susan] Baystate Med Ctr, Springfield, MA USA. [Miller, Alice] Univ Massachusetts, Mem Hlth Ctr, Dept Pediat, Worcester, MA 01605 USA. [Pasternak, Steve] DeVos Childrens Hosp, Grand Rapids, MI USA. [McQuiston, Susan] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Price, Joan] Michigan State Univ, Sparrow Med Ctr, Early Childhood Serv Referrals, Lansing, MI USA. [Romano, Elaine] Yale Univ, Med Ctr, New Haven, CT USA. [Westra, Sjirk] Harvard Univ, Dept Pediat Radiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP O'Shea, TM (reprint author), Wake Forest Univ Hlth Sci, Dept Pediat, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM moshea@wfubmc.edu OI Kuban, Karl/0000-0001-5299-3567 FU National Institute of Neurological Disorders; Stroke grant [NS 40069] FX Financial support for this research was provided by National Institute of Neurological Disorders and Stroke grant NS 40069.; We thank Rebecca Helms, PhD (East Carolina University) and Lynn Whitley, PhD (East Carolina University) for completing some of the developmental assessments on which this article was based. NR 60 TC 62 Z9 62 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2008 VL 122 IS 3 BP E662 EP E669 DI 10.1542/peds.2008-0594 PG 8 WC Pediatrics SC Pediatrics GA 342ZR UT WOS:000258822600071 PM 18762501 ER PT J AU Tracy, EE AF Tracy, Erin E. TI Prospects and problems of direct-to-public genetic tests SO PERSONALIZED MEDICINE LA English DT Article DE direct-to-consumer advertising; direct-to-consumer genetic tests; genetic counseling ID MANAGED CARE ORGANIZATION; PRESCRIPTION DRUGS; BREAST-CANCER; HEALTH; PHYSICIANS; IMPACT; PHARMACEUTICALS; PROMOTION; SERVICES; SALES AB Direct-to-consumer advertising of genetic tests is prevalent, poorly regulated and fraught with potential negative public-health ramifications. While some genetic tests are available through means that safeguard patient understanding of the implications of having genetic tests performed, others are available to anyone who has a credit card, without any individualized counseling, assessment of whether such tests are indicated, or interpretation of test results. While the US FDA, the Centers for Medicare and Medicaid Services and the Federal Trade Commission all have a regulatory role, most experts agree that the industry is not adequately being reigned in to best protect the public it serves. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tracy, EE (reprint author), Massachusetts Gen Hosp, 55 Fruit St,406 Founders House, Boston, MA 02114 USA. EM eetracy@partners.org NR 41 TC 2 Z9 2 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD SEP PY 2008 VL 5 IS 5 BP 511 EP 520 DI 10.2217/17410541.5.5.511 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 349JZ UT WOS:000259278400018 ER PT J AU Platt, AB Localio, AR Brensinger, CM Cruess, DG Christie, JD Gross, R Parker, CS Price, M Metlay, JP Cohen, A Newcomb, CW Strom, BL Laskin, MS Kimmel, SE AF Platt, Alec B. Localio, A. Russell Brensinger, Colleen M. Cruess, Dean G. Christie, Jason D. Gross, Robert Parker, Catherine S. Price, Maureen Metlay, Joshua P. Cohen, Abigail Newcomb, Craig W. Strom, Brian L. Laskin, Mitchell S. Kimmel, Stephen E. TI Risk factors for nonadherence to warfarin: results from the IN-RANGE study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE medication adherence; MEMS; warfarin; anticoagulation ID INTERNATIONAL NORMALIZED RATIO; ATRIAL-FIBRILLATION; PATIENT REPORTS; ADHERENCE; THERAPY; ANTICOAGULATION; MEDICATION; OUTCOMES; CARE AB Background Warfarin is widely used to prevent stroke and venous thromboembolism despite its narrow therapeutic window, Warfarin nonadherence is a substantial problem, but risk factors have not been well elucidated. Methods A prospective cohort study of adults initiating warfarin at two anticoagulation clinics (University and VA-affiliated) was performed to determine factors affecting nonadherence to warfarin. Nonadherence, defined by failure to record a correct pill bottle opening each day, was measured daily via electronic medication event monitoring systems (MEMS) caps. A multivariable explanatory model using logistic regression for longitudinal data was used to identify risk factors for nonadherence. Results One hundred eleven subjects were followed for a median of 137 days. Warfarin nonadherence was common (4787 of 22 425 or 21 % of patient-days observed). Factors independently associated with higher odds of nonadherence included education beyond high school (odds ratio (OR) 1.8 (95%CI 1.2-2.7)), lower Short Form (SF)-36 mental component score (OR 1.4 (1.1-1.6) for each 10 point decrease); and impaired cognition (! 19 points) on the Cognitive Capacity Screening Examination (CCSE) (OR 2.9 (1.7-4.8)). Compared to currently employed subjects, unemployed (OR 0.6 (0.3-1.2)) and retired (OR 0.5 (0.3-0.8)) subjects had somewhat improved adherence; disabled subjects over age 55 had worse adherence (OR 1.8 (1.1-3.1)) than younger disabled subjects (OR 0.8 (0.4-1.5)). Conclusions Poor adherence to warfarin is common and risk factors are related to education level, employment status, mental health functioning, and cognitive impairment. Within the carefully controlled anticoagulation clinic setting, such patient-specific factors may be the basis of future interventions to improve nonadherence. Copyright (C) 2008 John Wiley & Sons. Ltd. C1 [Platt, Alec B.; Localio, A. Russell; Brensinger, Colleen M.; Christie, Jason D.; Gross, Robert; Price, Maureen; Metlay, Joshua P.; Cohen, Abigail; Newcomb, Craig W.; Strom, Brian L.; Kimmel, Stephen E.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Dept Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Platt, Alec B.; Christie, Jason D.; Gross, Robert; Metlay, Joshua P.; Strom, Brian L.; Kimmel, Stephen E.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Localio, A. Russell; Gross, Robert; Metlay, Joshua P.; Strom, Brian L.] Univ Penn, Ctr Educ & Res Therapeut, Philadelphia, PA 19104 USA. [Cruess, Dean G.] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. [Gross, Robert; Metlay, Joshua P.; Kimmel, Stephen E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Parker, Catherine S.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Boston, MA 02215 USA. [Laskin, Mitchell S.] Hosp Univ Penn, Dept Pharm Serv, Philadelphia, PA 19104 USA. RP Kimmel, SE (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Dept Clin Epidemiol & Biostat, 717 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM stevek@mail.med.upenn.edu RI Cohen, Abigail/K-9180-2013 OI Cohen, Abigail/0000-0002-7425-7218 FU NIH [R01-HL66176]; AHRQ [P01-HS11530]; [P20RR020741]; [K24HL070936] FX This study was supported by grants from the NIH (R01-HL66176) and AHRQ (P01-HS11530). Dr Kimmel is supported by P20RR020741 and K24HL070936. The funder had no role in tie design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr Kimmel has 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. We thank Mabel Chin, PharmD, for her dedication to our field work. NR 28 TC 54 Z9 58 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2008 VL 17 IS 9 BP 853 EP 860 DI 10.1002/pds.1556 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 348NR UT WOS:000259217700001 PM 18271059 ER PT J AU Cotsapas, C AF Cotsapas, Chris TI Identifying genetic components of drug response in mice SO PHARMACOGENOMICS LA English DT Review DE association; mapping; chemical screening; expression profiling; pharmacogenomics ID INBRED MOUSE STRAINS; COMPLEX TRAIT ANALYSIS; LABORATORY MOUSE; DEFINED FACTORS; COPY NUMBER; EXPRESSION; ASSOCIATION; EXPOSURE; DISEASE; GENOME AB Individual variations in drug response are crucial factors in both the development and deployment of therapy, yet we are still woefully ignorant of the majority of this genetic basis. Here we discuss the convergence of genetics and genomics to dissect such pharmacological variation, with emphasis on satisfying the requirements of both genetics and pharmacology itself, the appropriate use of model organisms and the often overlooked power of genetic dissection to inform understanding of physiological process. C1 [Cotsapas, Chris] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotsapas, Chris] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Cotsapas, Chris] Broad Inst Harvard, Boston, MA 02114 USA. [Cotsapas, Chris] MIT, Boston, MA 02114 USA. RP Cotsapas, C (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM chrisc@chgr.mgh.harvard.edu FU Broad Institute/SPARC FX The author is an FMD Postdoctoral Fellow at Massachusetts General Hospital and is also supported by a Broad Institute/SPARC grant. He would like to thank Mark Daly, Sangeeta Bhatia, Robert Gould, Salman Khetani and many other colleagues at MGH and the Broad Institutefor mentorship and helping guide the evolution of the ideas presented here. He declares that he has no financial conflicts of interest. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.; No writing assistance was utilized in the production of this manuscript. NR 56 TC 1 Z9 1 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD SEP PY 2008 VL 9 IS 9 BP 1323 EP 1330 DI 10.2217/14622416.9.9.1323 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 352YL UT WOS:000259533200018 PM 18781858 ER PT J AU Smith, JP AF Smith, Jason P. TI Treatment options for patients with hepatitis C: Role of pharmacists in optimizing treatment response and managing adverse events SO PHARMACOTHERAPY LA English DT Review DE hepatitis; pegylated interferon alfa-2a; pegylated interferon alfa-2b; ribavirin; epidemiology; mortality; treatment outcome; safety ID ALPHA-2A PLUS RIBAVIRIN; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; EARLY VIROLOGICAL RESPONSE; HIV-INFECTED PATIENTS; INJECTION-DRUG USERS; INTERFERON-ALPHA; PEGINTERFERON ALPHA-2A; VIRUS-INFECTION; COMBINATION THERAPY AB Chronic hepatitis C is associated with substantial morbidity and mortality and poses a considerable socioeconomic burden. Improved treatment regimens, including the standard of care pegylated interferon alfa and ribavirin, have increased sustained virologic response rates, however, treatment has a long duration and is often associated with adverse events that may affect adherence. The goal of therapy is viral eradication and reduced disease-related complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. The clinical outcome of hepatitis C virus infection is altered with antiviral treatment, which can be influenced by host (e.g., weight, ethnicity, health) and viral (e.g., genotype, baseline viremia) factors. Overall, sustained virologic response was attained by 54-63% of patients in clinical trials treated with pegylated interferon alfa-2a or -2b and ribavirin. However, this benefit is not without risk. Interferon-induced adverse events include flu-like symptoms, bone marrow suppression, and emotional or cognitive effects, whereas hemolytic anemia accounts for most ribavirin dosage reductions. These adverse events may be ameliorated with dosage adjustments, symptom therapy, and judicious use of preventive strategies (e.g., anti depressants, hematopoietic growth factors). Appropriate management of adverse events can increase treatment adherence, thereby enhancing outcomes and improving quality of life. Pharmacists are in an ideal position to improve the treatment of patients with chronic hepatitis C by providing education about the disease and its treatments and associated adverse events and by emphasizing the importance of treatment adherence for successful outcomes. C1 VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol & Hepatol, Los Angeles, CA 90073 USA. RP Smith, JP (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol & Hepatol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM glaliver@yahoo.com NR 68 TC 9 Z9 11 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD SEP PY 2008 VL 28 IS 9 BP 1151 EP 1161 DI 10.1592/phco.28.9.1151 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 344FI UT WOS:000258911800009 PM 18752386 ER PT J AU Brams, M Mao, AR Doyle, RL AF Brams, Matthew Mao, Alice R. Doyle, Robert L. TI Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder SO POSTGRADUATE MEDICINE LA English DT Article DE attention-deficit/hyperactivity disorder; ADHD; extended-release; sustained-release; methylphenidate; amphetamine ID DEFICIT-HYPERACTIVITY DISORDER; ONCE-A-DAY; EXTENDED-RELEASE DEXMETHYLPHENIDATE; PLACEBO-CONTROLLED TRIAL; SLI381 ADDERALL XR; DOUBLE-BLIND; METHYLPHENIDATE FORMULATIONS; LISDEXAMFETAMINE DIMESYLATE; LABORATORY CLASSROOM; D,L-THREO-METHYLPHENIDATE HYDROCHLORIDE AB Background: Attention-deficit/hyperactivity disorder (ADHD) adversely impacts the educational achievement, mood and emotion processing, and interpersonal relationships of children and adolescents. Effective treatments include a number extended-re I ease (ER) methylphenidate- (MPH) and amphetamine-based drugs. Some formulations release a comparatively larger bolus after dosing and can result in different onset and duration of efficacy. Objective: Provide an evidence-based description of the time course of efficacy of psycho-stimulant medications used in ADHD treatment of children and adolescents. Data Sources: A literature search from 1998 to 2008 was conducted using a MEDLINE database and the keywords "attention-deficit/hyperactivity disorder," "extended-release," "sustained-release," methylphenidate," "amphetamine," "randomized," "controlled," "placebo," "efficacy," "time course," and "classroom study." Data Extraction: Selection criteria included randomized, blinded, placebo- or active comparator-controlled clinical studies that evaluated an ER formulation of a psychostimulant treatment for ADHD in at least 30 children and adolescents aged 6 to 17 years. Study Selection: Eighteen clinical trials met the chosen criteria and evaluated: d, l-MPH, long-acting (d, l-MPH-LA); d, l-MPH-OR; d, l-MPH-CD (MCD); d-MPH-ER; MPH transdermal system (MTS); mixed amphetamine salts, ER (MAS-XR); and lisdexamfetamine dimesylate (LDX). Data Synthesis: Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at I to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at I to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. Duration of efficacy for each treatment was: MCD 7.5 hours; d, l-MPH-LA 8 to 12 hours; and 12 hours for NITS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX. However, data should be interpreted with caution given the different trial designs and assessment time points. Conclusions: d-MPH-ER has the earliest onset of efficacy at 0.5 hours postdose, and MTS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX have a long duration of action at 12 hours postdose. Clinicians should consider differences in the onset of efficacy of each drug in the context of individual patient needs. C1 [Brams, Matthew; Mao, Alice R.] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77007 USA. [Doyle, Robert L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Brams, M (reprint author), Baylor Coll Med, Dept Psychiat & Behav Sci, 550 Westcott St,520, Houston, TX 77007 USA. EM bramsmaooffice@aol.com FU Novartis Pharmaceutical Corp FX The authors would like to gratefully acknowledge the contributions by George Rogan of Phase Five Communications, who helped to coordinate, edit, and finalize this manuscript for submission with funding provided by Novartis Pharmaceutical Corp. NR 73 TC 10 Z9 10 U1 2 U2 12 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 SEP PY 2008 VL 120 IS 3 BP 69 EP 88 DI 10.3810/pgm.2008.09.1909 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 354QN UT WOS:000259654200009 PM 18824827 ER PT J AU Helton, TJ Bavry, AA Rajagopal, V Anderson, RD Yadav, JS Bhatt, DL AF Helton, Thomas J. Bavry, Anthony A. Rajagopal, Vivek Anderson, R. David Yadav, Jay S. Bhatt, Deepak L. TI The optimal treatment of carotid atherosclerosis: A 2008 update and literature review SO POSTGRADUATE MEDICINE LA English DT Review DE carotid atherosclerosis; carotid artery disease; carotid artery stenting; cerebrovascular accident; stroke; peripheral arterial disease ID HIGH-RISK PATIENTS; CEREBRAL PROTECTION; RANDOMIZED-TRIAL; ARTERY STENOSIS; EMBOLIC PROTECTION; FLOW BLOCKAGE; ENDARTERECTOMY; REGISTRY; ANGIOPLASTY; PREVENTION AB Carotid and cerebrovascular disease have major public health implications given the associated morbidity and mortality. However, the best treatment for this disease is uncertain. Carotid endarterectomy has proven useful in primary and secondary prevention of strokes for patients with significant internal carotid artery stenoses. Many patients are considered at high risk for such surgical procedures and therefore have relatively few treatment options. Carotid stenting is currently being investigated as an alternative therapeutic intervention for these patients. This article reviews the literature pertaining to carotid intervention and its current status in 2008. C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, Intervent Cardiovasc Program, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Helton, Thomas J.] Cleveland Clin, Cleveland, OH 44106 USA. [Bavry, Anthony A.; Anderson, R. David] Univ Florida, Shands Hosp, Gainesville, FL USA. [Rajagopal, Vivek; Yadav, Jay S.] Piedmont Hosp, Atlanta, GA USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, Intervent Cardiovasc Program, VA Boston Healthcare Syst, 75 Francis St, Boston, MA 02115 USA. EM dlbhattmd@alum.mit.edu NR 65 TC 7 Z9 7 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 SEP PY 2008 VL 120 IS 3 BP 103 EP 112 DI 10.3810/pgm.2008.09.1911 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 354QN UT WOS:000259654200011 PM 18824829 ER PT J AU Colli, JL Amling, CL AF Colli, J. L. Amling, C. L. TI Prostate cancer mortality rates compared to urologist population densities and prostate-specific antigen screening levels on a state-by-state basis in the United States of America SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE ecology; prostate cancer; United States; epidemiology ID VITAMIN-D METABOLITES; SUBSEQUENT DEVELOPMENT; GEOGRAPHIC PATTERNS; RISK; COHORT; CARE AB We hypothesized that prostate cancer screening and availability of urologists among states may be associated with reduced prostate cancer mortality in the United States. To test this hypothesis, statespecific prostate cancer mortality rates for white males were compared to urologist population densities and prostate-specific antigen (PSA) screening rates on a state-by-state basis. The urologist population density was calculated by dividing the number of urologists per state by the population. We found that prostate cancer mortality rates correlated inversely with urologist population densities (P<0.01) and PSA screening (P<0.01) suggesting that screening and treatment reduce prostate cancer mortality. C1 [Colli, J. L.; Amling, C. L.] Univ Alabama, Dept Urol, Birmingham, AL 35294 USA. [Colli, J. L.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Colli, JL (reprint author), Univ Alabama, Dept Urol, 1530 3rd Ave S, Birmingham, AL 35294 USA. EM jan.colli@ccc.uab.edu NR 24 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD SEP PY 2008 VL 11 IS 3 BP 247 EP 251 DI 10.1038/pcan.2008.7 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 338KB UT WOS:000258505500006 PM 18268527 ER PT J AU New, AS Goodman, M Triebwasser, J Siever, LJ AF New, Antonia S. Goodman, Marianne Triebwasser, Joseph Siever, Larry J. TI Recent advances in the biological study of personality disorders SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; SEROTONIN TRANSPORTER GENE; SELF-INJURIOUS-BEHAVIOR; POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD SEXUAL-ABUSE; ACTIVATED FDG-PET; OPEN-LABEL TRIAL; IMPULSIVE AGGRESSION; PREFRONTAL CORTEX; FEMALE-PATIENTS AB While it is premature to provide a simple model for the vulnerability to the development of either borderline (BPD) or schizotypal (SPD) personality disorder, it is clear that these heritable disorders lend themselves to fruitful neurobiological exploration. The most promising findings in BPD suggest that a diminished top-down control of affective responses, which is likely to relate to deceased responsiveness of specific midline regions of prefrontal cortex, May Underlie the affective hyperresponsiveness in this disorder. In addition, genetic and neuroendocrine and molecular neuro-imaging finding point to a role for serotonin in this affective disinhibition. Clearly SPD falls within the schizophrenia spectrum, but precisely the nature of what predicts full-blown schizophrenia as opposed to the milder Symptoms of SPD is not yet clear. C1 [New, Antonia S.; Goodman, Marianne; Triebwasser, Joseph; Siever, Larry J.] Mt Sinai Sch Med, New York, NY 10029 USA. [New, Antonia S.; Goodman, Marianne; Triebwasser, Joseph; Siever, Larry J.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP New, AS (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1217, New York, NY 10029 USA. EM antonia.new@mssm.edu NR 161 TC 45 Z9 47 U1 5 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2008 VL 31 IS 3 BP 441 EP + DI 10.1016/j.psc.2008.03.011 PG 22 WC Psychiatry SC Psychiatry GA 340WZ UT WOS:000258677000007 PM 18638645 ER PT J AU Plotnick, DF Salzer, MS AF Plotnick, Debbie F. Salzer, Mark S. TI Clubhouse Costs and Implications for Policy Analysis in the Context of System Transformation Initiatives SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE clubhouse costs systems; transformation; psychiatric rehabilitation programs; mental health policy ID SUPPORTED EMPLOYMENT; OUTCOMES AB Objective: Documenting service costs is important for psychiatric rehabilitation programs to make persuasive arguments to policymakers/funders about their role in system transformation efforts. The purpose of this study was to report program costs, annual costs per member, and costs per day over three years (2003-2006) for 29 clubhouses that are part of the Pennsylvania Clubhouse Coalition (PCC). Methods: This study utilized data elements that are submitted annually by coalition members to the Pennsylvania Clubhouse Coalition. Results: Our results indicate that clubhouses play a substantial role in the Pennsylvania mental health system, providing almost 180,000 units of contact to more than 2,400 people across the state. Conclusions: Most relevant to Pennsylvania's system transformation is our finding that clubhouse costs are substantially lower than the costs of partial hospital services. Clubhouses are likely serving an important role in lowering costs associated with supporting those who would otherwise utilize partial hospital programs. C1 [Salzer, Mark S.] Univ Penn, CMHPSR, Dept Psychiat, Philadelphia, PA 19104 USA. [Salzer, Mark S.] Philadelphia VA Med Ctr, VISN 4, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Salzer, MS (reprint author), Univ Penn, CMHPSR, Dept Psychiat, 3535 Market St,3rd Floor, Philadelphia, PA 19104 USA. EM Mark.Salzer@uphs.upenn.edu NR 10 TC 2 Z9 2 U1 1 U2 1 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD FAL PY 2008 VL 32 IS 2 BP 128 EP 131 DI 10.2975/32.2.2008.128.131 PG 4 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA 364GH UT WOS:000260323700008 PM 18840568 ER PT J AU Lindquist, KA Barrett, LF AF Lindquist, Kristen A. Barrett, Lisa Feldman TI Constructing Emotion The Experience of Fear as a Conceptual Act SO PSYCHOLOGICAL SCIENCE LA English DT Article ID MOOD DEPENDENT MEMORY; CORE AFFECT; VALENCE; EVENTS; ANGER; RISK AB This study examined the hypothesis that emotion is a psychological event constructed from the more basic elements of core affect and conceptual knowledge. Participants were primed with conceptual knowledge of fear, conceptual knowledge of anger, or a neutral prime and then proceeded through an affect-induction procedure designed to induce unpleasant, high-arousal affect or a neutral affective state. As predicted, only those individuals for whom conceptual knowledge of fear had been primed experienced unpleasant core affect as evidence that the world was threatening. This study provides the first experimental support for the hypothesis that people experience world-focused emotion when they conceptualize their core affective state using accessible knowledge about emotion. C1 [Lindquist, Kristen A.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Lindquist, KA (reprint author), Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. EM lindqukr@bc.edu FU NIA NIH HHS [R01 AG030311-02, AG030311, R01 AG030311]; NIH HHS [DP1 OD003312, DP1 OD003312-01, DP1OD003312]; NIMH NIH HHS [K02 MH001981, K02MH001981] NR 26 TC 60 Z9 61 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD SEP PY 2008 VL 19 IS 9 BP 898 EP 903 DI 10.1111/j.1467-9280.2008.02174.x PG 6 WC Psychology, Multidisciplinary SC Psychology GA 358YX UT WOS:000259954500011 PM 18947355 ER PT J AU Siegle, GJ Ichikawa, N Steinhauer, S AF Siegle, Greg J. Ichikawa, Naho Steinhauer, Stuart TI Blink before and after you think: Blinks occur prior to and following cognitive load indexed by pupillary responses SO PSYCHOPHYSIOLOGY LA English DT Article DE blinks; pupil dilation; cognitive load; attention; Stroop ID LATERAL EYE-MOVEMENTS; EYEBLINK ACTIVITY; MEMORY TASK; PERFORMANCE; ACTIVATION; DEPRESSION; LIGHT; FMRI AB Pupil dilation and blinks provide complementary, mutually exclusive indices of information processing. Though each index is associated with cognitive load, the occurrence of a blink precludes the measurement of pupil diameter. These indices have generally been assessed in independent literatures. We examine the extent to which these measures are related on two cognitive tasks using a novel method that quantifies the proportion of trials on which blinks occur at each sample acquired during the trial. This measure allows cross-correlation of continuous pupil-dilation and blink waveforms. Results indicate that blinks occur during early sensory processing and following sustained information processing. Pupil dilation better reflects sustained information processing. Together these indices provide a rich picture of the time course of information processing, from early reactivity through sustained cognition, and after stimulus-related cognition ends. C1 [Siegle, Greg J.; Ichikawa, Naho; Steinhauer, Stuart] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Ichikawa, Naho] Nagoya Univ, Dept Psychol, Nagoya, Aichi 4648601, Japan. [Steinhauer, Stuart] VA Pittsburgh Healthcare Syst, Dept Psychol, Pittsburgh, PA USA. RP Siegle, GJ (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM gsiegle@pitt.edu FU NIMH NIH HHS [K02 MH082998, MH064159, MH55762] NR 37 TC 54 Z9 56 U1 3 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2008 VL 45 IS 5 BP 679 EP 687 DI 10.1111/j.1469-8986.2008.00681.x PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 336KD UT WOS:000258361800001 PM 18665867 ER PT J AU Sainani, NI Catalano, OA Holalkere, NS Zhu, AX Hahn, PF Sahani, DV AF Sainani, Nisha I. Catalano, Onofrio A. Holalkere, Nagaraj-Setty Zhu, Andrew X. Hahn, Peter F. Sahani, Dushyant V. TI Cholangiocarcinoma: Current and novel imaging techniques SO RADIOGRAPHICS LA English DT Article ID PRIMARY SCLEROSING CHOLANGITIS; POSITRON-EMISSION-TOMOGRAPHY; FINE-NEEDLE-ASPIRATION; FOCAL HEPATIC-LESIONS; BILE-DUCT STRICTURES; HILAR CHOLANGIOCARCINOMA; BILIARY OBSTRUCTION; INTRAHEPATIC CHOLANGIOCARCINOMA; LIVER-TRANSPLANTATION; CT CHOLANGIOGRAPHY AB The radiologic manifestations of cholangiocarcinomas are extremely diverse, since these tumors vary greatly in location, growth pattern, and histologic type. Familiarity with the imaging manifestations of cholangiocarcinomas is important for accurate detection and characterization of these tumors and assessment of resectability. Advances in imaging techniques have led to the availability of an array of modalities that, used independently or in combination, can aid in the accurate diagnosis and evaluation of cholangiocarcinomas in preparation for advanced surgical procedures and treatment planning. Response to novel targeted therapies can also be assessed with newer imaging tools. Hence, knowledge of current and emerging imaging applications is essential for correct diagnosis and appropriate management of these tumors. C1 [Sainani, Nisha I.; Catalano, Onofrio A.; Holalkere, Nagaraj-Setty; Hahn, Peter F.; Sahani, Dushyant V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org OI Holalkere, Nagaraj/0000-0001-6324-7682 NR 84 TC 38 Z9 43 U1 0 U2 3 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 SEP-OCT PY 2008 VL 28 IS 5 BP 1263 EP 1287 DI 10.1148/rg.285075183 PG 25 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 351VS UT WOS:000259454600005 PM 18794305 ER PT J AU Martinez, S Heyneman, LE McAdams, HP Rossi, SE Restrepo, CS Eraso, A AF Martinez, Santiago Heyneman, Laura E. McAdams, H. Page Rossi, Santiago E. Restrepo, Carlos S. Eraso, Andres TI Mucoid impactions: Finger-in-glove sign and other CT and radiographic features SO RADIOGRAPHICS LA English DT Article ID ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; CONGENITAL BRONCHIAL ATRESIA; HIGH-RESOLUTION CT; THIN-SECTION CT; ENDOBRONCHIAL LIPOMA; CYSTIC-FIBROSIS; COMPUTED-TOMOGRAPHY; BUD PATTERN; CELLULOSE GRANULOMATOSIS; RADIOLOGIC FINDINGS AB Mucoid impaction is a relatively common finding at chest radiography and computed tomography (CT). Both congenital and acquired abnormalities may cause mucoid impaction of the large airways that often manifests as tubular opacities known as the finger-in-glove sign. The congenital conditions in which this sign most often appears are segmental bronchial atresia and cystic fibrosis. The sign also may be observed in many acquired conditions, include inflammatory and infectious diseases (allergic bronchopulmonary aspergillosis, broncholithiasis, and foreign body aspiration), benign neoplastic processes (bronchial hamartoma, lipoma, and papillomatosis), and malignancies (bronchogenic carcinoma, carcinoid tumor, and metastases). To point to the correct diagnosis, the radiologist must be familiar with the key radiographic and CT features that enable differentiation among the various likely causes. CT is more useful than chest radiography for differentiating between mucoid impaction and other disease processes, such as arteriovenous malformation, and for directing further diagnostic evaluation. In addition, knowledge of the patient's medical history, clinical symptoms and signs, and predisposing factors is important. (C) RSNA, 2008 . radiographics.rsnajnls.org. C1 [Martinez, Santiago; Heyneman, Laura E.; McAdams, H. Page] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Rossi, Santiago E.] Ctr Diagnost Dr Enrique Rossi, Dept Radiol, Buenos Aires, DF, Argentina. [Restrepo, Carlos S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Eraso, Andres] US Dept Vet Affairs, Med Ctr, Dept Radiol, Washington, DC USA. RP Martinez, S (reprint author), Duke Univ, Med Ctr, Dept Radiol, Box 3808,Erwin Rd, Durham, NC 27710 USA. EM santiago.martinez@duke.edu RI McAdams, Holman/N-8218-2015 OI McAdams, Holman/0000-0002-7044-3320 NR 45 TC 24 Z9 29 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 SEP-OCT PY 2008 VL 28 IS 5 BP 1369 EP 1382 DI 10.1148/rg.285075212 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 351VS UT WOS:000259454600013 PM 18794313 ER PT J AU Pomerantz, SR AF Pomerantz, Stuart R. TI Net assets: Special collections SO RADIOLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dept Neuroradiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pomerantz, SR (reprint author), Harvard Univ, Sch Med, Dept Neuroradiol, Massachusetts Gen Hosp, 55 Fruit St,Gray 2-B285, Boston, MA 02114 USA. EM netassets@rsna.org NR 3 TC 1 Z9 1 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 SEP PY 2008 VL 248 IS 3 BP 721 EP 724 DI 10.1148/radiol.2483080952 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338XA UT WOS:000258541500007 PM 18710971 ER PT J AU Gee, MS Upadhyay, R Bergquist, H Alencar, H Reynolds, F Maricevich, M Weissleder, R Josephson, L Mahmood, U AF Gee, Michael S. Upadhyay, Rabi Bergquist, Henry Alencar, Herlen Reynolds, Fred Maricevich, Marco Weissleder, Ralph Josephson, Lee Mahmood, Umar TI Human breast cancer tumor models: Molecular imaging of drug susceptibility and dosing during HER2/neu-targeted therapy SO RADIOLOGY LA English DT Article ID NEOADJUVANT CHEMOTHERAPY; ANTIBODY FRAGMENTS; CELL-LINES; EXPRESSION; MICE; RESPONSIVENESS; TOMOGRAPHY; XENOGRAFTS; ERBB2; HER2 AB Purpose: To use near-infrared (NIR) optical imaging to assess the therapeutic susceptibility and drug dosing of orthotopic human breast cancers implanted in mice treated with molecularly targeted therapy. Materials and Methods: This study was approved by the institutional animal care and use committee. Imaging probes were synthesized by conjugating the human epidermal growth factor receptor type 2 (HER2)-specific antibody trastuzumab with fluorescent dyes. In vitro probe binding was assessed with flow cytometry. HER2-normal and HER2-overexpressing human breast cancer cells were orthotopically implanted in nude mice. Intravital laser scanning fluorescence microscopy was used to evaluate the in vivo association of the probe with the tumor cells. Mice bearing 3-5-mm-diameter tumors were intravenously injected with 0.4 nmol of HER2 probe before or after treatment. A total of 123 mice were used for all in vivo tumor growth and imaging experiments. Tumor fluorescence intensity was assessed, and standard fluorescence values were determined. Statistical significance was determined by performing standard analysis of variance across the imaging cohorts. Results: HER2 probe enabled differentiation between HER2-normal and HER2-overexpressing human breast cancer cells in vitro and in vivo, with binding levels correlating with tumor trastuzumab susceptibility. Serial imaging before and during trastuzumab therapy revealed a significant reduction (P < .05) in probe binding with treatment and thus provided early evidence of successful HER2 inhibition days before the overall reduction in tumor growth was apparent. Conclusion: NIR imaging with HER2-specific imaging probes enables evaluation of the therapeutic susceptibility of human mammary tumors and of drug dosing during HER2-targeted therapy with trastuzumab. This approach, combined with tomographic imaging techniques, has potential in the clinical setting for determining patient eligibility for and adequate drug dosing in molecularly targeted cancer therapies. (C) RSNA, 2008. C1 [Mahmood, Umar] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Mahmood, U (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Simches 8226,185 Cambridge St, Boston, MA 02114 USA. EM mahmood@helix.mgh.harvard.edu FU NIH [R01-EB001872, R01-EB004472, R24-CA92782, P50-CA86355.] FX From the Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Simches 8226, 185 Cambridge St, Boston, MA 02114. Received August 22, 2007; revision requested October 10; revision received November 16; accepted December 28; final version accepted March 3, 2008. Supported by Susan G. Komen for the Cure and by NIH grants R01-EB001872, R01-EB004472, R24-CA92782, and P50-CA86355. NR 30 TC 45 Z9 47 U1 2 U2 12 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 SEP PY 2008 VL 248 IS 3 BP 925 EP 935 DI 10.1148/radiol.2482071496 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338XA UT WOS:000258541500030 PM 18647846 ER PT J AU Nair, RT vanSonnenberg, E Shankar, S Morrison, PR Gill, RR Tuncali, K Silverman, SG AF Nair, Rashmi T. vanSonnenberg, Eric Shankar, Sridhar Morrison, Paul R. Gill, Ritu Randhawa Tuncali, Kemal Silverman, Stuart G. TI Visceral and soft-tissue tumors: Radiofrequency and alcohol ablation for pain relief - Initial experience SO RADIOLOGY LA English DT Article ID METASTASES INVOLVING BONE; CANCER; MULTICENTER; INJECTION AB Purpose: To determine retrospectively the effectiveness of percutaneous radiofrequency ablation (RFA) alone, alcohol ablation alone, or combined RFA and alcohol ablation (hereafter, combined ablation) to treat pain in patients with visceral and soft-tissue malignancies. Materials and Methods: This HIPAA-compliant study was institutional review board approved; the informed consent requirement was waived. Twenty patients, with 28 tumors, who underwent percutaneous computed tomography (CT) or magnetic resonance (MR)-guided RFA and/or alcohol ablation for pain relief over a 2-year period were retrospectively identified, and their medical and imaging data were studied: Nineteen patients were referred for ablation because of persistent pain despite use of analgesics, and one patient had refused analgesics. The 28 tumors were located in the liver, lung, adrenal gland, retroperitoneum, gluteal muscle, inguinal mass, and subcutaneous tissues on the back. Fifteen tumors were treated with RFA alone, 12 were treated with combined ablation (when lesions were > 4 cm in diameter, except in lung or renal tumors), and one was treated with alcohol ablation alone. Pain was quantified on a 0-10 scale before, 1 day after, and 1-6 weeks after ablation. On the basis of changes in pain score and pain medication use, pain was reported with a composite measure as complete, partial, or no pain response. Quantitative pain scale values were compared by using Friedman and Tukey post hoc tests to assess significant changes. Results: At 1-6-week follow-up, pain relief was complete in nine patients (45%) and partial in six (30%); pain relief did not occur in five patients (25%). There was a significant (P < .05) decrease in pain at 1-day and 1-6-week follow-up compared with pain at baseline. Three adverse events were caused by therapy: Two were major complications (femoral neuropathy in one patient, perinephric hematoma and hemobilia in one patient), and one was a side effect of ablation (right shoulder pain) that resolved spontaneously. Conclusion: Percutaneous RFA alone or in combination with alcohol ablation provided pain relief from visceral tumors in most patients with intractable pain. (C) RSNA, 2008. C1 [Nair, Rashmi T.; vanSonnenberg, Eric; Shankar, Sridhar; Morrison, Paul R.; Gill, Ritu Randhawa; Tuncali, Kemal; Silverman, Stuart G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Dept Radiol, Boston, MA 02115 USA. RP vanSonnenberg, E (reprint author), St Josephs Hosp, Dept Radiol, 350 W Thomas Rd, Phoenix, AZ 85013 USA. EM ericvansonnenberg@yahoo.com NR 15 TC 8 Z9 9 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 SEP PY 2008 VL 248 IS 3 BP 1067 EP 1076 DI 10.1148/radiol.2483061883 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338XA UT WOS:000258541500047 PM 18710995 ER PT J AU Neal, JM Bernards, CM Hadzic, A Hebl, JR Hogan, QH Horlocker, TT Lee, LA Rathmell, JP Sorenson, EJ Suresh, S Wedel, DJ AF Neal, Joseph M. Bernards, Christopher M. Hadzic, Admir Hebl, James R. Hogan, Quinn H. Horlocker, Terese T. Lee, Lorri A. Rathmell, James P. Sorenson, Eric J. Suresh, Santhanarn Wedel, Denise J. TI ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine SO REGIONAL ANESTHESIA AND PAIN MEDICINE LA English DT Article DE complications of anesthesia; nerve injury; spinal anesthesia; epidural anesthesia; peripheral nerve block; regional anesthesia; pain medicine; transforaminal block ID CERVICAL TRANSFORAMINAL INJECTION; PREVIOUS SPINAL SURGERY; BRACHIAL-PLEXUS BLOCK; NEURAXIAL ANESTHESIA; INTERSCALENE BLOCK; NERVE-STIMULATION; INTERVERTEBRAL FORAMINA; MULTIPLE-SCLEROSIS; EPIDURAL INJECTION; LOCAL-ANESTHETICS AB Neurologic complications associated with regional anesthesia and pain medicine practice are extremely rare. The ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine addresses the etiology, differential diagnosis, prevention, and treatment of these complications. This Advisory does not focus on hemorrhagic and infectious complications, because they have been addressed by other recent ASRA Practice Advisories. The current Practice Advisory offers recommendations to aid in the understanding and potential limitation of neurologic complications that may arise during the practice of regional anesthesia and pain medicine. C1 [Neal, Joseph M.; Bernards, Christopher M.] Virginia Mason Med Ctr, Dept Anesthesiol, Seattle, WA 98101 USA. [Neal, Joseph M.; Bernards, Christopher M.; Lee, Lorri A.] Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA. [Hadzic, Admir] St Lukes Roosevelt Hosp, Dept Anesthesiol, New York, NY USA. [Hebl, James R.; Horlocker, Terese T.; Wedel, Denise J.] Mayo Clin, Dept Anesthesiol, Rochester, MN USA. [Sorenson, Eric J.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Hogan, Quinn H.] Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Suresh, Santhanarn] Northwestern Univ, Childrens Mem Hosp, Dept Anesthesiol, Chicago, IL 60614 USA. RP Neal, JM (reprint author), Virginia Mason Med Ctr, Dept Anesthesiol, Seattle, WA 98101 USA. FU NINDS NIH HHS [R01 NS042150, R01 NS042150-05A2] NR 65 TC 110 Z9 112 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-7339 EI 1532-8651 J9 REGION ANESTH PAIN M JI Region. Anesth. Pain Med. PD SEP-OCT PY 2008 VL 33 IS 5 BP 404 EP 415 DI 10.1016/j.rapm.2008.07.527 PG 12 WC Anesthesiology SC Anesthesiology GA 353BC UT WOS:000259540100003 PM 18774509 ER PT J AU Gianetti, E Seminara, S AF Gianetti, Elena Seminara, Stephanie TI Kisspeptin and KISS1R: a critical pathway in the reproductive system SO REPRODUCTION LA English DT Review ID GONADOTROPIN-RELEASING-HORMONE; METASTASIS-SUPPRESSOR GENE; PROTEIN-COUPLED RECEPTOR; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; DIABETIC MALE-RATS; RIBONUCLEIC-ACID EXPRESSION; PITUITARY-GONADAL AXIS; MONKEY MACACA-MULATTA; NEUROBIOLOGICAL MECHANISMS; DOWN-REGULATION AB In 2003, three groups around the world simultaneously discovered that KISS1R (GPR54) is a key gatekeeper of sexual maturation in both mice and men. Developmental changes in the expression of the ligand for KISS1R, kisspeptin, support its critical role in the pubertal transition. In addition, kisspeptin, a powerful stimulus of GNRH-induced gonadotropin secretion and may modulate both positive and negative sex steroid feedback effects at the hypothalamic level. Genetic studies in humans have revealed both loss-of-function and gain-of-function mutations in patients with idiopathic hypogonadotropic hypogonadism and precocious puberty respectively. This review examines the kisspeptin/KISS1R pathway in the reproductive system. C1 [Gianetti, Elena; Seminara, Stephanie] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. RP Gianetti, E (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM egianetti@partners.org FU NICHD NIH HHS [U54 HD028138, R01 HD043341, R01 HD043341-07, U54 HD028138-195884] NR 70 TC 24 Z9 27 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD SEP PY 2008 VL 136 IS 3 BP 295 EP 301 DI 10.1530/REP-08-0091 PG 7 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 359KW UT WOS:000259986600002 PM 18515314 ER PT J AU Medina-Lezama, J Morey-Vargas, OL Zea-Diaz, H Bolanos-Salazar, JF Corrales-Medina, F Cuba-Bustinza, C Chirinos-Medina, DA Chirinos, JA AF Medina-Lezama, Josefina Morey-Vargas, Oscar L. Zea-Diaz, Humberto Bolanos-Salazar, Juan F. Corrales-Medina, Fernando Cuba-Bustinza, Carolina Chirinos-Medina, Diana A. Chirinos, Julio A. TI Prevalence of lifestyle-related cardiovascular risk factors in Peru: the PREVENCION study SO REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article DE Alcohol drinking; cardiovascular diseases; diet; physical activity; prevalence; risk factors; smoking; Peru ID PHYSICAL-ACTIVITY QUESTIONNAIRE; ACUTE MYOCARDIAL-INFARCTION; ISCHEMIC-HEART-DISEASE; ALCOHOL-CONSUMPTION; BINGE DRINKING; LATIN-AMERICA; EPIDEMIOLOGIC TRANSITION; POPULATION; HEALTH; MORTALITY AB Objectives. To estimate the prevalence of lifestyle-related cardiovascular risk factors in the adult population of Arequipa, the second largest city in Peru. Methods. The prevalence and patterns of smoking, alcohol drinking, lack of physical activity, high-fat diet, and low fruit and vegetable intake were evaluated among 1 878 subjects (867 men and 1 011 women) in a population-based study. Results. The age-standardized prevalence of current smoking, former smoking, and never smoking were 21.6%, 14.3%, and 64.1%, respectively. The prevalence of current smoking was significantly higher in men than women (31.1% vs. 12.1%; P < 0.01). The prevalence of current alcohol use was 37.7% and significantly higher in men than women (55.5% vs. 19.7%; P < 0.01). Similarly, the prevalence of binge drinking was 21.2%, and the percentage of men who binge drink (36.1%) was significantly higher than for women (6.4%; P < 0.01). The vast majority of alcohol drinkers reported a pattern of alcohol consumption mainly on weekends and holidays rather than regular drinking with meals during the week. The proportion of insufficiently active people was 57.6% and was significantly higher in women than men (63.3% vs. 51.9%; P < 0.01). Overall, 42.0% of adults reported consuming high-fat diets, 34.5% reported low fruit intake, and 33.3% reported low vegetable intake. Conclusions. The high prevalence of lifestyle-related cardiovascular risk factors found in this Andean population is of concern. Preventive programs are urgently needed to deal with this growing problem. C1 [Medina-Lezama, Josefina; Morey-Vargas, Oscar L.; Zea-Diaz, Humberto; Bolanos-Salazar, Juan F.; Corrales-Medina, Fernando; Cuba-Bustinza, Carolina; Chirinos-Medina, Diana A.] Santa Maria Catholic Univ, Sch Med, Arequipa, Peru. [Medina-Lezama, Josefina; Morey-Vargas, Oscar L.; Zea-Diaz, Humberto; Bolanos-Salazar, Juan F.; Corrales-Medina, Fernando; Cuba-Bustinza, Carolina; Chirinos-Medina, Diana A.] Santa Maria Catholic Univ, Sch Psychol, Arequipa, Peru. [Medina-Lezama, Josefina; Morey-Vargas, Oscar L.; Zea-Diaz, Humberto; Bolanos-Salazar, Juan F.; Corrales-Medina, Fernando; Cuba-Bustinza, Carolina; Chirinos-Medina, Diana A.] Santa Maria Catholic Univ, Santa Maria Res Inst, Arequipa, Peru. [Chirinos, Julio A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Chirinos, JA (reprint author), Philadelphia VA Med Ctr, Div Cardiol, 8B111,3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Julio.chirinos@uphs.upenn.edu NR 52 TC 16 Z9 17 U1 0 U2 0 PU PAN AMER HEALTH ORGANIZATION PI WASHINGTON PA 525 23RD ST NW, WASHINGTON, DC 20037 USA SN 1020-4989 J9 REV PANAM SALUD PUBL JI Rev. Panam. Salud Publica PD SEP PY 2008 VL 24 IS 3 BP 169 EP 179 DI 10.1590/S1020-49892008000900003 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 361ZR UT WOS:000260168500003 PM 19115544 ER PT J AU Bertram, L AF Bertram, Lars TI Genetic research in schizophrenia: New tools and future perspectives SO SCHIZOPHRENIA BULLETIN LA English DT Article DE epidemiologic methods; genetic associations; meta-analysis; schizophrenia ID GENOME-WIDE ASSOCIATION; SYSTEMATIC METAANALYSES; BIPOLAR DISORDER; REELIN GENE; DISEASE; LINKAGE; SUSCEPTIBILITY; REPLICATION; DATABASE; FALSE AB Genetically, schizophrenia is a complex disease whose pathogenesis is likely governed by a number of different risk factors. While substantial efforts have been made to identify the underlying susceptibility alleles over the past 2 decades, they have been of only limited success. Each year, the field is enriched with nearly 150 additional genetic association studies, each of which either proposes or refutes the existence of certain schizophrenia genes. To facilitate the evaluation and interpretation of these findings, we have recently created a database for genetic association studies in schizophrenia ("SzGene"; available at http://www.szgene.org). In addition to systematically screening the scientific literature for eligible studies, SzGene also reports the results of allele-based meta-analyses for polymorphisms with sufficient genotype data. Currently, these meta-analyses highlight not only over 20 different potential schizophrenia genes, many of which represent the "usual suspects" (eg, various dopamine receptors and neuregulin 1), but also several that were never meta-analyzed previously. All the highlighted loci contain at least one variant showing modest (summary odds ratios approximately 1.20 [range 1.06-1.45]) but nominally significant risk effects. This review discusses some of the strengths and limitations of the SzGene database, which could become a useful bioinformatics tool within the schizophrenia research community. C1 [Bertram, Lars] Massachusetts Gen Hosp, Genet & Aging Res Unit, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Bertram, L (reprint author), Massachusetts Gen Hosp, Genet & Aging Res Unit, Dept Neurol, MGH E MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM bertram@helix.mgh.harvard.edu RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X FU National Alliance on Research in Schizophrenia and Depression FX National Alliance on Research in Schizophrenia and Depression (to L.B.). NR 26 TC 26 Z9 26 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2008 VL 34 IS 5 BP 806 EP 812 DI 10.1093/schbul/sbn079 PG 7 WC Psychiatry SC Psychiatry GA 349ZQ UT WOS:000259322600003 PM 18644854 ER PT J AU Horan, WP Blanchard, JJ Clark, LA Green, MF AF Horan, William P. Blanchard, Jack J. Clark, Lee Anna Green, Michael F. TI Affective traits in schizophrenia and schizotypy SO SCHIZOPHRENIA BULLETIN LA English DT Review DE schizophrenia; schizotypy; emotion; affective traits; review ID QUALITY-OF-LIFE; PSYCHOSIS PRONENESS SCALES; RECENT-ONSET SCHIZOPHRENIA; TRIDIMENSIONAL PERSONALITY QUESTIONNAIRE; HIGH-RISK PROJECT; 5-FACTOR MODEL; SOCIAL ANHEDONIA; NEGATIVE SYMPTOMS; SCHIZOAFFECTIVE DISORDER; INDIVIDUAL-DIFFERENCES AB This article reviews empirical studies of affective traits in individuals with schizophrenia spectrum disorders, population-based investigations of vulnerability to psychosis, and genetic and psychometric high-risk samples. The review focuses on studies that use self-report trait questionnaires to assess Negative Affectivity (NA) and Positive Affectivity (PA), which are conceptualized in contemporary models of personality as broad, temperamentally-based dispositions to experience corresponding emotional states. Individuals with schizophrenia report a pattern of stably elevated NA and low PA throughout the illness course. Among affected individuals, these traits are associated with variability in several clinically important features, including functional outcome, quality of life, and stress reactivity. Furthermore, evidence that elevated NA and low PA (particularly the facet of anhedonia) predict the development of psychosis and are detectable in high-risk samples suggests that these traits play a role in vulnerability to schizophrenia, though they are implicated in other forms of psychopathology as well. Results are discussed in terms of their implications for treatment, etiological models, and future research to advance the study of affective traits in schizophrenia and schizotypy. C1 [Horan, William P.; Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Blanchard, Jack J.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Clark, Lee Anna] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Green, Michael F.] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Horan, WP (reprint author), 300 UCLA Med Plaza,Suite 2240, Los Angeles, CA 90095 USA. EM horan@ucla.edu FU National Institute of Mental Health [MH-077141, MH-079231, MH-43292, MH-65707] FX National Institute of Mental Health (MH-077141 to Horan; MH-079231 to Blanchard; MH-43292, MH-65707 to Green). NR 217 TC 129 Z9 129 U1 5 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2008 VL 34 IS 5 BP 856 EP 874 DI 10.1093/schbul/sbn083 PG 19 WC Psychiatry SC Psychiatry GA 349ZQ UT WOS:000259322600009 PM 18667393 ER PT J AU Phillips, LK Seidman, LJ AF Phillips, Laura K. Seidman, Larry J. TI Emotion processing in persons at risk for schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Review DE high risk; schizophrenia; emotion; review ID RANDOMIZED CONTROLLED-TRIAL; DORSOLATERAL PREFRONTAL CORTEX; SCHIZOTYPAL PERSONALITY; 1ST-DEGREE RELATIVES; SOCIAL ANHEDONIA; PSYCHOSIS PRODROME; FACIAL EXPRESSION; WORKING-MEMORY; PERSECUTORY DELUSIONS; TAXOMETRIC ANALYSIS AB Evidence suggests that individuals with schizophrenia demonstrate emotion-processing deficits. However, the nature and extent of emotion abnormalities in individuals considered at risk for schizophrenia have not been previously summarized. This article provides a review of the recent literature pertaining to emotion processing in 3 at-risk populations: those at familial high risk, those with schizotypal characteristics, and those in the putative prodrome to psychosis. Studies are reviewed across the components of emotion perception, experience, and expression. Further, we discuss investigations into psychophysiology, brain structure, and brain function that employ emotion probes. Review of the literature suggests that individuals at high risk demonstrate similar abnormalities to those with schizophrenia but at an attenuated level. The most robust findings in at-risk groups are in the areas of reduced emotion perception, self-reported anhedonia, and increased negative affect. We conclude with an agenda for future research. C1 [Phillips, Laura K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Phillips, Laura K.; Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Dept Psychiat,Publ Psychiat Div,Sch Med, Cambridge, MA 02138 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Phillips, LK (reprint author), Harvard Univ, Dept Psychol, William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM laurak.phillips@gmail.com FU National Research Service Award [F31 MH073279-01]; National Institute of Mental Health [MH-43518, MH-63951, MH-65562] FX Sackler Scholar in Psychobiology Research grant; a Harvard University Research grant; National Institutes of Health predoctoral National Research Service Award (F31 MH073279-01); a Scudder Association grant (to L.K.P.); 2 National Association for Research in Schizophrenia and Depression Independent Investigator Awards including support from Donald and Jean Stone, "Specificity of Pre-illness Vulnerability in Bipolar Disorder versus Schizophrenia"; the Stanley Medical Research Institute; the Mental Illness Neuroscience Discovery Foundation; National Institute of Mental Health grants (MH-43518, MH-63951, and MH-65562) (to L.J.S.). NR 117 TC 87 Z9 89 U1 8 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2008 VL 34 IS 5 BP 888 EP 903 DI 10.1093/schbul/sbn085 PG 16 WC Psychiatry SC Psychiatry GA 349ZQ UT WOS:000259322600011 PM 18644853 ER PT J AU Leyba, L Mayer, AR Gollub, RL Andreasen, NC Clark, VP AF Leyba, Leonard Mayer, Andrew R. Gollub, Randy L. Andreasen, Nancy C. Clark, Vincent P. TI Smoking status as a potential confound in the BOLD response of patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; functional magnetic resonance imaging; cigarette; nicotine; atherosclerosis; vascular disease ID CAROTID-ARTERY ATHEROSCLEROSIS; BASE-LINE HEMATOCRIT; CEREBRAL BLOOD-FLOW; CIGARETTE-SMOKING; FUNCTIONAL MRI; FMRI DATA; HEMODYNAMIC-RESPONSES; BRAIN ACTIVATION; TEST-RETEST; SIGNAL AB Background: Functional magnetic resonance imaging (FMRI) studies comparing schizophrenia patients and controls may have been confounded by the vascular effects of heavier long-term cigarette use in patients. Methods: The blood oxygen level dependent (BOLD) response to a simple sensorimotor task was compared between schizophrenia patient with a smoking history (mean 17 pack years) and carefully matched patient non-smokers and control non-smokers. Results: Group differences in activation magnitude and spatial extent were non-significant. Conclusions: Typical smoking histories in schizophrenia patients do not significantly confound FMRI results ill simple sensorimotor tasks when patient demographics are carefully controlled. (C) 2008 Elsevier B.V. All rights reserved. C1 [Leyba, Leonard; Mayer, Andrew R.; Gollub, Randy L.; Andreasen, Nancy C.; Clark, Vincent P.] Mind Res Network, Albuquerque, NM 87131 USA. [Leyba, Leonard; Clark, Vincent P.] Univ New Mexico, Hlth Sci Ctr, Dept Neurosci, Albuquerque, NM 87131 USA. [Mayer, Andrew R.] Univ New Mexico, Hlth Sci Ctr, Dept Neurol, Albuquerque, NM 87131 USA. [Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Andreasen, Nancy C.] Univ Iowa, Roy J & Lucille A Carver Col Med, Dept Psychiat, Iowa City, IA USA. [Clark, Vincent P.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Clark, VP (reprint author), Mind Res Network, Pete & Nancy Domenici Hall,1101 Yale Blvd NE, Albuquerque, NM 87131 USA. EM lleyba@salud.unm.edu; amayer@mm.org; rgollub@partners.org; andreasen@uiowa.edu; vclark@mrn.org RI Clark, Vincent/B-3343-2010; OI Clark, Vincent/0000-0002-9151-2102; Gollub, Randy L./0000-0002-9434-4044 FU NCRR NIH HHS [UL1 RR024979]; NIDA NIH HHS [R01 DA012852, R01 DA012852-05] NR 49 TC 4 Z9 4 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2008 VL 104 IS 1-3 BP 79 EP 84 DI 10.1016/j.schres.2008.06.008 PG 6 WC Psychiatry SC Psychiatry GA 357XE UT WOS:000259879700009 PM 18684594 ER PT J AU Meda, SA Bhattarai, M Morris, NA Astur, RS Calhoun, VD Mathalon, DH Kiehl, KA Pearlson, GD AF Meda, Shashwath A. Bhattarai, Manish Morris, Nicholas A. Astur, Robert S. Calhoun, Vince D. Mathalon, Daniel H. Kiehl, Kent A. Pearlson, Godfrey D. TI An fMRI study of working memory in first-degree unaffected relatives of schizophrenia patients SO SCHIZOPHRENIA RESEARCH LA English DT Article DE fMRI; prefrontal cortex; Sternberg; working memory; schizophrenia; relatives ID DORSOLATERAL PREFRONTAL CORTEX; CONTEXT-PROCESSING DEFICITS; NONPSYCHOTIC RELATIVES; INDIVIDUAL-DIFFERENCES; CLINICAL SYMPTOMS; BRAIN; SIBLINGS; TASKS; MANIPULATION; MAINTENANCE AB Identifying intermediate phenotypes of genetically complex psychiatric illnesses such as schizophrenia is important. First-degree relatives of persons with schizophrenia have increased genetic risk for the disorder and tend to show deficits on working memory (WM) tasks. An open question is the relationship between such behavioral endophenotypes and the Corresponding brain activation patterns revealed during functional imaging. We measured task performance during a Sternberg WM task and used functional magnetic resonance imaging (fMRI) to assess whether 23 non-affected first-degree relatives showed altered performance and functional activation compared to 43 matched healthy controls. We predicted that a significant proportion of unaffected first-degree relatives would show either aberrant task performance and/or abnormal related fMRI blood oxygen level dependent (BOLD) patterns. While task performance in the relatives was not different than that of controls they were significantly slower in responding to probes., Schizophrenia relatives displayed reduced activation, most markedly in bilateral dorsolateral/ventrolateral (DLPFC/VLPFC) prefrontal and posterior parietal cortex when encoding stimuli and in bilateral DLPFC and parietal areas during response selection. Additionally, fMRI differences in both conditions were modulated by load, with a parametric increase in between-group differences with load in several key regions during encoding and an opposite effect during response selection. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meda, Shashwath A.; Bhattarai, Manish; Morris, Nicholas A.; Astur, Robert S.; Calhoun, Vince D.; Kiehl, Kent A.; Pearlson, Godfrey D.] Hartford Hosp, Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT 06106 USA. [Astur, Robert S.; Calhoun, Vince D.; Kiehl, Kent A.; Pearlson, Godfrey D.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Calhoun, Vince D.; Pearlson, Godfrey D.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. [Calhoun, Vince D.; Kiehl, Kent A.] MIND Res Network, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Meda, SA (reprint author), 200 Retreat Ave, Hartford, CT 06106 USA. EM smeda01@harthosp.org RI Calhoun, Vince/H-7146-2013; OI Calhoun, Vince/0000-0001-9058-0747; Mathalon, Daniel/0000-0001-6090-4974 FU NIMH NIH HHS [R01 MH052886-07, MH43326, MH43775, MH52886, MH60504, R01 MH043326, R01 MH043326-10, R01 MH043326-11, R01 MH043775, R01 MH043775-09A1, R01 MH043775-10, R01 MH043775-11, R01 MH043775-11S1, R01 MH043775-12, R01 MH043775-13, R01 MH052886, R01 MH052886-03, R01 MH052886-04A1, R01 MH052886-05, R01 MH052886-06, R01 MH052886-08, R01 MH060504, R01 MH060504-04, R01 MH060504-05, R01 MH060504-06, R01 MH060504-07, R01 MH060504-08, R01 MH085010, R37 MH043775, R37 MH043775-17] NR 45 TC 37 Z9 39 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2008 VL 104 IS 1-3 BP 85 EP 95 DI 10.1016/j.schres.2008.06.013 PG 11 WC Psychiatry SC Psychiatry GA 357XE UT WOS:000259879700010 PM 18678469 ER PT J AU Takahashi, S Cui, YH Han, YH Fagerness, JA Galloway, B Shen, YC Kojima, T Uchiyama, M Faraone, SV Tsuang, MT AF Takahashi, Sakae Cui, Yu-hu Han, Yong-hua Fagerness, Jesen A. Galloway, Brian Shen, Yu-cun Kojima, Takuya Uchiyama, Makoto Faraone, Stephen V. Tsuang, Ming T. TI Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; chromosome 22; APOL gene family cluster; APOL1; AOPL2; APOL4 ID D22S278 MARKER ALLELES; GENOME-WIDE SEARCH; SUSCEPTIBILITY LOCUS; TRANSMISSION DISEQUILIBRIUM; AFRICAN-AMERICAN; LINKAGE ANALYSIS; CHROMOSOME-22; FAMILY; GENE; HETEROGENEITY AB Prior work found the A POL1, 2 and 4 genes, located on chromosome 22q12.3-q113.1, to be upreaulated in brains of schizophrenic patients, We performed a family-based association study using 130 SNPs tagging the APOL gene family (APOL1-6). The Subjects were 112 African-American (AA), 114 European-American (EA), 109 Chinese (Ch) and 42 Japanese (Jp) families with schizophrenia (377 families, 1161 genotyped members and 647 genotyped affected in total). Seven SNPs had p-values< 0.05 in the APOL1, 2 and 4 regions for the AA, EA and combined (AA and EA) samples. In the AA sample, two SNPs, rs9610449 and rs6000200 showed low p-values; and a haplotype which comprised these two SNPs yielded a p-value of 0.00029 using the global test (GT) and the allele specific test (AST). The two SNPs and the haplotype were associated with risk for schizophrenia in African-Americans. In the combined (AA and EA) sample, two SNPs, rs2003813 and rs2157249 showed low p-values; and a three SNP haplotype including these two SNPs was significant using the GT (p = 0.0013) and the AST (p = 0.000090). The association of this haplotype with schizophrenia was significant for the entire (AA, EA, Ch and Jp) sample using the GT (p = 0.00054) and the AST (p = 0.00011). Although our study is not definitive, it suggests that the APOL genes should be more extensively studied in schizophrenia, (C) 2008 Elsevier B.V. All rights reserved. C1 [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, La Jolla, CA 92093 USA. [Takahashi, Sakae; Kojima, Takuya; Uchiyama, Makoto] Nihon Univ, Sch Med, Dept Psychiat, Div Psychiat, Tokyo, Japan. [Tsuang, Ming T.] Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA 02115 USA. [Tsuang, Ming T.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tsuang, Ming T.] Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. [Tsuang, Ming T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tsuang, Ming T.] Univ Calif San Diego, San Diego, CA 92103 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Neurosci & Physiol, Syracuse, NY USA. [Fagerness, Jesen A.; Galloway, Brian] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA USA. [Fagerness, Jesen A.; Galloway, Brian] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Charlestown, MA USA. [Cui, Yu-hu; Han, Yong-hua; Shen, Yu-cun] Peking Univ, Inst Mental Hlth, Beijing, Peoples R China. RP Tsuang, MT (reprint author), Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, MTF 453,MC 0603,9500 Gilman Dr, La Jolla, CA 92093 USA. EM mtsuang@ucsd.edu OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R01MH43518, 1 R01MH41874-01, 1 R37MH43518, 5 U01MH46318, R01 MH043518, R01 MH044292, R01MH44292, R01MH59624, R01MH60485, R25 MH060485, R25MH60485, R37 MH043518, U01 MH046276, U01 MH046289, U01 MH046318, U01 MH046318-08] NR 22 TC 9 Z9 11 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2008 VL 104 IS 1-3 BP 153 EP 164 DI 10.1016/j.schres.2008.05.028 PG 12 WC Psychiatry SC Psychiatry GA 357XE UT WOS:000259879700017 PM 18632255 ER PT J AU Hough, S AF Hough, Sigmund TI From the editor SO SEXUALITY AND DISABILITY LA English DT Editorial Material C1 VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, W Roxbury, MA 02132 USA. RP Hough, S (reprint author), VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Sigmund_Hough@hms.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD SEP PY 2008 VL 26 IS 3 BP 121 EP 121 DI 10.1007/s11195-008-9087-7 PG 1 WC Rehabilitation SC Rehabilitation GA 338YU UT WOS:000258546100001 ER PT J AU Hough, S AF Hough, Sigmund TI Waguih William Ishak, the guidebook of sexual medicine SO SEXUALITY AND DISABILITY LA English DT Book Review C1 [Hough, Sigmund] VA Boston Healthcare System, Spinal Cord Injury Serv SCI 128, W Roxbury, MA 02132 USA. [Hough, Sigmund] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Hough, Sigmund] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Hough, S (reprint author), VA Boston Healthcare System, Spinal Cord Injury Serv SCI 128, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM sigmund_hough@hms.harvard.edu OI IsHak, Waguih/0000-0003-1970-4756 NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD SEP PY 2008 VL 26 IS 3 BP 183 EP 184 DI 10.1007/s11195-008-9086-8 PG 2 WC Rehabilitation SC Rehabilitation GA 338YU UT WOS:000258546100009 ER PT J AU Huang, YM Pliego, JF Henrichs, B Bowyer, MW Siddall, VJ McGaghie, WC Raemer, DB AF Huang, Yue Ming Pliego, Jose F. Henrichs, Bernadette Bowyer, Mark W. Siddall, Viva J. McGaghie, William C. Raemer, Daniel B. CA 2007 Summit Consortium TI 2007 Simulation Education Summit SO SIMULATION IN HEALTHCARE LA English DT Editorial Material AB The Society for Simulation in Healthcare convened the second Simulation Education Summit meeting in October 2007 in Chicago, Illinois. The purpose of the Summit was to bring together leaders of public, private, and government organizations, associations, and agencies involved in healthcare education for a focused discussion of standards for simulation-based applications. Sixty-eight participants representing 36 organizations discussed in structured small and large groups the criteria needed for various training and assessment applications using simulation. Although consensus was reached for many topics, there were also areas that required further thought and dialogue. This article is a summary of the results of these discussions along with a preliminary draft of a guideline for simulation-based education. (Sim Healthcare 3: 186-191, 2008) C1 [Huang, Yue Ming] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Pliego, Jose F.] Texas A&M Univ Syst HSC Coll Med, Sect Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, College Stn, TX USA. [Henrichs, Bernadette] Barnes Jewish Coll Nursing, Dept Anesthesiol, St Louis, MO USA. [Henrichs, Bernadette] Washington Univ, St Louis, MO USA. [Bowyer, Mark W.] Uniformed Serv Univ Hlth Sci, Dept Surg, Div Trauma & Combat Surg, Bethesda, MD 20814 USA. [Siddall, Viva J.] Amer Coll Chest Phys, Northbrook, IL USA. [McGaghie, William C.] Northwestern Univ, Feinberg Sch Med, Off Med Educ, Chicago, IL 60611 USA. [Raemer, Daniel B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Med Simulat,Dept Anesthesia & Crit Care, Boston, MA USA. RP Huang, YM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, 10833 Le Conte Ave,BH-428 CHS, Los Angeles, CA 90095 USA. EM yhuang@mednet.ucla.edu OI McGaghie, William/0000-0003-1672-0398 NR 17 TC 1 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-2332 J9 SIMUL HEALTHC JI Simul. Healthc. PD FAL PY 2008 VL 3 IS 3 BP 186 EP 191 DI 10.1097/SIH.0b013e3181828156 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA V11MR UT WOS:000207536200010 PM 19088663 ER PT J AU Nichols, AC Chan, AW Curry, WT Barker, FG Deschler, DG Lin, DT AF Nichols, Anthony C. Chan, Annie W. Curry, William T. Barker, Fred G., II Deschler, Daniel G. Lin, Derrick T. TI Esthesioneuroblastoma: The Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital Experience with Craniofacial Resection, Proton Beam Radiation, and Chemotherapy SO SKULL BASE-AN INTERDISCIPLINARY APPROACH LA English DT Article DE Esthesioneuroblastoma; proton radiation; craniofacial resection ID OLFACTORY NEUROBLASTOMA; SKULL BASE; NEUROENDOCRINE CARCINOMA; FOLLOW-UP; THERAPY; MANAGEMENT AB Objectives: To determine the efficacy of craniofacial resection and proton radiation for the management of esthesioneuroblastoma (ENB). Design: A retrospective chart review was performed of all patients presenting with ENB and completely managed at the Massachusetts General Hospital (MGH) and the Massachusetts Eye and Ear Infirmary (MEEI) from 1997 to 2006. Setting: A tertiary referral center. Main Outcome Measures: Disease-free and overall survival. Participants: All patients presenting with ENB and completely managed at the MGH and the MEEI from 1997 to 2006. Results: Ten patients were identified with a median follow-up time of 52.8 months. Average age at presentation was 45 years. Nasal obstruction was the most common presenting symptom. Three patients presented with Kadish stage B disease and seven with stage C. No patient had evidence of cervical or metastatic disease at presentation. Seven patients were treated with craniofacial resections (CFR) followed by proton beam radiation with or without chemotherapy. Three patients were treated with initial chemotherapy with no response. They subsequently underwent CFR followed by proton beam radiation. The 5-year disease-free and overall survival rates were 90% and 85.7%, respectively, by Kaplan-Meier analysis. No patient suffered any severe radiation toxicity. Conclusion: ENB can be safely and effectively treated with CFR followed by proton beam irradiation. Proton irradiation may be associated with less toxicity than photon irradiation. The role of chemotherapy remains unclear. C1 [Nichols, Anthony C.; Deschler, Daniel G.; Lin, Derrick T.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Chan, Annie W.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Curry, William T.; Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Nichols, AC (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Anthony_Nichols@meei.harvard.edu NR 36 TC 19 Z9 19 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1531-5010 J9 SKULL BASE-INTERD AP JI Skull Base-Interdiscip. Appr. PD SEP PY 2008 VL 18 IS 5 BP 327 EP 337 DI 10.1055/s-2008-1076098 PG 11 WC Clinical Neurology; Otorhinolaryngology; Surgery SC Neurosciences & Neurology; Otorhinolaryngology; Surgery GA 363FM UT WOS:000260253200005 PM 19240832 ER PT J AU Alessi, CA Martin, JL Webber, AP Alam, T Littner, MR Harker, JO Josephson, KR AF Alessi, Cathy A. Martin, Jennifer L. Webber, Adam P. Alam, Tarannum Littner, Michael R. Harker, Judith O. Josephson, Karen R. TI More daytime sleeping predicts less functional recovery among older people undergoing inpatient post-acute rehabilitation SO SLEEP LA English DT Article DE sleep; aged; rehabilitation; recovery of function ID ILLNESS RATING-SCALE; HIP FRACTURE; STROKE REHABILITATION; CIRCADIAN-RHYTHMS; NURSING FACILITY; LONG-SLEEP; ADULTS; HEALTH; HOME; HOSPITALIZATION AB Study Objectives: To study the association between sleep/wake patterns among older adults during inpatient post-acute rehabilitation and their immediate and long-term functional recovery Design: Prospective, observational cohort study Setting: Two inpatient post-acute rehabilitation sites (one community and one Veterans Administration) Participants: Older patients (aged : 65 years, N = 245) admitted for inpatient post-acute rehabilitation Interventions: None Measurements and Results: Based on 7-day wrist actigraphy during the rehabilitation stay, mean nighttime percent sleep was only 52.2% and mean daytime percent sleep was 15.8% (16.3% based on structured behavioral observations). Using the Pittsburgh Sleep Quality Index (PSQI), participants reported their sleep was worse during rehabilitation compared to their premorbid sleep. Functional recovery between admission and discharge from rehabilitation (measured by the motor component of the Functional Independence Measure) was not significantly associated with reported sleep quality (PSQI scores) or actigraphically measured nighttime sleep. However, more daytime percent sleep (estimated by actigraphy and observations) during the rehabilitation stay was associated with less functional recovery from admission to discharge, even after adjusting for other significant predictors of functional recovery (mental status, hours of rehabilitation therapy received, rehospitalization, and reason for admission; adjusted R-2 = 0.267, P < 0.0001). More daytime sleeping during rehabilitation remained a significant predictor of less functional recovery in adjusted analyses at 3-month follow-up. Conclusions: Sleep disturbance is common among older people undergoing inpatient post-acute rehabilitation. These data suggest that more daytime sleeping during the rehabilitation stay is associated with less functional recovery for up to three months after admission for rehabilitation. C1 [Alessi, Cathy A.] GRECC, VA Med Ctr, Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. [Alessi, Cathy A.; Martin, Jennifer L.; Webber, Adam P.; Littner, Michael R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Littner, Michael R.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Alessi, CA (reprint author), GRECC, VA Med Ctr, Vet Adm Greater Los Angeles Healthcare Syst, 11E,16111 Plummer St,N Hills, Sepulveda, CA 91343 USA. EM cathy.alessi@va.gov FU Veterans Administration Health Services Research and Development Service [11R 01-053-1, AIA 03047]; Veterans Administration Greater Los Angeles Healthcare System Geriatric Research, Education and Clinical Center (GRECC); UCLA Claude Pepper Older Americans Independence Center [AG-10415] FX Financial Support: Veterans Administration Health Services Research and Development Service (11R 01-053-1; AIA 03047); Veterans Administration Greater Los Angeles Healthcare System Geriatric Research, Education and Clinical Center (GRECC); and UCLA Claude Pepper Older Americans Independence Center (AG-10415) NR 43 TC 21 Z9 24 U1 3 U2 5 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 SEP 1 PY 2008 VL 31 IS 9 BP 1291 EP 1300 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 343YA UT WOS:000258891100012 PM 18788654 ER PT J AU Righart, R de Gelder, B AF Righart, Ruthger de Gelder, Beatrice TI Rapid influence of emotional scenes on encoding of facial expressions: an ERP study SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE context; face perception; emotion; event-related potentials; P1; N170 ID EVENT-RELATED POTENTIALS; BRAIN POTENTIALS; FACE PERCEPTION; VISUAL-CORTEX; CONTEXT; ATTENTION; AMYGDALA; STIMULI; OBJECTS; N170 AB In daily life, we perceive a persons facial reaction as part of the natural environment surrounding it. Because most studies have investigated how facial expressions are recognized by using isolated faces, it is unclear what role the context plays. Although it has been observed that the N170 for facial expressions is modulated by the emotional context, it was not clear whether individuals use context information on this stage of processing to discriminate between facial expressions. The aim of the present study was to investigate how the early stages of face processing are affected by emotional scenes when explicit categorizations of fearful and happy facial expressions are made. Emotion effects were found for the N170, with larger amplitudes for faces in fearful scenes as compared to faces in happy and neutral scenes. Critically, N170 amplitudes were significantly increased for fearful faces in fearful scenes as compared to fearful faces in happy scenes and expressed in left-occipito-temporal scalp topography differences. Our results show that the information provided by the facial expression is combined with the scene context during the early stages of face processing. C1 [Righart, Ruthger; de Gelder, Beatrice] Tilburg Univ, Dept Psychol, Cognit & Affect Neurosc Lab, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. RP de Gelder, B (reprint author), Tilburg Univ, Dept Psychol, Cognit & Affect Neurosc Lab, Warandelaan 2,POB 90153, NL-5000 LE Tilburg, Netherlands. EM B.deGelder@uvt.nl NR 47 TC 80 Z9 84 U1 5 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD SEP PY 2008 VL 3 IS 3 BP 270 EP 278 DI 10.1093/scan/nsn021 PG 9 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 348JQ UT WOS:000259207200011 PM 19015119 ER PT J AU Pichon, S de Gelder, B Grezes, J AF Pichon, Swann de Gelder, Beatrice Grezes, Julie TI Emotional modulation of visual and motor areas by dynamic body expressions of anger SO SOCIAL NEUROSCIENCE LA English DT Article ID FACIAL EXPRESSIONS; BIOLOGICAL MOTION; PREFRONTAL CORTEX; BRAIN-AREAS; FUSIFORM GYRUS; FRONTAL-CORTEX; HUMAN AMYGDALA; TIME-COURSE; PERCEPTION; RECOGNITION AB The ability to detect emotional meaning in others' behavior constitutes a central component of social competence. Expressions of anger in particular present salient signals that play a major role in the regulation of social interactions. Investigations of human anger signals have to date used still Pictures of facial expressions but so far the neurobiological basis of bodily communication of anger remains largely unknown. Using functional magnetic resonance imaging. the present Study investigated the neural bases involved in perceiving anger signals emanating from the whole body. Our study also investigates what the presence of dynamic information adds to the perception of body expressions of anger. Participants were scanned while viewing stimuli (stills or videos) of angry and neutral whole-body expressions. Whole-body expressions of anger elicit activity in regions including the amygdala and the lateral orbitofrontal cortex. which play a role in the affective evaluation of the stimuli. Importantly, the perception of dynamic body expressions of anger additionally engages the hypothalamus, the ventromedial prefrontal cortex, the temporal pole and the premotor cortex, brain regions that are coupled with autonomic reactions and motor responses related to defensive behaviors. C1 [Pichon, Swann; Grezes, Julie] Coll France, CNRS, LPPA, F-75005 Paris, France. [de Gelder, Beatrice] Donders Lab, Tilburg, Netherlands. [de Gelder, Beatrice] FC Donders Ctr, Nijmegen, Netherlands. [de Gelder, Beatrice] Harvard Univ, Sch Med, Charlestown, MA USA. [de Gelder, Beatrice] Massachusetts Gen Hosp, Charlestown, MA USA. RP Grezes, J (reprint author), Coll France, CNRS, LPPA, 11 Pl Marcelin Berthelot, F-75005 Paris, France. EM julie.grezes@college-de-france.fr RI pichon, swann/M-2966-2014; Grezes, Julie/E-5060-2016 OI pichon, swann/0000-0001-5697-702X; FU Human Frontier Science Program [HFSP-RGP0054/2004-C]; EC [FP6-NEST-2005-Path-IMP-043403]; NWO (Netherlands Organisation for Scientific Research) FX We are grateful to D. A. Hopkins for comments on the manuscript, to W. van de Riet for recruiting the subjects, P. Gaalman and F. Maloumian for technical assistance. NR 72 TC 73 Z9 73 U1 4 U2 14 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI JI Soc. Neurosci. PD SEP-DEC PY 2008 VL 3 IS 3-4 BP 199 EP 212 DI 10.1080/17470910701394368 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 382FE UT WOS:000261589800002 PM 18979376 ER PT J AU Basile, JN AF Basile, Jan N. TI Rationale for fixed-dose combination therapy to reach lower blood pressure goals SO SOUTHERN MEDICAL JOURNAL LA English DT Review DE angiotensin receptor blockers; calcium channel blockers; cardiovascular disease; combination therapy; hypertension ID RANDOMIZED CONTROLLED-TRIAL; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; KIDNEY-DISEASE; HYPERTENSIVE PATIENTS; RISK-FACTOR; SYSTOLIC HYPERTENSION; CLINICAL CARDIOLOGY; CALCIUM-ANTAGONIST; METABOLIC SYNDROME AB Expert committees in the United States and Europe formulated their currently recommended target blood pressures of < 140/90 mm Hg or < 130/80 mm Hg in persons with diabetes, chronic kidney disease, or coronary artery disease based on the totality of clinical data available at the time. However, accumulating evidence indicates that increased risk for cardiovascular and renal complications of hypertension may begin at a threshold of 115/75 mm Hg, suggesting that benefit from treatment may occur when blood pressure targets are lower than those currently recommended. Combination therapy with two or more agents having complementary mechanisms of action is the most effective method for achieving strict blood pressure goals in high-risk patients. Several clinical trials are under way to further determine the risks and benefits of lowering blood pressure beyond the currently recommended threshold. C1 [Basile, Jan N.] Med Univ S Carolina, Charleston, SC 29425 USA. [Basile, Jan N.] Ralph H Johnson VA Med Ctr, Primary Care Serv Line, Charleston, SC 29403 USA. RP Basile, JN (reprint author), Ralph H Johnson VA Med Ctr, Primary Care Serv Line, 109 Bee St, Charleston, SC 29403 USA. EM jan.basile@va.gov FU Novartis Pharmaceuticals Corp.; National Heart, Lung , and Blood Institute; Boehringer Ingelheim; Novartis FX Development of this article was supported by Novartis Pharmaceuticals Corp.; Dr Basile receives grant/research support from the National Heart, Lung, and Blood Institute, Boehringer Ingelheim, and Novartis. He has served as a consultant for AstraZeneca, Merck, Novartis, and Daiichi Sankyo and has served on the Speakers' Bureau of Abbott, AstraZeneca, Boehringer Ingelheim, Forest, Merck, Novartis, Pfizer, and Daiichi Sankyo. NR 55 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD SEP PY 2008 VL 101 IS 9 BP 918 EP 924 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 353QL UT WOS:000259583200014 PM 18708973 ER PT J AU Hess, MJ Hess, PE Sullivan, MR Nee, M Yalla, SV AF Hess, M. J. Hess, P. E. Sullivan, M. R. Nee, M. Yalla, S. V. TI Evaluation of cranberry tablets for the prevention of urinary tract infections in spinal cord injured patients with neurogenic bladder SO SPINAL CORD LA English DT Article DE cranberry; spinal cord injury; neurogenic bladder; urinary tract infection ID FIMBRIATED ESCHERICHIA-COLI; JUICE; BACTERIURIA; ADHERENCE; REDUCTION; INGESTION; SECONDARY; PYURIA; CELLS AB Study Design: Randomized, double blind, placebo-controlled trial with a crossover design. Objective: To evaluate cranberry tablets for the prevention of urinary tract infection (UTI) in spinal cord injured (SCI) patients. Setting: Spinal Cord Injury Unit of a Veterans Administration Hospital, MA, USA. Methods: Subjects with spinal cord injury and documentation of neurogenic bladder were randomized to receive 6 months of cranberry extract tablet or placebo, followed by the alternate preparation for an additional 6 months. The primary outcome was the incidence of UTI. Results: Forty-seven subjects completed the trial. We found a reduction in the likelihood of UTI and symptoms for any month while receiving the cranberry tablet (P < 0.05 for all). During the cranberry period, 6 subjects had 7 UTI, compared with 16 subjects and 21 UTI in the placebo period (P < 0.05 for both number of subjects and incidence). The frequency of UTI was reduced to 0.3 UTI per year vs 1.0 UTI per year while receiving placebo. Subjects with a glomerular filtration rate (GFR) greater than 75 ml min(-1) received the most benefit. Conclusion: Cranberry extract tablets should be considered for the prevention of UTI in SCI patients with neurogenic bladder. Patients with a high GFR may receive the most benefit. Sponsorship: Spinal Cord Research Foundation, sponsored by the Paralyzed Veterans of America. C1 [Hess, M. J.] VA Boston Hlth Care Syst, Dept Spinal Cord Injury, W Roxbury, MA 02132 USA. [Hess, P. E.; Nee, M.] Beth Israel Deaconess Med Ctr, Dept Anesthesiol Crit Care & Pain Med, Dept Anesthesiol, Boston, MA 02215 USA. [Sullivan, M. R.; Yalla, S. V.] VA Boston Hlth Care Syst, Dept Urol, W Roxbury, MA 02132 USA. RP Hess, MJ (reprint author), VA Boston Hlth Care Syst, Dept Spinal Cord Injury, Bldg 2,1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Marika.hess@med.va.gov RI Hess, Philip/A-8577-2013 OI Hess, Philip/0000-0002-1206-0102 NR 20 TC 39 Z9 41 U1 0 U2 2 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 SEP PY 2008 VL 46 IS 9 BP 622 EP 626 DI 10.1038/sc.2008.25 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 344GX UT WOS:000258916000007 PM 18392039 ER PT J AU Jin, G Arai, K Murata, Y Wang, S Stins, MF Lo, EH van Leyen, K AF Jin, Guang Arai, Ken Murata, Yoshihiro Wang, Sophia Stins, Monique F. Lo, Eng H. van Leyen, Klaus TI Protecting against cerebrovascular injury - Contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia SO STROKE LA English DT Article DE baicalein; blood-brain barrier; edema; endothelial cell; lipoxygenase ID BLOOD-BRAIN-BARRIER; CEREBRAL-ISCHEMIA; ORGANELLE DEGRADATION; ENDOTHELIAL-CELLS; RAT; STROKE; INHIBITION; 15-LIPOXYGENASE; DISRUPTION; MODEL AB Background and Purpose-The concept of the neurovascular unit suggests that effects on brain vasculature must be considered if neuroprotection is to be achieved in stroke. We previously reported that 12/15-lipoxygenase (12/15-LOX) is upregulated in the peri-infarct area after middle cerebral artery occlusion in mice, and 12/15-LOX contributes to brain damage after ischemia-reperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain. Methods-In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H2O2-induced oxidative stress with or without lipoxygenase inhibitors. For in vivo studies, mice were subjected to 90 minutes middle cerebral artery occlusion, and the effects of either 12/15-LOX gene knockout or treatment with lipoxygenase inhibitors were compared. Expression of 12/15-LOX and claudin-5 as well as extravasation of immunoglobulin G were detected by immunohistochemistry. Edema was measured as water content of brain hemispheres according to the wet-dry weight method. Results-Brain endothelial cells were protected against hypoxia and H(2)O(2) by the lipoxygenase inhibitor baicalein. After focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. The vascular tight junction protein claudin-5 underwent extensive degradation in the peri-infarct area, which was partially prevented by the lipoxygenase inhibitor baicalein. Leakage of immunoglobulin G into the brain parenchyma was significantly reduced in 12/15-LOX knockout mice as well as wild-type mice treated with baicalein. Likewise, brain edema was significantly ameliorated. Conclusion-12/15-LOX may contribute to ischemic brain damage not just by causing neuronal cell death, but also by detrimental effects on the brain microvasculature. 12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants. C1 [Jin, Guang; Arai, Ken; Murata, Yoshihiro; Wang, Sophia; Lo, Eng H.; van Leyen, Klaus] Massachusetts Gen Hosp, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Stins, Monique F.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RP van Leyen, K (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, 149 13th St,R 2401, Charlestown, MA 02129 USA. EM klaus_vanleyen@hms.harvard.edu RI van Leyen, Klaus/C-9126-2013 FU National Institutes of Health [R01NS049430, R01NS53560, P01NS555104]; American Heart Association FX Support through grants from the National Institutes of Health (R01NS049430 to KvL, R01NS53560 and P01NS555104 to EHL) and a Scientist Development Grant from the American Heart Association (to KvL) is gratefully acknowledged. NR 38 TC 62 Z9 67 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2008 VL 39 IS 9 BP 2538 EP 2543 DI 10.1161/STROKEAHA.108.514927 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 341PP UT WOS:000258727000022 PM 18635843 ER PT J AU Robinson, TM Alexander, SC Hays, M Jeffreys, AS Olsen, MK Rodriguez, KL Pollak, KI Abernethy, AP Arnold, R Tulsky, JA AF Robinson, Tracy M. Alexander, Stewart C. Hays, Margie Jeffreys, Amy S. Olsen, Maren K. Rodriguez, Keri L. Pollak, Kathryn I. Abernethy, Amy P. Arnold, Robert Tulsky, James A. TI Patient-oncologist communication in advanced cancer: predictors of patient perception of prognosis SO SUPPORTIVE CARE IN CANCER LA English DT Article DE communication; cancer; medical oncology; prognosis; physician-patient relations ID TREATMENT PREFERENCES; ILL PATIENTS; DISCLOSURE; DOCTORS; HOPE; INFORMATION; PHYSICIANS; CAREGIVERS; COLLUSION; SURVIVAL AB Goals of work Advanced cancer patients' perceptions of prognosis, which are often overly optimistic compared to oncologist estimates, influence treatment preferences. The predictors of patients' perceptions and the effect of oncologist communication on patient understanding are unclear. This study was designed to identify the communication factors that influence patient-oncologist concordance about chance of cure. Materials and methods We analyzed audiorecorded encounters between 51 oncologists and 141 advanced cancer patients with good (n=69) or poor (n=72) concordance about chance of cure. Encounters were coded for communication factors that might influence oncologist-patient concordance, including oncologist statements of optimism and pessimism. Main results Oncologists made more statements of optimism (mean=3.3 per encounter) than statements of pessimism (mean=1.2 per encounter). When oncologists made at least one statement of pessimism, patients were more likely to agree with their oncologist's estimated chance of cure (OR=2.59, 95%CI=1.31-5.12). Statements of optimism and uncertainty were not associated with an increased likelihood that patients would agree or disagree with their oncologists about chance of cure. Conclusions Communication of pessimistic information to patients with advanced cancer increases the likelihood that patients will report concordant prognostic estimates. Communication of optimistic information does not have any direct effect. The best communication strategy to maximize patient knowledge for informed decision making while remaining sensitive to patients' emotional needs may be to emphasize optimistic aspects of prognosis while also consciously and clearly communicating pessimistic aspects of prognosis. C1 [Robinson, Tracy M.] Vanderbilt Univ, Med Ctr, Dept Internal Med, Nashville, TN 37203 USA. [Robinson, Tracy M.] Duke Univ, Sch Med, Durham, NC USA. [Alexander, Stewart C.; Jeffreys, Amy S.; Olsen, Maren K.; Tulsky, James A.] Durham VA Med Ctr, Hlth Serv Res & Dev, Durham, NC USA. [Alexander, Stewart C.; Abernethy, Amy P.; Tulsky, James A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Alexander, Stewart C.; Abernethy, Amy P.; Tulsky, James A.] Duke Univ, Med Ctr, Ctr Palliat Care, Durham, NC USA. [Hays, Margie; Rodriguez, Keri L.; Arnold, Robert] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. [Olsen, Maren K.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Rodriguez, Keri L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Pollak, Kathryn I.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Pollak, Kathryn I.; Abernethy, Amy P.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Duke Canc Prevent Detect & Control Res Program, Durham, NC 27710 USA. [Abernethy, Amy P.] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Arnold, Robert] Univ Pittsburgh, Sch Med, Inst Doctor Patient Commun, Pittsburgh, PA USA. [Arnold, Robert] Univ Pittsburgh, Sch Med, Inst Enhance Palliat Care, Pittsburgh, PA USA. [Tulsky, James A.] Duke Univ, Med Ctr, Ctr Aging & Human Dev, Durham, NC USA. RP Robinson, TM (reprint author), Vanderbilt Univ, Med Ctr, Dept Internal Med, Nashville, TN 37203 USA. EM tracy.robinson@vanderbilt.edu OI Abernethy, Amy/0000-0001-6930-8722 FU NCI NIH HHS [R01 CA 100387, R01 CA100387, R01 CA100387-05] NR 32 TC 43 Z9 43 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2008 VL 16 IS 9 BP 1049 EP 1057 DI 10.1007/s00520-007-0372-2 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 335JI UT WOS:000258286500010 PM 18196288 ER PT J AU Fauza, DO Jennings, RW Teng, YD Snyder, EY AF Fauza, Dario O. Jennings, Russell W. Teng, Yang D. Snyder, Evan Y. TI Neural stem cell delivery to the spinal cord in an ovine model of fetal surgery for spina bifida SO SURGERY LA English DT Article ID TUBE DEFECTS; IN-UTERO; NEUROLOGICAL FUNCTION; NEUROTROPHIC FACTOR; MOTOR-NEURONS; HUMAN FETUSES; MYELOMENINGOCELE; INJURY; BIRTH; MENINGOMYELOCELE AB Background. We introduce the notion of prenatal neural stein cell (NSC) delivery, to the spinal cord as an adjuvant to fetal repair of spina bifida. Methods. Fetal lambs with experimental myelomeningocele (MMC; n = 25) were divided in 3 groups: group I, no repair; group II, standard surgical MMC coverage; and group III, MMC coverage plus delivery, of a murine NSCs clone into the spinal cord defect. Donor cells constitutively expressed lacZ encoding for Escherichia coli beta-galactosidase, yet they were further labeled by exposure either BrdU and/or to the fluorescent membrane dye PKH-26. Blinded initial clinical evaluations and multiple spinal cord analyses were undertaken soon after birth. Results. Both survival and the incidence of major paraparesis were significantly worse in group I compared with groups II and III. In group III, NSC density was highest within the most damaged areas of the signal cord, with selective engraftment within those regions. Donor NSCs retained an undifferentiated state in vivo, producing neurotrophic factors within the defect. No animals in group III had a worsened condition following this intervention. Conclusions. Neural stem cells retain an undifferentiated state and produce neurotrophic factors in the short term after delivery to the fetal spinal cord, in the setting of experimental MMC. Further scrutiny of NSC delivery to the spinal cord as a therapeutic strategy against spina bifida is warranted. C1 [Fauza, Dario O.; Jennings, Russell W.] Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Fauza, Dario O.; Jennings, Russell W.] Childrens Hosp, Adv Fetal Care Ctr, Boston, MA 02115 USA. [Fauza, Dario O.; Jennings, Russell W.; Teng, Yang D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Teng, Yang D.] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Teng, Yang D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Teng, Yang D.] VA Boston Healthcare Syst, Spinal Cord Injury Res, Boston, MA USA. [Snyder, Evan Y.] Burnham Inst, Stem Cell Ctr, San Diego, CA USA. RP Fauza, DO (reprint author), Childrens Hosp, Dept Surg Fegan 3, 300 Longwood Ave, Boston, MA 02115 USA. EM dario.fauza@childrens.harvard.edu FU Harvard Center for Minimally Invasive Surgery; Kevin and Kate McCarey Fund for Surgical Research; Children's Hospital Boston FX Supported by a grant from the Harvard Center for Minimally Invasive Surgery and by the Kevin and Kate McCarey Fund for Surgical Research, at Children's Hospital Boston. NR 39 TC 29 Z9 34 U1 0 U2 3 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 SEP PY 2008 VL 144 IS 3 BP 367 EP 373 DI 10.1016/j.surg.2008.05.009 PG 7 WC Surgery SC Surgery GA 341VO UT WOS:000258743500002 PM 18707035 ER PT J AU Listgarten, J Brumme, Z Kadie, C Walker, B Carrington, M Goulder, P Heckerman, D AF Listgarten, J. Brumme, Z. Kadie, C. Walker, B. Carrington, M. Goulder, P. Heckerman, D. TI Statistical resolution of ambiguous HLA typing data SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 15th International Histocompatibility and Immunogenetics Workshop and Conference CY SEP 13-20, 2008 CL Rio de Janeiro, BRAZIL C1 [Brumme, Z.; Walker, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA USA. [Carrington, M.] NCI, SAIC, Frederick, MD 21701 USA. [Goulder, P.] Univ Oxford, Dept Paediat, Oxford, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2008 VL 72 IS 3 BP 248 EP 249 PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 337OD UT WOS:000258444500053 ER PT J AU Adams, DS AF Adams, Dany Spencer TI A new tool for tissue engineers: Ions as regulators of morphogenesis during development and regeneration SO TISSUE ENGINEERING PART A LA English DT Article ID LEFT-RIGHT ASYMMETRY; GAP-JUNCTIONAL COMMUNICATION; LEFT-RIGHT AXIS; PLANARIAN REGENERATION; LIMB REGENERATION; EARLY STEP; CELL; CURRENTS; XENOPUS; SIGNALS AB Currently, most of the research on how to encourage stem cells to replace missing tissues focuses on biochemical control, such as signaling by growth factors. In addition to basic questions, such as how are stem cells induced to differentiate into particular cell types, also inherent in those studies are practical questions about how to identify, grow, induce, and safely deliver stems cells to the proper target. At the Forsyth Center for Regenerative and Developmental Biology, we are examining a different set of signals, specifically bioelectric signals (the regulated movement of ions across membranes), including membrane voltage, pH, and gap junction activity and gating. We have found strong evidence that bioelectrical signals function at many critical, early points, both up- and downstream of transcriptional regulation, during the processes of normal morphogenesis and adult stem cell-based regeneration. Examples described include gap-junction-dependent regulation of stem cell identity in a flatworm, proton-flux-regulated establishment of left-right asymmetry in vertebrates, and proton-flux-initiated regeneration of a complex structure that includes spinal cord-the tadpole tail-in frogs. C1 Harvard Univ, Sch Dent Med, Dept Dev Biol, Forsyth Ctr Regenerat & Dev Biol,Forsyth Inst, Boston, MA 02115 USA. RP Adams, DS (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, Forsyth Ctr Regenerat & Dev Biol,Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. EM dadams@forsyth.org FU National Institutes of Health [1-K22-DE016633] FX The author thanks co-authors and colleagues at the Forsyth Center for Regenerative and Developmental Biology for permission to present their work, especially Michael Levin, who also provided important insights, suggestions, and contributions to the manuscript and to all of the work reviewed. Anonymous reviewers at Tissue Engineering likewise made helpful suggestions. This work was supported by National Institutes of Health Grant 1-K22-DE016633 to DSA. NR 33 TC 32 Z9 32 U1 2 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD SEP PY 2008 VL 14 IS 9 SI SI BP 1461 EP 1468 DI 10.1089/ten.tea.2008.0080 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 350UG UT WOS:000259378000003 PM 18601591 ER PT J AU Bomikova, L Kaufman, R Ellis, M Kao, G AF Bomikova, L. Kaufman, R. Ellis, M. Kao, G. TI Increasing leukapheresis volume does not improve collection efficiency or CD34+yield in poorly mobilized autologous donors SO TRANSFUSION LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-of-Blood-Banks and TXPO CY OCT 04-07, 2008 CL Montreal, CANADA SP Amer Assoc Blood Banks C1 [Bomikova, L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kaufman, R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ellis, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. EM Grace_Kao@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2008 VL 48 IS 2 SU S BP 128A EP 128A PG 1 WC Hematology SC Hematology GA 347CO UT WOS:000259118400376 ER PT J AU McCullough, J Kahn, J Adamson, J Anderlini, P Benjamin, R Confer, D Eapen, M Hirsch, B Kuter, D Lazarus, E Pamphilon, D Stroncek, D Sugarman, J Wilson, R AF McCullough, Jeffrey Kahn, Jeffrey Adamson, John Anderlini, Paolo Benjamin, Richard Confer, Dennis Eapen, Mary Hirsch, Betsy Kuter, David Lazarus, Ellen Pamphilon, Derwood Stroncek, David Sugarman, Jeremy Wilson, Robert TI Hematopoietic growth factors - use in normal blood and stem cell donors: clinical and ethical issues SO TRANSFUSION LA English DT Editorial Material ID COLONY-STIMULATING FACTOR; ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL PROGENITOR CELLS; PLACEBO-CONTROLLED TRIAL; RECOMBINANT-HUMAN-ERYTHROPOIETIN; THROMBOPOIETIN RECEPTOR AGONIST; IMMUNE THROMBOCYTOPENIC PURPURA; HUMAN MEGAKARYOCYTE GROWTH; MESSENGER-RNA EXPRESSION; ACUTE MYELOID-LEUKEMIA C1 [McCullough, Jeffrey] Univ Minnesota, Minneapolis, MN 55455 USA. Natl Marrow Donor Program, Minneapolis, MN USA. Blood Ctr Wisconsin, Milwaukee, WI USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. Amer Red Cross, Biomed Serv, Washington, DC 20006 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. US FDA, Rockville, MD 20857 USA. Univ Bristol, Bristol, Avon, England. Natl Inst Hlth, Bethesda, MD USA. Johns Hopkins Univ, Baltimore, MD USA. RP McCullough, J (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM mccu1001@umn.edu NR 139 TC 18 Z9 18 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2008 VL 48 IS 9 BP 2008 EP 2025 DI 10.1111/j.1537-2995.2008.01788.x PG 18 WC Hematology SC Hematology GA 347CN UT WOS:000259118300033 PM 18564401 ER PT J AU Jensen, AA Davies, PA Brauner-Osborne, H Krzywkowski, K AF Jensen, Anders A. Davies, Paul A. Brauner-Osborne, Hans Krzywkowski, Karen TI 3B but which 3B? And that's just one of the questions: the heterogeneity of human 5-HT(3) receptors SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID NICOTINIC ACETYLCHOLINE-RECEPTORS; CENTRAL-NERVOUS-SYSTEM; GATED ION-CHANNEL; 3A HTR3A GENE; SEROTONIN RECEPTOR; SCHIZOPHRENIC-PATIENTS; MAJOR DEPRESSION; VARIANT C178T; EXPRESSION; POLYMORPHISMS AB The 5-hydroxytryptamine 3 (5-HT(3)) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT(3) receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cys-loop receptors, native 5-HT(3) receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT(3) subunits and the dawning realization that central and peripheral 5-HT(3) receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT(3) receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT(3) receptor system by genetic variations will be outlined. C1 [Jensen, Anders A.; Brauner-Osborne, Hans; Krzywkowski, Karen] Univ Copenhagen, Dept Med Chem, Fac Pharmaceut Sci, DK-2100 Copenhagen, Denmark. [Davies, Paul A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Jensen, AA (reprint author), Univ Copenhagen, Dept Med Chem, Fac Pharmaceut Sci, Univ Sparken 2, DK-2100 Copenhagen, Denmark. EM aaj@farma.ku.dk RI Brauner-Osborne, Hans/D-7260-2011; OI Brauner-Osborne, Hans/0000-0001-9495-7388; Jensen, Anders/0000-0002-7927-5052; Davies, Paul/0000-0002-3973-3143 FU Lundbeck Foundation; Danish Medical Research Council; Center for Pharmacogenomics, Denmark; Department of Anesthesia and Critical Care FX The authors thank the Lundbeck Foundation and the Danish Medical Research Council (A.A.J.), Center for Pharmacogenomics, Denmark (K.K., H.B.O.) and the Department of Anesthesia and Critical Care (P.A.D.) for financial support. NR 63 TC 40 Z9 41 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD SEP PY 2008 VL 29 IS 9 BP 437 EP 444 DI 10.1016/j.tips.2008.06.001 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 351HJ UT WOS:000259415000003 PM 18597859 ER PT J AU Baena-Gonzalez, E Sheen, J AF Baena-Gonzalez, Elena Sheen, Jen TI Convergent energy and stress signaling SO TRENDS IN PLANT SCIENCE LA English DT Review ID ADP-GLUCOSE PYROPHOSPHORYLASE; ELECTRON-TRANSFER FLAVOPROTEIN; MESSENGER-RNA TRANSLATION; SNRK1 PROTEIN-KINASE; ARABIDOPSIS-THALIANA; GENE-EXPRESSION; PLANT-GROWTH; TRANSCRIPTION NETWORKS; SUCROSE STARVATION; SUGAR STARVATION AB Plants are constantly confronted by multiple types of stress. Despite their distinct origin and mode of perception, nutrient deprivation and most stresses have an impact on the overall energy status of the plant, leading to convergent downstream responses that include largely overlapping transcriptional patterns. The emerging view is that this transcriptome reprogramming in energy and stress signaling is partly regulated by the evolutionarily conserved energy sensor protein kinases, SNF1 (sucrose non-fermenting 1) in yeast, AMPK (AMP-activated protein kinase) in mammals and SnRK1 (SNF1-related kinase 1) in plants. Upon sensing the energy deficit associated with stress, nutrient deprivation and darkness, SnRK1 triggers extensive transcriptional changes that contribute to restoring homeostasis, promoting cell survival and elaborating longer-term responses for adaptation, growth and development. C1 [Sheen, Jen] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Sheen, J (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard.edu RI Baena-Gonzalez, Elena/G-5811-2013 OI Baena-Gonzalez, Elena/0000-0001-6598-3579 FU US National Science Foundation; National Institutes of Health FX We apologize to all authors whose work could not be cited here because of space constraints. This work was supported by grants from the US National Science Foundation and the National Institutes of Health. NR 82 TC 232 Z9 241 U1 6 U2 76 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 SEP PY 2008 VL 13 IS 9 BP 474 EP 482 DI 10.1016/j.tplants.2008.06.006 PG 9 WC Plant Sciences SC Plant Sciences GA 355ZC UT WOS:000259747500003 PM 18701338 ER PT J AU Wo, JY Zietman, AL AF Wo, Jennifer Y. Zietman, Anthony L. TI Why does androgen deprivation enhance the results of radiation therapy? SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE androgen deprivation; prostate cancer; external beam radiotherapy; brachytherapy ID LOCALIZED PROSTATE-CANCER; ENDOTHELIAL GROWTH-FACTOR; PHASE-III TRIAL; COMPARING RADICAL PROSTATECTOMY; RANDOMIZED CONTROLLED-TRIAL; LOCALLY ADVANCED-CARCINOMA; ACUTE URINARY RETENTION; FOLLOW-UP; SEED IMPLANTATION; METASTATIC DISSEMINATION AB The role of androgen deprivation therapy (ADT) has been explored in combination with surgery, brachytherapy, and external beam radiotherapy with the goal of improving local control and overall survival. Multiple cooperative groups' studies strongly Support the use of neoadjiuvant ADT treated with definitive external beam radiotherapy. Neoadjuvant androgen deprivation improves intraprostatic local control with external beam radiotherapy and reduces the second wave of distant metastases. Neoadjuvant androgen deprivation achieves this endpoint through "sensitization" of the tumor to radiation and through improved oxygenation. However, the use of neoadjuvant ADT before radical prostatectomy and brachytherapy is controversial. There are ongoing clinical trials that will hopefully better define patient populations that will benefit from hormonal deprivation therapy. Published by Elsevier Inc. C1 [Wo, Jennifer Y.] Harvard Radiat Oncol Program, Boston, MA 02114 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Wo, JY (reprint author), Harvard Radiat Oncol Program, Boston, MA 02114 USA. EM jwo@partners.org NR 50 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD SEP-OCT PY 2008 VL 26 IS 5 BP 522 EP 529 DI 10.1016/j.urolonc.2008.03.008 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 351IC UT WOS:000259416900014 PM 18774467 ER PT J AU Montgomery, B Lavori, P Garzotto, M Lee, K Brophy, M Thaneemit-Chen, S Kelly, W Basler, J Ringer, R Yu, W Whittemore, A Lin, DW AF Montgomery, Bruce Lavori, Philip Garzotto, Mark Lee, Kelvin Brophy, Mary Thaneemit-Chen, Surai Kelly, William Basler, Joseph Ringer, Robert Yu, Wei Whittemore, Alice Lin, Daniel W. TI Veterans affairs cooperative studies program study 553: Chemotherapy after prostatectomy, a phase III randomized study of prostatectomy versus prostatectomy with adjuvant docetaxel for patients with high-risk, localized prostate cancer SO UROLOGY LA English DT Review ID CELL LUNG-CANCER; ANDROGEN-INDEPENDENT PROGRESSION; EXTERNAL-BEAM RADIOTHERAPY; RADICAL PROSTATECTOMY; RADIATION-THERAPY; HORMONAL-THERAPY; COLON-CANCER; RECURRENCE; TRIAL; FLUOROURACIL C1 [Montgomery, Bruce] Vet Affairs Puget Sound Hlth Care Syst, Div Med Oncol, Seattle, WA 98109 USA. Univ Washington, Seattle, WA 98195 USA. Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. Vet Affairs Portland, Dept Surg, Div Urol, Portland, OR USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Vet Affairs Cooperat Studies Coordinating Ctr, Palo Alto, CA USA. Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. Yale Univ, Dept Med, Div Oncol, New Haven, CT 06520 USA. S Texas Vet Adm Hlth Care Syst, San Antonio, TX USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. Cooperat Studies Pharm Coordinating Ctr, Albuquerque, NM USA. RP Montgomery, B (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Div Med Oncol, S-111-ONC,1660 S Columbian Way, Seattle, WA 98109 USA. EM rbmontgo@u.washington.edu FU Department of Veterans Affairs, Cooperative Studies Program FX This work was supported by the Department of Veterans Affairs, Cooperative Studies Program. NR 42 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2008 VL 72 IS 3 BP 474 EP 480 DI 10.1016/j.urology.2008.02.050 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 357NQ UT WOS:000259853800003 PM 18407333 ER PT J AU Eisner, BH Pedro, R Namasivayarn, S Karnbadakone, A Sahani, DV Dretier, SP Monga, M AF Eisner, Brian H. Pedro, Renato Namasivayarn, Saravanan Karnbadakone, Avinash Sahani, Dushyant V. Dretier, Stephen P. Monga, Manoj TI Differences in stone size and ureteral dilation between obstructing proximal and distal ureteral calculi SO UROLOGY LA English DT Article ID UNENHANCED HELICAL CT; INTRAVENOUS UROGRAPHY; CONE; MIGRATION; DEVICE AB OBJECTIVES To examine the differences in ureteral dilation and calculus size between obstructing proximal and distal ureteral stones. METHODS A retrospective review of computed tomography (CT) scans from 176 consecutive patients with obstructing ureteral calculi was performed. For the calculi, the axial diameter was defined as the largest stone diameter on the axial CT images, and the coronal length was defined as the cephalocaudal length of the stone measured on the coronal CT images. Univariate and multivariate statistical analyses were performed. RESULTS A total of 65 proximal and 111 distal ureteral calculi were analyzed. On univariate analysis, the proximal calculi were associated with a greater degree of ureteral dilation (mean 6.1 mm vs 5.3 mm, P = .01) and had a greater coronal length (mean 9.9 mm vs 8.3 mm, P = .005) than distal calculi. This association was also true on the multivartate analysis, which controlled for age and sex (P = .0004). No statistically significant difference was found in the axial calculus diameter for the proximal and distal stones (mean 5.3 mm vs 5.0 mm, P = .29). In a subset of 50 patients whose contralateral ureters (without stones) were measured for control comparison, the ureteral dilation in the ureters with stones was significantly greater than in the control ureters (proximal ureter 6.2 mm vs 4.3 mm, P = .001; distal ureter 4.7 mm vs 3.8 mm, P = .004). For proximal calculi, 72.3% were associated with ureteral dilation of less than 7 mm, 23.1% with 7-10 mm, and 4.6% with greater than 10 mm. For the distal calculi, 90.1% were associated with ureteral dilation of less than 7 mm, 6.3% with 7-10 mm, and 3.6% with greater than 10 mm. The coronal length was the largest measured diameter in 94% of the calculi, and the mean calculus coronal length was significantly greater than the mean axial diameter (8.9 mm vs 5.1 MITI, respectively, P < .001). CONCLUSIONS The results of our study have shown that proximal ureteral calculi are associated with a significantly greater degree of ureteral dilation and larger coronal length than are distal calculi. These findings should guide the endoscopist in planning intracorporeal ureteroscopic lithotripsy. We suggest obtaining CT coronal images to more accurately characterize obstructing ureteral stones. C1 Harvard Univ, Sch Med, Massachusetts & Gen Hosp, Dept Urol, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts & Gen Hosp, Dept Radiol, Boston, MA USA. Univ Minnesota, Sch Med, Dept Urol Surg, Minneapolis, MN 55455 USA. RP Eisner, BH (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org FU PercSys, Mountainview, CA FX This study was supported by PercSys, Mountainview, CA. NR 10 TC 7 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2008 VL 72 IS 3 BP 517 EP 520 DI 10.1016/j.urology.2008.03.034 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 357NQ UT WOS:000259853800013 PM 18502478 ER PT J AU Prasad, SM Keating, NL Wang, Q Pashos, CL Lipsitz, S Richie, JP Hu, JC AF Prasad, Sandip M. Keating, Nancy L. Wang, Qin Pashos, Chris L. Lipsitz, Stuart Richie, Jerome P. Hu, Jim C. TI Variations in surgeon volume and use of pelvic lymph node dissection with open and minimally invasive radical prostatectomy SO UROLOGY LA English DT Article ID CANCER-SPECIFIC SURVIVAL; TRENDS; LYMPHADENECTOMY; VALIDATION; CARCINOMA; OUTCOMES; IMPACT; TIME AB OBJECTIVES Although pelvic lymph node dissection (PLND) during radical prostatectomy (RP) improves staging, controversy remains concerning its indications and benefits on cancer control. We examined the factors associated with PLND use among men undergoing open RP (ORP) and minimally invasive RP (MIRP). METHODS Using a 5% national sample of Medicare beneficiaries from 2003 to 2005, we identified 2702 men who had undergone RP. Multivariate logistic regression analysis was used to assess whether the surgical approach, surgeon volume, patient demographics, comorbidity, and geographic region were associated with the likelihood of performing PLND. RESULTS Overall, 68% of men underwent PLND, although the rates varied by surgical approach (17% vs 83% for MIRP vs ORP, respectively, P < .001). In adjusted analyses, men undergoing MIRP vs ORP (odds ratio [OR] 0.02, 95% confidence interval [CI], 0.02-0.03), men >= 75 vs 65-69 years old (OR 0.23, 95% CI 0.17-0.31), and men with multiple vs no comorbidities (OR 0.48, 95% CI 0.35-0.66 for Charlson score >= 3 vs 0) were less likely to undergo PLND. High-volume minimally invasive surgeons were more likely to perform PLND (OR 1.19, 95% CI 1.14-1.25). Finally, men in the Western vs Southern United States (OR 1.61, 95% CI 1.19-2.17) were more likely to undergo PLND. CONCLUSIONS Men undergoing MIRP vs ORP were less likely to undergo PLND, although rates of the procedure increased with surgical volume. Additional studies are needed to determine the indications and benefits of this procedure for men with prostate cancer. C1 [Hu, Jim C.] Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02478 USA. Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02478 USA. Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02478 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Abt Associate Clin Trials, Bethesda, MD USA. Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), Brigham & Womens Hosp, Div Urol Surg, ASBII-3,45 Francis St, Boston, MA 02478 USA. EM jhu2@partners.org FU Lance Armstrong Young Investigator Award FX This study was funded by a Lance Armstrong Young Investigator Award to J. Hu. NR 19 TC 24 Z9 25 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 SEP PY 2008 VL 72 IS 3 BP 647 EP 652 DI 10.1016/j.urology.2008.03.067 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 357NQ UT WOS:000259853800053 PM 18649928 ER PT J AU Hu, JC Prasad, SM AF Hu, Jim C. Prasad, Sandip M. TI Variations in surgeon volume and use of pelvic lymph node dissection with open and minimally invasive radical prostatectomy - Reply SO UROLOGY LA English DT Editorial Material ID LYMPHADENECTOMY; CANCER; MEN C1 [Hu, Jim C.; Prasad, Sandip M.] Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02115 USA. [Hu, Jim C.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Hu, Jim C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), Brigham & Womens Hosp, Div Urol Surg, 75 Francis St, Boston, MA 02115 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2008 VL 72 IS 3 BP 653 EP 653 DI 10.1016/j.urology.2008.05.013 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 357NQ UT WOS:000259853800055 ER PT J AU Diaz-Griffero, F Perron, M McGee-Estrada, K Hanna, R Maillard, PV Trono, D Sodroski, J AF Diaz-Griffero, Felipe Perron, Michel McGee-Estrada, Kathleen Hanna, Robert Maillard, Pierre V. Trono, Didier Sodroski, Joseph TI A human TRIM5 alpha B30.2/SPRY domain mutant gains the ability to restrict and prematurely uncoat B-tropic murine leukemia virus SO VIROLOGY LA English DT Article DE retrovirus; restriction factor; uncoating; tripartite motif; mechanism; capsid; reverse transcription ID HUMAN-IMMUNODEFICIENCY-VIRUS; RETROVIRUS RESTRICTION; REVERSE TRANSCRIPTION; B30.2(SPRY) DOMAIN; ANTIVIRAL ACTIVITY; HIV-1 REPLICATION; OLD-WORLD; INFECTION; PROTEASOME; REQUIREMENTS AB Human TRIM5 alpha restricts N-tropic murine leukemia virus (N-MLV) but not B-tropic MLV (B-MLV) infection. Here we study B30.2/SPRY domain mutants of human TRIM5 alpha that acquire the ability to inhibit B-MLV infection prior to reverse transcription Without losing the ability to restrict N-MLV infection. Remarkably, these Mutants gain the ability to decrease the amount of particulate B-MIV capsids in the cytosol of infected cells. In addition, these mutants gain the ability to restrict SIVmac and HIV-2 infection. B-MLV and SIVmac infections were blocked by the mutant TRIM5 alpha proteins prior to reverse transcription. Thus, the range of retroviruses restricted by human TRIM5a can be increased by changes in the B30.2/SPRY domain, which also result in the ability to cause premature uncoating of the restricted retroviral capsid. (C) 2008 Elsevier Inc. All rights reserved. C1 [Diaz-Griffero, Felipe; Perron, Michel; McGee-Estrada, Kathleen; Hanna, Robert; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, Boston, MA 02115 USA. [Maillard, Pierre V.; Trono, Didier] Ecole Polytech Fed Lausanne, Global Hlth Inst, Sch Life Sci, Frontiers Genet Natl Ctr Competence Res, CH-1015 Lausanne, Switzerland. [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,Dept Pathol,Div AIDS, 44 Binney St,JFB 824, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [AI063987, AI076094]; Center for AIDS Research Award [AI60354]; International AIDS Vaccine Initiative; Bristol-Myers Squibb Foundation; Swiss National Science Foundation; amfAR Mathilde Krim Fellowship FX We thank Ms. Yvette McLaughlin and Ms. Elizabeth Carpelan for the manuscript preparation Drs. Gregory Towers, Jeremy Luban and Andrew Lever for providing recombinant HIV-2, and the National Institutes of Health (AI063987, AI076094 and a Center for AIDS Research Award AI60354), the International AIDS Vaccine Initiative, the Bristol-Myers Squibb Foundation, the Swiss National Science Foundation, and file late William F. McCarty-Cooper for research funding. F.D.-G. was the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research. NR 32 TC 46 Z9 47 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2008 VL 378 IS 2 BP 233 EP 242 DI 10.1016/j.virol.2008.05.008 PG 10 WC Virology SC Virology GA 340FN UT WOS:000258631600005 PM 18586294 ER PT J AU Baldwin, SB Solorio, R Washington, DL Yu, HJ Huang, YC Brown, ER AF Baldwin, Susie B. Solorio, Rosa Washington, Donna L. Yu, Hongjian Huang, Yii-Chieh Brown, E. Richard TI Who is using emergency contraception? Awareness and use of emergency contraception among California women and teens SO WOMENS HEALTH ISSUES LA English DT Article ID UNINTENDED PREGNANCY; BEHAVIORAL-MODEL; INCREASED ACCESS; MEDICAL-CARE; KNOWLEDGE; LEVONORGESTREL; REGIMEN; RATES AB Introduction. Emergency contraception (EC) reduces women's risk for pregnancy after unprotected intercourse, and women's awareness of the method is increasingly important for expanding access. However, knowledge of EC alone does not predict use, and few population data exist to describe EC use among those aware of the method. Methods. Using data from the 2003 California Health Interview Survey, we measured EC awareness among 11,392 women ages 15-44, and EC use among 7,178 respondents who were aware of EC and at risk for pregnancy. Using chi(2) analyses and multivariable logistic regression, we examined population characteristics that epidemiologically predict EC awareness and use, including age, race/ethnicity, income, health insurance status, usual source of health care, immigration status, languages spoken at home, and urban versus rural residence. Results. Nearly 76% of respondents had heard of EC, but awareness was lower among teens, women of color, poor women, women with publicly funded health insurance, those without a usual source of care, immigrants, non-English-language speakers, and rural residents. Among women aware of EC, about 4% reported having used the method in the previous year; young age, low income, attending a community/government clinic for care or not having a source of care, and living in an urban area significantly increased the odds for using EC. Conclusions. Among California women in 2003, awareness and use of EC remained low. However, similar rates of use were reported among racial, ethnic, and linguistic subgroups. Those most likely to report use of the method included population groups at high risk for unintended pregnancy. C1 [Baldwin, Susie B.] Los Angeles Cty Dept Pubic Hlth, Off Hlth Assessment & Epidemiol, Los Angeles, CA 90012 USA. [Solorio, Rosa] Univ Washington, Sch Publ Hlth & Community Med, Dept Hlth Serv, Seattle, WA 98195 USA. [Washington, Donna L.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Washington, Donna L.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Yu, Hongjian; Huang, Yii-Chieh; Brown, E. Richard] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Hlth Policy Res, Los Angeles, CA 90024 USA. RP Baldwin, SB (reprint author), Los Angeles Cty Dept Pubic Hlth, Off Hlth Assessment & Epidemiol, 313 N Figueroa St,Room 127, Los Angeles, CA 90012 USA. EM sbaldwin@ph.lacounty.gov NR 24 TC 19 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 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2008 VL 18 IS 5 BP 360 EP 368 DI 10.1016/j.whi.2008.06.005 PG 9 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 350DF UT WOS:000259332100004 PM 18774454 ER PT J AU Haspot, F Bardwell, PD Zhao, GL Sykes, M AF Haspot, Fabienne Bardwell, Philip D. Zhao, Guiling Sykes, Megan TI High antigen levels do not preclude B-cell tolerance induction to alpha 1,3-Gal via mixed chimerism SO XENOTRANSPLANTATION LA English DT Article DE alpha Gal; antigen density; bone marrow transplantation; natural Ab; tolerance ID ALPHA-GAL EPITOPES; T-CELL; ALPHA-1,3-GALACTOSYLTRANSFERASE-DEFICIENT MICE; GAL-ALPHA-1,3GAL EPITOPES; KNOCKOUT PIGS; ANTIBODIES; BABOONS; TOLERIZATION; REJECTION; SURVIVAL AB Background: Studies of bone marrow transplantation (BMT) from wild-type mice or rats to alpha 1,3-galactosyltransferase (GalT) knockout mice have demonstrated that induction of mixed chimerism tolerizes not only T cells, but also natural antibody-producing B cells, even across xenogeneic barriers. Given that rodent cells express lower levels of the alpha Gal epitope than the more clinically relevant porcine species, the consequences of exposure to cells expressing high levels of alpha Gal on the ability to induce B-cell tolerance are unknown. Methods: The effects on chimerism and anti-alpha Gal B-cell tolerance of an i.p. injection of 10(9) porcine RBC were evaluated in GalT knockout mice receiving wild-type allogeneic BMT after non-myeloablative conditioning with T-cell depleting monoclonal antibodies, thymic irradiation, and low-dose total body irradiation. Results: Achievement of mixed chimerism and tolerance of anti-alpha Gal-producing B cells was not affected by exposure to high-density alpha Gal at the time of BMT. The absence of induced anti-alpha Gal or anti-pig antibody responses in conditioned control mice suggested that the B-cell xeno-response to pig is T-cell-dependent. Conclusion: High alpha Gal density on pig cells might not preclude the ability to achieve tolerance of pre-existing alpha Gal-reactive human B cells via induction of mixed chimerism. This strategy has the potential to induce B-cell tolerance to non-alpha Gal epitopes, against which natural antibodies have been found in the sera of healthy humans. C1 [Haspot, Fabienne; Bardwell, Philip D.; Zhao, Guiling; Sykes, Megan] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Sykes, M (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH E Bldg,149-5102 13th St, Boston, MA 02129 USA. EM megan.sykes@tbrc.mgh.harvard.edu RI Bardwell, Philip/H-2219-2014 OI Bardwell, Philip/0000-0002-3835-255X FU NIH [PO1 HL18646]; FRM (Fondation pour la Recherche Medicale, France); AST/ASBMT (American Society of Transplantation/American Society of Blood and Marrow Transplantation) [5T32HL07623-18] FX This work was supported by NIH grant PO1 HL18646. Fabienne Haspot was supported by a research fellowship of the FRM (Fondation pour la Recherche Medicale, France) and a research fellowship of the AST/ASBMT (American Society of Transplantation/American Society of Blood and Marrow Transplantation). Philip D. Bardwell was supported by NIH training grant 5T32HL07623-18. NR 29 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP-OCT PY 2008 VL 15 IS 5 BP 313 EP 320 DI 10.1111/j.1399-3089.2008.00487.x PG 8 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 367CD UT WOS:000260529200017 PM 19134161 ER PT J AU Jezewski, PA Fang, PK Payne-Ferreira, TL Yelick, PC AF Jezewski, Peter A. Fang, Ping-Ke Payne-Ferreira, Tracie L. Yelick, Pamela Crotty TI Zebrafish wnt9b Synteny and Expression During First and Second Arch, Heart, and Pectoral Fin Bud Morphogenesis SO ZEBRAFISH LA English DT Article ID CLEFT-PALATE; GENE; LIP; ROLES; MICE AB Roles for Wnt9b in craniofacial development are indicated by the cleft lip mutant phenotype observed in the A/WySn mouse strain,(1) caused by a retrotransposon insertion mutation at the Wnt9b locus. Analyses of the zebrafish Wnt9b ortholog, wnt9b, were pursued to provide insight into early vertebrate craniofacial patterning events mediated by Wnt9b signaling. Zebrafish wnt9b cDNA clones were isolated and found to encode an open reading frame of 358 amino acids, with 68% amino acid identity to mouse Wnt9b and 70% amino acid identity to human WNT9B. Syntenic analyses demonstrated that wnt9b and wnt3 exist as a contiguous pair in amniote vertebrate species, and that these genes are separate in the zebrafish and Takifugu genomes. During the pharyngula period, a time of extensive growth and morphogenesis, zebrafish wnt9b exhibits discrete expression in dorsal and ventral first and second branchial arch tissues, the heart, and pectoral fin buds. These analyses suggest that in zebrafish, as in humans, wnt9b plays distinct roles in directing morphogenetic movements of developing branchial arch elements, and identify the zebrafish as a useful developmental model for the study of human craniofacial cleft lip and palate. C1 [Yelick, Pamela Crotty] Tufts Univ, Dept Oral & Maxillofacial Pathol, Div Craniofacial & Mol Genet, Boston, MA 02111 USA. [Jezewski, Peter A.] Harvard Univ, Sch Dent Med, Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. [Jezewski, Peter A.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Fang, Ping-Ke] Childrens Hosp, Dept Urol, Boston, MA 02115 USA. [Fang, Ping-Ke; Payne-Ferreira, Tracie L.] Univ Massachusetts Dartmouth, Dept Biol, N Dartmouth, MA USA. RP Yelick, PC (reprint author), Tufts Univ, Dept Oral & Maxillofacial Pathol, Div Craniofacial & Mol Genet, 136 Harrison Ave, Boston, MA 02111 USA. EM pamela.yelick@tufts.edu FU NIH/NIDCR [DE12076, DE14528, DE14683] FX We wish to thank all the members of the Yelick Lab for helpful discussions, advice, and expertise, and Loic Fabricant and Seija Cope for expert zebrafish husbandry. We thank The Forsyth Institute DNA Sequencing Core staff for their expertise. This research was supported in part by NIH/NIDCR grants DE12076 (P.C.Y.), DE14528 (P.A.J.), and DE14683 (T.L.F.). NR 21 TC 6 Z9 6 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PD SEP PY 2008 VL 5 IS 3 BP 169 EP 177 DI 10.1089/zeb.2007.0517 PG 9 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA 368UI UT WOS:000260647600004 PM 18694329 ER PT J AU Adibhatla, RM Hatcher, JF AF Adibhatla, Rao Muralikrishna Hatcher, J. F. TI Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies SO BMB REPORTS LA English DT Review DE arachidonic acid; CNS pathologies; neurodegenerative disorders; oxidative stress; phosphatidylcholine; 4-hydroxynonenal ID TRANSIENT CEREBRAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA PEPTIDE; OXIDATIVE STRESS; NEURODEGENERATIVE DISEASES; NADPH OXIDASE; BRAIN-INJURY; RAT-BRAIN; GROUP IIA; A(2) AB The importance of lipids in cell signaling and tissue physiology is demonstrated by the many CNS pathologies involving deregulated lipid metabolism. One such critical metabolic event is the activation of phospholipase A(2) (PLA(2)), which results in the hydrolysis of membrane phospholipids and the release of free fatty acids, including arachidonic acid, a precursor for essential cell-signaling eicosanoids. Reactive oxygen species (ROS, a product of arachidonic acid metabolism) react with cellular lipids to generate lipid peroxides, which are degraded to reactive aldehydes (oxidized phospholipid, 4-hydroxynonenal, and acrolein) that bind covalently to proteins, thereby altering their function and inducing cellular damage. Dissecting the contribution of PLA2 to lipid peroxidation in CNS injury and disorders is a challenging proposition due to the multiple forms of PLA2, the diverse sources of ROS, and the lack of specific PLA2 inhibitors. In this review, we summarize the role of PLA(2) in CNS pathologies, including stroke, spinal cord injury, Alzheimer's, Parkinson's, Multiple sclerosis-Experimental autoimmune encephalomyelitis and Wallerian degeneration. C1 [Adibhatla, Rao Muralikrishna; Hatcher, J. F.] Univ Wisconsin, Dept Neurol Surg, Madison, WI 53706 USA. [Adibhatla, Rao Muralikrishna] Univ Wisconsin, Cardiovasc Res Ctr, Madison, WI USA. [Adibhatla, Rao Muralikrishna] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Adibhatla, Rao Muralikrishna] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Adibhatla, RM (reprint author), Univ Wisconsin, Dept Neurol Surg, Madison, WI 53706 USA. EM adibhatl@neurosurg.wisc.edu FU NIH/NINDS [NS42008]; American Heart Association Greater Midwest [0655757Z]; UW/-School of Medicine and Public Health Research Committee [161-PRJ13MX]; UW-School of Medicine and Public Health; UW-Graduate school; UW-Neurological Surgery Department and laboratory resources FX This work was supported by grants from NIH/NINDS (NS42008), American Heart Association Greater Midwest Affiliate Grant-in-Aid (0655757Z), UW/-School of Medicine and Public Health Research Committee (161-PRJ13MX), UW-School of Medicine and Public Health, UW-Graduate school and UW-Neurological Surgery Department and laboratory resources provided by William S. Middleton VA Hospital (to RMA). The EO6 antibodies were generously provided by Dr Joseph Witztum, Univ. of California-San Diego, La Jolla, CA. NR 54 TC 82 Z9 85 U1 0 U2 12 PU KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER, # 801, 635-4 , YEOKSAM-DONG, KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-6696 J9 BMB REP JI BMB Rep. PD AUG 31 PY 2008 VL 41 IS 8 BP 560 EP 567 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343PO UT WOS:000258866200002 PM 18755070 ER PT J AU Kim, SS Gwak, SJ Han, J Park, MH Song, KW Kim, BS AF Kim, Sang-Soo Gwak, So-Jung Han, Joungho Park, Moon Hyang Song, Kang Won Kim, Byung-Soo TI Regeneration of kidney tissue using in vitro cultured fetal kidney cells SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE apoptosis; cell aging; cell proliferation; cell transplantation; fetal stem cells; kidney; tissue engineering ID REPLICATIVE SENESCENCE; PRECURSOR CELLS; TRANSPLANTATION; VIVO; TELOMERASE; SCAFFOLDS; GROWTH; RAT AB Transplanting fetal kidney cells (FKCs) can regenerate kidney. This requires in vitro expansion in cell number to acquire enough cells for transplantation. However, FKCs may change their cellular characteristics during expansion and, thus, may not regenerate kidney tissue upon transplantation. We investigated how cell culture period affects cellular characteristics and in vivo regenerative potential of FKCs. As the passage number increased, cell growth rate and colony forming ability decreased while senescence and apoptosis increased. To examine in vivo regenerative potential, FKCs cultured through different numbers of passages were implanted into the parenchyma of kidneys of immunodeficient mice using fibrin gel for 4 wk. Histological analyses showed passage-dependent kidney tissue regeneration, and the regeneration was better when cells from lower number of passages were implanted. This result shows that in vitro culture of FKCs significantly affects the cell characteristics and in vivo tissue regenerative potential. C1 [Kim, Sang-Soo; Kim, Byung-Soo] Hanyang Univ, Dept Bioengn, Seoul 133791, South Korea. [Kim, Sang-Soo] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Gwak, So-Jung] Hanyang Univ, Dept Chem Engn, Seoul 133791, South Korea. [Han, Joungho] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul 135710, South Korea. [Park, Moon Hyang; Song, Kang Won] Hanyang Univ, Dept Pathol, Seoul 133791, South Korea. RP Kim, BS (reprint author), Hanyang Univ, Dept Bioengn, Seoul 133791, South Korea. EM bskim@hanyang.ac.kr RI kim, sang-soo/C-6573-2009; Kim, Byung-Soo/O-2352-2013 FU Ministry of Science and Technology, Republic of Korea [SC 3220] FX This work was supported by a grant (SC 3220) from the Stem Cell Research Center of the 21st Century Frontier Program, funded by the Ministry of Science and Technology, Republic of Korea. NR 24 TC 5 Z9 5 U1 0 U2 3 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD AUG 31 PY 2008 VL 40 IS 4 BP 361 EP 369 DI 10.3858/emm.2008.40.4.361 PG 9 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 346SF UT WOS:000259088800001 PM 18779648 ER PT J AU Asaad, WF Eskandar, EN AF Asaad, Wael F. Eskandar, Emad N. TI Achieving behavioral control with millisecond resolution in a high-level programming environment SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE neurophysiology; psychophysics; matlab; behavioral control; software; cognition; human; monkey AB The creation of psychophysical tasks for the behavioral neurosciences has generally relied upon low-level software running on a limited range of hardware. Despite the availability of software that allows the coding of behavioral tasks in high-level programming environments, many researchers are still reluctant to trust the temporal accuracy and resolution of programs running in such environments, especially when they run atop non-real-time operating systems. Thus, the creation of behavioral paradigms has been slowed by the intricacy of the coding required and their dissemination across labs has been hampered by the various types of hardware needed. However, we demonstrate here that, when proper measures are taken to handle the various sources of temporal error, accuracy can be achieved at the 1 ms time-scale that is relevant for the alignment of behavioral and neural events. (c) 2008 Elsevier B.V. All rights reserved. C1 [Asaad, Wael F.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Asaad, WF (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Edwards Bldg,Room 426, Boston, MA 02114 USA. EM wfasaad@alum.mit.edu RI Asaad, Wael/I-8485-2012 OI Asaad, Wael/0000-0003-4406-9096 FU Tosteson Fellowship from the Massachusetts Biomedical Research Council (WFA); NSF [IOB 0645886]; HHMI; [NEI 1R01DA026297] FX The authors thank David Freedman, Andrew Mitz, Ming Cheng, Tim Buschman, John Gale, Earl Miller and Camillo Pacloa-Schioppa for helpful discussions regarding the design and testing of our behavioral control software. We also thank Jeffrey Perry for making the low-level graphics drivers publicly available and for his advice regarding their implementation. Funding was provided by a Tosteson Fellowship from the Massachusetts Biomedical Research Council (WFA), NEI 1R01DA026297 (ENE), NSF IOB 0645886 (ENE) and the HHMI (ENE). NR 6 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2008 VL 173 IS 2 BP 235 EP 240 DI 10.1016/j.jneumeth.2008.06.003 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 344DO UT WOS:000258906300007 PM 18606188 ER PT J AU Magnotta, VA Adix, ML Caprahan, A Lim, K Gollub, R Andreasen, NC AF Magnotta, Vincent A. Adix, Michael L. Caprahan, Arvind Lim, Kelvin Gollub, Randy Andreasen, Nancy C. TI Investigating connectivity between the cerebellum and thalamus in schizophrenia using diffusion tensor tractography: A pilot study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE diffusion tensor; schizophrenia; tractography ID WHITE-MATTER; COGNITIVE DYSMETRIA; ANTERIOR CINGULUM; ABNORMALITIES; VALIDATION; DISRUPTION; INTEGRITY; CIRCUITRY; PEDUNCLE; MIDDLE AB Connections of the cortical-thalamic-cerebellar-cortical regions provide a framework for studying the neural substrates of schizophrenia. A novel diffusion tensor tractography method was used to evaluate the differences in white matter connectivity between 12 patients with schizophrenia and 10 controls. For the tract tracing, we focused on the connection between the cerebellum and the thalamus. Fractional anisotropy (FA) measures along the fiber tracks were compared between patients and the control sample. Fiber tracts located between the cerebellar white matter and the thalamus exhibit a reduced FA in patients with schizophrenia in comparison with controls. The FA values along the defined fiber tracts were not overall reduced but exhibited a reduction in the anisotropy in the region in the superior cerebellar peduncles projecting towards the red nucleus. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Magnotta, Vincent A.; Adix, Michael L.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Magnotta, Vincent A.; Andreasen, Nancy C.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Caprahan, Arvind] MIND Inst, Albuquerque, NM USA. [Lim, Kelvin] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Gollub, Randy] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Magnotta, VA (reprint author), Univ Iowa, Dept Radiol, 0453-D JCP,200 Hawkins Dr, Iowa City, IA 52242 USA. EM vincent-magnotta@uiowa.edu OI Gollub, Randy L./0000-0002-9434-4044 FU MIND Institute; NARSAD FX This work was supported in part by the MIND Institute, a NARSAD Young Investigator award and the Nellie Ball Foundation. The authors thank Ronald Pierson, Helen Keefe and Michael Kinguta for processing the structural images. NR 33 TC 21 Z9 24 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 30 PY 2008 VL 163 IS 3 BP 193 EP 200 DI 10.1016/j.pscychresns.2007.10.005 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 347IE UT WOS:000259133000001 PM 18656332 ER PT J AU Rouf, R Greytak, S Wooten, EC Wu, J Boltax, J Picard, M Svensson, EC Dillmann, WH Patten, RD Huggins, GS AF Rouf, Rosanne Greytak, Sarah Wooten, Eric C. Wu, Jing Boltax, Jay Picard, Michael Svensson, Eric C. Dillmann, Wolfgang H. Patten, Richard D. Huggins, Gordon S. TI Increased FOG-2 in Failing Myocardium Disrupts Thyroid Hormone-Dependent SERCA2 Gene Transcription SO CIRCULATION RESEARCH LA English DT Article DE friend of GATA-2; thyroid hormone receptor; sarcoplasmic reticulum calcium-activated ATPase-2; heart failure ID RETINOID-X-RECEPTOR; MYOSIN HEAVY-CHAIN; SARCOPLASMIC-RETICULUM CA-2+-ATPASE; INDUCED HEART-FAILURE; IN-VITRO; DILATED CARDIOMYOPATHY; CARDIAC-HYPERTROPHY; SIGNALING PATHWAYS; RESPONSE ELEMENTS; TRANSGENIC MICE AB Reduced expression of sarcoplasmic reticulum calcium ATPase (SERCA) 2 and other genes in the adult cardiac gene program has raised consideration of an impaired responsiveness to thyroid hormone (T3) that develops in the advanced failing heart. Here, we show that human and murine cardiomyopathy hearts have increased expression of friend of GATA (FOG)-2, a cardiac nuclear hormone receptor corepressor protein. Cardiac-specific overexpression of FOG-2 in transgenic mice led to depressed cardiac function, activation of the fetal gene program, congestive heart failure, and early death. SERCA2 transcript and protein levels were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically interacts with thyroid hormone receptor-alpha 1 and abrogated even high levels of T3-mediated SERCA2 promoter activity. These results demonstrate that SERCA2 is an important target of FOG-2 and that increased FOG-2 expression may contribute to a decline in cardiac function in end-stage heart failure by impaired T3 signaling. (Circ Res. 2008; 103: 493-501.) C1 [Huggins, Gordon S.] Tufts Univ, Sch Med, Tufts Med Ctr, MCRI Ctr Translat Genom,Mol Cardiol Res Inst, Boston, MA 02111 USA. [Picard, Michael] Massachusetts Gen Hosp, Cardiol Unit, Boston, MA 02114 USA. [Svensson, Eric C.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Dillmann, Wolfgang H.] Univ Calif San Diego, Div Endocrinol & Metab, San Diego, CA 92103 USA. RP Huggins, GS (reprint author), Tufts Univ, Sch Med, Tufts Med Ctr, MCRI Ctr Translat Genom,Mol Cardiol Res Inst, 750 Washington St,Box 8486, Boston, MA 02111 USA. EM ghuggins@tuftsmedicalcenter.org OI Wooten, Eric/0000-0002-8403-8668; Picard, Michael/0000-0002-9264-3243 FU NIH [R01-AA014140, T32-HL069770-01A1]; American Heart Association [0555877T] FX This work was supported by NIH grant R01-AA014140 (to G. S. H.) and T32-HL069770-01A1 (to R. R.) and American Heart Association Grant 0555877T (to G. S. H.). NR 52 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 29 PY 2008 VL 103 IS 5 BP 493 EP 501 DI 10.1161/CIRCRESAHA.108.181487 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 343HX UT WOS:000258845200009 PM 18658259 ER PT J AU Brown, RH AF Brown, Robert H., Jr. TI Developmental biology - Neuron research leaps ahead SO SCIENCE LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; MOTOR-NEURONS; HUMAN FIBROBLASTS; DEFINED FACTORS; ALS; DISEASE; MODEL C1 [Brown, Robert H., Jr.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Brown, RH (reprint author), Massachusetts Gen Hosp, 16th St,Navy Yard, Charlestown, MA 02129 USA. EM rhbrown@partners.org NR 14 TC 4 Z9 5 U1 0 U2 1 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 AUG 29 PY 2008 VL 321 IS 5893 BP 1169 EP 1170 DI 10.1126/science.1163475 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341ZM UT WOS:000258754400031 PM 18755965 ER PT J AU San Miguel, JF Schlag, R Khuageva, NK Dimopoulos, MA Shpilberg, O Kropff, M Spicka, I Petrucci, MT Palumbo, A Samoilova, OS Dmoszynska, A Abdulkadyrov, KM Schots, R Jiang, B Mateos, M Anderson, KC Esseltine, DL Liu, K Cakana, A van de Velde, H Richardson, PG AF San Miguel, Jesus F. Schlag, Rudolf Khuageva, Nuriet K. Dimopoulos, Meletios A. Shpilberg, Ofer Kropff, Martin Spicka, Ivan Petrucci, Maria T. Palumbo, Antonio Samoilova, Olga S. Dmoszynska, Anna Abdulkadyrov, Kudrat M. Schots, Rik Jiang, Bin Mateos, Maria-Victoria Anderson, Kenneth C. Esseltine, Dixie L. Liu, Kevin Cakana, Andrew van de Velde, Helgi Richardson, Paul G. CA VISTA Trial Investigators TI Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Hematology CY DEC 08-11, 2007 CL Atlanta, GA SP Amer Soc Hematol ID ELDERLY UNTREATED PATIENTS; PROGRESSION-FREE SURVIVAL; COMBINATION CHEMOTHERAPY; PERIPHERAL NEUROPATHY; ASSESSMENT SCHEDULE; REFRACTORY MYELOMA; PROGNOSTIC-FACTORS; RANDOMIZED-TRIAL; APEX TRIAL; TRANSPLANTATION AB Background: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. Methods: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. Results: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.). C1 [San Miguel, Jesus F.; Mateos, Maria-Victoria] Hosp Univ Salamanca, CIC, IBMCC USAL CSIC, Salamanca, Spain. [Schlag, Rudolf] Praxisklin Dr Schlag, Wurzburg, Germany. [Khuageva, Nuriet K.] SP Botkin Moscow City Clin Hosp, Moscow, Russia. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Shpilberg, Ofer] Rabin Med Ctr, Petah Tiqwa, Israel. [Kropff, Martin] Univ Munster, Munster, Germany. [Spicka, Ivan] Univ Hosp Prague, Prague, Czech Republic. [Petrucci, Maria T.] Univ Roma La Sapienza, Rome, Italy. [Palumbo, Antonio] Univ Turin, Turin, Italy. [Samoilova, Olga S.] Nizhnii Novgorod Reg Clin Hosp, Nizhnii Novgorod, Russia. [Dmoszynska, Anna] Med Univ Lublin, Lublin, Poland. [Abdulkadyrov, Kudrat M.] St Petersburg Clin Res Inst Hematol & Transfus, St Petersburg, Russia. [Schots, Rik] Belgian Hematol Soc, Myeloma Study Grp, Brussels, Belgium. [Jiang, Bin] Peking Univ, Peoples Hosp, Beijing 100871, Peoples R China. [Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Esseltine, Dixie L.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Liu, Kevin] Johnson & Johnson, Raritan, NJ USA. RP San Miguel, JF (reprint author), Hosp Univ Salamanca, CIC, IBMCC USAL CSIC, Paseo San Vicente 58-182, Salamanca, Spain. EM sanmigiz@usal.es RI Greil, Richard/C-7673-2017; OI Greil, Richard/0000-0002-4462-3694; abdulkadyrov, kudrat/0000-0002-3771-909X NR 38 TC 959 Z9 977 U1 11 U2 54 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 AUG 28 PY 2008 VL 359 IS 9 BP 906 EP 917 DI 10.1056/NEJMoa0801479 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 341IU UT WOS:000258708300005 PM 18753647 ER PT J AU Steinman, TI Samir, AE Cornell, LD Harris, NL Schopick, EL Tolkoff-Rubin, N Banks, P AF Steinman, Theodore I. Samir, Anthony E. Cornell, Lynn D. Harris, Nancy Lee Schopick, Emily L. Tolkoff-Rubin, Nina Banks, Peter TI A man with abdominal pain, nausea, and an elevated level of serum creatinine - Acute phosphate nephropathy due to ingestion of oral sodium phosphate solution SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE-RENAL-FAILURE; ACUTE INTERSTITIAL NEPHRITIS; PROTON PUMP INHIBITORS; ACUTE-PANCREATITIS; BOWEL PREPARATION; DISEASE C1 [Steinman, Theodore I.] Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA 02215 USA. [Samir, Anthony E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cornell, Lynn D.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Steinman, Theodore I.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Samir, Anthony E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Cornell, Lynn D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Steinman, TI (reprint author), Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA 02215 USA. FU American Renal Associates; Advance Medical; Advanced Magnetics; Otsuka Pharmaceutical; CardioKine Biopharma FX Dr. Steinman reports receiving consulting fees from American Renal Associates, Advance Medical, and Advanced Magnetics; holding stock options and stock in Advanced Magnetics; and receiving research support from Otsuka Pharmaceutical and CardioKine Biopharma. No other potential conflict of interest relevant to this article was reported. NR 23 TC 10 Z9 10 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 AUG 28 PY 2008 VL 359 IS 9 BP 951 EP 960 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 341IU UT WOS:000258708300011 PM 18753652 ER PT J AU Aiello, LP AF Aiello, Lloyd Paul TI Targeting intraocular neovascularization and edema - One drop at a time SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID VASCULAR-PERMEABILITY; KINASE INHIBITOR C1 [Aiello, Lloyd Paul] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Aiello, Lloyd Paul] Joslin Diabet Ctr, Sect Eye Res, Boston, MA 02215 USA. [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. NR 5 TC 27 Z9 27 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 AUG 28 PY 2008 VL 359 IS 9 BP 967 EP 969 DI 10.1056/NEJMcibr0804551 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 341IU UT WOS:000258708300014 PM 18753655 ER PT J AU Strate, LL Liu, YL Syngal, S Aldoori, WH Giovannucci, EL AF Strate, Lisa L. Liu, Yan L. Syngal, Sapna Aldoori, Walid H. Giovannucci, Edward L. TI Nut, corn, and popcorn consumption and the incidence of diverticular disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BLEEDING COLONIC DIVERTICULOSIS; COLORECTAL-CANCER RISK; NATURAL-HISTORY; PROSTATE-CANCER; PROSPECTIVE COHORT; MAGNESIUM INTAKE; HEART-DISEASE; MEN; MANAGEMENT AB Context Patients with diverticular disease are frequently advised to avoid eating nuts, corn, popcorn, and seeds to reduce the risk of complications. However, there is little evidence to support this recommendation. Objective To determine whether nut, corn, or popcorn consumption is associated with diverticulitis and diverticular bleeding. Design and Setting The Health Professionals Follow- up Study is a cohort of US men followed up prospectively from 1986 to 2004 via self- administered questionnaires about medical ( biennial) and dietary ( every 4 years) information. Men reporting newly diagnosed diverticulosis or diverticulitis were mailed supplemental questionnaires. Participants The study included 47 228 men aged 40 to 75 years who at baseline were free of diverticulosis or its complications, cancer, and inflammatory bowel disease and returned a food- frequency questionnaire. Main Outcome Measures Incident diverticulitis and diverticular bleeding. Results During 18 years of follow- up, there were 801 incident cases of diverticulitis and 383 incident cases of diverticular bleeding. We found inverse associations between nut and popcorn consumption and the risk of diverticulitis. The multivariate hazard ratios for men with the highest intake of each food ( at least twice per week) compared with men with the lowest intake ( less than once per month) were 0.80 ( 95% confidence interval, 0.63- 1.01; P for trend=. 04) for nuts and 0.72 ( 95% confidence interval, 0.56- 0.92; P for trend=. 007) for popcorn. No associations were seen between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis. Conclusions In this large, prospective study of men without known diverticular disease, nut, corn, and popcorn consumption did not increase the risk of diverticulosis or diverticular complications. The recommendation to avoid these foods to prevent diverticular complications should be reconsidered. C1 [Strate, Lisa L.] Harborview Med Ctr, Div Gastroenterol, Dept Med, Seattle, WA 98104 USA. [Strate, Lisa L.] Univ Washington, Sch Med, Seattle, WA USA. [Liu, Yan L.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Syngal, Sapna; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Syngal, Sapna] Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Aldoori, Walid H.] Wyeth Consumer Healthcare Inc, Mississauga, ON, Canada. RP Strate, LL (reprint author), Harborview Med Ctr, Div Gastroenterol, Dept Med, 325 9th Ave,Box 359773, Seattle, WA 98104 USA. EM lstrate@u.washington.edu FU Agency for Healthcare Research and Quality [K08 HS14062]; National Cancer Institute [P01 CA055075, K24CA113433]; National Heart, Lung, and Blood Institute [R01HL035464] FX This study was funded by grant K08 HS14062 from the Agency for Healthcare Research and Quality (Dr Strate); grants P01 CA055075 (Dr Giovannucci) and K24CA113433(Dr Syngal) from the National Cancer Institute; and grant R01HL035464 from the National Heart, Lung, and Blood Institute (Dr Giovannucci). NR 48 TC 71 Z9 72 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 27 PY 2008 VL 300 IS 8 BP 907 EP 914 DI 10.1001/jama.300.8.907 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 341AR UT WOS:000258687100025 PM 18728264 ER PT J AU Kaaro, J Partonen, T Naik, P Hadjikhani, N AF Kaaro, Jani Partonen, Timo Naik, Paulami Hadjikhani, Nouchine TI Is migraine a lateralization defect? SO NEUROREPORT LA English DT Article DE development; lateralization; migraine; pineal gland; serotonin ID LEFT-RIGHT AXIS; BRAIN; AGONISTS; RISK; AURA; STEM; RAT AB Migraine often co-occurs with patent foramen ovale (PFO), and some people have suggested surgical closure as an efficient treatment for migraine. Prospective studies, however, do not report radical effect of PFO surgery on migraine. Here, we examined the hypothesis that PFO and migraine may cooccur as two independent manifestations of lateralization defect during embryonic development. We measured the absolute displacement of a midline structure, the pineal gland, on brain scans of 39 migraineurs and 26 controls. We found a significant asymmetry of the pineal gland in migraineurs compared with controls. Our data suggest that migraine's circadian component and its association with PFO may be linked to a lateralization defect during embryogenesis, which could be a result from abnormal serotonin regulation. NeuroReport 19:1351-1353 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Naik, Paulami; Hadjikhani, Nouchine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Kaaro, Jani] AV Torppa Oy, Lohja, Finland. [Partonen, Timo] Natl Publ Hlth Inst, Helsinki, Finland. [Hadjikhani, Nouchine] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA USA. [Hadjikhani, Nouchine] Ecole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland. RP Hadjikhani, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM nouchine@nmr.mgh.harvard.edu RI Hadjikhani, Nouchine/C-2018-2008; Partonen, Timo/G-1105-2012 OI Hadjikhani, Nouchine/0000-0003-4075-3106; Partonen, Timo/0000-0003-1951-2455 FU NIH [5PO1NS 35611-09] FX The authors thank Dr Alexandre DaSilva for his assistance in data collection. This work was supported by NIH grant 5PO1NS 35611-09. NR 26 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 27 PY 2008 VL 19 IS 13 BP 1351 EP 1353 DI 10.1097/WNR.0b013e32830c4698 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 342EP UT WOS:000258767700021 PM 18695522 ER PT J AU Shimizu, I Fudaba, Y Shimizu, A Yang, YG Sykes, M AF Shimizu, Ichiro Fudaba, Yashuhiro Shimizu, Akira Yang, Yong-Guang Sykes, Megan TI Comparison of human T cell repertoire generated in xenogeneic porcine and human thymus grafts SO TRANSPLANTATION LA English DT Article DE xenotransplantation; thymus; thymopoiesis; T cell repertoire; spectratyping ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I GENES; MINIATURE SWINE; NEGATIVE SELECTION; BABOON MODEL; LOBE TRANSPLANTATION; TOLERANCE INDUCTION; XENOGRAFT SURVIVAL; MHC; MICE AB Background. Xenogeneic thymus transplantation is an effective approach to achieving T cell tolerance across highly disparate xenogeneic species barriers. We have previously demonstrated that phenotypically normal, specifically tolerant human T cells are generated in porcine thymic grafts. In this study, we assessed the diversity of the human T cell repertoire generated in porcine thymic xenografts. We also examined the ability of porcine thymus grafts to coexist with human thymus grafts. Methods. Fetal swine (SW) or human (HU) thymus with human fetal liver fragments were transplanted under the kidney capsule of 3Gy irradiated NOD/SCID mouse recipients. Thymus tissue was harvested approximately 16 weeks post-transplant for analysis of mixed lymphocyte reactions and spectratyping of human CD4 and CD8 single positive thymocytes. Results. T cell receptor beta genes of human CD4 and CD8 single positive cells developing in HU and SW thymus grafts showed similar, normal CDR3 length distributions. Human T cells developing in SW thymus grafts showed specific unresponsiveness to the major histocompatibility complex of the donor swine in mixed leukocyte reaction assays. In two of three animals receiving SW and HU thymus grafts under opposite kidney capsules, both grafts functioned. In animals with surviving SW grafts, thymocytes from the SW but not the HU grafts showed specific unresponsiveness to the SW donor. Conclusion. Swine thymus grafts support generation of human T cells with a diverse T cell receptor repertoire. Human thymocytes in human thymus grafts are not tolerized by the presence of an additional porcine thymus, but tolerance might be achieved by postthymic encounter with porcine antigens. C1 [Sykes, Megan] Harvard Univ, Massachusetts Gen Hosp, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr,Med Sch, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr,Med Sch, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. EM megan.sykes@tbrc.mgh.harvard.edu FU NIH [PO1 HL 18646, PO1 A1 045897] FX This work was supported by NIH Grant nos. PO1 HL 18646 and PO1 A1 045897. NR 48 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2008 VL 86 IS 4 BP 601 EP 610 DI 10.1097/TP.0b013e318182d47a PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 342VG UT WOS:000258811100019 PM 18724231 ER PT J AU Sogawa, H Boskovic, S Nadazdin, O Abrahamian, G Colvin, RB Sachs, DH Cosimi, AB Kawai, T AF Sogawa, Hiroshi Boskovic, SvJ'etlan Nadazdin, Ognjenka Abrahamian, Greg Colvin, Robert B. Sachs, David H. Cosimi, A. Benedict Kawai, Tatsuo TI Limited efficacy and unacceptable toxicity of cyclophosphamide for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys SO TRANSPLANTATION LA English DT Article DE mixed chimerism; kidney transplantation; tolerance; monkeys; cyclophosphamide ID LYMPHOHEMATOPOIETIC CHIMERISM; MULTIPLE-MYELOMA; BONE-MARROW; TRANSPLANTATION; REGIMEN; CELLS; SURVIVAL; DISEASE; KIDNEY AB To induce mixed chimerism and renal allograft tolerance in cynomolgus monkeys, cyclophosphamide (CP) and total body irradiation (TBI) were compared as part of a nonmyeloablative conditioning regimen. CP induced dose-dependent neutropenia and lymphopenia, but hematopoietic recovery was more rapid than that observed in the TBI group. Absolute B cell counts after CP were significantly higher (P < 0.01) than those in the TBI group. With CP, a total dose of 200 mg/kg with CD154 blockade regularly induced multilineage chimerism. Nevertheless, the recipients failed to achieve long-term survival because of rejection (3 of 5), post transplantation B cell lymphoma (1 of 5), and toxicities of CP (1 of 5). As previously reported, 3 Gy of TBI with either splenectomy or CD154 blockade induced mixed chimerism and renal allograft tolerance, with significantly less morbidity and mortality than that produced by CP. Thus, TBI is more effective and less toxic than CP as part of a nomnyeloablative regimen for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. C1 [Boskovic, SvJ'etlan; Nadazdin, Ognjenka; Cosimi, A. Benedict; Kawai, Tatsuo] Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, Boston, MA 02114 USA. [Boskovic, SvJ'etlan; Nadazdin, Ognjenka; Colvin, Robert B.; Sachs, David H.; Cosimi, A. Benedict; Kawai, Tatsuo] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sachs, David H.] Massachusetts Gen Hosp, Dept Surg, Transplant Biol Res Ctr, Boston, MA 02114 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, White 510,55 Fruit St, Boston, MA 02114 USA. EM tkawai@partners.org FU NIAID NIH HHS [R21 AI037692-06, R21 AI037692, R01 AI037692-10, R01 AI037692-09, R01 AI037692] NR 14 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2008 VL 86 IS 4 BP 615 EP 619 DI 10.1097/TP.0b013e3181821bac PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 342VG UT WOS:000258811100021 PM 18724233 ER PT J AU Zhu, BJ Ascher-Svanum, H Faries, DE Peng, XM Salkever, D Slade, EP AF Zhu, Baojin Ascher-Svanum, Haya Faries, Douglas E. Peng, Xiaomei Salkever, David Slade, Eric P. TI Costs of treating patients with schizophrenia who have illness-related crisis events SO BMC PSYCHIATRY LA English DT Article ID BEHAVIORAL HEALTH-CARE; ANTIPSYCHOTIC MEDICATION; ASSESSMENT PROGRAM; RISK ADJUSTMENT; OUTCOMES; RELAPSE; NONADHERENCE; ADHERENCE; HOSPITALIZATION; DISORDERS AB Background: Relatively little is known about the relationship between psychosocial crises and treatment costs for persons with schizophrenia. This naturalistic prospective study assessed the association of recent crises with mental health treatment costs among persons receiving treatment for schizophrenia. Methods: Data were drawn from a large multi-site, non-interventional study of schizophrenia patients in the United States, conducted between 1997 and 2003. Participants were treated at mental health treatment systems, including the Department of Veterans Affairs (VA) hospitals, community mental health centers, community and state hospitals, and university health care service systems. Total costs over a 1-year period for mental health services and component costs (psychiatric hospitalizations, antipsychotic medications, other psychotropic medications, day treatment, emergency psychiatric services, psychosocial/rehabilitation group therapy, individual therapy, medication management, and case management) were calculated for 1557 patients with complete medical information. Direct mental health treatment costs for patients who had experienced 1 or more of 5 recent crisis events were compared to propensity-matched samples of persons who had not experienced a crisis event. The 5 non-mutually exclusive crisis event subgroups were: suicide attempt in the past 4 weeks (n = 18), psychiatric hospitalization in the past 6 months (n = 240), arrest in the past 6 months (n = 56), violent behaviors in the past 4 weeks (n = 62), and diagnosis of a co-occurring substance use disorder (n = 413). Results: Across all 5 categories of crisis events, patients who had a recent crisis had higher average annual mental health treatment costs than patients in propensity-score matched comparison samples. Average annual mental health treatment costs were significantly higher for persons who attempted suicide ($46,024), followed by persons with psychiatric hospitalization in the past 6 months ($37,329), persons with prior arrests ($31,081), and persons with violent behaviors ($18,778). Total cost was not significantly higher for those with co-occurring substance use disorder ($19,034). Conclusion: Recent crises, particularly suicide attempts, psychiatric hospitalizations, and criminal arrests, are predictive of higher mental health treatment costs in schizophrenia patients. C1 [Zhu, Baojin; Ascher-Svanum, Haya; Faries, Douglas E.; Peng, Xiaomei] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Salkever, David] Univ Maryland Baltimore Cty, Dept Publ Policy, Baltimore, MD 21228 USA. [Slade, Eric P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Slade, Eric P.] US Dept Vet Affairs, VA VISN5 Mental Illness Res & Educ Clin Ctr, Baltimore, MD USA. RP Ascher-Svanum, H (reprint author), Eli Lilly & Co, Indianapolis, IN 46285 USA. EM ZHU_BAOJIN@LILLY.COM; haya@lilly.com; FARIES_DOUGLAS_E@LILLY.COM; PENG_XIAOMEI@lilly.com; SALKEVER@UMBC.EDU; ESLADE@PSYCH.UMARYLAND.EDU FU Eli Lilly and company FX Financial support for this research was provided by a grant from Eli Lilly and company. The authors also wish to thank the US-SCAP site investigators and others who collaborated in the research. By site, they include Maryland: A. F. Lehman, M. D., M. S. P. H., University of Maryland School of Medicine, and G. Gallucci, M. D., M. H. S., Johns Hopkins Bayview Medical Center ( previously); Colorado: C. Harding, Ph. D., University of Colorado ( previously); Florida: D. Shern, Ph. D., Florida Mental Health Institute, University of South Florida ( previously), and T. Saunders, M. S., Florida Mental Health Institute ( previously); North Carolina: J. Swanson, Ph. D., L. A. Dunn, M. D., and M. Swartz, M. D., Duke University Medical School; California: R. L. Hough, Ph. D., and C. Barrio, Ph. D., Child and Adolescent Services Research Center and San Diego State University; Connecticut: R. A. Rosenheck, M. D., and R. Desai, Ph. D., VA Connecticut Health Care System; Medstat Group: P. Russo, Ph. D., M. S. W., R. N., ( previously), L. Palmer, Ph. D., L. Torres, M. B. A., and B. Cuffel, Ph. D. ( previously); Eli Lilly and Co.: D. Buesching, Ph. D., Bryan M. Johnstone, Ph. D., and T. Croghan, M. D. ( previously); Consultants: D. Salkever, Ph. D., Johns Hopkins University ( previously), E. Slade, Ph. D., Johns Hopkins University ( previously), and W. Hargreaves, Ph. D., and M. Shumway, Ph. D., University of California, San Francisco. The authors wish to thank Paul Crits- Christoph, PhD, who was compensated by Eli Lilly and Company, for his valuable assistance with the preparation of the manuscript. NR 32 TC 9 Z9 10 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD AUG 26 PY 2008 VL 8 AR 72 DI 10.1186/1471-244X-8-72 PG 10 WC Psychiatry SC Psychiatry GA 350EC UT WOS:000259334400001 PM 18727831 ER PT J AU Otipoby, KL Sasaki, Y Schmidt-Supprian, M Patke, A Gareus, R Pasparakis, M Tarakhovsky, A Rajewsky, K AF Otipoby, Kevin L. Sasaki, Yoshiteru Schmidt-Supprian, Marc Patke, Alina Gareus, Ralph Pasparakis, Manolis Tarakhovsky, Alexander Rajewsky, Klaus TI BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NF-KAPPA-B; LYMPHOCYTE STIMULATOR; TRANSCRIPTION FACTORS; AUTOIMMUNE-DISEASE; SIGNALING PATHWAYS; KINASE-ALPHA; SURVIVAL; RECEPTOR; NF-KAPPA-B2; MICE AB B cell activating factor (BAFF) signals through BAFF-R to promote mature B cell survival. Recent analyses of BAFF-induced signaling revealed direct association between augmented B cell metabolic fitness and activation of Akt, one of the key regulators of cell survival. The strongest and most reproducible induction of Akt occurs with significant delay (24 h) after BAFF treatment, where it precedes activation of anabolism. It was also recently shown that BAFF induces sustained Erk activation and increased turnover of the proapoptotic molecule Bim. Here we show that these BAFF-induced signaling pathways are mediated by BAFF-R and represent previously unknown arms of 1 kappa B kinase (IKK)1-dependent signaling. In combination with the known role of IKK1 in regulating transcription of prosurvival genes, our data underscore the central role of IKK1 in coordinating multiple BAFF-R-mediated signaling pathways controlling mature B cell homeostasis. C1 [Otipoby, Kevin L.; Sasaki, Yoshiteru; Schmidt-Supprian, Marc; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Patke, Alina; Tarakhovsky, Alexander] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10021 USA. [Gareus, Ralph; Pasparakis, Manolis] Univ Cologne, Inst Genet, D-50674 Cologne, Germany. [Gareus, Ralph; Pasparakis, Manolis] European Mol Biol Lab, Mouse Biol Unit, I-00016 Monterotondo, Italy. RP Rajewsky, K (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 200 Long Wood Ave, Boston, MA 02115 USA. EM rajewsky@cbr.med.harvard.edu RI Schmidt-Supprian, Marc/F-5893-2011; OI Schmidt-Supprian, Marc/0000-0002-8543-6166; Pasparakis, Manolis/0000-0002-9870-0966 FU National Institute of Health [A1057947, A1054636]; Uehara Memorial Foundation FX We thank Drs. Yen-Ming Hsu and Martin Scott for the gift of recombinant human BAFF. We are grateful to Junrong Xia, Dvora Ghitza, and Anthony Monti for technical support and Emmanuel Derudder and Jane Seagal for critical reading of the manuscript. This work was supported by National Institute of Health Grants A1057947 and A1054636. Y.S. received a fellowship from the Uehara Memorial Foundation. NR 31 TC 56 Z9 57 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 AUG 26 PY 2008 VL 105 IS 34 BP 12435 EP 12438 DI 10.1073/pnas.0805460105 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 344DJ UT WOS:000258905700061 PM 18713867 ER PT J AU Szotek, PP Chang, HL Brennand, K Fujino, A Pieretti-Vanmarcke, R Lo Celso, C Dombkowski, D Preffer, F Cohen, KS Teixeira, J Donahoe, PK AF Szotek, Paul P. Chang, Henry L. Brennand, Kristen Fujino, Akihiro Pieretti-Vanmarcke, Rafael Lo Celso, Cristina Dombkowski, David Preffer, Frederic Cohen, Kenneth S. Teixeira, Jose Donahoe, Patricia K. TI Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE somatic stem cells; ovarian coelomic epithelium ID HEMATOPOIETIC STEM-CELLS; SIDE-POPULATION; MAMMARY-GLAND; CANCER-CELLS; OVULATION; IDENTIFICATION; MECHANISMS; NICHE; MICE; MAINTENANCE AB Ovulation induces cyclic rupture and regenerative repair of the ovarian coelomic epithelium. This process of repeated disruption and repair accompanied by complex remodeling typifies a somatic stem/progenitor cell-mediated process. Using BrdU incorporation and doxycycline inducible histone2B-green fluorescent protein pulse-chase techniques, we identify a label-retaining cell population in the coelomic epithelium of the adult mouse ovary as candidate somatic stem/progenitor cells. The identified population exhibits quiescence with asymmetric label retention, functional response to estrous cycling in vivo by proliferation, enhanced growth characteristics by in vitro colony formation, and cytoprotective mechanisms by enrichment for the side population. Together, these characteristics identify the label-retaining cell population as a candidate for the putative somatic stem/progenitor cells of the coelomic epithelium of the mouse ovary. C1 [Szotek, Paul P.; Chang, Henry L.; Fujino, Akihiro; Pieretti-Vanmarcke, Rafael; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Lab, Boston, MA 02114 USA. [Szotek, Paul P.; Chang, Henry L.; Fujino, Akihiro; Pieretti-Vanmarcke, Rafael; Donahoe, Patricia K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Dombkowski, David; Preffer, Frederic] Massachusetts Gen Hosp, Flow Cytometry Lab, Dept Pathol, Boston, MA 02114 USA. [Brennand, Kristen] Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Cambridge, MA 02139 USA. [Brennand, Kristen] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02139 USA. [Teixeira, Jose] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Lo Celso, Cristina; Cohen, Kenneth S.] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Ctr Regenerat Med, Boston, MA 02114 USA. RP Donahoe, PK (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Lab, 185 Cambridge St,CPZN 6-100, Boston, MA 02114 USA. EM pdonahoe@partners.org RI Brennand, Kristen/J-8704-2012; OI Brennand, Kristen/0000-0003-0993-5956; Lo Celso, Cristina/0000-0002-1163-4207; Teixeira, Jose/0000-0002-6438-5064 FU NCI NIH HHS [2T32CA071345-11, 5R01CA017393-33]; NICHD NIH HHS [R01 HD052701, R01 HD052701-01A2] NR 38 TC 68 Z9 69 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 26 PY 2008 VL 105 IS 34 BP 12469 EP 12473 DI 10.1073/pnas.0805012105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 344DJ UT WOS:000258905700067 PM 18711140 ER PT J AU Rothenberg, SM Engelman, JA Le, S Riese, DJ Haber, DA Settleman, J AF Rothenberg, S. Michael Engelman, Jeffrey A. Le, Sheila Riese, David J., II Haber, Daniel A. Settleman, Jeffrey TI Modeling oncogene addiction using RNA interference SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EGF receptor; RNAi ID EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; FACTOR RECEPTOR; TYROSINE KINASE; INCREASED SENSITIVITY; GEFITINIB; MUTATIONS; ERLOTINIB; SURVIVAL; TUMORIGENESIS AB The clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. RNAi has been increasingly used to understand such "oncogene addiction" and validate new therapeutic targets. However, RNAi approaches suffer from significant off-target effects that limit their utility. Here, we combine carefully titrated lentiviral-mediated short hairpin RNA knockdown of the epidermal growth factor receptor (EGFR) with heterologous reconstitution by EGFR mutants to rigorously analyze the structural features and signaling activities that determine addiction to the mutationally activated EGFR in human lung cancer cells. EGFR dependence is differentially rescued by distinct EGFR variants and oncogenic mutants, is critically dependent on its heterodimerization partner ErbB-3, and surprisingly, does not require autophosphorylation sites in the cytoplasmic domain. Quantitative "oncogene rescue" analysis allows mechanistic dissection of oncogene addiction, and, when broadly applied, may provide functional validation for potential therapeutic targets identified through large-scale RNAi screens. C1 [Rothenberg, S. Michael; Engelman, Jeffrey A.; Le, Sheila; Haber, Daniel A.; Settleman, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Rothenberg, S. Michael; Haber, Daniel A.] Howard Hughes Med Inst, Charlestown, MA 02129 USA. [Rothenberg, S. Michael; Engelman, Jeffrey A.; Haber, Daniel A.; Settleman, Jeffrey] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Riese, David J., II] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, 13th St,Bldg 149,7th Floor, Charlestown, MA 02129 USA. EM haber@helix.mgh.harvard.edu; settleman@helix.mgh.harvard.edu FU National Institutes of Health [CA115830, CA94281, CA120060-01]; V foundation award (JS); T32 Institutional Ruth L. Kirstein National Research Service Award FX We thank the members of the Settleman and Haber laboratories for helpful discussions. This work was supported by National Institutes of Health Grant CA115830 (JS), a V foundation award (JS), National Institutes of Health Grant CA94281 (DAH), and National Institutes of Health K08 Grant CA120060-01 (JAE). SMR is supported by a T32 Institutional Ruth L. Kirstein National Research Service Award. NR 28 TC 24 Z9 25 U1 1 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 AUG 26 PY 2008 VL 105 IS 34 BP 12480 EP 12484 DI 10.1073/pnas.0803217105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 344DJ UT WOS:000258905700069 PM 18711136 ER PT J AU Springer, TA Zhu, JH Xiao, T AF Springer, Timothy A. Zhu, Jianghai Xiao, Tsan TI Structural basis for distinctive recognition of fibrinogen gamma C peptide by the platelet integrin alpha(IIb)beta(3) SO JOURNAL OF CELL BIOLOGY LA English DT Article ID GLYCOPROTEIN-IIB-IIIA; PROTEIN-DRIVEN CRYSTALLIZATION; BINDING-SITE; INTEGRIN ALPHA(IIB)BETA(3); LIGAND-BINDING; CRYSTAL-STRUCTURE; GPIIB-IIIA; 3-DIMENSIONAL STRUCTURE; STRUCTURE VALIDATION; TERMINAL FRAGMENT AB Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to integrin alpha(IIb)beta(3) on platelets, resulting in platelet aggregation. alpha(V)beta(3) binds fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's alpha subunit. alpha(IIb)beta(3) also binds to fibrinogen; however, it does so via an unstructured RGD-lacking C-terminal region of the gamma subunit (gamma C peptide). These distinct modes of fibrinogen binding enable alpha(IIb)beta(3) and alpha(V)beta(3) to function cooperatively in hemostasis. In this study, crystal structures reveal the integrin alpha(IIb)beta(3)-gamma C peptide interface, and, for comparison, integrin alpha(IIb)beta(3) bound to a lamprey gamma C primordial RGD motif. Compared with RGD, the GAKQA-GDV motif in gamma C adopts a different backbone configuration and binds over a more extended region. The integrin metal ion-dependent adhesion site (MIDAS) Mg(2+) ion binds the gamma C Asp side chain. The adjacent to MIDAS (ADMIDAS) Ca(2+) ion binds the gamma C C terminus, revealing a contribution for ADMIDAS in ligand binding. Structural data from this natively disordered gamma C peptide enhances our understanding of the involvement of gamma C peptide and integrin alpha(IIb)beta(3) in hemostasis and thrombosis. C1 [Springer, Timothy A.; Zhu, Jianghai; Xiao, Tsan] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Springer, Timothy A.; Zhu, Jianghai; Xiao, Tsan] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM springeroffice@idi.harvard.edu RI Xiao, Tsan/A-8590-2010; Xiao, Tsan/I-7616-2013; Zhu, Jianghai/B-7339-2014 OI Xiao, Tsan/0000-0001-9688-475X; FU NHLBI NIH HHS [HL48675, P01 HL048675] NR 53 TC 105 Z9 108 U1 0 U2 8 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 AUG 25 PY 2008 VL 182 IS 4 BP 791 EP 800 DI 10.1083/jcb.200801146 PG 10 WC Cell Biology SC Cell Biology GA 346EA UT WOS:000259050000018 PM 18710925 ER PT J AU Elder, GA Ragnauth, A Dorr, N Franciosi, S Schmeidler, J Haroutunian, V Buxbaum, JD AF Elder, Gregory A. Ragnauth, Andre Dorr, Nathan Franciosi, Sonia Schmeidler, James Haroutunian, Vahram Buxbaum, Joseph D. TI Increased locomotor activity in mice lacking the low-density lipoprotein receptor SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Alzheimer's disease; acoustic startle; cholesterol; light/dark preference; low-density lipoprotein receptor; Morris water maze; null mutation; open field ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; ALZHEIMERS-DISEASE; KNOCKOUT MICE; MESSENGER-RNA; UP-REGULATION; LOW-FAT; CHOLESTEROL; ATHEROSCLEROSIS; EXPRESSION AB While the low-density lipoprotein receptor (LDLR) is best known for its role in regulating serum cholesterol, LDLR is expressed in brain, suggesting that it may play a role in CNS function as well. Here, using mice with a null mutation in LDLR (LDLR-/-), we investigated whether the absence of LDLR affects a series of behavioral functions. We also utilized the fact that plasma cholesterol levels can be regulated in LDLR-/- mice by manipulating dietary cholesterol to investigate whether elevated plasma cholesterol might independently affect behavioral performance. LDLR-/- mice showed no major deficits in general sensory or motor function. However, LDLR-/- mice exhibited increased locomotor activity in an open field test without evidence of altered anxiety in either an open field or a light/dark emergence test. By contrast, modulating dietary cholesterol produced only isolated effects. While both C57BL/6J and LDLR-/- mice fed a high cholesterol diet showed increased anxiety in a light/dark task, and LDLR-/- mice fed a high cholesterol diet exhibited longer target latencies in the probe trial of the Morris water maze, no other findings supported a general effect of cholesterol on anxiety or spatial memory. Collectively these studies suggest that while LDLR-/- mice exhibit no major developmental defects, LDLR nevertheless plays a significant role in modulating locomotor behavior in the adult. (C) 2008 Elsevier B.V. All rights reserved. C1 [Elder, Gregory A.; Ragnauth, Andre; Franciosi, Sonia; Schmeidler, James; Haroutunian, Vahram; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Elder, Gregory A.] James J Peters Dept Vet Affairs Med Ctr, Rehabil Med Serv, Bronx, NY 10468 USA. [Franciosi, Sonia; Buxbaum, Joseph D.] Mt Sinai Sch Med, Lab Mol Neuropsychiat, New York, NY 10029 USA. [Elder, Gregory A.; Ragnauth, Andre; Dorr, Nathan; Buxbaum, Joseph D.] Mt Sinai Sch Med, Mouse & Rat Rhenotyping Facil, New York, NY 10029 USA. RP Buxbaum, JD (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1668,1 Gustave Levy Pl, New York, NY 10029 USA. EM joseph.buxbaum@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU NIA NIH HHS [AG010491, AG002219, P01 AG002219, P01 AG010491, P01 AG010491-06A29001, P01 AG010491-10A20006, P01 AG010491-11] NR 32 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 22 PY 2008 VL 191 IS 2 BP 256 EP 265 DI 10.1016/j.bbr.2008.03.036 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 317WF UT WOS:000257050400015 PM 18466986 ER PT J AU Lieber, CS Leo, MA Wang, X DeCarli, LM AF Lieber, Charles S. Leo, Maria Anna Wang, Xiaolei DeCarli, Leonore M. TI Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE alcohol; liver; Foxo1; p53; mitochondria; SIRT5 ID TRANSCRIPTION FACTORS; SKELETAL-MUSCLE; GENE-EXPRESSION; LIVER-DISEASE; ETHANOL; ACETYLATION; METABOLISM; SIRTUINS; PHOSPHORYLATION; TOXICITY AB Chronic alcohol consumption affects the gene expression of a NAD-depenclent cleacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1 alpha (PGC-1 alpha). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days. Alcohol increased hepatic mRNA expression of FoxO1 (p = 0.003) and p53 (p = 0.001) while corresponding protein levels remained unchanged. However phospho-FoxO1 and phospho-Akt (protein kinase) were both decreased by alcohol consumption (p = 0.04 and p = 0.02, respectively) while hepatic p53 was found hyperacetylated (p = 0.017). Furthermore, mitochondrial SIRT5 was reduced (p = 0.0025), and PGC-1 alpha hyperacetylated (p = 0.027), establishing their role in protein modification. Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5. (C) 2008 Elsevier Inc. All rights reserved. C1 [Lieber, Charles S.; Leo, Maria Anna; DeCarli, Leonore M.] James J Peters VA Med Ctr, Sect Liver Dis & Nutr, Bronx, NY 10468 USA. [Lieber, Charles S.; Leo, Maria Anna; Wang, Xiaolei] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. RP Lieber, CS (reprint author), James J Peters VA Med Ctr, Sect Liver Dis & Nutr, 130 W Kingsbridge Rd 151-2, Bronx, NY 10468 USA. EM liebercs@aol.com NR 30 TC 41 Z9 43 U1 1 U2 8 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 AUG 22 PY 2008 VL 373 IS 2 BP 246 EP 252 DI 10.1016/j.bbrc.2008.06.006 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327WH UT WOS:000257758700013 PM 18555008 ER PT J AU Kumar, P Ban, HS Kim, SS Wu, HQ Pearson, T Greiner, DL Laouar, A Yao, JH Haridas, V Habiro, K Yang, YG Jeong, JH Lee, KY Kim, YH Kim, SW Peipp, M Fey, GH Manjunath, N Shultz, LD Lee, SK Shankar, P AF Kumar, Priti Ban, Hong-Seok Kim, Sang-Soo Wu, Haoquan Pearson, Todd Greiner, Dale L. Laouar, Amale Yao, Jiahong Haridas, Viraga Habiro, Katsuyoshi Yang, Yong-Guang Jeong, Ji-Hoon Lee, Kuen-Yong Kim, Yong-Hee Kim, Sung Wan Peipp, Matthias Fey, Georg H. Manjunath, N. Shultz, Leonard D. Lee, Sang-Kyung Shankar, Premlata TI T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice SO CELL LA English DT Article ID SMALL INTERFERING RNA; LENTIVIRAL VECTOR; CHAIN IMMUNOTOXIN; MOUSE MODEL; HU MICE; IN-VIVO; C-MYB; ANTIBODY; INHIBITION; THERAPY AB Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD79R) for T cell-specific siRNA delivery in NOD/SCIDIL2r gamma(-/-) mice reconstituted with human lymphocytes (Hu-PBL) or CD34(+) hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model. C1 [Ban, Hong-Seok; Lee, Kuen-Yong; Kim, Yong-Hee; Lee, Sang-Kyung] Hanyang Univ, Dept Bioengn, Seoul 133791, South Korea. [Ban, Hong-Seok; Lee, Kuen-Yong; Kim, Yong-Hee; Lee, Sang-Kyung] Hanyang Univ, Hanyang Fus Mat Program, Seoul 133791, South Korea. [Kumar, Priti; Kim, Sang-Soo; Wu, Haoquan; Laouar, Amale; Yao, Jiahong; Haridas, Viraga; Manjunath, N.; Shankar, Premlata] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kumar, Priti; Kim, Sang-Soo; Wu, Haoquan; Laouar, Amale; Yao, Jiahong; Haridas, Viraga; Manjunath, N.; Shankar, Premlata] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pearson, Todd; Greiner, Dale L.] Univ Massachusetts, Sch Med, Dept Med, Div Diabet, Worcester, MA 01605 USA. [Habiro, Katsuyoshi; Yang, Yong-Guang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Jeong, Ji-Hoon; Kim, Sung Wan] Univ Utah, Ctr Controlled Chem Delivery, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA. [Peipp, Matthias] Univ Kiel, Div Stem Cell Transplantat & Immunotherapy, D-24105 Kiel, Germany. [Fey, Georg H.] Univ Erlangen Nurnberg, D-91058 Erlangen, Germany. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Lee, SK (reprint author), Hanyang Univ, Dept Bioengn, Seoul 133791, South Korea. EM sangkyunglee@hanyang.ac.kr; premlata.shankar@ttuhsc.edu RI kim, sang-soo/C-6573-2009; Kumar, Priti/C-5699-2009; Peipp, Matthias/A-8775-2013 FU NIH/National Institute of Allergy and Infectious Diseases [RO1 A1071882, R21 AI06532, AI075419]; Korea Ministry of Education and Science Technology [R01-2006-000-10506-0, F104AA010005-07A0101-00510]; Seoul RBD [CR070027]; CFAR [P30 A060354]; NIH [CA34196]; Juvenile Diabetes Research Foundation; MOEHRD [KRF-2006-352-D00070]; Wilhelm Sander Foundation FX We thank Changseon Choi and Nahyun Kim for technical assistance and Luke Jasenosky for editing the manuscript. This work was supported by the following grants: NIH/National Institute of Allergy and Infectious Diseases RO1 A1071882 and R21 AI06532 to P. S., Korea Ministry of Education and Science Technology R01-2006-000-10506-0 and F104AA010005-07A0101-00510 and Seoul R&BD CR070027 to S. K. L., CFAR fellowship P30 A060354 to P. K., NIH/NIAID Autoimmunity Prevention Center grant to D. L. G., NIH CA34196 to L. D. S., Juvenile Diabetes Research Foundation to D. L. G., L. D. S., and T. P., MOEHRD KRF-2006-352-D00070 to S. S. K., NIH/NIAID UO1 AI075419 to M. N., a Wilhelm Sander Foundation research grant to G. H. F, and the Seoul Fellowship to H. S. B. NR 47 TC 342 Z9 363 U1 11 U2 65 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 22 PY 2008 VL 134 IS 4 BP 577 EP 586 DI 10.1016/j.cell.2008.06.034 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340SR UT WOS:000258665800012 PM 18691745 ER PT J AU Hartleben, B Schweizer, H Lubben, P Bartram, MP Moller, CC Herr, R Wei, CL Neumann-Haefelin, E Schermer, B Zentgraf, H Kerjaschki, D Reiser, J Walz, G Benzing, T Huber, TB AF Hartleben, Bjoern Schweizer, Heiko Luebben, Pauline Bartram, Malte P. Moeller, Clemens C. Herr, Ronja Wei, Changli Neumann-Haefelin, Elke Schermer, Bernhard Zentgraf, Hanswalter Kerjaschki, Dontscho Reiser, Jochen Walz, Gerd Benzing, Thomas Huber, Tobias B. TI Neph-nephrin proteins bind the Par3-Par6-atypical protein kinase C (aPKC) complex to regulate podocyte cell polarity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLOMERULAR SLIT DIAPHRAGM; ADHESION MOLECULE JAM; NEURONAL POLARITY; KIDNEY; GENE; MECHANISM; PAR-3; MICE AB The kidney filter represents a unique assembly of podocyte epithelial cells that tightly enwrap the glomerular capillaries with their foot processes and the interposed slit diaphragm. So far, very little is known about the guidance cues and polarity signals required to regulate proper development and maintenance of the glomerular filtration barrier. We now identify Par3, Par6, and atypical protein kinase C( aPKC) polarity proteins as novel Neph1-Nephrin-associated proteins. The interaction was mediated through the PDZ domain of Par3 and conserved carboxyl terminal residues in Neph1 and Nephrin. Par3, Par6, and aPKC localized to the slit diaphragm as shown in immunofluorescence and immunoelectron microscopy. Consistent with a critical role for aPKC activity in podocytes, inhibition of glomerular aPKC activity with a pseudosubstrate inhibitor resulted in a loss of regular podocyte foot process architecture. These data provide an important link between cell recognition mediated through the Neph1-Nephrin complex and Par-dependent polarity signaling and suggest that this molecular interaction is essential for establishing the three-dimensional architecture of podocytes at the kidney filtration barrier. C1 [Bartram, Malte P.; Schermer, Bernhard; Benzing, Thomas] Univ Hosp Cologne, Div Renal, D-50937 Cologne, Germany. [Hartleben, Bjoern; Schweizer, Heiko; Luebben, Pauline; Herr, Ronja; Neumann-Haefelin, Elke; Walz, Gerd; Huber, Tobias B.] Univ Hosp Freiburg, Div Renal, D-79106 Freiburg, Germany. [Moeller, Clemens C.; Wei, Changli; Reiser, Jochen] Massachusetts Gen Hosp East, Div Nephrol, Boston, MA 02129 USA. [Moeller, Clemens C.; Wei, Changli; Reiser, Jochen] Massachusetts Gen Hosp East, Program Glomerular Dis, Boston, MA 02129 USA. [Zentgraf, Hanswalter] Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria. [Kerjaschki, Dontscho] German Canc Res Ctr, Dept Tumor Virol, D-69120 Heidelberg, Germany. RP Benzing, T (reprint author), Univ Hosp Cologne, Div Renal, Kerpener Str 62, D-50937 Cologne, Germany. EM thomas.benzing@uk-koeln.de; tobias.huber@uniklinik-freiburg.de RI Schermer, Bernhard/E-9972-2014 OI Schermer, Bernhard/0000-0002-5194-9000 FU National Institutes of Health [DK073495]; Kristyna M. Driehaus foundation; Deutsche Forschungsgemeinschaft [BE 2212, HU 1016/2-1]; Deutsche Forschungsgemeinschaft Sonderforschungsbereich [592] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK073495 (to J.R). This work was also supported by a grant from the Kristyna M. Driehaus foundation (to J.R.), by Deutsche Forschungsgemeinschaft Grants BE 2212 (to T.B.) and HU 1016/2-1) (to T.B.H.), and by Deutsche Forschungsgemeinschaft Sonderforschungsbereich 592 (to T.B.H.). NR 31 TC 55 Z9 56 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 AUG 22 PY 2008 VL 283 IS 34 BP 23033 EP 23038 DI 10.1074/jbc.M803143200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337SI UT WOS:000258455400016 PM 18562307 ER PT J AU Jo, OD Martin, J Bernath, A Masri, J Lichtenstein, A Gera, J AF Jo, Oak D. Martin, Jheralyn Bernath, Andrew Masri, Janine Lichtenstein, Alan Gera, Joseph TI Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-BINDING-PROTEINS; FORKHEAD TRANSCRIPTION FACTOR; STRAND ANNEALING ACTIVITY; TRANS-ACTING FACTORS; MESSENGER-RNA; HNRNP A1; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; SUBCELLULAR-DISTRIBUTION; TRANSLATIONAL CONTROL; MEDIATED TRANSLATION AB The translation of the cyclin D1 and c-myc mRNAs occurs via internal ribosome entry site (IRES)-mediated initiation under conditions of reduced eIF-4F complex formation and Akt activity. Here we identify hnRNP A1 as an IRES trans-acting factor that regulates cyclin D1 and c-myc IRES activity, depending on the Akt status of the cell. hnRNP A1 binds both IRESs in vitro and in intact cells and enhances in vitro IRES-dependent reporter expression. Akt regulates this IRES activity by inducing phosphorylation of hnRNP A1 on serine 199. Serine 199-phosphorylated hnRNP A1 binds to the IRESs normally but is unable to support IRES activity in vitro. Reducing expression levels of hnRNP A1 or overexpressing a dominant negative version of the protein markedly inhibits rapamycin-stimulated IRES activity in cells and correlated with redistribution of cyclin D1 and c-myc transcripts from heavy polysomes to monosomes. Importantly, knockdown of hnRNP A1 also renders quiescent Akt-containing cells sensitive to rapamycin-induced G(1) arrest. These results support a role for hnRNP A1 in mediating rapamycin-induced alterations of cyclin D1 and c-myc IRES activity in an Akt-dependent manner and provide the first direct link between Akt and the regulation of IRES activity. C1 [Jo, Oak D.; Martin, Jheralyn; Bernath, Andrew; Masri, Janine; Lichtenstein, Alan; Gera, Joseph] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, Los Angeles, CA 91343 USA. [Lichtenstein, Alan; Gera, Joseph] David Geffen Sch Med, Dept Med, Los Angeles, CA 90048 USA. [Lichtenstein, Alan] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90048 USA. RP Gera, J (reprint author), Univ Calif Los Angeles, Dept Res & Dev, Med Ctr, 16111 Plummer St 151,Bldg 1,Rm C111A, Los Angeles, CA 91343 USA. EM gera@ucla.edu FU NCI NIH HHS [CA-16042, P30 CA016042, R01CA109312, R01CA111448]; NIAID NIH HHS [AI-28697, P30 AI028697] NR 55 TC 46 Z9 47 U1 0 U2 0 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 AUG 22 PY 2008 VL 283 IS 34 BP 23274 EP 23287 DI 10.1074/jbc.M801185200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337SI UT WOS:000258455400040 PM 18562319 ER PT J AU Sole, RV Rodriguez-Caso, C Deisboeck, TS Saldana, J AF Sole, Ricard V. Rodriguez-Caso, Carlos Deisboeck, Thomas S. Saldana, Joan TI Cancer stem cells as the engine of unstable tumor progression SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE cancer; tumor growth; genomic instability; error threshold ID MITOTIC CHECKPOINT; MUTATOR PHENOTYPE; DNA STRANDS; CHEMOTHERAPY; BIOLOGY; CARCINOGENESIS; EVOLUTION; TUMORIGENESIS; POPULATIONS; INSTABILITY AB Genomic instability is considered by many authors the key engine of tumorigenesis. However, mounting evidence indicates that a small population of drug resistant cancer cells can also be a key component of tumor progression. Such cancer stem cells would define a compartment effectively acting as the source of most tumor cells. Here we study the interplay between these two conflicting components of cancer dynamics using two types of tissue architecture. Both mean field and multicompartment models are studied. It is shown that tissue architecture affects the pattern of cancer dynamics and that unstable cancers spontaneously organize into a heterogeneous population of highly unstable cells. This dominant population is in fact separated from the low-mutation compartment by an instability gap, where almost no cancer cells are observed. The possible implications of this prediction are discussed. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Sole, Ricard V.; Rodriguez-Caso, Carlos] Complex Syst Lab ICREA UPF, Barcelona 08003, Spain. [Sole, Ricard V.] Santa Fe Inst, Santa Fe, NM 87501 USA. [Deisboeck, Thomas S.] Massachusetts Gen Hosp, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Complex Biosyst Modeling Lab, Charlestown, MA 02129 USA. [Saldana, Joan] Univ Girona, Dept Informat & Matemat Aplicada, Girona 17071, Spain. RP Sole, RV (reprint author), Complex Syst Lab ICREA UPF, Barcelona Biomed Res Pk PRBB GRIB,Dr Aiguader 88, Barcelona 08003, Spain. EM ricard.sole@upf.edu RI Rodriguez-Caso, Carlos/K-7774-2014; Saldana, Joan/L-3255-2014; Sole, Ricard/I-3379-2015 OI Rodriguez-Caso, Carlos/0000-0002-0423-6681; Saldana, Joan/0000-0001-6174-8029; NR 55 TC 15 Z9 16 U1 0 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD AUG 21 PY 2008 VL 253 IS 4 BP 629 EP 637 DI 10.1016/j.jtbi.2008.03.034 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 339DH UT WOS:000258557800001 PM 18534628 ER PT J AU Seale, P Bjork, B Yang, WL Kajimura, S Chin, S Kuang, SH Scime, A Devarakonda, S Conroe, HM Erdjument-Bromage, H Tempst, P Rudnicki, MA Beier, DR Spiegelman, BM AF Seale, Patrick Bjork, Bryan Yang, Wenli Kajimura, Shingo Chin, Sherry Kuang, Shihuan Scime, Anthony Devarakonda, Srikripa Conroe, Heather M. Erdjument-Bromage, Hediye Tempst, Paul Rudnicki, Michael A. Beier, David R. Spiegelman, Bruce M. TI PRDM16 controls a brown fat/skeletal muscle switch SO NATURE LA English DT Article ID ADIPOSE-TISSUE; PPAR-GAMMA; ADIPOCYTE DIFFERENTIATION; WHITE FAT; UNCOUPLING PROTEIN; SKELETAL-MUSCLE; GENE-EXPRESSION; SATELLITE CELLS; ADULT HUMANS; STEM-CELLS AB Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 ( PRD1- BF1- RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis. C1 [Seale, Patrick; Yang, Wenli; Kajimura, Shingo; Chin, Sherry; Devarakonda, Srikripa; Conroe, Heather M.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Seale, Patrick; Yang, Wenli; Kajimura, Shingo; Chin, Sherry; Devarakonda, Srikripa; Conroe, Heather M.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Bjork, Bryan; Beier, David R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Kuang, Shihuan; Scime, Anthony; Rudnicki, Michael A.] Ottawa Hlth Res Inst, Program Mol Med, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada. [Erdjument-Bromage, Hediye; Tempst, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu OI Tempst, Paul/0000-0002-6680-3987; Kuang, Shihuan/0000-0001-9180-3180 FU American Heart Association; Japan Society for the Promotion of Science; Susan Komen Breast Cancer Foundation; Picower Foundation; National Institutes of Health; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases FX We thank V. Seale and F. LeGrand for help with the lineage tracing studies and R. Gupta for discussions. We are grateful to P. Soriano for the Myf5-Cre mice and F. Constantini for the R26R3-YFP reporter mice. P. S. is supported by a fellowship from the American Heart Association. S. Kajimura is supported by a fellowship from the Japan Society for the Promotion of Science. S. D. is supported by the Susan Komen Breast Cancer Foundation. This work is funded by the Picower Foundation and a National Institutes of Health grant to B. M. S. and an National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant to M. A. R. NR 44 TC 875 Z9 932 U1 8 U2 128 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 21 PY 2008 VL 454 IS 7207 BP 961 EP U27 DI 10.1038/nature07182 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 339QB UT WOS:000258591000031 PM 18719582 ER PT J AU Tseng, YH Kokkotou, E Schulz, TJ Huang, TL Winnay, JN Taniguchi, CM Tran, TT Suzuki, R Espinoza, DO Yamamoto, Y Ahrens, MJ Dudley, AT Norris, AW Kulkarni, RN Kahn, CR AF Tseng, Yu-Hua Kokkotou, Efi Schulz, Tim J. Huang, Tian Lian Winnay, Jonathon N. Taniguchi, Cullen M. Tran, Thien T. Suzuki, Ryo Espinoza, Daniel O. Yamamoto, Yuji Ahrens, Molly J. Dudley, Andrew T. Norris, Andrew W. Kulkarni, Rohit N. Kahn, C. Ronald TI New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure SO NATURE LA English DT Article ID ADIPOCYTE DIFFERENTIATION; TRANSCRIPTIONAL CONTROL; GLUCOSE-UPTAKE; INSULIN; FAT; STIMULATION; CELLS; COMMITMENT; EXPRESSION; C3H10T1/2 AB Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity61. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood(2,3). Here we demonstrate that whereas some members of the family of bone morphogenetic proteins ( BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 ( PR- domain- containing 16; ref. 4) and PGC-1 alpha ( peroxisome proliferator- activated receptor-gamma ( PPAR gamma) coactivator-1 alpha; ref. 5), increased expression of the brown- fat- defining marker uncoupling protein 1 ( UCP1) and adipogenic transcription factors PPAR gamma and CCAAT/ enhancer- binding proteins ( C/ EBPs), and induction of mitochondrial biogenesis via p38 mitogen- activated protein ( MAP) kinase-( also known as Mapk14) and PGC- 1- dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-ediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity. C1 [Tseng, Yu-Hua; Schulz, Tim J.; Huang, Tian Lian; Winnay, Jonathon N.; Taniguchi, Cullen M.; Tran, Thien T.; Suzuki, Ryo; Espinoza, Daniel O.; Yamamoto, Yuji; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Obes & Hormone Act, Boston, MA 02215 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Cell & Mol Physiol, Boston, MA 02215 USA. [Kokkotou, Efi] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02215 USA. [Ahrens, Molly J.; Dudley, Andrew T.] Northwestern Univ, Dept Biochem, Evanston, IL 60208 USA. [Norris, Andrew W.] Univ Iowa, Childrens Hosp, Div Pediat Endocrinol, Iowa City, IA 52242 USA. RP Tseng, YH (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Obes & Hormone Act, Boston, MA 02215 USA. EM yu-hua.tseng@joslin.harvard.edu RI Schulz, Tim/F-4842-2013; OI Schulz, Tim/0000-0002-8413-3972; Norris, Andrew/0000-0001-8396-9543 FU National Institutes of Health [R01 DK077097, R21 DK070722, P30 DK46200, P30 DK040561, R01 DK67536, K08 DK64906, R01 DK 060837]; Tanita Healthy Weight Community; Eleanor and Miles Shore 50th Anniversary Scholar Program FX We acknowledge T.-C. He for providing adenoviruses expressing BMPs. We thank M. Rourk and L. Mazzola for help with the animal experiments, J. Hu, C. Cahill, A. McSweeney, L. Polivy and R. Bronson for technical assistance, and P. Zhang for statistical consultation. We thank A. Butte and P. Laustsen for inputs on initiation of this project. We thank M. Uldry and B. Spiegelman for providing the PGC- 1 null cells. This work was supported in part by the National Institutes of Health grants R01 DK077097, R21 DK070722, P30 DK46200 and P30 DK040561 ( to Y.- H. T.), R01 DK67536 ( to R. N. K.), K08 DK64906 ( to A. W. N.) and R01 DK 060837 ( to C. R. K), the Tanita Healthy Weight Community, and the Eleanor and Miles Shore 50th Anniversary Scholar Program from Harvard Medical School ( to Y.- H. T.). NR 36 TC 456 Z9 493 U1 7 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 21 PY 2008 VL 454 IS 7207 BP 1000 EP U44 DI 10.1038/nature07221 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 339QB UT WOS:000258591000040 PM 18719589 ER PT J AU Rauch, SD AF Rauch, Steven D. TI Idiopathic sudden sensorineural hearing loss SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BLIND CLINICAL-TRIAL; INTRATYMPANIC DEXAMETHASONE; STEROID PERFUSION; INNER-EAR; THERAPY; DEAFNESS; CARBOGEN; FAILURE; JAPAN C1 [Rauch, Steven D.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Rauch, SD (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM steven_rauch@meei.harvard.edu FU Best Doctors; IMEDECS; Partners Online Specialty Consultations FX Dr. Rauch reports receiving consulting fees from Best Doctors, IMEDECS, and Partners Online Specialty Consultations. No other potential conflict of interest relevant to this article was reported. NR 36 TC 94 Z9 116 U1 4 U2 19 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 AUG 21 PY 2008 VL 359 IS 8 BP 833 EP 840 DI 10.1056/NEJMcp0802129 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 339HL UT WOS:000258568600008 PM 18716300 ER PT J AU Sabin, TD Jednacz, JA Staats, PN Cummings, TJ Harris, NL Sims, JR Kolp, R Scott, BJ AF Sabin, Thomas D. Jednacz, Jeffrey A. Staats, Paul N. Cummings, Thomas J., Jr. Harris, Nancy Lee Sims, John R., II Kolp, Rebecca Scott, Brian J. TI A woman with headache and behavioral changes - Probable paraneoplastic limbic encephalitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OVARIAN TERATOMA; RECEPTOR ENCEPHALITIS C1 [Sabin, Thomas D.] Massachusetts Gen Hosp, Tufts Med Ctr, Dept Neurol, Boston, MA 02114 USA. [Jednacz, Jeffrey A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Staats, Paul N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sabin, Thomas D.] Tufts Univ, Sch Med, Dept Neurol, Boston, MA 02111 USA. [Jednacz, Jeffrey A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Staats, Paul N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Sabin, TD (reprint author), Massachusetts Gen Hosp, Tufts Med Ctr, Dept Neurol, Boston, MA 02114 USA. NR 10 TC 25 Z9 29 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 AUG 21 PY 2008 VL 359 IS 8 BP 842 EP 853 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 339HL UT WOS:000258568600011 PM 18716302 ER PT J AU Thadhani, R Solomon, CG AF Thadhani, Ravi Solomon, Caren G. TI Preeclampsia - A glimpse into the future? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ISCHEMIC-HEART-DISEASE; PREGNANCY; COHORT; WOMEN; RISK C1 [Thadhani, Ravi; Solomon, Caren G.] Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. [Thadhani, Ravi; Solomon, Caren G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. NR 16 TC 13 Z9 13 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 AUG 21 PY 2008 VL 359 IS 8 BP 858 EP 860 DI 10.1056/NEJMe0804637 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 339HL UT WOS:000258568600014 PM 18716304 ER PT J AU Cui, Y Dy, JG Alexander, B Jiang, SB AF Cui, Ying Dy, Jennifer G. Alexander, Brian Jiang, Steve B. TI Fluoroscopic gating without implanted fiducial markers for lung cancer radiotherapy based on support vector machines SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID PULMONARY NODULES; TRACKING; NEEDLE; BIOPSY; TUMORS AB Various problems with the current state-of-the-art techniques for gated radiotherapy have prevented this new treatment modality from being widely implemented in clinical routine. These problems are caused mainly by applying various external respiratory surrogates. There might be large uncertainties in deriving the tumor position from external respiratory surrogates. While tracking implanted fiducial markers has sufficient accuracy, this procedure may not be widely accepted due to the risk of pneumothorax. Previously, we have developed a technique to generate gating signals from fluoroscopic images without implanted fiducial markers using template matching methods (Berbeco et al 2005 Phys. Med. Biol. 50 4481 - 90, Cui et al 2007b Phys. Med. Biol. 52 741 - 55). In this note, our main contribution is to provide a totally different new view of the gating problem by recasting it as a classification problem. Then, we solve this classification problem by a well-studied powerful classification method called a support vector machine (SVM). Note that the goal of an automated gating tool is to decide when to turn the beam ON or OFF. We treat ON and OFF as the two classes in our classification problem. We create our labeled training data during the patient setup session by utilizing the reference gating signal, manually determined by a radiation oncologist. We then preprocess these labeled training images and build our SVM prediction model. During treatment delivery, fluoroscopic images are continuously acquired, pre-processed and sent as an input to the SVM. Finally, our SVM model will output the predicted labels as gating signals. We test the proposed technique on five sequences of fluoroscopic images from five lung cancer patients against the reference gating signal as ground truth. We compare the performance of the SVM to our previous template matching method Cui et al 2007b Phys. Med. Biol. 52 741 - 55). We find that the SVM is slightly more accurate on average (1 - 3%) than the template matching method, when delivering the target dose. And the average duty cycle is 4 - 6% longer. Given the very limited patient dataset, we cannot conclude that the SVM is more accurate and efficient than the template matching method. However, our preliminary results show that the SVM is a potentially precise and efficient algorithm for generating gating signals for radiotherapy. This work demonstrates that the gating problem can be considered as a classification problem and solved accordingly. C1 [Cui, Ying; Dy, Jennifer G.] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. [Alexander, Brian] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Jiang, Steve B.] Univ Calif San Diego, Dept Radiat Oncol, La Jolla, CA 92093 USA. RP Cui, Y (reprint author), Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. EM sbjiang@ucsd.edu FU NCI NIH HHS [1R21 CA 110177-01A1] NR 18 TC 23 Z9 23 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD AUG 21 PY 2008 VL 53 IS 16 BP N315 EP N327 DI 10.1088/0031-9155/53/16/N01 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 333HT UT WOS:000258144300018 PM 18660557 ER PT J AU Matthews, QL Yang, P Wu, Q Belousova, N Rivera, AA Stoff-Khalili, MA Waehler, R Hsu, HC Li, Z Li, J Mountz, JD Wu, HJ Curiel, DT AF Matthews, Qiana L. Yang, PingAr Wu, Qi Belousova, Natalya Rivera, Angel A. Stoff-Khalili, Mariam A. Waehler, Reinhard Hsu, Hui-Chen Li, Zan Li, Jing Mountz, John D. Wu, Hongju Curiel, David T. TI Optimization of capsid-incorporated antigens for a novel adenovirus vaccine approach SO VIROLOGY JOURNAL LA English DT Article ID GENE-TRANSFER; DENDRITIC CELLS; VIRAL VECTORS; RECOMBINANT ADENOVIRUSES; IMMUNE-RESPONSES; VIRUS-INFECTION; FIBER PROTEIN; T-CELLS; IN-VIVO; HEXON AB Despite the many potential advantages of Ad vectors for vaccine application, the full utility of current Ad vaccines may be limited by the host anti-vector immune response. Direct incorporation of antigens into the adenovirus capsid offers a new and exciting approach for vaccination strategies; this strategy exploits the inherent antigenicity of the Ad vector. Critical to exploiting Ad in this new context is the placement of antigenic epitopes within the major Ad capsid protein, hexon. In our current study we illustrate that we have the capability to place a range of antigenic epitopes within Ad5 capsid protein hexon hypervariable regions (HVRs) 2 or 5, thus producing viable Ad virions. Our data define the maximal incorporation size at HVR2 or HVR5 as it relates to identical antigenic epitopes. In addition, this data suggests that Ad5 HVR5 is more permissive to a range of insertions. Most importantly, repeated administration of our hexon-modified viruses resulted in a secondary anti-antigen response, whereas minimal secondary effect was present after administration of Ad5 control. Our study describes antigen placement and optimization within the context of the capsid incorporation approach of Ad vaccine employment, thereby broadening this new methodology. C1 [Matthews, Qiana L.; Rivera, Angel A.; Waehler, Reinhard; Li, Jing; Wu, Hongju; Curiel, David T.] Univ Alabama, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Matthews, Qiana L.; Rivera, Angel A.; Waehler, Reinhard; Li, Jing; Wu, Hongju; Curiel, David T.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Matthews, Qiana L.; Rivera, Angel A.; Waehler, Reinhard; Li, Jing; Wu, Hongju; Curiel, David T.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Matthews, Qiana L.; Rivera, Angel A.; Waehler, Reinhard; Li, Jing; Wu, Hongju] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Matthews, Qiana L.; Rivera, Angel A.; Waehler, Reinhard; Li, Jing; Wu, Hongju; Curiel, David T.] Univ Alabama, Gene Therapy Ctr, Birmingham, AL 35294 USA. [Yang, PingAr; Wu, Qi; Hsu, Hui-Chen; Mountz, John D.] Univ Alabama, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Belousova, Natalya] Univ Texas Houston, MD Anderson Canc Ctr, Dept Expt Diagnost Imaging, Houston, TX 77030 USA. [Stoff-Khalili, Mariam A.] Univ Dusseldorf, Dept Obstet & Gynecol, Med Ctr, Dusseldorf, Germany. [Li, Zan] Alabama Sch Fine Arts, Birmingham, AL USA. [Mountz, John D.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Curiel, DT (reprint author), Univ Alabama, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA. EM qlm@uab.edu; shuang@uab.edu; qiwu@uab.edu; Natalya.Belousova@di.mdacc.tmc.edu; aarivera@uab.edu; mariam.stoff-khalili@uk-koeln.de; waehler@uab.edu; HuiChen.Hsu@ccc.uab.edu; parisintherain@gmail.com; jili@uab.edu; John.Mountz@ccc.uab.edu; hongjuwu@uab.edu; curiel@uab.edu FU National Institutes of Health [5T32AI07493-11, 1R21AI076096-01] FX The authors would also like to acknowledge Dr. Maaike Everts and Erin E. Thacker as well as Yizhe Tang for their critical reading of the manuscript. This work was supported by grants from the National Institutes of Health: 5T32AI07493-11 ( Dr. Casey Morrow), and 1R21AI076096-01 ( Dr. David T. Curiel). NR 44 TC 24 Z9 24 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD AUG 21 PY 2008 VL 5 AR 98 DI 10.1186/1743-422X-5-98 PG 13 WC Virology SC Virology GA 360AM UT WOS:000260029400001 PM 18718011 ER PT J AU Kaplan, RC Kingsley, LA Gange, SJ Benning, L Jacobson, LP Lazar, J Anastos, K Tien, PC Sharrett, R Hodis, HN AF Kaplan, Robert C. Kingsley, Lawrence A. Gange, Stephen J. Benning, Lorie Jacobson, Lisa P. Lazar, Jason Anastos, Kathryn Tien, Phyllis C. Sharrett, Richey Hodis, Howard N. TI Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men SO AIDS LA English DT Article DE AIDS; carotid arteries; epidemiology ID INTIMA-MEDIA THICKNESS; MULTICENTER AIDS COHORT; COMBINATION ANTIRETROVIRAL THERAPY; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MYOCARDIAL-INFARCTION; INTERAGENCY HIV; CAROTID ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; FAT DISTRIBUTION AB Objective: To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication Use With SLII)Clinical carotid artery atherosclerosis. Design: Cross-sectional study nested within a prospective cohort study. Methods: Among participants in the Women's Interagency HIV Study (1331 HIV-infected woman, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study(600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness Using B-mode ultrasound. We estimated adjusted mean carotid artery intima-media thickness differences and prevalence rations for carotid lesions associated with HIV-related disease and treatments with multivariate adjustment to control for possible confounding variables. Results: Among HIV-infected individuals, a low CD4+ T-cell count was independently associated with an increased prevalence of carotid lesions. Compared with the reference group of HIV-uninfected individuals, the adjusted prevalence ratio for lesions among HIV-infected individuals with CD4+ T-cell count less than 200 cells/mu l was 2.00 (95% confidence interval, 1.22-3.28) in women and 1.74 (950% confidence interval, 1.04-2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor Use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis. Conclusion: Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men. (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Kaplan, Robert C.; Anastos, Kathryn] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Kingsley, Lawrence A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Kingsley, Lawrence A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Gange, Stephen J.; Benning, Lorie; Jacobson, Lisa P.; Sharrett, Richey] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lazar, Jason] SUNY Hlth Sci Ctr, Dept Med Cardiol, Brooklyn, NY 11203 USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Hodis, Howard N.] Univ So Calif, Keck Sch Med, Atherosclerosis Res Unit, Dept Med, Los Angeles, CA 90033 USA. [Hodis, Howard N.] Univ So Calif, Keck Sch Med, Atherosclerosis Res Unit, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Kaplan, RC (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer 1306C,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM rkaplan@aecom.yu.edu RI Kaplan, Robert/A-2526-2011; OI Gange, Stephen/0000-0001-7842-512X FU NCRR NIH HHS [5-MO1-RR-00722, M01 RR000071, M01 RR000079, M01 RR000083, M01 RR000722, M01 RR023942, M01RR-023942-01, MO1-RR-00071, MO1-RR-00079, MO1-RR-00083]; NHLBI NIH HHS [1R01HL083760-01, R01 HL083760, R01 HL083760-01, R01 HL083760-02, R01 HL083760-03]; NIAID NIH HHS [K23 AI066943, K23 AI066943-05, U01 AI031834, U01 AI034989, U01 AI034993, U01 AI034994, U01 AI035004, U01 AI035039, U01 AI035040, U01 AI035041, U01 AI035042, U01 AI035043, U01 AI037613, U01 AI037984, U01 AI042590, UO1-AI-31834, UO1-AI-34989, UO1-AI-34993, UO1-AI-34994, UO1-AI-35004, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041, UO1-AI-35042, UO1-AI-35043, UO1-AI-37613, UO1-AI-37984, UO1-AI-42590]; NICHD NIH HHS [UO1-HD-32632, U01 HD032632] NR 39 TC 149 Z9 152 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 20 PY 2008 VL 22 IS 13 BP 1615 EP 1624 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 342CG UT WOS:000258761600011 PM 18670221 ER PT J AU Kollef, MH Afessa, B Anzueto, A Veremakis, C Kerr, KM Margolis, BD Craven, DE Roberts, PR Arroliga, AC Hubmayr, RD Restrepo, MI Auger, WR Schinner, R AF Kollef, Marin H. Afessa, Bekele Anzueto, Antonio Veremakis, Christopher Kerr, Kim M. Margolis, Benjamin D. Craven, Donald E. Roberts, Pamela R. Arroliga, Alejandro C. Hubmayr, Rolf D. Restrepo, Marcos I. Auger, William R. Schinner, Regina CA NASCENT Invest Grp TI Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia - The NASCENT Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 20th Annual Congress of the European-Society-of-Intensive-Care-Medicine CY OCT 07-10, 2007 CL Berlin, GERMANY SP European Soc Intens Care Med ID CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; LARGE US DATABASE; MECHANICAL VENTILATION; DOUBLE-BLIND; IN-VITRO; AIRWAY COLONIZATION; DECONTAMINATION; PREVENTION; CATHETERS AB Context Ventilator-associated pneumonia (VAP) causes substantial morbidity. A silver-coated endotracheal tube has been designed to reduce VAP incidence by preventing bacterial colonization and biofilm formation. Objective To determine whether a silver-coated endotracheal tube would reduce the incidence of microbiologically confirmed VAP. Design, Setting, and Participants Prospective, randomized, single-blind, controlled study conducted in 54 centers in North America. A total of 9417 adult patients (>= 18 years) were screened between 2002 and 2006. A total of 2003 patients expected to require mechanical ventilation for 24 hours or longer were randomized. Intervention Patients were assigned to undergo intubation with 1 of 2 high-volume, low-pressure endotracheal tubes, similar except for a silver coating on the experimental tube. Main Outcome Measures Primary outcome was VAP incidence based on quantitative bronchoalveolar lavage fluid culture with 10(4) colony-forming units/mL or greater in patients intubated for 24 hours or longer. Other outcomes were VAP incidence in all intubated patients, time to VAP onset, length of intubation and duration of intensive care unit and hospital stay, mortality, and adverse events. Results Among patients intubated for 24 hours or longer, rates of microbiologically confirmed VAP were 4.8% (37/766 patients; 95% confidence interval [Cl], 3.4%-6.6%) in the group receiving the silver-coated tube and 7.5% (56/743; 95% Cl, 5.7%-9.7%) (P=.03) in the group receiving the uncoated tube (all intubated patients, 3.8% [37/968; 95% Cl, 2.7%-5.2%] and 5.8% [56/964; 95% Cl, 4.4%-7.5%] [P=.04]), with a relative risk reduction of 35.9% (95% Cl, 3.6%-69.0%; all intubated patients, 34.2% [95% Cl, 1.2%-67.9%]). The silver-coated endotracheal tube was associated with delayed occurrence of VAP (P=.005). No statistically significant between-group differences were observed in durations of intubation, intensive care unit stay, and hospital stay; mortality; and frequency and severity of adverse events. Conclusion Patients receiving a silver-coated endotracheal tube had a statistically significant reduction in the incidence of VAP and delayed time to VAP occurrence compared with those receiving a similar, uncoated tube. Trial Registration clinicaltrials.gov Identifier: NCT00148642. C1 [Kollef, Marin H.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Afessa, Bekele; Hubmayr, Rolf D.] Mayo Clin, Coll Med, Rochester, MN USA. [Anzueto, Antonio; Restrepo, Marcos I.] S Texas Vet Hlth Care Syst Audie L Murphy Div, San Antonio, TX USA. [Anzueto, Antonio] Univ Hosp, San Antonio, TX USA. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Veremakis, Christopher] St Johns Mercy Med Ctr, St Louis, MO 63141 USA. [Kerr, Kim M.; Auger, William R.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Margolis, Benjamin D.] W Suburban Hosp, Oak Pk, IL USA. [Craven, Donald E.] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Craven, Donald E.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Roberts, Pamela R.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Arroliga, Alejandro C.] Cleveland Clin, Cleveland, OH 44106 USA. [Restrepo, Marcos I.] VERDICT, San Antonio, TX USA. [Schinner, Regina] FGK Clin Res GmbH, Munich, Germany. RP Kollef, MH (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. EM mkollef@im.wustl.edu RI Restrepo, Marcos/H-4442-2014 NR 47 TC 225 Z9 249 U1 3 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 20 PY 2008 VL 300 IS 7 BP 805 EP 813 DI 10.1001/jama.300.7.805 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 338VM UT WOS:000258537500020 PM 18714060 ER PT J AU Anderson, JR Cain, KC Gelber, RD AF Anderson, James R. Cain, Kevin C. Gelber, Richard D. TI Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID HER2-POSITIVE BREAST-CANCER; ADJUVANT CHEMOTHERAPY; CLINICAL-TRIALS; DOSE-RESPONSE; TRASTUZUMAB; GUIDELINES; DISEASE; LUNG C1 [Anderson, James R.] Univ Nebraska, Coll Publ Hlth, Omaha, NE 68182 USA. [Cain, Kevin C.] Univ Washington, Seattle, WA 98195 USA. [Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Anderson, JR (reprint author), Univ Nebraska, Coll Publ Hlth, Omaha, NE 68182 USA. NR 20 TC 95 Z9 96 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2008 VL 26 IS 24 BP 3913 EP 3915 DI 10.1200/JCO.2008.16.1000 PG 3 WC Oncology SC Oncology GA 338RN UT WOS:000258526200001 PM 18711176 ER PT J AU Hoffman, KE Chen, MH Punglia, RS Beard, CJ D'Amico, AV AF Hoffman, Karen E. Chen, Ming-Hui Punglia, Rinaa S. Beard, Clair J. D'Amico, Anthony V. TI Influence of year of diagnosis, patient age, and sociodemographic status on recommending adjuvant radiation treatment for stage I testicular seminoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURVEILLANCE FOLLOWING ORCHIECTOMY; LONG-TERM SURVIVORS; CANCER DATA-BASE; RANDOMIZED-TRIAL; CARDIOVASCULAR-DISEASE; 2ND MALIGNANCIES; FOLLOW-UP; RADIOTHERAPY; IRRADIATION; TESTIS AB Purpose Adjuvant radiation therapy ( ART) for stage I seminoma can cause adverse late effects and alternative postorchiectomy management strategies have been developed. This study evaluated ART trends in the United States and the impact of clinical and sociodemographic factors on ART recommendations. Methods Of men diagnosed with stage I seminoma from 1990 through 2004, 3,125 were identified using the Surveillance, Epidemiology, and End Results cancer registry. A multivariable logistic regression analysis was performed to assess whether there was a significant association between diagnosis year, diagnosis age, race, county education level, region, tumor size, tumor category, and the recommendation for ART. Results There was a significant association (P < .001) between later year of diagnosis and a decrease in ART recommendation. Compared with men diagnosed in 1990 to 1994, men diagnosed in 1995 to 1999, and 2000 to 2004 were less likely to have ART ( adjusted odds ratio [ OR], 0.63; 95% Cl, 0.48 to 0.84; and OR, 0.49; 95% Cl, 0.37 to 0.63, respectively). There also was a significant association ( P < .001) between county education level and ART recommendation. Men residing in counties with the highest education level were more likely to receive ART than men residing in counties with the lowest education level (OR, 2.12; 95% Cl, 1.59 to 2.82). Also, men older than 30 years were more likely to receive ART than men age 30 or younger ( OR, 1.26; 95% Cl, 1.03 to 1.55). Conclusion ART recommendations for stage I seminoma are declining. Men in less educated regions and the youngest men were less likely to receive a recommendation for ART. C1 [Hoffman, Karen E.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. Univ Connecticut, Dept Stat, Storrs, CT USA. RP Hoffman, KE (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 375 Longwood Ave, Boston, MA 02115 USA. EM khoffman1@partners.org NR 40 TC 31 Z9 31 U1 0 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 AUG 20 PY 2008 VL 26 IS 24 BP 3937 EP 3942 DI 10.1200/JCO.2008.16.5043 PG 6 WC Oncology SC Oncology GA 338RN UT WOS:000258526200007 PM 18711182 ER PT J AU Bar, M Aminoff, E Schacter, DL AF Bar, Moshe Aminoff, Elissa Schacter, Daniel L. TI Scenes unseen: The parahippocampal cortex intrinsically subserves contextual associations, not scenes or places per se SO JOURNAL OF NEUROSCIENCE LA English DT Article DE context; PPA; scenes; associations; parahippocampal cortex; fMRI ID MEDIAL TEMPORAL-LOBE; SURFACE-BASED ANALYSIS; ENTORHINAL CORTEX; CORTICAL SURFACE; SPATIAL REPRESENTATION; COORDINATE SYSTEM; EPISODIC MEMORY; BRAIN ACTIVITY; FMRI; RECOGNITION AB The parahippocampal cortex (PHC) has been implicated in both place/scene processing and episodic memory. We proposed that this region should instead be seen as intrinsically mediating contextual associations and not place/scene processing or episodic memory exclusively. Given that place/scene processing and episodic memory both rely on associations, this modified framework provides a platform for reconciling what seemed like different roles assigned to the same region. Comparing scenes with scenes, we show here that the PHC responds significantly more strongly to scenes with rich contextual associations compared with scenes of equal visual qualities but less associations. This result adds unequivocal support to the view that the PHC mediates contextual associations in general rather than places or scenes proper, and necessitates a revision of the current view that the PHC contains a dedicated place/scenes "module.". C1 [Bar, Moshe; Aminoff, Elissa; Schacter, Daniel L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Aminoff, Elissa; Schacter, Daniel L.] Harvard Univ, Dept Psychol, Cambridge, MA 02115 USA. RP Bar, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, 149,13th St, Charlestown, MA 02129 USA. EM bar@nmr.mgh.harvard.edu OI Schacter, Daniel/0000-0002-2460-6061; Aminoff, Elissa/0000-0002-6455-8930 FU NIMH NIH HHS [MH-NS60941, T32MH070328, T32 MH070328]; NINDS NIH HHS [NS050615, R01 NS050615, R01 NS050615-05] NR 43 TC 113 Z9 117 U1 3 U2 8 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 AUG 20 PY 2008 VL 28 IS 34 BP 8539 EP 8544 DI 10.1523/JNEUROSCI.0987-08.2008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 339US UT WOS:000258603400018 PM 18716212 ER PT J AU Bowers, A West, N Taunton, J Schreiber, SL Bradner, JE Williams, RM AF Bowers, Albert West, Nathan Taunton, Jack Schreiber, Stuart L. Bradner, James E. Williams, Robert M. TI Total synthesis and biological mode of action of largazole: A potent Class I histone deacetylase inhibitor SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHROMOBACTERIUM-VIOLACEUM NO-968; CYCLIC TETRAPEPTIDES; TRICHOSTATIN-A; DEPSIPEPTIDE; FR901228; CYSTEINE; CANCER; FK228 AB The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances. C1 [Bowers, Albert; Williams, Robert M.] Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA. [Williams, Robert M.] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. [West, Nathan; Bradner, James E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Taunton, Jack] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Schreiber, Stuart L.] Harvard Univ, Broad Inst Harvard, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Schreiber, Stuart L.] MIT, Cambridge, MA 02142 USA. RP Williams, RM (reprint author), Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA. EM rmw@lamar.colostate.edu FU NCI NIH HHS [1K08 CA128972-01A1, K08 CA128972, N01-CO-12400, N01CO12400, R01 CA152314, R01 CA152314-01, R01 CA152314-02]; NIGMS NIH HHS [GM49631] NR 35 TC 103 Z9 103 U1 2 U2 22 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 AUG 20 PY 2008 VL 130 IS 33 BP 11219 EP 11222 DI 10.1021/ja8033763 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 337DO UT WOS:000258415900068 PM 18642817 ER PT J AU Ganda, OP AF Ganda, Om P. TI A targeted, multifactorial intervention reduced mortality in patients with type 2 diabetes and microalbuminuria SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Ganda, OP (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 19 PY 2008 VL 149 IS 4 AR JC2-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 338RQ UT WOS:000258526700018 ER PT J AU Cury, RC Shash, K Nagurney, JT Rosito, G Shapiro, MD Nomura, CH Abbara, S Bamberg, F Ferencik, M Schmidt, EJ Brown, DF Hoffmann, U Brady, TJ AF Cury, Ricardo C. Shash, Khalid Nagurney, John T. Rosito, Guido Shapiro, Michael D. Nomura, Cesar H. Abbara, Suhny Bamberg, Fabian Ferencik, Maros Schmidt, Ehud J. Brown, David F. Hoffmann, Udo Brady, Thomas J. TI Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute coronary syndrome in the emergency department SO CIRCULATION LA English DT Article DE magnetic resonance imaging; angina; myocardial infarction; diagnosis ID ST-SEGMENT ELEVATION; CHEST-PAIN; MYOCARDIAL-INFARCTION; HEART-ASSOCIATION; ISCHEMIA; ECHOCARDIOGRAPHY; METAANALYSIS; MULTICENTER; DIAGNOSIS; COMMITTEE AB Background - Cardiac magnetic resonance (CMR) imaging permits early triage of patients presenting to the emergency department with acute chest pain but has been limited by the inability to differentiate new from old myocardial infarction. Our objective was to evaluate a CMR protocol that includes T2-weighted imaging and assessment of left ventricular wall thickness in detecting patients with acute coronary syndrome in the emergency department. Methods and Results - In this prospective cohort observational study, we enrolled patients presenting to the emergency department with acute chest pain, negative cardiac biomarkers, and no ECG changes indicative of acute ischemia. The CMR protocol consisted of T2-weighted imaging, first-pass perfusion, cine function, delayed-enhancement magnetic resonance imaging, and assessment of left ventricular wall thickness. The clinical outcome (acute coronary syndrome) was defined by review of clinical charts by a consensus panel that used American Heart Association/American College of Cardiology guidelines. Among 62 patients, 13 developed acute coronary syndrome during the index hospitalization. The mean CMR time was 32 +/- 8 minutes. The new CMR protocol (with the addition of T2-weighted and left ventricular wall thickness) increased the specificity, positive predictive value, and overall accuracy from 84% to 96%, 55% to 85%, and 84% to 93%, respectively, compared with the conventional CMR protocol (cine, perfusion, and delayed-enhancement magnetic resonance imaging). Moreover, in a logistic regression analysis that contained information on clinical risk assessment (c-statistic = 0.695) and traditional cardiac risk factors (c-statistic = 0.771), the new CMR protocol significantly improved the c-statistic to 0.958 (P < 0.0001). Conclusions - The present study indicates that a new CMR protocol improves the detection of patients with acute coronary syndrome in the emergency department and adds significant value over clinical assessment and traditional cardiac risk factors. C1 [Cury, Ricardo C.; Shash, Khalid; Rosito, Guido; Shapiro, Michael D.; Nomura, Cesar H.; Abbara, Suhny; Bamberg, Fabian; Ferencik, Maros; Hoffmann, Udo; Brady, Thomas J.] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Cury, Ricardo C.; Shash, Khalid; Rosito, Guido; Shapiro, Michael D.; Nomura, Cesar H.; Abbara, Suhny; Bamberg, Fabian; Hoffmann, Udo; Brady, Thomas J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nagurney, John T.; Brown, David F.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Ferencik, Maros; Schmidt, Ehud J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Cury, RC (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM ricardocury@hotmail.com RI Nomura, Cesar/H-1636-2012 FU New York Cardiac Center and General Electric Healthcare; National Institutes of Health [1T32 HL076136-02] FX This work was supported in part by the New York Cardiac Center and General Electric Healthcare. Drs Shash, Shapiro, and Ferencik received support from National Institutes of Health grant 1T32 HL076136-02. NR 23 TC 128 Z9 130 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 19 PY 2008 VL 118 IS 8 BP 837 EP 844 DI 10.1161/CIRCULATIONAHA.107.740597 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 340AS UT WOS:000258619000007 PM 18678772 ER PT J AU Chaput, M Handschumacher, MD Tournoux, F Hua, LQ Guerrero, JL Vlahakes, GJ Levine, RA AF Chaput, Miguel Handschumacher, Mark D. Tournoux, Francois Hua, Lanqi Guerrero, J. Luis Vlahakes, Gus J. Levine, Robert A. TI Mitral leaflet adaptation to ventricular remodeling - Occurrence and adequacy in patients with functional mitral regurgitation SO CIRCULATION LA English DT Article DE regurgitation; heart failure; echocardiography; mitral valve; valves ID ACUTE MYOCARDIAL-INFARCTION; PAPILLARY-MUSCLE DYSFUNCTION; VALVE LEAFLETS; HEART-FAILURE; DOPPLER-ECHOCARDIOGRAPHY; COLLAGEN-SYNTHESIS; IN-VITRO; SEVERITY; MECHANISM; GROWTH AB Background - Functional mitral regurgitation (MR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about whether chronic tethering causes the mitral leaflet area to adapt to the geometric needs imposed by tethering, in part because of inability to reconstruct leaflet area in vivo. Our aim was to explore whether adaptive increases in leaflet area occur in patients with functional MR compared with normal subjects and to test the hypothesis that leaflet area influences MR severity. Methods and Results - A new method for 3-dimensional echocardiographic measurement of mitral leaflet area was developed and validated in vivo against 15 sheep heart valves, later excised. This method was then applied in 80 consecutive patients from 3 groups: patients with normal hearts by echocardiography (n = 20), patients with functional MR caused by isolated inferior wall-motion abnormality or dilated cardiomyopathy (n = 29), and patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (n = 31). Leaflet area was increased by 35 +/- 20% in patients with LV dysfunction compared with normal subjects. The ratio of leaflet to annular area was 1.95 +/- 0.40 and was not different among groups, which indicates a surplus leaflet area that adapts to left-heart changes. In contrast, the ratio of total leaflet area to the area required to close the orifice in midsystole was decreased in patients with functional MR compared with those with normal hearts (1.29 +/- 0.15 versus 1.78 +/- 0.39, P = 0.001) and compared with patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (1.81 +/- 0.38, P = 0.001). After adjustment for measures of LV remodeling and tethering, a leaflet-to-closure area ratio < 1.7 was associated with significant MR (odds ratio 23.2, 95% confidence interval 2.0 to 49.1, P = 0.02). Conclusions - Mitral leaflet area increases in response to chronic tethering in patients with inferior wall-motion abnormality and dilated cardiomyopathy, but the development of significant MR is associated with insufficient leaflet area relative to that demanded by tethering geometry. The varying adequacy of leaflet adaptation may explain in part the heterogeneity of this disease among patients. The results suggest the need to understand the mechanisms that underlie leaflet adaptation and whether leaflet area can potentially be modified as part of the therapeutic approach. C1 [Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiothorac Surg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiothorac Surg, Yawkey 5068,55 Fruit St, Boston, MA 02114 USA. EM rlevine@partners.org FU Fondation Leducq, Paris, France [07CVD04]; National Institutes of Health [R01 HL38176, K24 HL67434] FX This study was supported by grant 07CVD04 from the Fondation Leducq, Paris, France, for the Transatlantic MITRAL Network of Excellence, and by grants R01 HL38176 and K24 HL67434 of the National Institutes of Health, Bethesda, Md. NR 46 TC 91 Z9 94 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 19 PY 2008 VL 118 IS 8 BP 845 EP 852 DI 10.1161/CIRCULATIONAHA.107.749440 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 340AS UT WOS:000258619000008 PM 18678770 ER PT J AU Dukkipati, SR Mallozzi, R Schmidt, EJ Holmvang, G d'Avila, A Guhde, R Darrow, RD Slavin, G Fung, M Malchano, Z Kampa, G Dando, JD McPherson, C Foo, TK Ruskin, JN Dumoulin, CL Reddy, VY AF Dukkipati, Srinivas R. Mallozzi, Richard Schmidt, Ehud J. Holmvang, Godtfred d'Avila, Andre Guhde, Renee Darrow, Robert D. Slavin, Glenn Fung, Maggie Malchano, Zachary Kampa, Greg Dando, Jeremy D. McPherson, Christina Foo, Thomas K. Ruskin, Jeremy N. Dumoulin, Charles L. Reddy, Vivek Y. TI Electroanatomic mapping of the left ventricle in a porcine model of chronic myocardial infarction with magnetic resonance-based catheter tracking SO CIRCULATION LA English DT Article DE catheter ablation; magnetic resonance imaging; mapping; myocardial infarction ID RADIOFREQUENCY ABLATION LESIONS; COMPUTED TOMOGRAPHIC-IMAGES; DEVICES; VISUALIZATION; FLUOROSCOPY; HEART; SWINE AB Background - X-ray fluoroscopy constitutes the fundamental imaging modality for catheter visualization during interventional electrophysiology procedures. The minimal tissue discriminative capability of fluoroscopy is mitigated in part by the use of electroanatomic mapping systems and enhanced by the integration of preacquired 3-dimensional imaging of the heart with computed tomographic or magnetic resonance (MR) imaging. A more ideal paradigm might be to use intraprocedural MR imaging to directly image and guide catheter mapping procedures. Methods and Results - An MR imaging - based electroanatomic mapping system was designed to assess the feasibility of navigating catheters to the left ventricle in vivo using MR tracking of microcoils incorporated into the catheters, measuring intracardiac ventricular electrograms, and integrating this information with 3-dimensional MR angiography and myocardial delayed enhancement images to allow ventricular substrate mapping. In all animals (4 normal, and 10 chronically infarcted swine), after transseptal puncture under fluoroscopic guidance, catheters were successfully navigated to the left ventricle with MR tracking (13 to 15 frames per second) by both transseptal and retrograde aortic approaches. Electrogram artifacts related to the MR imaging gradient pulses were successfully removed with analog and digital signal processing. In all animals, it was possible to map the entire left ventricle and to project electrogram voltage amplitude maps to identify the scarred myocardium. Conclusions - It is possible to use MR tracking to navigate catheters to the left ventricle, to measure electrogram activity, and to render accurate 3-dimensional voltage maps in a porcine model of chronic myocardial infarction, completely in the MR imaging environment. Myocardial delayed enhancement guidance provided dense sampling of the proximity of the infarct and accurate localization of complex infarcts. C1 [Dukkipati, Srinivas R.; Holmvang, Godtfred; d'Avila, Andre; Malchano, Zachary; McPherson, Christina; Ruskin, Jeremy N.; Reddy, Vivek Y.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Dukkipati, Srinivas R.; Holmvang, Godtfred; d'Avila, Andre; Malchano, Zachary; McPherson, Christina; Ruskin, Jeremy N.; Reddy, Vivek Y.] Harvard Univ, Sch Med, Boston, MA USA. [Mallozzi, Richard; Guhde, Renee; Darrow, Robert D.; Foo, Thomas K.; Dumoulin, Charles L.] GE Global Res, Niskayuna, NY USA. [Schmidt, Ehud J.; Slavin, Glenn; Fung, Maggie] GE Healthcare Appl Sci Lab, Boston, MA USA. [Kampa, Greg; Dando, Jeremy D.] St Jude Med Inc, Minnetonka, MI USA. RP Reddy, VY (reprint author), Univ Miami Hosp, 1400 NW 12th Ave,Suite 4062, Miami, FL 33136 USA. EM vreddy@med.miami.edu RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; FU General Electric Co; St Jude Medical, Inc; National Institutes of Health K23 [HL 68064] FX This study was supported in part by research grants from General Electric Co and St Jude Medical, Inc, as well as a National Institutes of Health K23 award (HL 68064) to Dr Reddy. NR 17 TC 33 Z9 33 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 AUG 19 PY 2008 VL 118 IS 8 BP 853 EP 862 DI 10.1161/CIRCULATIONAHA.107.738229 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 340AS UT WOS:000258619000009 PM 18678773 ER PT J AU Gelber, RP Gaziano, JM Orav, EJ Manson, JE Buring, JE Kurth, T AF Gelber, Rebecca P. Gaziano, J. Michael Orav, E. John Manson, Joann E. Buring, Julie E. Kurth, Tobias TI Measures of obesity and cardiovascular risk among men and women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE obesity; cardiovascular disease; epidemiology ID CORONARY-HEART-DISEASE; RANDOMIZED CONTROLLED-TRIAL; WAIST HEIGHT RATIO; LOW-DOSE ASPIRIN; PRIMARY PREVENTION; FAT DISTRIBUTION; INTEROBSERVER AGREEMENT; ABDOMINAL ADIPOSITY; PHYSICIANS HEALTH; USEFUL PREDICTOR AB Objectives This study examined associations between anthropometric measures (body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio [WHtR]) and risk of incident cardiovascular disease (CVD) (including non-fatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular death). Background Controversy exists regarding the optimal approach to measure adiposity, and the utility of body mass index has been questioned. Methods Participants included 16,332 men in the Physicians' Health Study (mean age 61 years in 1991) and 32,700 women in the Women's Health Study (mean age 61 years in 1999). We used Cox proportional hazards models to determine relative risks and 95% confidence intervals (CIs) for developing CVD according to self-reported anthropometric indexes. Results A total of 1,505 CVD cases occurred in men and 414 occurred in women (median follow-up 14.2 and 5.5 years, respectively). Although WHtR demonstrated statistically the strongest associations with CVD and best model fit, CVD risk increased linearly and significantly with higher levels of all indexes. Adjusting for confounders, the relative risk for CVD was 0.58 (95% CI: 0.32 to 1.05) for men with the lowest WHtR (< 0.45) and 2.36 (95% CI: 1.61 to 3.47) for the highest WHtR (>= 0.69; vs. WHtR 0.49 to < 0.53). Among women, the relative risk was 0.65 (95% CI: 0.33 to 1.31) for those with the lowest WHtR (<0.42) and 2.33 (95% CI: 1.66 to 3.28) for the highest WHtR (>= 0.68; vs. WHtR 0.47 to <0.52). Conclusions The WHtR demonstrated statistically the best model fit and strongest associations with CVD. However, compared with body mass index, differences in cardiovascular risk assessment using other indexes were small and likely not clinically consequential. Our findings emphasize that higher levels of adiposity, however measured, confer increased risk of CVD. C1 [Gelber, Rebecca P.; Gaziano, J. Michael; Buring, Julie E.; Kurth, Tobias] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Aging, Boston, MA 02120 USA. [Gaziano, J. Michael; Manson, Joann E.; Buring, Julie E.; Kurth, Tobias] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Prevent Med, Boston, MA 02120 USA. [Orav, E. John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Gen Med & Primary Care, Boston, MA 02120 USA. [Manson, Joann E.; Buring, Julie E.; Kurth, Tobias] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Orav, E. John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gaziano, J. Michael] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA 02120 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02120 USA. [Gelber, Rebecca P.] Harvard Vanguard Med Associates, Boston, MA USA. RP Kurth, T (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Aging, 1620 Tremont St, Boston, MA 02120 USA. EM tkurth@rics.bwh.harvard.edu RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU NCI NIH HHS [CA-097193, CA-34944, CA-047988, CA-40360, R01 CA034944, R01 CA034944-03, R01 CA040360, R01 CA040360-14, R01 CA040360-15, R01 CA040360-16, R01 CA040360-17, R01 CA047988, R01 CA047988-09, R01 CA047988-10, R01 CA047988-11, R01 CA047988-12, R01 CA047988-13, R01 CA047988-14, R01 CA047988-15, R01 CA047988-16, R01 CA047988-17, R01 CA047988-18, R01 CA097193]; NHLBI NIH HHS [HL-043851, HL-080467, HL-26490, HL-34595, R01 HL026490, R01 HL026490-03, R01 HL034595, R01 HL034595-07, R01 HL043851, R01 HL043851-09, R01 HL043851-10]; NIA NIH HHS [T32 AG000158, T32 AG000158-18] NR 37 TC 159 Z9 164 U1 0 U2 9 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 AUG 19 PY 2008 VL 52 IS 8 BP 605 EP 615 DI 10.1016/j.jacc.2008.03.066 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 336VX UT WOS:000258394000003 PM 18702962 ER PT J AU Corboy, JR Elkind, MSV AF Corboy, John R. Elkind, Mitchell S. V. TI Maintenance of certification - Ready or not, here it comes SO NEUROLOGY LA English DT Editorial Material ID CLINICAL-EXPERIENCE; HEALTH-CARE; QUALITY C1 [Corboy, John R.] Univ Colorado, Sch Med, Aurora, CO USA. [Corboy, John R.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Elkind, Mitchell S. V.] Columbia Univ, Sch Med, New York, NY USA. RP Corboy, JR (reprint author), 12631 E 17th Ave,Box B185,POB 6511,Room 5221, Aurora, CO 80045 USA. EM john.corboy@uchsc.edu NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 19 PY 2008 VL 71 IS 8 BP 544 EP 545 DI 10.1212/01.wnl.0000323935.26470.c3 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 338RO UT WOS:000258526400002 PM 18711107 ER PT J AU Berman, SD Calo, E Landman, AS Danielian, PS Miller, ES West, JC Fonhoue, BD Caron, A Bronson, R Bouxsein, ML Mukherjee, S Lees, JA AF Berman, Seth D. Calo, Eliezer Landman, Allison S. Danielian, Paul S. Miller, Emily S. West, Julie C. Fonhoue, Borel Djouedjong Caron, Alicia Bronson, Roderick Bouxsein, Mary L. Mukherjee, Siddhartha Lees, Jacqueline A. TI Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE osx-cre; Sca-1; hibernoma mouse model ID LI-FRAUMENI-SYNDROME; TUMOR-SUPPRESSOR ACTIVITY; GENE; MUTATIONS; DIFFERENTIATION; MICE; SARCOMA; CANCER; TP53 AB Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance. These tumors display many of the characteristics of human osteosarcomas, including being highly metastatic. We established cell lines from the DKO osteosarcomas to further investigate their properties. These immortalized cell lines are highly proliferative and they retain their tumorigenic potential, as judged by their ability to form metastatic tumors in immunocompromised mice. Moreover, they can be induced to differentiate and, depending on the inductive signal, will adopt either the osteogenic or adipogenic fate. Consistent with this multipotency, a significant portion of these tumor cells express Sca-1, a marker that is typically associated with stem cells/uncommitted progenitors. By assaying sorted cells in transplant assays, we demonstrate that the tumorigenicity of the osteosarcoma cell lines correlates with the presence of the Sca-1 marker. Finally, we show that loss of Rb and p53 in Sca-1-positive mesenchymal stem/progenitor cells is sufficient to yield transformed cells that can initiate osteosarcoma formation in vivo. C1 [Berman, Seth D.; Calo, Eliezer; Landman, Allison S.; Danielian, Paul S.; Miller, Emily S.; West, Julie C.; Fonhoue, Borel Djouedjong; Caron, Alicia; Lees, Jacqueline A.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Bronson, Roderick] Tufts Univ, Cummings Sch Vet Med, North Grafton, MA 01536 USA. [Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. [Mukherjee, Siddhartha] Harvard Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Mukherjee, Siddhartha] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Lees, JA (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM jalees@mit.edu FU National Cancer Institute [CA121921]; Massachusetts Institute of Technology FX We thank Stephen Rodda and Andrew McMahon for the Osx1-GFP::Cre transgenics, Tyler Jacks and Anton Berns for the Rb and pS3 conditional strains, University of Iowa Gene Transfer Vector Core for Ad5CMVCre-eGFP, and Lees laboratoy members for helpful discussions. This project was supported by National Cancer Institute Grant CA121921 (to J.A.L.), a David H. Koch Graduate Fellowship (to 5.D.B.), and a Ludwig Graduate Fellowship (to A.S.L.). J.A.L. is a Ludwig Scholar at Massachusetts Institute of Technology. NR 26 TC 106 Z9 114 U1 2 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 19 PY 2008 VL 105 IS 33 BP 11851 EP 11856 DI 10.1073/pnas.0805462105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341OM UT WOS:000258723800049 PM 18697945 ER PT J AU Lettre, G Sankaran, VG Bezerra, MAC Araujo, AS Uda, M Sanna, S Cao, A Schlessinger, D Costa, FF Hirschhorn, JN Orkin, SH AF Lettre, Guillaume Sankaran, Vijay G. Bezerra, Marcos Andre C. Araujo, Aderson S. Uda, Manuela Sanna, Serena Cao, Antonio Schlessinger, David Costa, Fernando F. Hirschhorn, Joel N. Orkin, Stuart H. TI DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetic modifier; single nucleotide polymorphism; globin gene regulation ID GENOME-WIDE ASSOCIATION; RISK-FACTORS; CHROMOSOME 6Q23; GENE; HEIGHT; CHOLESTEROL; THALASSEMIA; EXPRESSION; VARIANTS; HUMANS AB Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008)Proc Natl Acad Sci USA 105:1620-1625]. Here, we genotyped additional BCL11A SNIPS, HBS1L-MYB SNIPS, and an SNP upstream of (G)gamma-globin (HBG2; the Xmnl polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNIPS on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 x 10(-42)). Together, common SNIPS at the BCL11A, HBS1L-MYB, and beta-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease. C1 [Lettre, Guillaume; Hirschhorn, Joel N.] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Harvard Univ, Cambridge, MA 02142 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bezerra, Marcos Andre C.; Araujo, Aderson S.] Fdn Hematol & Hemoterapia Pernambuco, BR-52011000 Recife, PE, Brazil. [Uda, Manuela; Sanna, Serena; Cao, Antonio] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy. [Schlessinger, David] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Costa, Fernando F.] Univ Estadual Campinas, Ctr Hemotherapy & Hematol, BR-13083970 Campinas, SP, Brazil. RP Lettre, G (reprint author), MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM lettre@broad.mit.edu; joselh@broad.mit.edu; stuart_orkin@dfci.harvard.edu RI Costa, Fernando/D-1566-2012; Sangue, Inct/I-1919-2013; OI sanna, serena/0000-0002-3768-1749 FU National Institutes of Health (NIH); Howard Hughes Medical Institute (S.H.O.); Medical Scientist Training Program FX We thank all of the patients who participated in this study, and we thank members of our laboratories for comments. We thank D. Nathan, D. Altshuler, F. Bunn, and M. Weiss for critical reading of this manuscript; the CSSCD investigators for allowing us access to data and DNA samples from the study; and S. Coady for support. Funding for this project was provided by grants from National Institutes of Health (NIH) and the Howard Hughes Medical Institute (S.H.O.). V.G.S. was supported by a Medical Scientist Training Program award from the NIH. NR 30 TC 227 Z9 238 U1 3 U2 19 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 AUG 19 PY 2008 VL 105 IS 33 BP 11869 EP 11874 DI 10.1073/pnas.0804799105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341OM UT WOS:000258723800052 PM 18667698 ER PT J AU Ergorul, C Ray, A Huang, W Darland, D Luo, ZHK Grosskreutz, CL AF Ergorul, Ceren Ray, Arjun Huang, Wei Darland, Diane Luo, Zhonghui K. Grosskreutz, Cynthia L. TI Levels of vascular endothelial growth factor-A(165b) (VEGF-A(165b)) are elevated in experimental glaucoma SO MOLECULAR VISION LA English DT Article ID OPEN-ANGLE GLAUCOMA; OCULAR BLOOD-FLOW; SPLICE VARIANT; RETINAL NEOVASCULARIZATION; DIABETIC-RETINOPATHY; GENE-EXPRESSION; POSTURE CHANGE; MESSENGER-RNA; VEGF; VEGF(165)B AB Purpose: Although ischemia has previously been suggested to contribute to the pathogenesis of glaucoma, neovascularization is not implicated in glaucoma. Because vascular endothelial growth factor-A (VEGF-A) is a key mediator in neovascularization response, we investigated the levels of the major pro-angiogenic (VEGF-A(164)) and antiangiogenic VEGF-A subtypes (VEGF-A(165b)) in the retina during experimental glaucoma. Methods: Glaucoma was induced unilaterally in rats by injecting 1.9 M hypertonic saline solution in the episcleral veins. The contralateral eye served as the control. The intraocular pressure (IOP) of each eye was measured via Tonopen in conscious rats. Eyes were enucleated either on the 5th or the 10th day of elevated IOP. Whole retinal lysates were separated by SDS-PAGE and transferred to PVDF membranes. Levels of VEGF-A164 and VEGF-A165b were analyzed by western blotting using specific antibodies. In a different group of rats, retinal ganglion cells were retrogradely labeled by injecting Fluorogold in the superior colliculus a week before the induction of glaucoma. After the eyes were enucleated on the fifth day of elevated IOP, posterior eye cups were sectioned using a cryostat. Levels and localization of VEGF-A164 and VEGFA(165b) were examined in retinal sections by immunohistochemistry. Results: VEGF-A164 levels remained unchanged between the control and glaucomatous retinas after five days (p= 0.341) and 10 days of elevated IOP (p= 0.117). The presence of the anti-angiogenic VEGF-A isoform has not been previously reported in the rat. An antibody specific to VEGF-A165b detected the anti-angiogenic protein in the rat retina. VEGFA165b levels were significantly increased (2.33+/-0.44 fold, p= 0.014) in the glaucomatous retinas compared to those in controls after five days of elevated IOP. VEGF-A165b levels were not different (p= 0.864) between the control and glaucomatous retinas following 10 days of elevated IOP. Expression of both VEGF-A164 and VEGF-A165b were observed in the retinal ganglion cells (RGC) and inner nuclear layer (INL). Conclusions: Five day elevation of IOP leads to an increase in the anti-angiogenic VEGF-A165b levels but not in the proangiogenic VEGF-A164 levels in the glaucomatous retina. VEGF-A165b levels return to baseline after 10 days of elevated IOP, and VEGF-A164 levels remain unchanged. We speculate that the short-term elevation of VEGF-A165b levels and/or the unchanged levels of VEGF-A164 contribute to the lack of neovascularization in the glaucomatous retina. C1 [Ergorul, Ceren; Ray, Arjun; Huang, Wei; Luo, Zhonghui K.; Grosskreutz, Cynthia L.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab Ophthalmol, Boston, MA 02114 USA. [Darland, Diane] Univ N Dakota, Dept Biol, Grand Forks, ND 58202 USA. RP Grosskreutz, CL (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM cynthia_grosskreutz@meei.harvard.edu FU NEI NIH HHS [R01 EY013399, EY014104, R01-EY13399, T32 EY007145, T32-EY07145, P30 EY014104] NR 40 TC 21 Z9 23 U1 0 U2 3 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 AUG 18 PY 2008 VL 14 IS 179-81 BP 1517 EP 1524 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 344JW UT WOS:000258923900003 PM 18728749 ER PT J AU Anton, PA Ibarrondo, FJ Boscardin, WJ Zhou, Y Schwartz, EJ Ng, HL Hausner, MA Shih, R Elliott, J Hultin, PM Hultin, LE Price, C Fuerst, M Adler, A Wong, JT Yang, OO Jamieson, BD AF Anton, Peter A. Ibarrondo, F. Javier Boscardin, W. John Zhou, Ying Schwartz, Elissa J. Ng, Hwee L. Hausner, Mary Ann Shih, Roger Elliott, Julie Hultin, Patricia M. Hultin, Lance E. Price, Charles Fuerst, Marie Adler, Amy Wong, Johnson T. Yang, Otto O. Jamieson, Beth D. TI Differential immunogenicity of vaccinia and HIV-1 components of a human recombinant vaccine in mucosal and blood compartments SO VACCINE LA English DT Article DE mucosal immunity; HIV; vaccine ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; T-CELLS; SYSTEMIC IMMUNITY; BOOST VACCINE; CTL RESPONSE; IMMUNIZATION; INFECTION; MACAQUES; ANKARA AB Mucosal immune responses induced by HIV-1 vaccines are likely critical for prevention. We report a Phase 1 safety and immunogenicity trial in eight participants using the vaccinia-based TBC-3B vaccine given subcutaneously to determine the relationship between HIV-1 specific systemic and gastrointestinal mucosal responses. Across all subjects, detectable levels of blood vaccinia- and HIV-1-specific antibodies were elicited but none were seen mucosally. While the vaccinia component was immunogenic for CD8(+) T lymphocyte (CTL) responses in both blood and mucosa, it was greater in blood. The HIV-1 component of the vaccine was poorly immunogenic in both blood and mucosa. Although only eight volunteers were studied intensively, the discordance between mucosal and blood responses may highlight mechanisms contributing to recent vaccine failures. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Anton, Peter A.; Ibarrondo, F. Javier; Boscardin, W. John; Zhou, Ying; Ng, Hwee L.; Hausner, Mary Ann; Shih, Roger; Elliott, Julie; Hultin, Patricia M.; Hultin, Lance E.; Price, Charles; Adler, Amy; Yang, Otto O.; Jamieson, Beth D.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [Anton, Peter A.; Ibarrondo, F. Javier; Boscardin, W. John; Zhou, Ying; Ng, Hwee L.; Hausner, Mary Ann; Shih, Roger; Elliott, Julie; Hultin, Patricia M.; Hultin, Lance E.; Price, Charles; Adler, Amy; Yang, Otto O.; Jamieson, Beth D.] Univ Calif Los Angeles, Ctr Prevent Res, Los Angeles, CA 90095 USA. [Yang, Otto O.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Iimmunol & Mol Genet, Los Angeles, CA 90095 USA. [Boscardin, W. John; Zhou, Ying; Ng, Hwee L.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Wong, Johnson T.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Schwartz, Elissa J.] Washington State Univ, Dept Math, Pullman, WA 99164 USA. [Schwartz, Elissa J.] Washington State Univ, Sch Biol Sci, Pullman, WA 99164 USA. [Fuerst, Marie] Tower Canc Res Fdn, Beverly Hills, CA USA. RP Anton, PA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, 675 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM panton@mednet.ucla.edu FU Therion, Inc; American Foundation for AIDS Research (amFAR) [02620]; NIH [R01 (A150467), T32 Al07370]; UCLA Center for AIDS Research (CFAR) [P30 #A1028697]; MACY*s Foundation; Oppenheimer Brother's Foundation FX This study was supported by Therion, Inc. for IND assistance, vaccine and vaccinia wild type and technical assistance in vaccinia antibody assays. Pallotta Teamworks (TM) and the riders of the Vaccine Rides as well as American Foundation for AIDS Research (amFAR) (#02620) provided initial seed funding.; National Institutes of Health (NIH) funding provided the following support: NIH R01 (#A150467); the UCLA Center for AIDS Research (CFAR) grant (P30 #A1028697), including the Cores of Mucosal Immunology, Flow Cytometry, Virology, ELISPOTs and Biostatistics; NIH 1(24 Al01610 (PAA); NIH T32 Al07370. Additionally, the following reagents were obtained throughout NIH AIDS Research and Reference Reagent Program, Division of AIDS, MAID, NIH: HIV-1 Consensus Subtype B Peptides (15-mer), Complete Sets for gag, pal, env, nef, tat rev, vif, vpu, vpr. Ying Zhou and Xin Huang provided assistance with data management and analysis. Additional support was provided by the MACY*s Foundation and the Oppenheimer Brother's Foundation. NR 39 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 18 PY 2008 VL 26 IS 35 BP 4617 EP 4623 DI 10.1016/j.vaccine.2008.05.084 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 345BU UT WOS:000258971800031 PM 18621451 ER PT J AU Ackerman, JL Wu, YT Glimcher, MJ Cao, HH Graham, L Cho, G AF Ackerman, Jerome L. Wu, Yaotang Glimcher, Melvin J. Cao, Haihui Graham, Lila Cho, Gyunggoo TI PHYS 277-Zeugmatography today: Solid state MR imaging and spectroscopy of bone SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Ackerman, Jerome L.; Cho, Gyunggoo] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Ackerman, Jerome L.; Cho, Gyunggoo] Harvard Univ, Sch Med, Martinos Ctr, Charlestown, MA 02129 USA. [Wu, Yaotang; Glimcher, Melvin J.; Cao, Haihui; Graham, Lila] Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Wu, Yaotang; Glimcher, Melvin J.; Cao, Haihui; Graham, Lila] Harvard Univ, Sch Med, Lab Study Skeletal Disorders & Rehabil, Boston, MA 02115 USA. EM jerry@nmr.mgh.harvard.edu; yaotang.wu@childrens.harvard.edu; melvin.glimcher@childrens.harvard.edu; hcao@nmr.mgh.harvard.edu; lila.graham@childrens.harvard.edu; gyunggoo@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 12 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 277-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256307330 ER PT J AU Dumas, S Koerner, S Sun, WC Zhang, ZD Spuentrup, E Caravan, P AF Dumas, Stephane Koerner, Steffi Sun, Wei-Chuan Zhang, Zhaoda Spuentrup, Elmar Caravan, Peter TI ANYL 359-Collagen targeted Gd-based MRI contrast agent for steady state myocardial perfusion imaging SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Dumas, Stephane; Koerner, Steffi; Sun, Wei-Chuan; Zhang, Zhaoda] Epix Pharmaceut, Lexington, MA 02421 USA. [Spuentrup, Elmar] Tech Univ RWTH, Univ Hosp, Dept Diagnost Radiol, Aachen, Germany. [Caravan, Peter] Harvard Univ, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. EM sdumas@epixpharma.com; zzhang@epixpharma.com; caravan@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 359-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256301133 ER PT J AU Gajiwala, KS Wu, J Lunney, E Demetri, G AF Gajiwala, Ketan S. Wu, Joe Lunney, Elizabeth Demetri, George TI COMP 375-Novel mechanisms of drug resistance in KIT mutants from patients with gastrointestinal stromal tumors: Structural biology of wild-type and mutated proteins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Gajiwala, Ketan S.] Pfizer, Struct & Computat Biol, San Diego, CA 92121 USA. [Wu, Joe] Pfizer, Res Technol Ctr, Biochem & Enzymol, Cambridge, MA 02139 USA. [Demetri, George] Dana Farber Canc Inst, Boston, MA 02115 USA. EM ketan.gajiwala@pfizer.com; Joe.C.Wu@pfizer.com; beth.lunney@pfizer.com; gdemetri@partners.org NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 375-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256304037 ER PT J AU Gallagher, M Preti, G Fakharzadeh, S Wysocki, CJ Kwak, J Miller, CJ Schmults, CD Spielman, AI Sun, XM AF Gallagher, Michelle Preti, George Fakharzadeh, Steve Wysocki, Charles J. Kwak, Jae Miller, Christopher J. Schmults, Chrysalyne D. Spielman, Andrew I. Sun, Xuming TI AGFD 227-Detecting skin cancer using volatile biomarkers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Gallagher, Michelle; Preti, George; Wysocki, Charles J.; Kwak, Jae] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Fakharzadeh, Steve; Wysocki, Charles J.; Miller, Christopher J.] Univ Penn, Philadelphia, PA 19104 USA. [Schmults, Chrysalyne D.] Dana Farber Brigham & Womens Canc Ctr, Mohs Microg Surg Ctr, Jamaica Plain, MA 02130 USA. [Spielman, Andrew I.] NYU, Dept Basic Sci, Coll Dent, New York, NY 10010 USA. [Sun, Xuming] NYU, Dept Basic Sci & Craniofacial Biol, Coll Dent, New York, NY 10010 USA. EM mgallagher@monell.org; preti@monell.org; ssf@mail.med.upenn.edu; wysocki@pobox.upenn.edu; jkwak@monell.org; Chris.Miller2@uphs.upenn.edu; cschmults@partners.org; andrew.spielman@nyu.edu; xs5@nyu.edu RI Kwak, Jae/E-5781-2011 OI Kwak, Jae/0000-0003-4216-2019 NR 0 TC 0 Z9 0 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 227-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256300244 ER PT J AU Garanger, E Reynolds, F Weissleder, R Josephson, L AF Garanger, E. Reynolds, F. Weissleder, R. Josephson, L. TI ANYL 196-Multifunctional single-attachment-point reagents for molecular imaging probe design. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Garanger, E.; Reynolds, F.; Weissleder, R.; Josephson, L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. EM egaranger@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 196-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256301302 ER PT J AU Gray, NS AF Gray, Nathanael S. TI MEDI 20-Discovery and characterization of allosteric inhibitors of Bcr-Abl kinase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM Nathanael_Gray@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 20-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256305687 ER PT J AU Gray, NS AF Gray, Nathanael S. TI COMP 376-Chemical approaches for making "inactive-conformation" kinase inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Gray, Nathanael S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. EM Nathanael-Gray@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 376-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256304363 ER PT J AU Grimes, CL Podolsky, DK O'Shea, EK AF Grimes, Catherine Leimkuhler Podolsky, Daniel K. O'Shea, Erin K. TI AEI 11-Development of tools to study the activation of the innate immune system SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [O'Shea, Erin K.] Harvard Univ, Dept Mol & Cellular Biol, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Podolsky, Daniel K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02144 USA. EM cleimkuh@fas.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 11-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256300049 ER PT J AU Kidambi, S AF Kidambi, Srivatsan TI AEI 81-Engineering novel surfaces for tissue engineering and drug delivery applications SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Kidambi, Srivatsan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Shriners Childrens Hosp,Ctr Engn Med, Boston, MA 02141 USA. EM srivatsan.kidambi@gmail.com RI KIDAMBI, SRIVATSAN/A-5689-2015 OI KIDAMBI, SRIVATSAN/0000-0002-0282-0411 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 81-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256300030 ER PT J AU Koerner, S Kolodziej, A Nair, S McMurry, T Nivoroshkin, A Pratt, C Sun, WC Wang, XF Zhang, ZD Caravan, P Uprichard, A AF Koerner, Steffi Kolodziej, Andrew Nair, Shrikumar McMurry, Thomas Nivoroshkin, Alexander Pratt, Curtis Sun, Wei-Chuan Wang, Xifang Zhang, Zhaoda Caravan, Peter Uprichard, Andrew TI MEDI 403-Optimization of fibrin-binding peptides as targeting vectors for thrombus-specific MRI-contrast agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Koerner, Steffi; Kolodziej, Andrew; Nair, Shrikumar; McMurry, Thomas; Nivoroshkin, Alexander; Pratt, Curtis; Sun, Wei-Chuan; Wang, Xifang; Zhang, Zhaoda; Uprichard, Andrew] EPIX Pharmaceut, Lexington, MA 02155 USA. [Caravan, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM skoerner@epixpharma.com; caravan@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 403-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256305606 ER PT J AU Koh, I Hong, R Weissleder, R Josephson, L AF Koh, Isaac Hong, Rui Weissleder, Ralph Josephson, Lee TI ANYL 9-Sensitive NMR sensors detect antibodies to influenza SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Koh, Isaac; Hong, Rui; Weissleder, Ralph; Josephson, Lee] Harvard Univ, Ctr Mol Imaging Res, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM ikoh@mgh.harvard.edu; rhong1@partners.org NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 9-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256301040 ER PT J AU Yun, CH Woo, MS Greulich, H Meyerson, M Eck, MJ Wong, KK AF Yun, Cai-Hong Woo, Michele S. Greulich, Heidi Meyerson, Matthew Eck, Michael J. Wong, Kwok-Kin TI COMP 373-Structural and mechanistic studies of lung cancer mutations in the EGFR kinase reveal a novel mechanism of drug resistance SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 236th National Meeting of the American-Chemical-Society CY AUG 17-21, 2008 CL Philadelphia, PA SP Amer Chem Soc C1 [Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yun, Cai-Hong; Woo, Michele S.; Greulich, Heidi; Meyerson, Matthew; Eck, Michael J.; Wong, Kwok-Kin] Dana Farber Canc Inst, Boston, MA 02115 USA. EM eck@red.dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 17 PY 2008 VL 236 MA 373-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 499WD UT WOS:000270256304064 ER PT J AU McCarthy, JR Weissleder, R AF McCarthy, Jason R. Weissleder, Ralph TI Multifunctional magnetic nanoparticles for targeted imaging and therapy SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE iron oxide; magnetic narroparticles; peptide targeting; small molecule targeting; molecular imaging; cancer; atherosclerosis; theranostic ID SUPERPARAMAGNETIC IRON-OXIDE; IN-VIVO TRACKING; CONTRAST AGENTS; PROSTATE-CANCER; E-SELECTIN; BIOMEDICAL APPLICATIONS; BRAIN-TUMORS; LYMPH-NODES; ATHEROSCLEROSIS; INFLAMMATION AB Magnetic nanoparticles have become important tools for the imaging of prevalent diseases, such as cancer, atherosclerosis, diabetes, and others. While first generation nanoparticles were fairly nonspecific, newer generations have been targeted to specific cell types and molecular targets via affinity ligands. Commonly, these ligands emerge from phage or small molecule screens, or are based on antibodies or aptamers. Secondary reporters and combined therapeutic molecules have further opened potential clinical applications of these materials. This review summarizes some of the recent biomedical applications of these newer magnetic nanomaterials. (c) 2008 Elsevier B.V. All rights reserved. C1 [McCarthy, Jason R.] Harvard Univ, Sch Med, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP McCarthy, JR (reprint author), Harvard Univ, Sch Med, Ctr Mol Imaging Res, 149 13th St,Rm 5406, Charlestown, MA 02129 USA. EM jason_mccarthy@hms.harvard.edu FU NCI NIH HHS [U54 CA126515-020002, U54 CA119349, U54 CA126515, U54 CA126515-010002, U54-CA119349, U54-CA126515]; NHLBI NIH HHS [U01 HL080731, U01 HL080731-01, U01 HL080731-02, U01 HL080731-03, U01 HL080731-04, U01-HL080731] NR 87 TC 494 Z9 509 U1 17 U2 237 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD AUG 17 PY 2008 VL 60 IS 11 BP 1241 EP 1251 DI 10.1016/j.addr.2008.03.014 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 335TO UT WOS:000258313900003 PM 18508157 ER PT J AU Dagda, RK Zhu, JH Kulich, SM Chu, CT AF Dagda, Ruben K. Zhu, Jianhui Kulich, Scott M. Chu, Charleen T. TI Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress SO AUTOPHAGY LA English DT Article DE autophagy; oxidative stress; mitochondria; mitogen activated protein kinases; 6-hydroxydopamine; Parkinson's disease ID NEUROBLASTOMA SH-SY5Y CELLS; PROTEIN-KINASE; PARKINSONS-DISEASE; CEREBRAL-ISCHEMIA; NEURONAL INJURY; MOUSE MODELS; ACTIVATION; 6-HYDROXYDOPAMINE; ERK1/2; NEURODEGENERATION AB Degenerating neurons of Parkinson's disease (PD) patient brains exhibit granules of phosphorylated extracellular signal-regulated protein kinase 1/2 (ERK1/2) that localize to autophagocytosed mitochondria. Here we show that 6-hydroxydopamine (6-OHDA) elicits activity-related localization of ERK1/2 in mitochondria of SH-SY5Y cells, and these events coincide with induction of autophagy and precede mitochondrial degradation. Transient transfection of wildtype (WT) ERK2 or constitutively active MAPK/ERK Kinase 2 (NIEK2-CA) was sufficient to induce mitophagy to a degree comparable with that elicited by 6-OHDA, while constitutively active ERK2 (ERK2-CA) had a greater effect. We developed green fluorescent protein (GFP) fusion constructs of WT, CA, and kinase-deficient (KD) ERK2 to study the role of ERK2 localization in regulating mitophagy and cell death. Under basal conditions, cells transfected with GFP-ERK2-WT or GFP-ERK2-CA, but not GFP-ERK2-KD, displayed discrete cytoplasmic ERK2 granules of which a significant fraction colocalized with mitochondria and markers of autophagolysosomal maturation. The colocalizing GFP-ERK2/mitochondria granules are further increased by 6-OHDA and undergo autophagic degradation, as bafilomycin-A, an inhibitor of autolysosomal degradation, robustly increased their detection. Interestingly, increasing ERK2-WT or ERK2-CA expression was sufficient to promote comparable levels of macroautophagy as assessed by analysis of the autophagy marker microtubule-associated protein I light chain 3 (LC3). In contrast, the level of mitophagy was more tightly correlated with ERK activity levels, potentially explained by the greater localization of ERK2-CA to mitochondria compared to ERK2-WT. These data indicate that mitochondrial localization of ERK2 activity is sufficient to recapitulate the effects of 6-OHDA on mitophagy and autophagic cell death. C1 [Dagda, Ruben K.; Zhu, Jianhui; Kulich, Scott M.; Chu, Charleen T.] Univ Pittsburgh, Dept Pathol, Sch Med, Pittsburgh, PA 15261 USA. [Chu, Charleen T.] Univ Pittsburgh, Ctr Neurosci, Sch Med, Pittsburgh, PA 15261 USA. [Kulich, Scott M.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Chu, CT (reprint author), Univ Pittsburgh, Dept Pathol, Sch Med, 200 Lothrop St, Pittsburgh, PA 15261 USA. EM ctc4@pitt.edu RI Chu, Charleen/B-1601-2008; OI Chu, Charleen/0000-0002-5052-8271; Dagda, Ruben/0000-0002-9946-9591 FU National Institutes of Health [AG026389, DC009120]; Veterans Administration Advanced Career Development Award; [T32 NS07495]; [F32 AG030821] FX We thank Simon Watkins and the Center for Biological Imaging (CBI) at the University of Pittsburgh for technical expertise with live confocal and EM imaging, Christopher Fung for constructing stable GFP-LC3 cell lines, Charlotte Diges for technical assistance, and all of the investigators listed in the methods section for providing molecular reagents. This research was supported by funding from the National Institutes of Health (AG026389 and DC009120, CTC) and a Veterans Administration Advanced Career Development Award (SMK). RKD was supported in part by T32 NS07495 and F32 AG030821. NR 72 TC 140 Z9 144 U1 2 U2 15 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD AUG 16 PY 2008 VL 4 IS 6 BP 770 EP 782 PG 13 WC Cell Biology SC Cell Biology GA 339TT UT WOS:000258600900006 PM 18594198 ER PT J AU Ketteler, R Seed, B AF Ketteler, Robin Seed, Brian TI Quantitation of autophagy by luciferase release assay SO AUTOPHAGY LA English DT Article DE autophagy; assay; gaussia; luciferase; secretion; screen; in vivo ID ISOLATED RAT HEPATOCYTES; IN-VIVO; MONITORING AUTOPHAGY; PROTEIN-DEGRADATION; REGULATES AUTOPHAGY; MAMMALIAN AUTOPHAGY; GAUSSIA LUCIFERASE; HUMAN ATG4B; LC3; CELLS AB Autophagy is a cellular process that has been defined and analyzed almost entirely by qualitative measures. In no small part, this is attributable to the absence of robust quantitative assays that can easily and reliably permit the progress of key steps in autophagy to be assessed. We have recently developed a cell-based assay that specifically measures proteolytic cleavage of a tripartite sensor protein by the autophagy protease ATG4B. Activation of ATG4B results in release of Gaussia luciferase from cells that can be non-invasively harvested from cellular supernatants. Here, we compare this technique to existing methods and propose that this type of assay will be suitable for genome-wide functional screens and in vivo analysis of autophagy. C1 [Ketteler, Robin; Seed, Brian] Harvard Univ, Sch Med, Dept Genet, Massachusetts Gen Hosp,Ctr Computat & Integrat Bi, Boston, MA 02114 USA. RP Seed, B (reprint author), Harvard Univ, Sch Med, Dept Genet, Massachusetts Gen Hosp,Ctr Computat & Integrat Bi, 185 Cambridge St, Boston, MA 02114 USA. EM bseed@ccib.mgh.harvard.edu FU Deutsche Forschungsgemeinschaft FX R.K. was supported by the Deutsche Forschungsgemeinschaft. NR 78 TC 25 Z9 26 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD AUG 16 PY 2008 VL 4 IS 6 BP 801 EP 806 PG 6 WC Cell Biology SC Cell Biology GA 339TT UT WOS:000258600900009 PM 18641457 ER PT J AU Kurth, T Schurks, M Logroscino, G Gaziano, JM Buring, JE AF Kurth, Tobias Schurks, Markus Logroscino, Giancarlo Gaziano, J. Michael Buring, Julie E. TI Migraine, vascular risk, and cardiovascular events in women: prospective cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID LOW-DOSE ASPIRIN; ISCHEMIC-STROKE; YOUNG-WOMEN; DISEASE; HEADACHE; METAANALYSIS; CHOLESTEROL; PREVENTION; HEALTH; GEM AB Objectives To evaluate whether the association between migraine with aura and increased risk of cardiovascular disease is modified by vascular risk groups as measured by the Framingham risk score for coronary heart disease. Design Prospective cohort study. Setting Women's health study, United States. Participants 27 519 women who were free from cardiovascular disease at baseline with available information on the Framingham risk score and migraine status. Main outcome measures Time to major cardiovascular disease event (non-fatal myocardial infarction, non-fatal ischaemic stroke, death from ischaemic cardiovascular disease), myocardial infarction, and ischaemic stroke. Results At baseline, 3577 (13.0%) women reported, active migraine, of whom 1418 (39.6%) reported migraine with aura. During 11.9 years of follow-up, there were 697 cardiovascular disease events. We stratified participants based on 10 year risk of coronary heart disease estimated from the Framingham risk score (1%, 2-4%, 5-9%, and >= 10%). Compared with women without migraine, the age adjusted hazard ratios in women with active migraine with aura were 1.93 (95% confidence interval 1.45 to 2.56) for major cardiovascular disease, 1.80 (1.16 to 2.79) for ischaemic stroke, and 1.94 (1.27 to 2.95) for myocardial infarction. When stratified by Framingham risk score, the association between migraine with aura and major cardiovascular disease was strongest in the lowest risk score group. There was a diametric association pattern for ischaemic stroke and myocardial infarction. Compared with women without migraine, the age adjusted hazard ratios in women who reported migraine with aura in the lowest Framingham risk score group were 3.88 (1.87 to 8.08) for ischaemic stroke and 1.29 (0.40 to 4.21) for myocardial infarction. Hazard ratios in women with migraine with aura in the highest Framingham risk score group were 1.00 (0.24 to 4.14) for ischaemic stroke and 3.34 (1.50 to 7.46) for myocardial infarction. Women with migraine without aura were not at increased risk of ischaemic stroke or myocardial infarction in any of the Framingham risk score groups. Conclusion The association between migraine with aura and cardiovascular disease varies by vascular risk status. Information on history of migraine and vascular risk status might help to identify women at increased risk for specific future cardiovascular disease events. Trial registration Clinical trials NCT00000479. C1 [Kurth, Tobias; Schurks, Markus; Gaziano, J. Michael; Buring, Julie E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med,Dept Med, Boston, MA 02115 USA. [Kurth, Tobias; Gaziano, J. Michael; Buring, Julie E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, Boston, MA 02115 USA. [Kurth, Tobias; Buring, Julie E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Logroscino, Giancarlo] Univ Bari, Sch Med, Dept Neurol & Psychiat, Bari, Italy. [Gaziano, J. Michael] Boston VA Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. RP Kurth, T (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med,Dept Med, Boston, MA 02115 USA. EM tkurth@rics.bwh.harvard.edu RI Kurth, Tobias/A-9243-2012; Potter, Joseph/A-3122-2008; LOGROSCINO, GIANCARLO/K-5148-2016 OI Kurth, Tobias/0000-0001-7169-2620; LOGROSCINO, GIANCARLO/0000-0003-0423-3242 FU National Heart. Lung, and Blood Institute [HL-043851, HL-080467]; National Cancer Institute [CA-47988]; Donald W Reynolds Foundation; Leducq Foundation; Doris Duke Charitable Foundation FX The women's health study is supported by grants and from the National Heart. Lung, and Blood Institute (HL-043851 and HL-080467). and the National Cancer Institute (CA-47988). The research for this work was supported by grants from the Donald W Reynolds Foundation, the Leducq Foundation, and the Doris Duke Charitable Foundation. NR 32 TC 106 Z9 106 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD AUG 16 PY 2008 VL 337 IS 7666 AR a636 DI 10.1136/bmj.a636 PG 23 WC Medicine, General & Internal SC General & Internal Medicine GA 340TZ UT WOS:000258669200024 PM 18687721 ER PT J AU Parikh, NI Hwang, SJ Larson, MG Hoffmann, U Levy, D Meigs, JB O'Donnell, CJ Fox, CS AF Parikh, Nisha I. Hwang, Shih-Jen Larson, Martin G. Hoffmann, Udo Levy, Daniel Meigs, James B. O'Donnell, Christopher J. Fox, Caroline S. TI Indexes of kidney function and coronary artery and abdominal aortic calcium (from the Framingham Offspring Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; CARDIOVASCULAR-DISEASE; SERUM CREATININE; COMPUTED-TOMOGRAPHY; MINERAL METABOLISM; RISK-FACTORS; CALCIFICATION; MICROALBUMINURIA; ATHEROSCLEROSIS AB It is uncertain whether moderate chronic kidney disease (CKD) or measures of kidney function are associated with subclinical atherosclerosis as represented by coronary artery calcium (CAC) or abdominal aortic calcium (AAC). We used logistic and linear regression analyses to relate CKD (glomerular filtration rate < 60 ml/min/1.73 m(2)), cystatin C (cysC), and microalbuminuria (MA) with CAC and AAC obtained using multidetector computed tomography in Framingham Heart Study Offspring participants (mean age 59 years, 55.3% women). Increased CAC and AAC were defined as >= 90th percentile age- and gender-specific cutpoints based on a healthy referent sample. Major cardiovascular disease risk factors were accounted for in multivariable models. Of 1,179 participants, 1,174 had AAC measurements and 1,147 had CAC measurements, 6.3% had CKD, and 8.3% had MA. CKD was not associated with CAC (multivariable-adjusted odds ratio [OR] for CKD 1.18, 95% confidence interval 0.59 to 2.36, p = 0.63) or AAC (multivariable-adjusted OR for CKD 1.11, 95% confidence interval 0.61 to 2.04, p = 0.73). CysC was associated with CAC in age- and gender-adjusted but not in multivariable models (age- and gender-adjusted OR for log cysC per SD increment and CAC 1.19, 95% confidence interval 1.01 to 1.41, p = 0.04; multivariable-adjusted OR 1.14, 95% confidence interval 0.95 to 1.38, p = 0.15). MA was not associated with CAC (OR 0.81, 95% confidence interval 0.41 to 1.61, p = 0.54). Neither cysC nor MA was significantly associated with AAC in age- and gender- or multivariable-adjusted models. In conclusion, CKD, cysC, and MA are not associated with CAC or AAC when accounting for cardiovascular disease risk factors. (C) 2008 Elsevier Inc. All rights reserved. C1 [Parikh, Nisha I.; Hwang, Shih-Jen; Larson, Martin G.; Levy, Daniel; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Parikh, Nisha I.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Dept Endocrinol Diabetol & Hypertens, Boston, MA 02115 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Meigs, James B.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254 FU National Heart, Lung and Blood Institute, Bethesda, Maryland [N01-HC-25195]; American Diabetes Association research; Roche Diagnostics (Indianapolis, Indiana); Career Development Award from the American Diabetes Association, Alexandria, Virginia; [NIDDK K24 DKO80140] FX The Framingham Heart Study is supported by Grant N01-HC-25195 from the National Heart, Lung and Blood Institute, Bethesda, Maryland. This study was supported by an American Diabetes Association research grant and by Roche Diagnostics (Indianapolis, Indiana) who donated assay reagents for measurement of urinary albumin and creatinine. Dr. Meigs was supported by a Career Development Award from the American Diabetes Association, Alexandria. Virginia, and by Grant NIDDK K24 DKO80140. Bethesda, Maryland. NR 30 TC 6 Z9 7 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2008 VL 102 IS 4 BP 440 EP 443 DI 10.1016/j.amjcard.2008.04.007 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 343IY UT WOS:000258848000013 PM 18678302 ER PT J AU Lopez-Posadas, R Ballester, I Abadia-Molina, AC Suarez, MD Zarzuelo, A Martinez-Augustin, O de Medina, FS AF Lopez-Posadas, Rocio Ballester, Isabel Abadia-Molina, Ana Clara Suarez, Maria Dolores Zarzuelo, Antonio Martinez-Augustin, Olga de Medina, Fermin Sanchez TI Effect of flavonoids on rat splenocytes, a structure-activity relationship study SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE lymphocyte; flavonoid; viability; toxicity; proliferation ID NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; GREEN TEA; EXPERIMENTAL COLITIS; INDUCED-APOPTOSIS; LYMPHOCYTE-PROLIFERATION; PLANT FLAVONOIDS; INHIBITION; QUERCETIN; POLYPHENOLS AB Flavonoids are polyphenols frequently consumed in the diet which have been suggested to exert a number of beneficial actions on human health, including intestinal anti-inflammatory activity. Their properties have been studied in numerous cell types, but little is known about their effect on leukocyte biology. We have selected 9 flavonoids (extended to 14 flavonoids plus the related polyphenol resveratrol in some cases) with different structural features to characterize their effects on leukocyte viability, proliferation, and expression of cyclooxygenase 2 (EC 1.14.99.1), inducible nitric oxide synthase (iNOS, EC 1.14.13.39) and proinflammatory cytokines (TNF-alpha, IFN-gamma, IL-2), as well as to elucidate the structural requirements in each case. Quiescent and concanavalin A-stimulated rat splenocytes were used as a model. Flavonoids (50 mu M) had a dramatic inhibitory effect on cytokine secretion. inducible nitric oxide synthase expression was also blocked largely by some flavonoids, especially quercetin, luteolin and apigenin, while cyclooxygenase 2 was downregulated only by apigenin, diosmetin and quercetin. Apigenin, luteolin, genistein and quercetin had substantial cytotoxic/proapoptotic effects, while chrysin, daidzein, hesperetin and kaempferol did not reduce cell viability. in contrast, all flavonoids had powerful antiproliferative effects. However, none of the compounds activated caspase 3 (EC 3.4.22.56), but actually lowered caspase 3 activation and expression in concanavalin A-stimulated cells. The activity of the quercetin metabolite isorhamnetin was generally lower than that of the parent compound. We conclude that flavonoids have powerful effects on lymphocytes with distinct structural requirements that may contribute to their intestinal anti-inflammatory activity. The bioactivity of orally administered flavonoids may be dampened by biotransformation in vivo, particularly in extraintestinal sites. (C) 2008 Elsevier Inc. All rights reserved. C1 [Ballester, Isabel] Harvard Univ, Gastrointestinal Unit GRJ716, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lopez-Posadas, Rocio; Zarzuelo, Antonio; de Medina, Fermin Sanchez] Univ Granada, Dept Pharmacol, Sch Pharm, Ctr Invest Biomed Red Enfermedades Hepat & Digest, E-18071 Granada, Spain. [Abadia-Molina, Ana Clara] Univ Granada, Sch Med, Dept Biochem & Mol Biol & Immunol 3, E-18071 Granada, Spain. [Suarez, Maria Dolores; Martinez-Augustin, Olga] Univ Granada, Sch Pharm, Dept Biochem & Mol Biol 2, Ctr Invest Biomed Red Enfermedades Hepat & Digest, E-18071 Granada, Spain. RP Ballester, I (reprint author), Harvard Univ, Gastrointestinal Unit GRJ716, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM iballester@partners.org RI Zarzuelo, Antonio/L-2840-2014; Lorente, M Dolores/N-1313-2014; Suarez Ortega, Maria Dolores/H-1240-2015; Martinez Augustin, Olga/K-6720-2014; OI Suarez Ortega, Maria Dolores/0000-0003-3197-2518; Martinez Augustin, Olga/0000-0001-8291-3468; Sanchez de Medina, Fermin/0000-0002-4516-5824 FU Instituto de Salud Carlos III [PI051625, PI051651]; Ministerio de Educacion y Ciencia, Spain,; Ministerio de Educacion y Ciencia, Spain; European Regional Development Fund [BFU2005-24983-E/BFI]; Instituto de Salud Carlos III; [SAF2006-08529] FX This work was supported by grants from the Instituto de Salud Carlos III (PI051625 and PI051651). RLP and IB are recipients of a predoctoral and a postdoctoral fellowship from the Ministerio de Educacion y Ciencia, Spain, respectively. ACA-Mis funded by the SAF2006-08529 grant and by the Ramon y Cajal program of the Ministerio de Educacion y Ciencia, Spain and OMA by the I3P program of the Ministerio de Educacion y Ciencia, Spain. The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), co-funded by the Ministerio de Educacion y Ciencia, Spain and the European Regional Development Fund (Grant BFU2005-24983-E/BFI). The CIBER-EHD is funded by the Instituto de Salud Carlos III. NR 58 TC 41 Z9 48 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2008 VL 76 IS 4 BP 495 EP 506 DI 10.1016/j.bcp.2008.06.001 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 338XM UT WOS:000258542700006 PM 18590707 ER PT J AU Tai, YT Dillon, M Song, W Leiba, M Li, XF Burger, P Lee, AI Podar, K Hideshima, T Rice, AG van Abbema, A Jesaitis, L Caras, I Law, D Weller, E Xie, W Richardson, P Munshi, NC Mathiot, C Avet-Loiseau, H Afar, DEH Anderson, KC AF Tai, Yu-Tzu Dillon, Myles Song, Weihua Leiba, Merav Li, Xian-Feng Burger, Peter Lee, Alfred I. Podar, Klaus Hideshima, Teru Rice, Audie G. van Abbema, Anne Jesaitis, Lynne Caras, Ingrid Law, Debbie Weller, Edie Xie, Wanling Richardson, Paul Munshi, Nilhil C. Mathiot, Claire Avet-Loiseau, Herve Afar, Daniel E. H. Anderson, Kenneth C. TI Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces aritibody-dependent cellular cytotoxicity in the bone marrow mitieu SO BLOOD LA English DT Article ID HUMAN MULTIPLE-MYELOMA; IMMUNOGLOBULIN SUPERFAMILY; CLINICAL-IMPLICATIONS; CD2 SUBSET; 2B4 CD244; THALIDOMIDE; CS1; DEXAMETHASONE; MALIGNANCIES; MECHANISMS AB Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination. C1 [Tai, Yu-Tzu; Song, Weihua; Leiba, Merav; Li, Xian-Feng; Burger, Peter; Lee, Alfred I.; Podar, Klaus; Hideshima, Teru; Richardson, Paul; Munshi, Nilhil C.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Dillon, Myles; Rice, Audie G.; van Abbema, Anne; Jesaitis, Lynne; Caras, Ingrid; Law, Debbie; Afar, Daniel E. H.] PDL BioPharma, Dept Res, Fremont, CA USA. [Weller, Edie; Xie, Wanling] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Munshi, Nilhil C.] Harvard Univ, Sch Med, Vet Adm Boston Hlth Care Syst, Boston, MA 02115 USA. [Mathiot, Claire] Inst Curie, Hematol Lab, Paris, France. [Avet-Loiseau, Herve] Inst Biol, Hematol Lab, Nantes, France. RP Tai, YT (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, M551,44 Binney St, Boston, MA 02115 USA. EM yu-tzu_tai@dfci.harvard.edu; Kenneth_Anderson@dfci.harvard.edu FU NCI NIH HHS [P50 CA100707, P50CA100707]; PHS HHS [P01-78378, R0-150947] NR 34 TC 181 Z9 184 U1 0 U2 4 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 AUG 15 PY 2008 VL 112 IS 4 BP 1329 EP 1337 DI 10.1182/blood-2007-08-107292 PG 9 WC Hematology SC Hematology GA 336VH UT WOS:000258392300059 PM 17906076 ER PT J AU Sharma, S Lichtenstein, A AF Sharma, Sanjai Lichtenstein, Alan TI Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors SO BLOOD LA English DT Article ID FACTOR-KAPPA-B; ACUTE LYMPHOBLASTIC-LEUKEMIA; DNA-BINDING DOMAIN; MULTIPLE-MYELOMA; BIM; IDENTIFICATION; INHIBITION; EXPRESSION; REPRESSION; RESISTANCE AB The mechanism by which the glucocorticoid (GC) dexamethasone induces apoptosis in multiple myeloma (MM) cells is unknown, although previous work suggests that either transactivation through the glucocorticoid response element (GRE), transrepression of NF-kappa B, phosphorylation of RAFTK (Pyk2), or induction of Bim is important. We studied this question by ectopically expressing mutant glucocorticoid receptors (GRs) in the dexamethasone-resistant MM1 R cell line, which has lost its GR. Lentiviral-mediated reexpression of wild-type GR restored GRE transactivation, NF-KB transrepression, RAFTK phosphorylation, Bim induction, and dexamethasone-induced apoptosis. We then reexpressed 4 GR mutants, each possessing various molecular effects, into MM1 R cells. A perfect correlation was present between induction of GRE transactivation and induction of apoptosis. In contrast, NF-KB transrepression and RAFTK phosphorylation were not required for apoptosis. Although not required for dexamethasone-mediated apoptosis, NF-KB inhibition achieved by gene transfer suggested that NF-KB trans-repression could contribute to apoptosis in dexamethasone-treated cells. Dexamethasone treatment of MM1R cells expressing a mutant incapable of inducing apoptosis successfully resulted in RAFTK (Pyk2) phosphorylation and Bim induction indicating the latter GR-mediated events were not sufficient to induce apoptosis. MM1R cells expressing mutant GRs will be helpful in defining the molecular mechanisms of dexamethasone-induced apoptosis of myeloma cells. C1 [Sharma, Sanjai; Lichtenstein, Alan] Univ Calif Los Angeles, W Los Angeles & VA Med Ctr, Div Hematol Oncol, Los Angeles, CA 90073 USA. RP Sharma, S (reprint author), Univ Calif Los Angeles, W Los Angeles & VA Med Ctr, Div Hematol Oncol, 11301 Wilshire Blvd,Bldg 304,E1-115, Los Angeles, CA 90073 USA. EM sasharma@mednet.ucla.edu FU NCI NIH HHS [R01 CA111448] NR 31 TC 27 Z9 30 U1 0 U2 2 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 AUG 15 PY 2008 VL 112 IS 4 BP 1338 EP 1345 DI 10.1182/blood-2007-11-124156 PG 8 WC Hematology SC Hematology GA 336VH UT WOS:000258392300060 PM 18515658 ER PT J AU Martin, NE Chen, MH Catalona, WJ Loeb, S Roehl, KA D'Amico, AV AF Martin, Neil E. Chen, Ming-Hui Catalona, William J. Loeb, Stacy Roehl, Kimberly A. D'Amico, Anthony V. TI The influence of serial prostate-specific antigen (PSA) screening on the PSA velocity at diagnosis SO CANCER LA English DT Article DE prostate cancer; prostate-specific antigen screening; prostate-specific antigen velocity; stage migration ID DIGITAL RECTAL EXAMINATION; CONTINUED STAGE MIGRATION; BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; CANCER; SERUM; RISK; CARCINOMA; SURVIVAL; OUTCOMES AB BACKGROUND. A prostate-specific antigen (PSA) velocity (PSAV) > 2 ng/mL during the year before diagnosis has been associated with an increased risk of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP) or radiation therapy. The objective of the current study was to examine whether the proportion of men with a PSAV > 2 ng/mL per year has changed significantly during the PSA era. METHODS. The authors evaluated 1095 men from a prospective prostate cancer screening study who underwent RP between 1989 and 2002. For the purposes of this analysis, clinicopathologic features were compared between men who were treated during the following 3 periods: before 1995, from 1995 to 1998, and after 1998. Logistic regression analysis was used to evaluate for an association between the year of diagnosis and the proportion of men with a PSAV > 2 ng/mL per year. RESULTS. Two hundred sixty-two of 1095 men (24%) had a PSAV > 2 ng/mL per year. There was a statistically significant reduction in the proportion of men presenting with a PSAV > 2 ng/mL per year over the study period. Specifically, 35% of men presented with a PSAV > 2 ng/mL per year in the early period compared with only 22% and 12% in the middle and late periods, respectively (P < .001). Over the studied periods, there also was a significantly greater proportion of men with > 2 PSA values obtained before diagnosis (P < .001). CONCLUSIONS. Men who were screened serially with PSA were less likely to present with a PSAV > 2 ng/mL per year. This association lends support to the hypothesis that serial PSA-based screening may lead to a decrease in PCSM. C1 [Martin, Neil E.] Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Catalona, William J.] NW Feinberg Sch Med, Dept Urol, Chicago, IL USA. [Loeb, Stacy] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Roehl, Kimberly A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Martin, NE (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, L-2 Level,75 Francis St, Boston, MA 02115 USA. EM nmartin@lroc.harvard.edu RI Martin, Neil/E-2193-2014; OI Martin, Neil/0000-0002-8164-8516; Loeb, Stacy/0000-0003-3933-9207 NR 32 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2008 VL 113 IS 4 BP 717 EP 722 DI 10.1002/cncr.23609 PG 6 WC Oncology SC Oncology GA 335SV UT WOS:000258311800010 PM 18615505 ER PT J AU Jackman, DM Kindler, HL Yeap, BY Fidias, P Salgia, R Lucca, J Morse, LK Ostler, PA Johnson, BE Janne, PA AF Jackman, David M. Kindler, Hedy L. Yeap, Below Y. Fidias, Panos Salgia, Ravi Lucca, Joan Morse, Linda K. Ostler, Patricia A. Johnson, Bruce E. Janne, Pasi A. TI Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma SO CANCER LA English DT Article DE mesothelioma; receptors; epidermal growth factor; receptors; vascular endothelial growth factor; bevacizumab; erlotinib ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; LEUKEMIA GROUP-B; PHASE-II TRIAL; COOPERATIVE-ONCOLOGY-GROUP; MONOCLONAL-ANTIBODY; CLINICAL-TRIALS; GEMCITABINE; COMBINATION; CISPLATIN AB BACKGROUND. We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non-small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity METHODS. Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 rng/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS. Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% Cl, 2.8 nionths-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment- related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS. The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy More therapeutic studies with effective agents are needed for these patients. C1 [Jackman, David M.; Lucca, Joan; Morse, Linda K.; Johnson, Bruce E.; Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kindler, Hedy L.; Salgia, Ravi] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Yeap, Below Y.; Fidias, Panos; Ostler, Patricia A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM pasi_janne@dfci.harvard.edu NR 33 TC 61 Z9 61 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2008 VL 113 IS 4 BP 808 EP 814 DI 10.1002/cncr.23617 PG 7 WC Oncology SC Oncology GA 335SV UT WOS:000258311800021 PM 18543326 ER PT J AU Temel, JS McCannon, J Greer, JA Jackson, VA Ostler, P Pirl, WF Lynch, TJ Billings, JA AF Temel, Jennifer S. McCannon, Jessica Greer, Joseph A. Jackson, Vicki A. Ostler, Patricia Pirl, William F. Lynch, Thomas J. Billings, J. Andrew TI Aggressiveness of care in a prospective cohort of patients with advanced NSCLC SO CANCER LA English DT Article DE end-of-life care; nonsmall-cell lung cancer; hospice care; chemotherapy ID CELL LUNG-CANCER; QUALITY-OF-LIFE; PHASE-III TRIAL; SUPPORTIVE CARE; RANDOMIZED-TRIAL; HOSPICE CARE; LAST PHASE; CHEMOTHERAPY; END; DOCETAXEL AB BACKGROUND. Optimal end of life care of patients with terminal cancer is poorly understood. In this study, the aggressiveness of care is described in a cohort of patients with newly diagnosed advanced nonsmall-cell lung cancer (NSCLC). METHODS. Patients within 8 weeks of diagnosis of stage IIIb (with effusions) or IV NSCLC were enrolled in a study to examine the feasibility of involving palliative care services early in the provision of cancer care. Participants received standard oncology treatment and integrated palliative care. All patients were followed prospectively to assess anticancer therapy usage, hospital admissions, hospice utilization, and location of death. RESULTS. At the time of analysis, 40/46 (87%) of enrolled patients had died, with a median length of follow-up of 29.3 months. Aggressive care measures in the final month of life included rates of anticancer therapy (40%), emergency department visits (48%), and hospital admissions (50%). Sixty-five percent of patients received hospice care before death, with a median length of stay of 16 days. Patients with heightened baseline anxiety and mood symptoms were more likely to receive anticancer therapy at the end of life compared with those without such symptoms. CONCLUSIONS. This study demonstrates the frequent use of aggressive measures at the end of life among patients with advanced NSCLC in a tertiary care center, as shown by the number of patients receiving anticancer therapy within 30 days of death and brief utilization of hospice services. further research is needed to identify predictors of aggressive care and to develop interventions enhancing decision-making at the end of life. C1 [Temel, Jennifer S.; Ostler, Patricia; Lynch, Thomas J.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [McCannon, Jessica] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Greer, Joseph A.] Massachusetts Gen Hosp, Dept Behav Med, Boston, MA 02114 USA. [Jackson, Vicki A.; Billings, J. Andrew] Massachusetts Gen Hosp, Dept Palliat Care, Boston, MA 02114 USA. [Pirl, William F.] Massachusetts Gen Hosp, Dept Psychiat Psychooncol, Boston, MA 02114 USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Dept Hematol Oncol, Yawkey 7B,55 Fruit St, Boston, MA 02114 USA. EM jtemel@partners.org FU NCI NIH HHS [R03CA128478] NR 46 TC 46 Z9 48 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2008 VL 113 IS 4 BP 826 EP 833 DI 10.1002/cncr.23620 PG 8 WC Oncology SC Oncology GA 335SV UT WOS:000258311800023 PM 18618579 ER PT J AU Zeng, LC Geng, Y Tretiakova, M Yu, XM Sicinski, P Kroll, TG AF Zeng, Lingchun Geng, Yan Tretiakova, Maria Yu, Xuemei Sicinski, Peter Kroll, Todd G. TI Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors SO CANCER RESEARCH LA English DT Article ID HUMAN COLON-CANCER; PPAR-GAMMA; EPITHELIAL-CELLS; HIGH PREVALENCE; BREAST-CANCER; E EXPRESSION; FATTY-ACIDS; CARCINOMA; NUCLEAR; GROWTH AB Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPAR delta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPAR delta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPAR delta increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPAR delta agonist GW501516 augmented these PPAR delta proliferation effects in a dose-dependent manner. Overexpression of PPAR delta increased cyclin Ell protein by 9-fold, whereas knockdown of PPAR delta by small inhibitory RNA reduced both cyclin El protein and cell proliferation by 2-fold. Induction of proliferation by PPAR delta was abrogated by knockdown of cyclin El by small inhibitory RNA in primary thyroid cells and by knockout of cyclin El in mouse embryo fibroblasts, confirming a cyclin El dependence for this PPAR delta pathway. In addition, the mean expression of native PPAR delta was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPAR delta mechanism that induces cell proliferation through cyclin El and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPAR delta antagonists as antineoplastic agents and implicate altered PPAR delta-cyclin E1 signaling in thyroid and other carcinomas. C1 [Zeng, Lingchun; Tretiakova, Maria; Yu, Xuemei; Kroll, Todd G.] Univ Chicago, Sch Med, Dept Pathol, Canc Res Ctr, Chicago, IL 60637 USA. [Geng, Yan; Sicinski, Peter] Harvard Univ, Dept Canc Biol, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Geng, Yan; Sicinski, Peter] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Kroll, TG (reprint author), 5841 S Maryland Ave,AMB P323 MC1089, Chicago, IL 60637 USA. EM t.kroll@bsd.uchicago.edu FU National Cancer Institute [CA75425]; Louis Block Fund of the University of Chicago FX Received 3/6/2008: revised 6/2/2008; accepted 6/5/2008.; Grant support: National Cancer Institute grant, CA75425 and the Louis Block Fund of the University of Chicago. 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 IS U.S.C. Section 1734 solely to indicate this fact.; We thank Drs. Don Steiner, Graham Bell and Sam Refetoff for sharing laboralory equipment. and Pablo Michalewicz for technical assistance. NR 54 TC 16 Z9 16 U1 0 U2 0 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 AUG 15 PY 2008 VL 68 IS 16 BP 6578 EP 6586 DI 10.1158/0008-5472.CAN-08-0855 PG 9 WC Oncology SC Oncology GA 338ZP UT WOS:000258548200014 PM 18701481 ER PT J AU Chiang, DY Villanueva, A Hoshida, Y Peix, J Newell, P Minguez, B LeBlanc, AC Donovan, DJ Thung, SN Sole, M Tovar, V Alsinet, C Ramos, AH Barretina, J Roayaie, S Schwartz, M Waxman, S Bruix, J Mazzaferro, V Ligon, AH Najfeld, V Friedman, SL Sellers, WR Meyerson, M Llovet, JM AF Chiang, Derek Y. Villanueva, Augusto Hoshida, Yujin Peix, Judit Newell, Philippa Minguez, Beatriz LeBlanc, Amanda C. Donovan, Diana J. Thung, Swan N. Sole, Manel Tovar, Victoria Alsinet, Clara Ramos, Alex H. Barretina, Jordi Roayaie, Sasan Schwartz, Myron Waxman, Samuel Bruix, Jordi Mazzaferro, Vincenzo Ligon, Azra H. Najfeld, Vesna Friedman, Scott L. Sellers, William R. Meyerson, Matthew Llovet, Josep M. TI Focal gains of VEGFA and molecular classification of hepatocellular carcinoma SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CHRONIC HEPATITIS-C; GENE-EXPRESSION; BETA-CATENIN; LIVER-CANCER; CHROMOSOMAL-ABERRATIONS; PROGNOSTIC-SIGNIFICANCE; PEGYLATED INTERFERON; THERAPEUTIC TARGETS; TUMOR PROGRESSION AB Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies. C1 [Chiang, Derek Y.; Ramos, Alex H.; Barretina, Jordi; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chiang, Derek Y.; Ramos, Alex H.; Barretina, Jordi; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genom Discovery, Boston, MA 02115 USA. [Hoshida, Yujin] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Donovan, Diana J.; Ligon, Azra H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chiang, Derek Y.; Hoshida, Yujin; Ramos, Alex H.; Barretina, Jordi; Meyerson, Matthew] Broad Inst Harvard, Canc Program, Cambridge, MA USA. [Chiang, Derek Y.; Hoshida, Yujin; Ramos, Alex H.; Barretina, Jordi; Meyerson, Matthew] MIT, Cambridge, MA 02139 USA. [Sellers, William R.] Novartis Inst Biomed Res, Cambridge, MA USA. [Villanueva, Augusto; Peix, Judit; Newell, Philippa; Minguez, Beatriz; Friedman, Scott L.; Llovet, Josep M.] Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY 10029 USA. [LeBlanc, Amanda C.; Waxman, Samuel; Najfeld, Vesna] Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, New York, NY 10029 USA. [LeBlanc, Amanda C.; Thung, Swan N.; Najfeld, Vesna] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Roayaie, Sasan; Schwartz, Myron] Mt Sinai Sch Med, Dept Surg, Div Surg Oncol, New York, NY 10029 USA. [Sole, Manel; Tovar, Victoria; Alsinet, Clara; Bruix, Jordi; Llovet, Josep M.] Hosp Clin Barcelona, HCC Translat Res Lab, BCLC Grp, Liver Unit, Barcelona, Spain. [Sole, Manel; Tovar, Victoria; Alsinet, Clara; Bruix, Jordi; Llovet, Josep M.] Hosp Clin Barcelona, CIBERehd, IDIBAPS, Dept Pathol, Barcelona, Spain. [Mazzaferro, Vincenzo] Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, I-20133 Milan, Italy. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 1537, Boston, MA 02115 USA. EM Matthew_Meyerson@dfci.harvard.edu; Josep.Llovet@mssm.edu RI Donovan, Diana/A-1256-2010; Meyerson, Matthew/E-7123-2012; Augusto, Villanueva/F-9378-2012; Minguez, Beatriz/N-4456-2014; Llovet, Josep M /D-4340-2014; Mazzaferro, Vincenzo/C-2726-2017; OI Bruix, Jordi/0000-0002-9826-0753; Augusto, Villanueva/0000-0003-3585-3727; Minguez, Beatriz/0000-0002-7276-9666; Llovet, Josep M /0000-0003-0547-2667; Mazzaferro, Vincenzo/0000-0002-4013-8085; Chiang, Derek/0000-0002-1131-6065 FU NIH [DK076986, CA109038, DK037340]; Samuel Waxman Cancer Research Foundation; Spanish National Health Institute [SAF-2007-61898]; Institucio Catalana de Recerca Avancada; Instituto de Salud Carlos III [PI 05/645, FIS CM04/00044]; Italian Association for Cancer Research; Davies Charitable Foundation; Fundacion Pedro Barrie de In Maza; National Cancer Center; European Association for the Study of the Liver; Charles A. King Trust.; Department d'Educacio i Universitats de la Generalitat de Catalunya; Instituto de Salud Carlos III FX Grant support: NIH grants DK076986 (J.M. Hovel), CA109038 (M. Meyerson). and DK037340 (S.L. Friedman): Samuel Waxman Cancer Research Foundation (J.M. Llovet): Spanish National Health Institute grant SAF-2007-61898 (J.M. Llovet); Institucio Catalana de Recerca Avancada (J.M. Llovet); Instituto de Salud Carlos III grants PI 05/645 (J. Bruix) and FIS CM04/00044 (B. Minguez); Italian Association for Cancer Research (V. Mazzaferro); Davies Charitable Foundation (D.Y. Chiang): Fundacion Pedro Barrie de In Maza (A. Villanueva); National Cancer Center (A. Villanueva); European Association for the Study of the Liver (A. Villanueva); Charles A. King Trust. (Y. Hoshida); and Department d'Educacio i Universitats de la Generalitat de Catalunya (J. Bruix). Ciberehd is funded by Instituto de Salud Carlos III.; 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.; We thank Rameen Beroukhim and Craig Mermel for assistance with the GISTIC algorithm. and Barbara Weir and Roel Verhaak for critical reading of the manuscript.; We dedicate this work to the memory of our friend and colleague. Eric Lemmer. NR 50 TC 237 Z9 240 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2008 VL 68 IS 16 BP 6779 EP 6788 DI 10.1158/0008-5472.CAN-08-0742 PG 10 WC Oncology SC Oncology GA 338ZP UT WOS:000258548200036 PM 18701503 ER PT J AU Ho-Tin-Noe, B Goerge, T Cifuni, SM Duerschmied, D Wagner, DD AF Ho-Tin-Noe, Benoit Goerge, Tobias Cifuni, Stephen M. Duerschmied, Daniel Wagner, Denisa D. TI Platelet granule secretion continuously prevents intratumor hemorrhage SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; GLYCOPROTEIN IB-ALPHA; IN-VIVO; P-SELECTIN; SPHINGOSINE 1-PHOSPHATE; HUMAN MEGAKARYOCYTES; TUMOR ANGIOGENESIS; PLASMA LEAKAGE; LEUKEMIA-CELLS; ANGIOPOIETIN-1 AB Cancer is associated with a prothrombogenic state capable of platelet activation. Platelets, on the other hand, can support angiogenesis, a process involved in the progression of tumor growth and metastasis. However, it is unclear whether platelet/tumor interactions substantially contribute to tumor physiology. We investigated whether platelets stabilize tumor vessels and studied the underlying mechanisms. We induced severe acute thrombocytopenia in mice bearing s.c. Lewis lung carcinoma or B16F10 melanoma. Intravital microscopy revealed that platelet depletion led to a rapid destabilization of tumor vessels with intratumor hemorrhage starting as soon as 30 min after induction of thrombocytopenia. Using an inhibitor of glycoprotein Ib alpha (GPIb alpha) and genetically engineered mice with platelet adhesion defects, we investigated the role of platelet adhesion receptors in stabilizing tumor vessels. We found that a single defect in either GPIb alpha, von Willebrand factor, P-selectin, or platelet integrin activation did not lead to intratumor hemorrhage. We then compared the ability of transfused resting and degranulated platelets to prevent intratumor hemorrhage. Whereas resting platelets prevented thrombocytopenia-induced tumor bleeding, circulating degranulated platelets did not. This suggests that the prevention of intratumor hemorrhage by platelets relies on the secretion of the content of platelet granules. Supporting this hypothesis, we further found that thrombocytopenia dramatically impairs the balance between propermeability and antipermeability factors in tumor-bearing animals, in particular depleting blood of angiopoietin-1 and serotonin. Our results show a crucial contribution of platelets to tumor homeostasis through continuous prevention of severe intratumor hemorrhage and consequent cell death. The study also suggests platelet function as a reasonable target for specific destabilization of tumor vessels. C1 [Ho-Tin-Noe, Benoit; Goerge, Tobias; Cifuni, Stephen M.; Duerschmied, Daniel; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Ho-Tin-Noe, Benoit; Goerge, Tobias; Duerschmied, Daniel; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 800 Huntington Ave, Boston, MA 02115 USA. EM wagner@idi.harvard.edu FU National Heart, Lung, and Blood Institute of the NIH [R37 HL041002, P01 HL066105]; La Fondation pour la Recherche Medicale; Deutsche Forschungsgemeinschaft [GO1360] FX Grant support: National Heart, Lung, and Blood Institute of the NIH grants R37 HL041002 and P01 HL066105 (D.D. Wagner); La Fondation pour la Recherche Medicale (B. Ho-Tin-Noe); and Deutsche Forschungsgemeinschaft grant. GO1360 (T. Goerge).; 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 In indicate this fact.; We thank Dr. Rakesh K. Jain and Julia Kahn for teaching its the dorsal skinfold chamber method, Dr. Robert Schaub for helpful discussion, and Lesley Cowan for assistance in the preparation of the manuscript. NR 58 TC 75 Z9 77 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2008 VL 68 IS 16 BP 6851 EP 6858 DI 10.1158/0008-5472.CAN-08-0718 PG 8 WC Oncology SC Oncology GA 338ZP UT WOS:000258548200044 PM 18701510 ER PT J AU Godinho, S Tavares, AA AF Godinho, Susana Tavares, Alvaro A. TI A role for Drosophila polo protein in chromosome resolution and segregation during mitosis SO CELL CYCLE LA English DT Article DE chromosome resolution; mitosis; polo; drosophila; Scc1 ID SISTER-CHROMATID RESOLUTION; TOPOISOMERASE-II; ROUGH-DEAL; SPINDLE POLES; COHESIN; CHECKPOINT; KINASE; PHOSPHORYLATION; IDENTIFICATION; PROGRESSION AB Correct chromosome structure is essential to ensure faithful segregation during mitosis. Chromosome condensation occurs at the same time as cohesion is released from the arms of the sister chromatids. It is not until metaphase-anaphase transition that chromosomes lose cohesion completely, by proteolysis of the component of the cohesin complex Scc1 (Sister chromatid cohesion 1). It has been shown in vertebrates that the Polo-like kinase, Plk1, is important for this process by inducing the destabilization of Scc1 from the chromosome arms. It is still unclear if this process is conserved in other high eukaryotes, namely in Drosophila. Here we analysed the consequences over chromosome resolution of the downregulation of Drosophila Polo, both by mutant analysis and by RNAi-depletion in S2 cells. We show that the depletion of Polo results in a strong prometa/metaphase arrest with the spindle checkpoint activated in response to lack of tension. In addition, the checkpoint protein ROD fails to stream over the kinetochore microtubules in the lack of Polo activity. We also show that loss of Polo causes strong defects in chromosome resolution, a phenotype we partially rescued by depleting Scc1. Importantly, we show Scc1 fails to accumulate on the kinetochores during mitosis and remains on the chromosome arms in the absence of Polo. We therefore propose an alternative role for Drosophila Polo in Scc1 redistribution during mitosis. C1 [Godinho, Susana; Tavares, Alvaro A.] Gulbenkian Inst Sci, P-2780156 Oeiras, Portugal. [Tavares, Alvaro A.] Univ Tecn Lisboa, Dept Engn Quim & Biol, Inst Super Tecn, Lisbon, Portugal. RP Tavares, AA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM tavares@igc.gulbenkian.pt RI Tavares, Alvaro/D-9436-2012 OI Tavares, Alvaro/0000-0002-7137-0944 FU FCT [POCTI/1999/BCI/34405, POCTI/BCI/41735/2001, Praxis XXI/BD/21648/99] FX We are grateful to M. Bettencourt-Dias, S. Chatterjee and S. Yoshida for careful reading the manuscript. We thank to R. Basto for sharing unpublished results. We also thank C. E. Sunkel for anti-Scc1 and anti-SMC4 antibodies and R. Karess for anti-ROD antibody. This work was supported by Funda ao para a Ciencia e Tecnologia (FCT; grants POCTI/1999/BCI/34405 and POCTI/BCI/41735/2001), Portugal. S. A. G. was supported by fellowship from FCT (Praxis XXI/BD/21648/99). NR 26 TC 6 Z9 6 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2008 VL 7 IS 16 BP 2529 EP 2534 PG 6 WC Cell Biology SC Cell Biology GA 343CJ UT WOS:000258829900014 PM 18719370 ER PT J AU Sawada, N Salomone, S Kim, HH Kwiatkowski, DJ Liao, JK AF Sawada, Naoki Salomone, Salvatore Kim, Hyung-Hwan Kwiatkowski, David J. Liao, James K. TI Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1 SO CIRCULATION RESEARCH LA English DT Article DE angiogenesis; endothelium; hypertension; nitric oxide synthase; signal transduction ID FACTOR-KAPPA-B; CELL-ADHESION; RHO; TRANSPORTER; ACTIVATION; AKT; RECEPTORS; MIGRATION; PATHWAYS; PROTEINS AB Diminished bioavailability of nitric oxide is a hallmark of endothelial dysfunction and is associated with a broad spectrum of vascular disorders such as impaired angiogenesis. Because Rac1, a Rho family member, mediates cellular motility and generation of reactive oxygen species, it could be involved in the regulation of endothelial nitric oxide production. However, the pathophysiological consequences of postnatal endothelial Rac1 deletion on endothelial function have not been determined. We generated endothelial-specific Rac1 haploinsufficient mice (EC-Rac1(+/-)) using Cre-loxP technology. The EC-Rac1(+/)-mice have decreased expression and activity of endothelial nitric oxide synthase (eNOS), impaired endothelium-dependent vasorelaxation, and mild hypertension compared with control (Rac1(+/flox)) mice. Hind limb ischemia model and aortic capillary sprouting assay showed that eNOS activity and angiogenesis was impaired in EC-Rac1(+/)-mice. Indeed, Rac1 promotes eNOS gene transcription through p21-activated kinase but not NADPH oxidase, increases eNOS mRNA stability, and enhances eNOS activity by promoting endothelial uptake of L-arginine. These findings indicate that endothelial Rac1 is essential for endothelium-dependent vasomotor response and ischemia-induced angiogenesis. These effects of Rac1 on endothelial function are largely due to the upregulation of eNOS through multiple mechanisms that are mediated, in part, by p21-activated kinase. Therapeutic strategies to enhance Rac1 function, therefore, may be important for preventing endothelial dysfunction. C1 [Sawada, Naoki; Kim, Hyung-Hwan; Liao, James K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Cardiovasc, Boston, MA 02115 USA. [Kwiatkowski, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Hematol, Boston, MA 02115 USA. [Salomone, Salvatore] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neurovasc Regulat Lab, Charlestown, MA USA. RP Liao, JK (reprint author), Brigham & Womens Hosp, 65 Landsdowne St,Room 275, Cambridge, MA 02139 USA. EM jliao@rics.bwh.harvard.edu OI Salomone, Salvatore/0000-0001-5307-6103 FU NHLBI NIH HHS [R01 HL052233, R01 HL052233-11, R01 HL070274-05, R01 HL070274-03, R01 HL052233-12, R01 HL080187, R01 HL080187-03, R01 HL052233-10, R01 HL070274, R01 HL070274-04, R01 HL080187-01A1, R01 HL080187-02]; NIDDK NIH HHS [R01 DK062729-05, R01 DK062729]; NINDS NIH HHS [P01 NS010828-330036, P01 NS010828] NR 31 TC 52 Z9 53 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 15 PY 2008 VL 103 IS 4 BP 360 EP 368 DI 10.1161/CIRCRESAHA.108.178897 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 337MZ UT WOS:000258441500009 PM 18599867 ER PT J AU Ofran, Y Ritz, J AF Ofran, Yishay Ritz, Jerome TI Targets of tumor immunity after allogeneic hematopoietic stem cell transplantation SO CLINICAL CANCER RESEARCH LA English DT Article ID MINOR HISTOCOMPATIBILITY ANTIGENS; CHRONIC MYELOGENOUS LEUKEMIA; REMISSION AB The effectiveness of allogeneic hematopoietic stem cell transplantation for hematologic malignancies results from the donor immunity to antigens expressed in leukemia cells in the recipient. Similar immune responses have now been identified in patients with renal cell cancer with tumor regression after allogeneic hematopoietic stem cell transplantation. Further studies to identify relevant antigens and mechanisms of resistance may improve the effectiveness of this approach in patients with solid tumors. C1 [Ofran, Yishay; Ritz, Jerome] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr,Div Hematol Malignancies, Boston, MA 02115 USA. RP Ritz, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr,Div Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. EM jerome_ritz@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU NIAID NIH HHS [U19 AI029530-170007, U19 AI029530] NR 13 TC 8 Z9 9 U1 0 U2 0 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 AUG 15 PY 2008 VL 14 IS 16 BP 4997 EP 4999 DI 10.1158/1078-0432.CCR-08-0857 PG 3 WC Oncology SC Oncology GA 338QX UT WOS:000258523800001 PM 18698016 ER PT J AU Sloss, CM Wang, F Liu, R Xia, LJ Houston, M Ljungman, D Palladino, MA Cusack, JC AF Sloss, Callum M. Wang, Fang Liu, Rong Xia, Lijun Houston, Michael Ljungman, David Palladino, Michael A. Cusack, James C., Jr. TI Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells SO CLINICAL CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA CELLS; ADVANCED SOLID TUMORS; ANTIAPOPTOTIC ROLE; INDUCED APOPTOSIS; CARCINOMA-CELLS; BREAST-CANCER; BORTEZOMIB; THERAPY; PS-341; ADENOCARCINOMA AB Purpose: In the current study, we investigate the activation of antiapoptotic signaling pathways in response to proteasome inhibitor treatment in pancreatic cancer and evaluate the use of concomitant inhibition of these pathways to augment proteasome inhibitor treatment responses. Experimental Design: Pancreatic cancer cell lines and mouse flank xenografts were treated with proteasome inhibitor alone or in combination with chemotherapeutic compounds (gemcitabine, erlotinib, and bevacizumab), induction of apoptosis and effects on tumor growth were assessed. The effect of bortezomib (a first-generation proteasome inhibitor) and NPI-0052 (a second-generation proteasome inhibitor) treatment on key pancreatic mitogenic and antiapoptotic pathways (epidermal growth factor receptor, extracellular signal-regulated kinase, and phosphoinositide-3-kinase (PI3K)/AKT] was determined and the ability of inhibitors of these pathways to enhance the effects of proteasome inhibition was assessed in vitro and in vivo. Results: Our data showed that proteasome inhibitor treatment activates antiapoptotic and mitogenic signaling pathways (epidermal growth factor receptor, extracellular signal-regulated kinase, c-Jun-NH(2)-kinase, and PI3K/AKT) in pancreatic cancer. Additionally, we found that activation of these pathways impairs tumor response to proteasome inhibitor treatment and inhibition of the c-Jun-NH2-kinase and PI3K/AKT pathways increases the antitumor effects of proteasome inhibitor treatment. Conclusion: These preclinical studies suggest that targeting proteasome inhibitor-induced antiapoptotic signaling pathways in combination with proteasome inhibition may augment treatment response in highly resistant solid organ malignancies. Further evaluation of these novel treatment combinations in clinical trials is warranted. C1 [Sloss, Callum M.; Wang, Fang; Liu, Rong; Xia, Lijun; Houston, Michael; Ljungman, David; Cusack, James C., Jr.] Harvard Univ, Div Surg Oncol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Palladino, Michael A.] Nereus Pharmaceut, San Diego, CA USA. RP Cusack, JC (reprint author), Harvard Univ, Div Surg Oncol, Massachusetts Gen Hosp, Sch Med, Yawkey 7th Floor,55 Fruit St, Boston, MA 02114 USA. EM jcusack@partners.org FU NIH [CA98871] FX NIH grant CA98871 (J.C. Cusack). NR 42 TC 56 Z9 56 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2008 VL 14 IS 16 BP 5116 EP 5123 DI 10.1158/1078-0432.CCR-07-4506 PG 8 WC Oncology SC Oncology GA 338QX UT WOS:000258523800015 PM 18698029 ER PT J AU Lipsky, BA AF Lipsky, Benjamin A. TI Bone of contention: Diagnosing diabetic foot osteomyelitis SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID PROCALCITONIN; INFECTIONS; PET C1 [Lipsky, Benjamin A.] VA Puget Sound HCS, Seattle, WA 98108 USA. [Lipsky, Benjamin A.] Univ Washington, Seattle, WA 98195 USA. RP Lipsky, BA (reprint author), VA Puget Sound HCS, S-111-PCC,1660 S Columbian Way, Seattle, WA 98108 USA. EM balipsky@u.washington.edu RI Lipsky, Benjamin/B-4645-2013; OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 19 TC 21 Z9 21 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2008 VL 47 IS 4 BP 528 EP 530 DI 10.1086/590012 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 327VD UT WOS:000257755700018 PM 18611161 ER PT J AU Effros, RB Fletcher, CV Gebo, K Halter, JB Hazzard, WR Horne, FM Huebner, RE Janoff, EN Justice, AC Kuritzkes, D Nayfield, SG Plaeger, SF Schmader, KE Ashworth, JR Campanelli, C Clayton, CP Rada, B Woolard, NF High, KP AF Effros, Rita B. Fletcher, Courtney V. Gebo, Kelly Halter, Jeffrey B. Hazzard, William R. Horne, Frances McFarland Huebner, Robin E. Janoff, Edward N. Justice, Amy C. Kuritzkes, Daniel Nayfield, Susan G. Plaeger, Susan F. Schmader, Kenneth E. Ashworth, John R. Campanelli, Christine Clayton, Charles P. Rada, Beth Woolard, Nancy F. High, Kevin P. TI Workshop on HIV infection and aging: What is known and future research directions SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; VARICELLA-ZOSTER-VIRUS; CHRONIC KIDNEY-DISEASE; HEPATITIS-C VIRUS; CD4 CELL COUNT; LYMPHATIC TISSUE FIBROSIS; IMMUNE RISK PHENOTYPE; AGE-RELATED-CHANGES AB Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging. C1 [High, Kevin P.] Wake Forest Univ, Sch Med, Dept Internal Med, Infect Dis Sect, Winston Salem, NC 27157 USA. [Effros, Rita B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Fletcher, Courtney V.] Univ Nebraska, Hlth Sci Ctr, Omaha, NE 68182 USA. [Gebo, Kelly] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Huebner, Robin E.; Plaeger, Susan F.] NIAID, Bethesda, MD 20892 USA. [Nayfield, Susan G.] NIA, Bethesda, MD 20892 USA. [Halter, Jeffrey B.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Hazzard, William R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Horne, Frances McFarland; Ashworth, John R.; Clayton, Charles P.] Assoc Specialty Prof, Washington, DC USA. [Janoff, Edward N.] Univ Colorado, Sch Med, Mucolsal & Vaccine Res Program Colorado, Denver, CO 80202 USA. [Justice, Amy C.] Yale Univ, West Haven, CT USA. [Kuritzkes, Daniel] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kuritzkes, Daniel] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rada, Beth] Infect Dis Society Amer, Arlington, VA USA. [Schmader, Kenneth E.] Duke Univ, Sch Med, Durham, NC 27710 USA. [Campanelli, Christine] Amer Geriatr Society, New York, NY USA. RP High, KP (reprint author), Wake Forest Univ, Sch Med, Dept Internal Med, Infect Dis Sect, 100 Med Ctr Blvd, Winston Salem, NC 27157 USA. EM khigh@wfubmc.edu RI Gebo, Kelly/B-9223-2009 FU NIAAA NIH HHS [U10 AA013566, U10 AA013566-08] NR 174 TC 267 Z9 270 U1 4 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2008 VL 47 IS 4 BP 542 EP 553 DI 10.1086/590150 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 327VD UT WOS:000257755700022 PM 18627268 ER PT J AU Kwon, M Godinho, SA Chandhok, NS Ganem, NJ Azioune, A Thery, M Pellman, D AF Kwon, Mijung Godinho, Susana A. Chandhok, Namrata S. Ganem, Neil J. Azioune, Ammar Thery, Manuel Pellman, David TI Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes SO GENES & DEVELOPMENT LA English DT Article DE centrosomes; mitosis; actin; adhesion; cancer; cell cycle ID PHENOTYPE-BASED SCREEN; DROSOPHILA S2 CELLS; HUMAN BREAST-TUMORS; MITOTIC SPINDLE; NEURITE OUTGROWTH; PROTEIN ASP; MYOSIN-X; ADHESION; ORGANIZATION; CYTOKINESIS AB Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses. In addition to proteins that organize microtubules at the spindle poles, we identified novel roles for the spindle assembly checkpoint, cortical actin cytoskeleton, and cell adhesion. Using live cell imaging and fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. These findings may identify cancer-selective therapeutic targets: HSET, a normally nonessential kinesin motor, was essential for the viability of certain extra centrosome-containing cancer cells. Thus, morphological features of cancer cells can be linked to unique genetic requirements for survival. C1 [Kwon, Mijung; Godinho, Susana A.; Chandhok, Namrata S.; Ganem, Neil J.; Pellman, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Azioune, Ammar] Inst Curie, CNRS, UMR Biol Cycle Cellulaire & Motilite 144, F-75005 Paris, France. [Thery, Manuel] CEA, DSV, iRTSV, Lab Biopuces, F-38054 Grenoble, France. [Pellman, David] Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. RP Pellman, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU Susan Komen; FCT; LLS; NIH [GM083299]; DFCI/Novartis Drug Discovery Grant FX We thank B. Mathey-Prevot and the HMS Drosophila RNAi Screening Center (DRSC) and Institute of Chemistry and Cell Biology (ICCB) Longwood for help with the screen; D. Glover, M. Bettencourt-Dias, J. Raff, R. Basto, G. Goshima, C. Sunkel, G. Rogers, S. Rogers, M. Bornens, S. Henikoff, C. Walczak, and S. Cai for reagents; R. Basto and J. Raff for communicating unpublished results; and M. Bettencourt-Dias, A. Kung, R. King, S. Rogers, and S. Yoshida for comments on the manuscript. This work was supported by a Susan Komen grant to M. K., by an FCT grant to S. A. G., by a fellow award from the LLS to N.J.G., and by NIH grant GM083299 and a DFCI/Novartis Drug Discovery Grant to D. P. NR 61 TC 265 Z9 267 U1 3 U2 23 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2008 VL 22 IS 16 BP 2189 EP 2203 DI 10.1101/gad.1700908 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 338DW UT WOS:000258486800006 PM 18662975 ER PT J AU Bandukwala, H Sundrud, MS Rao, A AF Bandukwala, Hozefa Sundrud, Mark S. Rao, Anjana TI Orphans against autolimmunity SO IMMUNITY LA English DT Editorial Material ID TRANSCRIPTIONAL REGULATION; CELL-DIFFERENTIATION; T-CELLS C1 [Bandukwala, Hozefa; Sundrud, Mark S.; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bandukwala, Hozefa; Sundrud, Mark S.; Rao, Anjana] 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 NR 10 TC 0 Z9 0 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 15 PY 2008 VL 29 IS 2 BP 167 EP 168 DI 10.1016/j.immuni.2008.07.008 PG 2 WC Immunology SC Immunology GA 339XO UT WOS:000258610800001 PM 18701076 ER PT J AU Puga, I Rao, A Macian, F AF Puga, Irene Rao, Anjana Macian, Fernando TI Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells SO IMMUNITY LA English DT Article ID E3 UBIQUITIN LIGASE; ADAPTER PROTEIN; LYMPHOCYTE STIMULATION; DEPENDENT CLEAVAGE; ANTIGEN RECEPTOR; IN-VIVO; B-CELLS; ACTIVATION; TRANSCRIPTION; SUBSTRATE AB T cell receptor (TCR) engagement in the absence of costimulation induces the calcium-dependent upregulation of a program of gene expression that leads to the establishment of T cell anergy. Casp3 is one of the genes activated during anergy induction. Here we show that caspase 3 is required for the induction of T cell unresponsiveness. Suboptimal T cell stimulation induced caspase 3 actvation, which did not result in cell death. Furthermore, caspase 3-deficient T cells showed impaired responses to anergizing stimuli. In anergic T cells, activated caspase 3 associated to the plasma membrane, where it cleaved and inactivated proteins such as the Grb2-related adaptor downstream of shc (GADS) and the guanine-nucleotide exchange factor Vav1, causing a blockade in TCR signaling. Our results identify a role for caspase 3 in nonapoptotic T cells and support that caspase 3-dependent proteolytic inactivation of signaling proteins is essential to maintain T cell tolerance. C1 [Puga, Irene; 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 Macian, Fernando/0000-0003-2666-035X FU National Institutes of Health [AI48213, AI059738]; Irene Diamond Foundation FX We thank members of our laboratories for helpful discussions and A.M. Cuervo and L. Santambrogio for critical reading of the manuscript. We thank T.W. Mak for the Casp3-/- mice and S. Bathia for the CHO-IAd and CHO-IAd-B7 cell lines. We also thank C.J. McGlade for the GADS constructs and X.R. Bustelo for the Vav-1 expression plasmid. Human IL-2 and antibodies against murine IL-4 were obtained from the Biological Resources Branch preclinical repository. This work was supported by National Institutes of Health grants AI48213 (A.R.) and AI059738 (F.M.) and by the Irene Diamond Foundation (F. M.). NR 50 TC 36 Z9 39 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 15 PY 2008 VL 29 IS 2 BP 193 EP 204 DI 10.1016/j.immuni.2008.06.010 PG 12 WC Immunology SC Immunology GA 339XO UT WOS:000258610800008 PM 18701083 ER PT J AU Zhang, H Zhang, Y Duan, HO Kirley, SD Lin, SX McDougal, WS Xiao, H Wu, CL AF Zhang, Hui Zhang, Yifen Duan, Hai On Kirley, Sandra D. Lin, Sharron X. McDougal, W. Scott Xiao, Hua Wu, Chin-Lee TI TIP30 is associated with progression and metastasis of prostate cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE TIP30; metastasis; progression; prostate cancer ID ESTROGEN-RECEPTOR-ALPHA; ANDROGEN RECEPTOR; BREAST-CARCINOMA; UP-REGULATION; IN-VITRO; EXPRESSION; GROWTH; CELLS; BETA; TRANSCRIPTION AB Tat-interacting protein 30 (TIP30), a transcriptional repressor for ER alpha-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis. (c) 2008 Wiley-Liss, Inc. C1 [Zhang, Hui; Zhang, Yifen; Duan, Hai On; Wu, Chin-Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Zhang, Hui; Zhang, Yifen; Duan, Hai On; Kirley, Sandra D.; Lin, Sharron X.; McDougal, W. Scott; Wu, Chin-Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. [Xiao, Hua] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA. RP Wu, CL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM cwu2@partners.org FU NIDDK NIH HHS [DK066110-01] NR 31 TC 14 Z9 17 U1 0 U2 4 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 AUG 15 PY 2008 VL 123 IS 4 BP 810 EP 816 DI 10.1002/ijc.23638 PG 7 WC Oncology SC Oncology GA 328SL UT WOS:000257818000009 PM 18528861 ER PT J AU Friedland, RP Tedesco, JM Wilson, AC Atwood, CS Smith, MA Perry, G Zagorski, MG AF Friedland, Robert P. Tedesco, Johnathan M. Wilson, Andrea C. Atwood, Craig S. Smith, Mark A. Perry, George Zagorski, Michael G. TI Antibodies to potato virus Y bind the amyloid beta peptide - Immunohistochemical and NMR studies SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE PATIENTS; A-BETA; MOUSE MODEL; NEUROFIBRILLARY TANGLES; APOLIPOPROTEIN-E; COAT PROTEIN; AUTOANTIBODIES; IMMUNIZATION; PATHOGENESIS; AGGREGATION AB Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid beta(A beta) protein or passive immunization with anti-A beta antibodies has beneficial effects on the development of disease. Although a trial of A beta vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on A beta deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-A beta antibodies and AD. Although these autoantibodies are thought to arise from exposure to A beta, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-A beta antibodies or antibodies to immunogens homologous to the A beta protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of A beta. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to A beta in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to A beta within the Phe(4) - Ser(8) and His(13)-Leu(17) regions. Immune responses generated from dietary exposure to proteins homologous to A beta may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD. C1 [Friedland, Robert P.] Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. [Tedesco, Johnathan M.; Zagorski, Michael G.] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA. [Smith, Mark A.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Wilson, Andrea C.; Atwood, Craig S.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Wilson, Andrea C.; Atwood, Craig S.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. [Perry, George] Univ Texas San Antonio, Coll Sci, San Antonio, TX 78249 USA. RP Friedland, RP (reprint author), Case Western Reserve Univ, Sch Med, Dept Neurol, 10900 Euclid Ave,T504 SOM, Cleveland, OH 44122 USA. EM robert.friedland@case.edu RI Smith, Mark/A-9053-2009; Perry, George/A-8611-2009; Friedland, Robert/A-2834-2010 OI Perry, George/0000-0002-6547-0172; Friedland, Robert/0000-0001-5721-1843 FU NIA NIH HHS [R01-AG017173, R01 AG017173-07, R01-AG027853] NR 60 TC 12 Z9 15 U1 0 U2 0 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 AUG 15 PY 2008 VL 283 IS 33 BP 22550 EP 22556 DI 10.1074/jbc.M802088200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 335VR UT WOS:000258321000023 PM 18505725 ER PT J AU Wang, LJ Johnson, EE Shi, HN Walker, WA Wessling-Resnick, M Cherayil, BJ AF Wang, Lijian Johnson, Erin E. Shi, Hai Ning Walker, W. Allan Wessling-Resnick, Marianne Cherayil, Bobby J. TI Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; NECROSIS-FACTOR-ALPHA; HEREDITARY HEMOCHROMATOSIS; SALMONELLA-TYPHIMURIUM; VIBRIO-VULNIFICUS; C282Y MUTATION; INFECTION; HEPCIDIN; FERROPORTIN; DEFICIENCY AB Disturbances of iron homeostasis are associated with altered susceptibility to infectious disease, but the underlying molecular mechanisms are poorly understood. To study this phenomenon, we examined innate immunity to oral Salmonella infection in Hfe knockout (Hfe(-/-)) mice, a model of the human inherited disorder of iron metabolism type I hemochromatosis. Salmonella- and LPS-induced inflammatory responses were attenuated in the mutant animals, with less severe enterocolitis observed in vivo and reduced macrophage TNF-alpha and IL-6 secretion measured in vitro. The macrophage iron exporter ferroportin (FPN) was up-regulated in the Hfe(-/-) mice, and correspondingly, intramacrophage iron levels were lowered. Consistent with the functional importance of these changes, the abnormal cytokine production of the mutant macrophages could be reproduced in wild-type cells by iron chelation, and in a macrophage cell line by overexpression of FPN. The results of analyzing specific steps in the biosynthesis of TNF-a and IL-6, including intracellular concentrations, posttranslational stability and transcript levels, were consistent with reduced translation of cytokine mRNAs in Hfe(-/-) macrophages. Polyribosorne profile analysis confirmed that elevated macrophage FPN expression and low intracellular iron impaired the translation of specific inflammatory cytokine transcripts. Our results provide molecular insight into immune function in type I hemochromatosis and other disorders of iron homeostasis, and reveal a novel role for iron in the regulation of the inflammatory response. C1 [Wang, Lijian; Shi, Hai Ning; Walker, W. Allan; Cherayil, Bobby J.] Massachusetts Gen Hosp, Mucosal Immunol Lab, Charlestown, MA 02129 USA. [Shi, Hai Ning; Walker, W. Allan; Cherayil, Bobby J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Walker, W. Allan; Wessling-Resnick, Marianne] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Johnson, Erin E.; Wessling-Resnick, Marianne] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. RP Cherayil, BJ (reprint author), Massachusetts Gen Hosp, Mucosal Immunol Lab, Bldg 114,16th St, Charlestown, MA 02129 USA. EM cherayil@helix.mgh.harvard.edu FU NIAID NIH HHS [R21 AI065619-02, R21 AI065619, R21 AI065619-01, R21AI06461]; NIDDK NIH HHS [R01 DK064750, R01DK064750, P30 DK040561-13, P30 DK040561]; NIEHS NIH HHS [R01 ES014638, R01ES014638] NR 56 TC 78 Z9 79 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2008 VL 181 IS 4 BP 2723 EP 2731 PG 9 WC Immunology SC Immunology GA 336DU UT WOS:000258345300052 PM 18684963 ER PT J AU Sugimoto, M Furuta, T Shirai, N Kodaira, C Nishino, M Yamade, M Ikuma, M Sugimura, H Ishizaki, T Hishida, A AF Sugimoto, Mitsushige Furuta, Takahisa Shirai, Naohito Kodaira, Chise Nishino, Masafumi Yamade, Mihoko Ikuma, Mutsuhiro Sugimura, Haruhiko Ishizaki, Takashi Hishida, Akira TI MDR1 C3435T polymorphism has no influence on developing Helicobacter pylori infection-related gastric cancer and peptic ulcer in Japanese SO LIFE SCIENCES LA English DT Article DE MDR1; Helicobacter pylori; gastric cancer; peptic ulcer; MDR1-C3435T polymorphism ID MULTIDRUG-RESISTANCE GENE; ACUTE LYMPHOBLASTIC-LEUKEMIA; P-GLYCOPROTEIN; COLORECTAL-CANCER; INCREASED RISK; EXPRESSION; SUSCEPTIBILITY; CYP2E1; TUMORS; CARCINOGENESIS AB Aims: P-glycoprotein, the gene product of multidrug-resistant transporter-1 (MDR1), confers multidrug resistance against antineoplastic agents but also affects the kinetic disposition of some drugs and carcinogens. MDR1 C3435T polymorphism influences the development of colon cancer and adult acute myeloid leukemia by the association with transporting carcinogen. The aim of this study was to clarify the association of MDR1 C3435T polymorphism with susceptibility to gastric cancer and peptic ulcers in patients with Japanese H. pylori infection. Main methods: We assessed the MDR1 C3435T polymorphism in H. pylori-positive gastritis alone patients (n = 150), gastric cancer (n = 292), gastric ulcer (n = 215), and duodenal ulcer (n = 163) and H. pylori-negative subjects (n = 168) as control by a PCR-based method. Key findings: No significant difference existed in frequencies of MDR1 C3435T polymorphisms between H. pylori-negative controls and H. pylori-positive gastritis alone patients. Moreover, MDR1-3435 T allele carriage didn't affect the risk of gastric cancer or peptic ulcer development. The age- and sex-adjusted odds ratios (ORs) of MDR1 3435 T allele carriers relative to the C/C genotype group for gastric cancer, gastric ulcer and duodenal ulcer risk were 0.96 (95%CI: 0.56-1.66),1.16 (95%CI: 0.72-1.84) and 1.00 (95%CI: 0.61-1.62), respectively. Significance: In this preliminary data, the association with MDR1 C3435T polymorphism and risk for developing H. pylori-related gastric cancer and peptic ulcer in Japanese was low. P-glycoprotein might not be involved in the carcinogenesis of H. pylori-related gastric cancer. (C) 2008 Elsevier Inc. All rights reserved. C1 [Sugimoto, Mitsushige; Kodaira, Chise; Nishino, Masafumi; Yamade, Mihoko; Ikuma, Mutsuhiro; Hishida, Akira] Hamamatsu Univ Sch Med, Dept Med 1, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. [Furuta, Takahisa] Hamamatsu Univ Sch Med, Clin Res Ctr, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. [Shirai, Naohito] Enshu Gen Hosp, Dept Gastroenterol, Naka Ku, Hamamatsu, Shizuoka 4300929, Japan. [Sugimura, Haruhiko] Hamamatsu Univ Sch Med, Dept Pathol 1, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. [Ishizaki, Takashi] Hamamatsu Univ Sch Med, Dept Clin Pharmacol & Therapeut, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. RP Sugimoto, M (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Med, 2002 Holcombe Blvd,Rm 3A-320B, Houston, TX 77030 USA. EM sugimoto@bcm.edu FU YOKOYAMA Foundation for Clinical Pharmacology; 21st century Center of Excellence (COE); Ministry of Education, Culture, Sports, Science and Technology of Japan [19790479] FX This work was supported in part by a Grant-in-Aid from the YOKOYAMA Foundation for Clinical Pharmacology, from the 21st century Center of Excellence (COE) program Medical Photonics (Hamamatsu University School of Medicine), and from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19790479). NR 38 TC 15 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD AUG 15 PY 2008 VL 83 IS 7-8 BP 301 EP 304 DI 10.1016/j.lfs.2008.06.022 PG 4 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 347DI UT WOS:000259120400010 PM 18644389 ER PT J AU Nazem, S Siderowf, AD Duda, JE Brown, GK Ten Have, T Stern, MB Weintraub, D AF Nazem, Sarra Siderowf, Andrew D. Duda, John E. Brown, Gregory K. Ten Have, Torn Stern, Matthew B. Weintraub, Daniel TI Suicidal and death ideation in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; suicide; depression ID PRIMARY-CARE PATIENTS; RISK-FACTORS; GERIATRIC DEPRESSION; RATING-SCALE; LATE-LIFE; POPULATION; SYMPTOMS; AGE; PREVALENCE; FREQUENCY AB Parkinson's disease (PD) is a chronic, disabling illness affecting primarily the elderly and is associated with a high prevalence of depression. Although these are known risk factors for suicidal and death ideation, little is known about the prevalence and correlates of such ideation in PD. A convenience sample of 116 outpatients with idiopathic PI) at two movement disorders centers were administered a modified Paykel Scale for Suicidal and death ideation, as well as an extensive psychiatric, neuropsychological, and neurological battery. Univariate and multivariate logistic regression models were used to determine the correlates Of Suicidal or death ideation. Current death ideation (28%) or suicide ideation (11%) were present in 30% of the sample, and 4% had a lifetime suicide attempt. On univariate logistic regression analysis, increasing severity of depression (odds ratio = 2.92, 95% CI 2.01-4.24, P < 0.001), impulse control disorder (ICD) behaviors sometime during PD (odds ratio = 6.08, 95% CI 1.90-19.49, P = 0.002), and psychosis (odds ratio = 2.45, 95% CI 1.05-5.69, P = 0.04) were associated with either ideation. On multivariate logistic regression analysis, only increasing severity of depressive symptoms (odds ratio = 2.76, 95% CI 1.88-4.07, P < 0.001) predicted Suicidal or death ideation. In conclusion, active suicidal or death ideation occurs in up to one-third of PD patients. Comorbid psychiatric disorders. more than PD-related disease variables, are associated with this ideation, highlighting the need for a comprehensive approach to the clinical care of PD patients. (C) 2008 Movement Disorder Society. C1 [Nazem, Sarra; Brown, Gregory K.; Weintraub, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Siderowf, Andrew D.; Duda, John E.; Stern, Matthew B.; Weintraub, Daniel] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Siderowf, Andrew D.; Duda, John E.; Stern, Matthew B.; Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, PADRECC, Philadelphia, PA USA. [Ten Have, Torn] Univ Penn, Ctr Clin & Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, MIRECC, Philadelphia, PA USA. RP Weintraub, D (reprint author), 3535 Market St,Room 3003, Philadelphia, PA 19104 USA. EM weintrau@mail.nied.upenn.edu FU National Institute of Mental Health [067894] FX Supported by a grant from the National Institute of Mental Health (#067894). NR 62 TC 33 Z9 35 U1 4 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2008 VL 23 IS 11 BP 1573 EP 1579 DI 10.1002/mds.22130 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 349AD UT WOS:000259250300011 PM 18618660 ER PT J AU McNicoll, CF Latourelle, JC MacDonald, ME Lew, MF Suchowersky, O Klein, C Golbe, LI Mark, MH Growdon, JH Wooten, GF Watts, RL Guttman, M Racette, BA Perlmutter, JS Ahmed, A Shill, HA Singer, C Saint-Hilaire, MH Massood, T Huskey, KW DeStefano, AL Gillis, T Mysore, J Goldwurm, S Pezzoli, G Baker, KB Itin, I Litvan, I Nicholson, G Corbett, A Nance, M Drasby, E Isaacson, S Burn, DJ Chinnery, PF Pramstaller, PP Al-Hinti, J Moller, AT Ostergaard, K Sherman, SJ Roxburgh, R Snow, B Slevin, JT Cambi, F Gusella, JF Myers, RH AF McNicoll, Christopher F. Latourelle, Jeanne C. MacDonald, Marcy E. Lew, Mark F. Suchowersky, Oksana Klein, Christine Golbe, Lawrence I. Mark, Margery H. Growdon, John H. Wooten, G. Frederick Watts, Ray L. Guttman, Mark Racette, Brad A. Perlmutter, Joel S. Ahmed, Anwar Shill, Holly A. Singer, Carlos Saint-Hilaire, Marie H. Massood, Tiffany Huskey, Karen W. DeStefano, Anita L. Gillis, Tammy Mysore, Jayalakshmi Goldwurm, Stefano Pezzoli, Gianni Baker, Kenneth B. Itin, Ilia Litvan, Irene Nicholson, Garth Corbett, Alastair Nance, Martha Drasby, Edward Isaacson, Stuart Burn, David J. Chinnery, Patrick F. Pramstaller, Peter P. Al-Hinti, Jomana Moller, Anette T. Ostergaard, Karen Sherman, Scott J. Roxburgh, Richard Snow, Barry Slevin, John T. Cambi, Franca Gusella, James F. Myers, Richard H. TI Huntington CAG repeat size does not modify onset age in familial Parkinson's disease: The GenePD study SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; Huntington's disease; CAG repeat; onset age; genetics; mitochondria ID TRINUCLEOTIDE REPEAT; MUTATIONS; ASSOCIATION; POPULATION; ACTIVATION; LOCUS AB The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495). with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis. including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD. (C) 2008 Movement Disorder Society. C1 [McNicoll, Christopher F.; Latourelle, Jeanne C.; Saint-Hilaire, Marie H.; Massood, Tiffany; Huskey, Karen W.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [MacDonald, Marcy E.; Gillis, Tammy; Mysore, Jayalakshmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Mol Neurogenet Unit, Boston, MA USA. [Lew, Mark F.] Univ So Calif, Dept Neurol, Los Angeles, CA USA. [Suchowersky, Oksana] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Suchowersky, Oksana] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Klein, Christine] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Golbe, Lawrence I.; Mark, Margery H.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, New Brunswick, NJ 08903 USA. [Growdon, John H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Wooten, G. Frederick] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. [Watts, Ray L.] Univ Alabama, Dept Neurol, Birmingham, VA USA. [Guttman, Mark] Univ Toronto, Dept Med, Toronto, ON, Canada. [Racette, Brad A.; Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Ahmed, Anwar] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Shill, Holly A.] Sun Hlth Res Inst, Sun City, AZ USA. [Singer, Carlos] Univ Miami, Dept Neurol, Miami, FL USA. [DeStefano, Anita L.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Goldwurm, Stefano; Pezzoli, Gianni] Ist Clin Perfezionamento, Parkinson Inst, Milan, Italy. [Itin, Ilia] Cleveland Clin Fdn, Dept Neurosci, Cleveland, OH 44195 USA. [Baker, Kenneth B.; Itin, Ilia] Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. [Litvan, Irene] Univ Louisville, Sch Med, Dept Neurol, Louisville, KY 40292 USA. [Nicholson, Garth; Corbett, Alastair] Univ Sydney, Concord Hosp, Dept Neurol, ANZAC Res Inst, Sydney, NSW 2006, Australia. [Nance, Martha] Pk Nicollet Clin, Struthers Parkinsons Ctr, Golden Valley, MN USA. [Drasby, Edward] Port City Neurol, Scarborough, ME USA. [Isaacson, Stuart] Parkinsons Dis & Movement Disorder Ctr Boca Raton, Boca Raton, FL USA. [Burn, David J.] Univ Newcastle Upon Tyne, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Chinnery, Patrick F.] Univ Newcastle Upon Tyne, Reg Neurosci Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pramstaller, Peter P.] Gen Reg Hosp Bolzano, Dept Neurol, Bolzano, Italy. [Al-Hinti, Jomana] Univ Arkansas Med Sci, Dept Neurol, Little Rock, AR 72205 USA. [Moller, Anette T.; Ostergaard, Karen] Aarhus Univ Hosp, Dept Neurol, DK-8000 Aarhus, Denmark. [Sherman, Scott J.] Univ Arizona, Dept Neurol, Tucson, AZ USA. [Roxburgh, Richard; Snow, Barry] Auckland City Hosp, Dept Neurol, Auckland, New Zealand. [Slevin, John T.; Cambi, Franca] Univ Kentucky, Coll Med, Dept Neurol, Lexington, KY USA. RP Myers, RH (reprint author), Boston Univ, Sch Med, Dept Neurol, 715 Albany St,E-304, Boston, MA 02118 USA. EM rmyers@bu.edu RI Pramstaller, Peter/C-2357-2008; Goldwurm, Stefano/Q-8978-2016; OI McNicoll, Christopher/0000-0002-6463-4526; Litvan, Irene/0000-0002-3485-3445; Goldwurm, Stefano/0000-0002-1651-567X; Saint-Hilaire, Marie-Helene/0000-0002-2355-5979; Latourelle, Jeanne/0000-0002-4218-9572; Roxburgh, Richard/0000-0002-8930-7003; Myers, Richard/0000-0002-8365-2674 FU PHS [R01 NS36711-09, P50 NS16367-27]; Huntington's Disease Society of America; Huntington Society of Canada; Hereditary Disease Foundation; Massachusetts Huntington's Disease Society of America; Coalition for the Cure of HDSA; Bumpus Foundation; Jerry MacDonald HD research fund; Italian Telethon [GTB07001]; Fondazione Grigioni Per il Morbo di Parkinson FX This Study was supported by PHS grants R01 NS36711-09 "Genetic Linkage Study in PD" and P50 NS16367-27 "Huntington disease Center without walls", the Huntington's Disease Society of America, the Huntington Society of Canada, the Hereditary Disease Foundation, the Massachusetts Huntington's Disease Society of America, the Coalition for the Cure of HDSA, the Bumpus Foundation, and the Jerry MacDonald HD research fund. DNA samples contributed by the Parkinson Institute - istituti Clinici di Perfezionamento, Milan, Italy, were from the "Human genetic bank of patients affected by PD and parkinsonisms," supported by Italian Telethon grant n. GTB07001 and by the "Fondazione Grigioni Per il Morbo di Parkinson." NR 33 TC 4 Z9 4 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2008 VL 23 IS 11 BP 1596 EP 1601 DI 10.1002/mds.22186 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 349AD UT WOS:000259250300014 PM 18649400 ER PT J AU Simuni, T Martel, A Zadikoff, C Videnovic, A Vainio, L Weaver, F Miskevics, S Williams, K Surmeier, J AF Simuni, T. Martel, A. Zadikoff, C. Videnovic, A. Vainio, L. Weaver, F. Miskevics, S. Williams, K. Surmeier, J. TI Safety and tolerability of isradipine, a dihydropyridine Ca channel antagonist, in patients with early Parkinson's disease SO MOVEMENT DISORDERS LA English DT Meeting Abstract CT 22nd Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinsons Disease and Other Movement Disorders CY SEP 21, 2008 CL Salt Lake City, UT C1 [Simuni, T.; Martel, A.; Zadikoff, C.; Videnovic, A.; Vainio, L.; Weaver, F.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Simuni, T.; Martel, A.; Zadikoff, C.; Videnovic, A.; Vainio, L.; Weaver, F.; Miskevics, S.; Williams, K.; Surmeier, J.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. NR 0 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 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2008 VL 23 IS 11 BP 1629 EP 1629 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 349AD UT WOS:000259250300030 ER PT J AU Peterson, A Orwoll, E Fink, H Quinn, J Barrett-Connor, E Shikany, J AF Peterson, A. Orwoll, E. Fink, H. Quinn, J. Barrett-Connor, E. Shikany, J. TI Vitamin D levels in men with Parkinson's disease (PD) SO MOVEMENT DISORDERS LA English DT Meeting Abstract CT 22nd Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinsons Disease and Other Movement Disorders CY SEP 21, 2008 CL Salt Lake City, UT C1 [Peterson, A.; Quinn, J.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. [Fink, H.] Univ Minnesota, Minneapolis VA Med Ctr, Minneapolis, MN USA. [Barrett-Connor, E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Shikany, J.] Univ Alabama, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2008 VL 23 IS 11 BP 1635 EP 1635 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 349AD UT WOS:000259250300052 ER PT J AU Borsook, D Bleakman, D Hargreaves, R Upadhyay, J Schmidt, KF Becerra, L AF Borsook, David Bleakman, David Hargreaves, Richard Upadhyay, Jaymin Schmidt, Karl F. Becerra, Lino TI A 'BOLD' experiment in defining the utility of fMRI in drug development SO NEUROIMAGE LA English DT Review ID RESEARCH-AND-DEVELOPMENT; CHRONIC BACK-PAIN; PHARMACEUTICAL-INDUSTRY; TRANSLATIONAL MEDICINE; FUNCTIONAL MRI; CENTRAL SENSITIZATION; BRAIN ACTIVITY; ANALGESIA; RATS; STIMULATION C1 [Borsook, David; Upadhyay, Jaymin; Schmidt, Karl F.; Becerra, Lino] McLean Hosp, Imaging Ctr Drug Dev, Brain Imaging Ctr, Imaging Consortium Drug Dev ICD, Belmont, MA 02178 USA. [Borsook, David; Schmidt, Karl F.; Becerra, Lino] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bleakman, David] Eli Lilly & Co, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. [Hargreaves, Richard] Merck Res Labs, West Point, PA USA. RP Borsook, D (reprint author), McLean Hosp, Imaging Ctr Drug Dev, Brain Imaging Ctr, Imaging Consortium Drug Dev ICD, 115 Mill St, Belmont, MA 02178 USA. EM dborsook@partners.org NR 49 TC 21 Z9 22 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2008 VL 42 IS 2 BP 461 EP 466 DI 10.1016/j.neuroimage.2008.04.268 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341DU UT WOS:000258695200001 PM 18598770 ER PT J AU Bendlin, BB Ries, ML Lazar, M Alexander, AL Dempsey, RJ Rowley, HA Sherman, JE Johnson, SC AF Bendlin, Barbara B. Ries, Michele L. Lazar, Mariana Alexander, Andrew L. Dempsey, Robert J. Rowley, Howard A. Sherman, Jack E. Johnson, Sterling C. TI Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging SO NEUROIMAGE LA English DT Article ID WHITE-MATTER; AXONAL INJURY; QUANTITATIVE-ANALYSIS; ATROPHY; LESIONS; FORNIX; IMAGES; MEMORY; DEGENERATION; MORPHOLOGY AB Traumatic brain injury (TBI) is associated with brain Volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage Such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit I to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MID compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stern fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences. Published by Elsevier Inc. C1 [Bendlin, Barbara B.; Ries, Michele L.; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI USA. [Bendlin, Barbara B.; Ries, Michele L.; Johnson, Sterling C.] Univ Wisconsin, Sch Med, Dept Med, Madison, WI USA. [Lazar, Mariana] NYU, Dept Radiol, Sch Med, New York, NY 10016 USA. [Alexander, Andrew L.] Univ Wisconsin, Sch Med, Dept Med Phys, Madison, WI 53706 USA. [Dempsey, Robert J.] Univ Wisconsin, Sch Med, Dept Neurosurg, Madison, WI USA. [Rowley, Howard A.] Univ Wisconsin, Dept Radiol, Sch Med, Madison, WI 53706 USA. [Sherman, Jack E.] Univ Wisconsin, Sch Med, Dept Rehabil Med & Orthoped Surg, Madison, WI USA. RP Johnson, SC (reprint author), William S Middleton Mem VA Hosp, Ctr Geriatr Res Educ & Clin, 2500 Overlook Terrace 11G, Madison, WI 53705 USA. EM scj@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875; Lazar, Mariana/0000-0001-9285-8124; Johnson, Sterling/0000-0002-8501-545X FU Department of Veterans Affairs; NIH [MH65723, MH62015] FX This study was supported by a Merit Review Grant from the Department of Veterans Affairs, the NIH MH65723 (SCJ), MH62015 (ALA), and by the facilities and resources at the William S. Middleton Memorial Veterans Hospital. The assistance of Britta Jabbar, Shelly Fitzgerald, Gemma Gliori, and Erik Kastman is greatly appreciated. We would also like to acknowledge the kind Support of researchers and staff at the Waisman Center, University of Wisconsin, Madison, where MR imaging took place. Finally, we thank all the patients who took part in this Study. NR 41 TC 149 Z9 150 U1 4 U2 17 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 AUG 15 PY 2008 VL 42 IS 2 BP 503 EP 514 DI 10.1016/j.neuroimage.2008.04.254 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341DU UT WOS:000258695200007 PM 18556217 ER PT J AU Stufflebeam, SM Witzel, T Mikulski, S Hamalainen, MS Temereanca, S Barton, JJS Tuch, DS Manoach, DS AF Stufflebeam, Steven M. Witzel, Thomas Mikulski, Szymon Hamalainen, Matti S. Temereanca, Simona Barton, Jason J. S. Tuch, David S. Manoach, Dara S. TI A non-invasive method to relate the timing of neural activity to white matter microstructural integrity SO NEUROIMAGE LA English DT Article DE magnetoencephalography; diffusion tensor imaging; visual evoked potentials; saccades; white matter; frontal eye field ID SURFACE-BASED ANALYSIS; CHOICE-REACTION TIME; FUNCTIONAL CONNECTIVITY; DIFFUSION ANISOTROPY; CORTICAL ACTIVITY; MACAQUE MONKEYS; VISUAL-CORTEX; EYE-MOVEMENTS; HUMAN BRAIN; ATTENTION AB The neurophysiological basis of variability in the latency of evoked neural responses has been of interest for decades. We describe a method to identify white matter pathways that may contribute to inter individual Variability in the timing of neural activity. We investigated the relation of the latency of peak Visual responses in occipital cortex as measured by magnetoencephalography (MEG) to fractional anisotropy(FA) in the entire brain as Measured with diffusion tensor imaging (DTI) in eight healthy young adults. This method makes no assumptions about the anatomy of white matter connections. Visual responses were evoked during a saccadic paradigm and were time-locked to arrival at a saccadic goal. The latency of the peak visual response was inversely related to FA in bilateral parietal and right lateral frontal white matter adjacent to Cortical regions that modulate early Visual responses. These relations suggest that biophysical properties of white matter affect the timing of early visual responses. This preliminary report demonstrates a non-invasive, unbiased method to relate the timing information from evoked-response experiments to the biophysical properties of white matter measured with DTI. (C) 2008 Elsevier Inc. All rights reserved. C1 [Mikulski, Szymon; Manoach, Dara S.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Stufflebeam, Steven M.; Mikulski, Szymon; Hamalainen, Matti S.; Temereanca, Simona; Tuch, David S.; Manoach, Dara S.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Stufflebeam, Steven M.; Hamalainen, Matti S.; Temereanca, Simona; Tuch, David S.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Stufflebeam, Steven M.; Hamalainen, Matti S.; Temereanca, Simona; Tuch, David S.; Manoach, Dara S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Stufflebeam, Steven M.; Witzel, Thomas] Harvard Univ, Sch Med, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Stufflebeam, Steven M.; Witzel, Thomas] MIT, Cambridge, MA 02139 USA. [Barton, Jason J. S.] Univ British Columbia, Dept Neurol, Vancouver, BC V5Z 1M9, Canada. [Barton, Jason J. S.] Univ British Columbia, Dept Ophthalmol & Visual Sci, Vancouver, BC V5Z 1M9, Canada. RP Manoach, DS (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2608, Charlestown, MA 02129 USA. EM dara@nmr.mgh.harvard.edu RI Barton, Jason/A-6362-2012; Hamalainen, Matti/C-8507-2013; Witzel, Thomas/P-1402-2014 FU National Institute for Mental Health [K08 MH067966, R01 MH67720]; National Institute of Child Health and Human Development [R03 HD050627]; National Center for Research Resources [P41-RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute [DOE-DE-FG02-99ER62764]; National Alliance for Research in Schizophrenia and Affective Disorder; Canada Research Chair program; Michael Smith Foundation for Health Research Senior Scholarship FX Support was provided by the National Institute for Mental Health (K08 MH067966, R01 MH67720), National Institute of Child Health and Human Development (R03 HD050627), National Center for Research Resources (P41-RR14075), Mental Illness and Neuroscience Discovery (MIND) Institute, (DOE-DE-FG02-99ER62764): National Alliance for Research in Schizophrenia and Affective Disorder; the Canada Research Chair program, and a Michael Smith Foundation for Health Research Senior Scholarship. NR 49 TC 21 Z9 22 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2008 VL 42 IS 2 BP 710 EP 716 DI 10.1016/j.neuroimage.2008.04.264 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341DU UT WOS:000258695200026 PM 18565766 ER PT J AU Wright, CI Negreira, A Gold, AL Britton, JC Williams, D Barrett, LF AF Wright, Christopher I. Negreira, Alyson Gold, Andrea L. Britton, Jennifer C. Williams, Danielle Barrett, Lisa Feldman TI Neural correlates of novelty and face-age effects in young and elderly adults SO NEUROIMAGE LA English DT Article DE functional magnetic resonance imaging; aging; human; face perception; emotion; neuroimaging; amygdala ID ALZHEIMERS-DISEASE CERAD; SURFACE-BASED ANALYSIS; HUMAN AMYGDALA; SUBSTANTIA INNOMINATA; SOCIAL INTERACTIONS; BRAIN ACTIVATION; NEUTRAL FACES; OWN-AGE; RESPONSES; STIMULI AB The human amygdala preferentially responds to objects of potential value, such as hedonically valenced and novel stimuli. Many studies have documented age-related differences in amygdala responses to valenced stimuli, but relatively little is known about age-related changes in the amygdala's response to novelty. This study examines whether there are differences in amygdala novelty responses in two different age groups. Healthy young and elderly adults viewed both young and elderly faces that were seen many times (familiar faces) or only once (novel faces) in the context of an fMRI study. We observed that amygdala responses to novel (versus familiar) faces were preserved with aging, suggesting that novelty processing in the amygdala remains stable across the lifespan. In addition, participants demonstrated larger amygdala responses to target faces of the same age group than to age out-group target faces (i.e., an age in-group effect). Differences in anatomic localization and behavioral results suggest that novelty and age in-group effects were differentially processed in the amygdala. (C) 2008 Elsevier Inc. All rights reserved. C1 [Wright, Christopher I.; Negreira, Alyson; Gold, Andrea L.; Britton, Jennifer C.; Williams, Danielle; Barrett, Lisa Feldman] Harvard Univ, Psychiat Neuroimaging Res Program, Lab Aging & Emot, Massachusetts Gen Hosp,Med Sch, Charlestown, MA 02129 USA. [Wright, Christopher I.; Negreira, Alyson; Gold, Andrea L.; Britton, Jennifer C.; Williams, Danielle; Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Biomed Imaging Ctr, Charlestown, MA 02129 USA. [Wright, Christopher I.] Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. RP Wright, CI (reprint author), Harvard Univ, Psychiat Neuroimaging Res Program, Lab Aging & Emot, Massachusetts Gen Hosp,Med Sch, 13th St,Bldg 149,CNY 2628, Charlestown, MA 02129 USA. EM ciwright@partners.org RI Britton, Jennifer/J-4501-2013; OI Gold, Andrea/0000-0003-4447-776X FU NIMH [K23MH64806]; National Institutes of Health Director's Pioneer Award [DP1OD003312]; National Institute of Mental Health's Independent Scientist Research Award [K02 MH001981]; National Institute of Aging [AG030311]; National Science Foundation [BCS 0721260, BCS 0527440]; NCRR [P41-RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute FX The authors wish to thank Mary Foley and Larry White for their technical assistance. This work was supported in part by NIMH grant K23MH64806 (Dr. Wright), a Research Incentive Award from Boston College and grants from the National Institutes of Health Director's Pioneer Award (DP1OD003312), a National Institute of Mental Health's Independent Scientist Research Award (K02 MH001981), a National Institute of Aging grant (AG030311) and National Science Foundation grants (BCS 0721260; BCS 0527440) (Dr. Barrett), as well as resource grants to the Martinos Center for Biomedical Imaging from the NCRR (P41-RR14075) and the Mental Illness and Neuroscience Discovery (MIND) Institute. NR 77 TC 36 Z9 37 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2008 VL 42 IS 2 BP 956 EP 968 DI 10.1016/j.neuroimage.2008.05.015 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341DU UT WOS:000258695200051 PM 18586522 ER PT J AU Kober, H Barrett, LF Joseph, J Bliss-Moreau, E Lindquist, K Wager, TD AF Kober, Hedy Barrett, Lisa Feldman Joseph, Josh Bliss-Moreau, Eliza Lindquist, Kristen Wager, Tor D. TI Functional grouping and cortical-subcortical interactions in emotion: A meta-analysis of neuroimaging studies SO NEUROIMAGE LA English DT Review ID MIDBRAIN PERIAQUEDUCTAL GRAY; MEDIAL PREFRONTAL CORTEX; TREATMENT-RESISTANT DEPRESSION; POSTERIOR CINGULATE CORTEX; HUMAN ORBITOFRONTAL CORTEX; DEEP BRAIN-STIMULATION; ANTERIOR CINGULATE; SPATIAL ATTENTION; NEURAL MECHANISMS; BASAL GANGLIA AB We performed an updated quantitative meta-analysis of 162 neuroimaging studies of emotion using a novel multi-level kernel-based approach, focusing on locating brain regions consistently activated in emotional tasks and their functional organization into distributed functional groups, independent of semantically defined emotion category labels (e.g., "anger," "fear"). Such brain-based analyses are critical if our ways of labeling emotions are to he evaluated and revised based on consistency with brain data. Consistent activations were limited to specific cortical sub-regions, including multiple functional areas within medial, orbital, and inferior lateral frontal cortices. Consistent with a wealth of animal literature, multiple subcortical activations were identified, including amygdala, ventral striatum, thalamus, hypothalamus, and periaqueductal gray. We used multivariate parcellation and clusterin techniques to identify groups of co-activated brain regions across studies. These analyses identified six distribute(] functional groups, including medial and lateral frontal groups, two posterior cortical groups, and paralimbic and core limbic/brainstem groups. These functional groups provide information on potential organization of brain regions into large-scale networks. Specific follow-up analyses focused on amygdala, periaque-ductal gray (PAC), and hypothalamic (Hy) activations, and identified frontal cortical areas co-activated with these core limbic structures. While multiple areas of frontal cortex co-activated with amygdala subregions, a specific region of dorsomedial prefrontal cortex (dmPFC, Brodmann's Area 9/32) was the only area co-activated with both PAG and Hy. Subsequent mediation analyses were consistent with a pathway from dmPFC through PAG to Hy. These results suggest that medial frontal areas are more closely associated with core limbic activation than their lateral counterparts, and that dmPFC may play a particularly important role in the cognitive generation of emotional states. (C) 2008 Published by Elsevier Inc. C1 [Kober, Hedy; Joseph, Josh; Wager, Tor D.] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Barrett, Lisa Feldman; Bliss-Moreau, Eliza; Lindquist, Kristen] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Psychiat Neuroimaging Res Program, Cambridge, MA 02138 USA. RP Wager, TD (reprint author), Columbia Univ, Dept Psychol, 1190 Amsterdam Ave, New York, NY 10027 USA. EM tor@psych.columbia.edu OI Joseph, Joshua/0000-0001-9704-6635 FU NIA NIH HHS [AG030311, R01 AG030311, R01 AG030311-02]; NIH HHS [DP1 OD003312, DP1 OD003312-01, DP1OD003312]; NIMH NIH HHS [R01 MH076136, K02 MH001981, R01MH076136] NR 194 TC 433 Z9 434 U1 13 U2 86 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 AUG 15 PY 2008 VL 42 IS 2 BP 998 EP 1031 DI 10.1016/j.neuroimage.2008.03.059 PG 34 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341DU UT WOS:000258695200055 PM 18579414 ER PT J AU Scholz, J Abele, A Marian, C Haussler, A Herbert, TA Woolf, CJ Tegeder, I AF Scholz, Joachim Abele, Andrea Marian, Claudiu Haeussler, Annett Herbert, Teri A. Woolf, Clifford J. Tegeder, Irmgard TI Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats SO PAIN LA English DT Article DE neuropathic pain; microglia; immunosuppression; methotrexate; dexamethasone ID RANDOMIZED CONTROLLED-TRIAL; GLIAL ACTIVATION; PROTEIN-KINASE; POSTHERPETIC NEURALGIA; MECHANICAL ALLODYNIA; INDUCED ARTHRITIS; ANIMAL-MODEL; DORSAL-HORN; MAP KINASE; P38 AB Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain in the rat: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker Cb11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionised calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrates that suppression of this cellular immune response is a promising approach for preventing neuropathic pain. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Scholz, Joachim; Herbert, Teri A.; Woolf, Clifford J.; Tegeder, Irmgard] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. [Scholz, Joachim; Herbert, Teri A.; Woolf, Clifford J.; Tegeder, Irmgard] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Abele, Andrea; Marian, Claudiu; Haeussler, Annett; Tegeder, Irmgard] Univ Frankfurt Klinikum, Inst Klin Pharmakol ZAFES, Pharmazentrum Frankfurt, D-6000 Frankfurt, Germany. RP Scholz, J (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 149 13th St,Room 4309, Charlestown, MA 02129 USA. EM scholz.joachim@mgh.harvard.edu OI Tegeder, Irmgard/0000-0001-7524-8025 FU Deutsche Forschungsgemeinschaft; GlaxoSmithKline; National Institutes of Health FX This work was supported by the Deutsche Forschungsgemeinschaft (I.T.), GlaxoSmithKline (C.J.W.), and the National Institutes of Health (J.S. and C.M.). NR 55 TC 47 Z9 53 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 AUG 15 PY 2008 VL 138 IS 1 BP 130 EP 142 DI 10.1016/j.pain.2007.11.019 PG 13 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 341WL UT WOS:000258746100017 PM 18215468 ER PT J AU Candrian, M Schwartz, F Farabaugh, A Perlis, RH Ehlert, U Fava, M AF Candrian, Michele Schwartz, Faye Farabaugh, Amy Perlis, Roy H. Ehlert, Ulrike Fava, Maurizio TI Personality disorders and perceived stress in major depressive disorder SO PSYCHIATRY RESEARCH LA English DT Article DE depression; axis II pathology; stress appraisal; diathesis-stress model; fluoxetine ID SHORT-TERM TREATMENT; SOCIAL SUPPORT; LIFE EVENTS; 5-FACTOR MODEL; PRIMARY-CARE; OUTPATIENTS; METAANALYSIS; ADOLESCENCE; BORDERLINE; PREDICTORS AB The investigation of comorbidity between major depressive disorder (MDD) and personality disorders (PDs) has attracted considerable interest. Whereas some studies found that the presence of PDs has adverse effects on the course and treatment of MDD, others have failed to demonstrate this link. These inconsistent findings suggest that specific PD comorbidity might affect the course of MDD by modulating factors that increase the overall risk of depression, including an elevated tendency to perceive stress. To investigate whether the presence of a specific PD cluster was associated with elevated levels of stress appraisal, we administered the Perceived Stress Scale (PSS) before and after treatment to 227 MDD outpatients enrolled in an 8-week open-label treatment with fluoxetine. Following treatment, multiple linear regression analyses revealed that the presence of Cluster A, but not Cluster B or C, was associated with higher levels of perceived stress, even after adjusting for baseline depression severity and PSS scores, as well as various sociodemographic variables. The presence of Cluster A PD comorbidity was uniquely associated with elevated stress appraisal after antidepressant treatment, raising the possibility that stress exacerbation might be an important factor linked to poor treatment outcome in MDD subjects with Cluster A pathology. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Candrian, Michele; Schwartz, Faye; Farabaugh, Amy; Perlis, Roy H.; Fava, Maurizio] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Depress Clin & Res Program,Dept Psychiat, Boston, MA 02114 USA. [Ehlert, Ulrike] Univ Zurich, Inst Psychol, Dept Clin Psychol & Psychotherapy, CH-8006 Zurich, Switzerland. RP Candrian, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Depress Clin & Res Program,Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM mcandrian@partners.org FU NIMH NIH HHS [R01 MH 48483-05, R01 MH074848-04, R01 MH074848] NR 51 TC 15 Z9 15 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2008 VL 160 IS 2 BP 184 EP 191 DI 10.1016/j.psychres.2007.06.014 PG 8 WC Psychiatry SC Psychiatry GA 336LN UT WOS:000258365400007 PM 18573540 ER PT J AU Blois, J Yuan, H Smith, A Pacold, ME Weissleder, R Cantley, LC Josephson, L AF Blois, Joseph Yuan, Hushan Smith, Adam Pacold, Michael E. Weissleder, Ralph Cantley, Lewis C. Josephson, Lee TI Slow self-activation enhances the potency of viridin prodrugs SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE INHIBITORS; PHOSPHATIDYLINOSITOL 3-KINASE; ANTITUMOR-ACTIVITY; IN-VITRO; WORTMANNIN; PROTEIN; CELL; LY294002; KINASES; ANALOGS AB When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compounds obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here we show that this improved potency results from an intramolecular attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. Our results provide a guide for selecting Wm-like compounds to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biological systems, or for achieving optimal therapeutic effects in vivo. In addition, the slow self-activation of WmC20 derivatives provides a mechanism that can be exploited to obtain kinase inhibitors endowed with physical and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites. C1 [Blois, Joseph; Yuan, Hushan; Smith, Adam; Pacold, Michael E.; Weissleder, Ralph; Josephson, Lee] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Blois, Joseph; Yuan, Hushan; Smith, Adam; Pacold, Michael E.; Weissleder, Ralph; Josephson, Lee] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Pacold, Michael E.] MIT, Ctr Canc Res, Cambridge, MA 02142 USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. RP Josephson, L (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 13th St, Charlestown, MA 02129 USA. EM josephso@helix.mgh.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NCI NIH HHS [P50 CA086355, P50 CA086355-08, T32 CA079443, T32 CA079443-07, T32-CA079443, T32P50-CA86355]; NIBIB NIH HHS [R01 EB004472, R01-EB004472]; NIGMS NIH HHS [R01 GM041890] NR 38 TC 13 Z9 13 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 14 PY 2008 VL 51 IS 15 BP 4699 EP 4707 DI 10.1021/jm800374f PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 335KP UT WOS:000258289800038 PM 18630894 ER PT J AU Weintraub, WS Spertus, JA Kolm, P Maron, DJ Zhang, ZF Jurkovitz, C Zhang, W Hartigan, PM Lewis, C Veledar, E Bowen, J Dunbar, SB Deaton, C Kaufman, S O'Rourke, RA Goeree, R Barnett, PG Teo, KK Boden, WE AF Weintraub, William S. Spertus, John A. Kolm, Paul Maron, David J. Zhang, Zefeng Jurkovitz, Claudine Zhang, Wei Hartigan, Pamela M. Lewis, Cheryl Veledar, Emir Bowen, Jim Dunbar, Sandra B. Deaton, Christi Kaufman, Stanley O'Rourke, Robert A. Goeree, Ron Barnett, Paul G. Teo, Koon K. Boden, William E. CA COURAGE Trial Res Grp TI Effect of PCI on quality of life in patients with stable coronary disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EVALUATION COURAGE TRIAL; ARTERY-DISEASE; MEDICAL THERAPY; HEALTH-STATUS; RITA-2 TRIAL; ANGIOPLASTY; ANGINA; OUTCOMES; REVASCULARIZATION; INTERVENTION AB Background: It has not been clearly established whether percutaneous coronary intervention (PCI) can provide an incremental benefit in quality of life over that provided by optimal medical therapy among patients with chronic coronary artery disease. Methods: We randomly assigned 2287 patients with stable coronary disease to PCI plus optimal medical therapy or to optimal medical therapy alone. We assessed angina-specific health status (with the use of the Seattle Angina Questionnaire) and overall physical and mental function (with the use of the RAND 36-item health survey [RAND-36]). Results: At baseline, 22% of the patients were free of angina. At 3 months, 53% of the patients in the PCI group and 42% in the medical-therapy group were angina-free (P<0.001). Baseline mean (+/-SD) Seattle Angina Questionnaire scores (which range from 0 to 100, with higher scores indicating better health status) were 66+/-25 for physical limitations, 54+/-32 for angina stability, 69+/-26 for angina frequency, 87+/-16 for treatment satisfaction, and 51+/-25 for quality of life. By 3 months, these scores had increased in the PCI group, as compared with the medical-therapy group, to 76+/-24 versus 72+/-23 for physical limitation (P=0.004), 77+/-28 versus 73+/-27 for angina stability (P=0.002), 85+/-22 versus 80+/-23 for angina frequency (P<0.001), 92+/-12 versus 90+/-14 for treatment satisfaction (P<0.001), and 73+/-22 versus 68+/-23 for quality of life (P<0.001). In general, patients had an incremental benefit from PCI for 6 to 24 months; patients with more severe angina had a greater benefit from PCI. Similar incremental benefits from PCI were seen in some but not all RAND-36 domains. By 36 months, there was no significant difference in health status between the treatment groups. Conclusions: Among patients with stable angina, both those treated with PCI and those treated with optimal medical therapy alone had marked improvements in health status during follow-up. The PCI group had small, but significant, incremental benefits that disappeared by 36 months. (ClinicalTrials.gov number, NCT00007657.). C1 [Weintraub, William S.; Kolm, Paul; Jurkovitz, Claudine; Zhang, Wei; Bowen, Jim] Christiana Care Hlth Syst, Cardiol Sect, Newark, DE 19718 USA. [Spertus, John A.] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Maron, David J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Zhang, Zefeng; Lewis, Cheryl; Veledar, Emir; Dunbar, Sandra B.] Emory Univ, Atlanta, GA 30322 USA. [Hartigan, Pamela M.] Vet Affairs Connecticut Healthcare Syst, Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Deaton, Christi] Univ Manchester, Manchester, Lancs, England. [Kaufman, Stanley] Epimetr Grp, San Francisco, CA USA. [O'Rourke, Robert A.] McMaster Univ, Hamilton, ON, Canada. [Goeree, Ron; Teo, Koon K.] San Antonio Vet Affairs Med Ctr, San Antonio, TX USA. [Barnett, Paul G.] Vet Affairs Hlth Econ Resource Ctr, Palo Alto, CA USA. [Boden, William E.] Western New York Vet Affairs Healthcare Network, Buffalo, NY USA. [Boden, William E.] Kaleida Hlth Syst, Buffalo, NY USA. RP Weintraub, WS (reprint author), Christiana Care Hlth Syst, Cardiol Sect, 4755 Ogletown Stanton Rd, Newark, DE 19718 USA. EM wweintraub@christianacare.org RI Deaton, Christi/F-6485-2010; Veledar, Emir/K-2808-2012 OI Veledar, Emir/0000-0002-3831-5433 NR 24 TC 286 Z9 300 U1 3 U2 13 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 AUG 14 PY 2008 VL 359 IS 7 BP 677 EP 687 DI 10.1056/NEJMoa072771 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 336XE UT WOS:000258397900004 PM 18703470 ER PT J AU Mills, JA Gonzalez, RG Jaffe, R Castelino, FV Harris, NL Neal, J Abraham, G AF Mills, John A. Gilberto Gonzalez, R. Jaffe, Ronald Castelino, Flavia V. Harris, Nancy Lee Neal, Joel Abraham, George TI A man with fatigue and lesions in the pituitary and cerebellum - Erdheim - Chester disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LANGERHANS-CELL HISTIOCYTOSIS; INTERFERON-ALPHA; INVOLVEMENT; SARCOIDOSIS C1 [Mills, John A.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Gilberto Gonzalez, R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mills, John A.] Harvard Univ, Sch Med, Dept Rheumatol, Boston, MA USA. [Gilberto Gonzalez, R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Jaffe, Ronald] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Neal, Joel] Dana Farber Canc Inst, Boston, MA 02115 USA. [Abraham, George] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Mills, JA (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. NR 20 TC 20 Z9 20 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 AUG 14 PY 2008 VL 359 IS 7 BP 736 EP 747 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 336XE UT WOS:000258397900012 PM 18703477 ER PT J AU Peterson, ED Rumsfeld, JS AF Peterson, Eric D. Rumsfeld, John S. TI Finding the courage to reconsider medical therapy for stable angina SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DISEASE C1 [Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Rumsfeld, John S.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Rumsfeld, John S.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Peterson, ED (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. NR 6 TC 13 Z9 13 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 AUG 14 PY 2008 VL 359 IS 7 BP 751 EP 753 DI 10.1056/NEJMe0804662 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 336XE UT WOS:000258397900014 PM 18703479 ER PT J AU Johnson, K Asher, J Rosborough, S Raja, A Panjabi, R Beadling, C Lawry, L AF Johnson, Kirsten Asher, Jana Rosborough, Stephanie Raja, Amisha Panjabi, Rajesh Beadling, Charles Lawry, Lynn TI Association of combatant status and sexual violence with health and mental health outcomes in postconflict Liberia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; INTERNALLY DISPLACED PERSONS; NORTHERN UGANDA; WAR; SYMPTOMS; CONFLICT; TRAUMA AB Context Liberia's wars since 1989 have cost tens of thousands of lives and left many people mentally and physically traumatized. Objectives To assess the prevalence and impact of war-related psychosocial trauma, including information on participation in the Liberian civil wars, exposure to sexual violence, social functioning, and mental health. Design, Setting, and Participants A cross-sectional, population-based, multi-stage random cluster survey of 1666 adults aged 18 years or older using structured interviews and questionnaires, conducted during a 3-week period in May 2008 in Liberia. Main Outcome Measures Symptoms of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), social functioning, exposure to sexual violence, and health and mental health needs among Liberian adults who witnessed or participated in the conflicts during the last 2 decades. Results In the Liberian adult household-based population, 40% (95% confidence interval [CI], 36%-45%; n = 672/1659) met symptom criteria for MDD, 44% (95% CI, 38%-49%; n = 718/1661) met symptom criteria for PTSD, and 8% (95% CI, 5%-10%; n = 133/1666) met criteria for social dysfunction. Thirty-three percent of respondents (549/1666) reported having served time with fighting forces, and 33.2% of former combatant respondents (182/549) were female. Former combatants experienced higher rates of exposure to sexual violence than noncombatants: among females, 42.3% (95% CI, 35.4%-49.1%) vs 9.2% (95% CI, 6.7%-11.7%), respectively; among males, 32.6% (95% CI, 27.6%-37.6%) vs 7.4% (95% CI, 4.5%-10.4%). The rates of symptoms of PTSD, MDD, and suicidal ideation were higher among former combatants than noncombatants and among those who experienced sexual violence vs those who did not. The prevalence of PTSD symptoms among female former combatants who experienced sexual violence (74%; 95% CI, 63%-84%) was higher than among those who did not experience sexual violence (44%; 95% CI, 33%-53%). The prevalence of PTSD symptoms among male former combatants who experienced sexual violence was higher (81%; 95% CI, 74%-87%) than among male former combatants who did not experience sexual violence (46%; 95% CI, 39%-52%). Male former combatants who experienced sexual violence also reported higher rates of symptoms of depression and suicidal ideation. Both former combatants and noncombatants experienced inadequate access to health care (33.0% [95% CI, 22.6%-43.4%] and 30.1% [95% CI, 18.7%-41.6%], respectively). Conclusions Former combatants in Liberia were not exclusively male. Both female and male former combatants who experienced sexual violence had worse mental health outcomes than noncombatants and other former combatants who did not experience exposure to sexual violence. C1 [Beadling, Charles; Lawry, Lynn] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Ctr Disaster & Humanitarian Assistance Med, Bethesda, MD 20814 USA. [Lawry, Lynn] Johns Hopkins Univ, Dept Int Hlth, Bloomberg Sch Publ Hlth, Bethesda, MD USA. [Johnson, Kirsten; Rosborough, Stephanie] Harvard Univ, Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. [Johnson, Kirsten] McGill Univ, Inst Hlth & Social Policy, Montreal, PQ, Canada. [Asher, Jana] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Rosborough, Stephanie] Brigham & Womens Hosp, Div Int Hlth, Humanitarian Program, Boston, MA 02115 USA. [Lawry, Lynn] Brigham & Womens Hosp, Div Womens Hlth, Humanitarian Program, Boston, MA 02115 USA. [Raja, Amisha] Univ Connecticut, Greater Hartford Consortium, VA Med Ctr, Newington, CT USA. [Raja, Amisha; Panjabi, Rajesh] HIV Equ Initiat Tiyatien Hlth, Zwedru, Liberia. [Panjabi, Rajesh] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Panjabi, Rajesh] Harvard Univ, Sch Med, Boston, MA USA. RP Lawry, L (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Ctr Disaster & Humanitarian Assistance Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM llawry@cdham.org NR 42 TC 65 Z9 65 U1 3 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 13 PY 2008 VL 300 IS 6 BP 676 EP 690 DI 10.1001/jama.300.6.676 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 336OM UT WOS:000258374500020 PM 18698066 ER PT J AU Salinthone, S Schillace, RV Marracci, GH Bourdette, DN Carr, DW AF Salinthone, Sonemany Schillace, Robynn V. Marracci, Gail H. Bourdette, Dennis N. Carr, Daniel W. TI Lipoic acid stimulates cAMP production via the EP2 and EN prostanoid receptors and inhibits IFN gamma synthesis and cellular cytotoxicity in NK cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; thioctic acid; natural killer cells; cAMP; IFN gamma ID NATURAL-KILLER-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; PROSTAGLANDIN E-2; PROTEIN-KINASE; T-CELLS; HUMAN OLIGODENDROCYTES; PERIPHERAL-BLOOD; INTERFERON-GAMMA AB The antioxidant lipoic acid (LA) treats, and prevents the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In an effort to understand the therapeutic potential of LA in MS, we sought to define the cellular mechanisms that mediate the effects of LA on human natural killer (NK) cells, which are important in innate immunity as the first line of defense against invading pathogens and tumor cells. We discovered that LA stimulates cAMP production in NK cells in a dose-dependent manner Studies using pharmacological inhibitors and receptor transfection experiments indicate that LA stimulates cAMP production via activation of the EP2 and EN prostanoid receptors and adenylyl cyclase. In addition, LA Suppressed interleukin (IL)-12/IL-18 induced IFN gamma secretion and cytotoxicity in NK cells. These novel findings suggest that LA may inhibit NK cell function via the cAMP signaling pathway Published by Elsevier B.V. C1 [Salinthone, Sonemany; Schillace, Robynn V.; Marracci, Gail H.; Bourdette, Dennis N.; Carr, Daniel W.] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97239 USA. [Salinthone, Sonemany; Schillace, Robynn V.; Marracci, Gail H.; Bourdette, Dennis N.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Carr, Daniel W.] Oregon Hlth & Sci Univ, Dept Endocrinol, Portland, OR 97239 USA. RP Carr, DW (reprint author), Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, RD-8,3710 US Vet Hosp Rd, Portland, OR 97239 USA. EM carrd@ohsu.edu FU Department of Veterans Affairs Biomedical Laboratory Research & Development Service; NIH [P50AT00066-01]; Nancy Davis Center Without Walls FX We would like to thank Sarah Fiedler and Casey Miller ror helpful critique of the manuscript. This research was Supported by the Department of Veterans Affairs Biomedical Laboratory Research & Development Service (D.W.C. and D.N.B.), NIH Grant P50AT00066-01 (D.N.B.), and the Nancy Davis Center Without Walls (D.N.B.). NR 52 TC 24 Z9 25 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 13 PY 2008 VL 199 IS 1-2 BP 46 EP 55 DI 10.1016/j.jneuroim.2008.05.003 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 343YL UT WOS:000258892200006 PM 18562016 ER PT J AU Hickman, SE Allison, EK El Khoury, J AF Hickman, Suzanne E. Allison, Elizabeth K. El Khoury, Joseph TI Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE microglia; Alzheimer's disease; transgenic mice; amyloid; phagocytosis; degradation ID TRANSGENIC MICE; SCAVENGER RECEPTOR; INTERFERON-GAMMA; PLAQUES; SECRETASE; FIBRILS; BRAINS; PHAGOCYTOSIS; ASSOCIATION; MACROPHAGES AB Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (A beta)before formation of senile plaques. However, persistent A beta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear A beta may decrease with age and progression of AD pathology. To determine the effects of aging and A beta deposition on microglial ability to clear A beta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the A beta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the A beta-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1 beta(interleukin-1 beta) and tumor necrosis factor alpha(TNF alpha), suggesting that there is an inverse correlation between cytokine production and A beta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNF alpha decreased the expression of SRA and CD36 and reduced A beta uptake. Our data indicate that, although early microglial recruitment promotes A beta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to A beta deposition downregulate genes involved in A beta clearance and promote A beta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration. C1 [Hickman, Suzanne E.; Allison, Elizabeth K.; El Khoury, Joseph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Charlestown, MA 02129 USA. [El Khoury, Joseph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Charlestown, MA 02129 USA. RP El Khoury, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, CNY 149,Room 8301,149 13th St, Charlestown, MA 02129 USA. EM jelkhoury@partners.org FU National Institute of Neurological Disorders and Stroke [NS059005]; The Dana Foundation Neuroimmunology Program FX This work was supported by National Institute of Neurological Disorders and Stroke Grant NS059005 and a grant from The Dana Foundation Neuroimmunology Program (J.E.K.). We thank David Borchelt for permission to use the PS1-APP mice. NR 28 TC 388 Z9 406 U1 13 U2 58 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 AUG 13 PY 2008 VL 28 IS 33 BP 8354 EP 8360 DI 10.1523/JNEUROSCI.0616-08.2008 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 337GL UT WOS:000258423400024 PM 18701698 ER PT J AU Gounaris, E Tung, CH Restaino, C Maehr, R Kohler, R Joyce, JA Plough, HL Barrett, TA Weissleder, R Khazaie, K AF Gounaris, Elias Tung, Ching H. Restaino, Clifford Maehr, Rene Kohler, Rainer Joyce, Johanna A. Plough, Hidde L. Barrett, Terrence A. Weissleder, Ralph Khazaie, Khashayarsha TI Live Imaging of Cysteine-Cathepsin Activity Reveals Dynamics of Focal Inflammation, Angiogenesis, and Polyp Growth SO PLOS ONE LA English DT Article AB It has been estimated that up to 30% of detectable polyps in patients regress spontaneously. One major challenge in the evaluation of effective therapy of cancer is the readout for tumor regression and favorable biological response to therapy. Inducible near infra-red (NIR) fluorescent probes were utilized to visualize intestinal polyps of mice hemizygous for a novel truncation of the Adenomatous Polyposis coli (APC) gene. Laser Scanning Confocal Microscopy in live mice allowed visualization of cathepsin activity in richly vascularized benign dysplastic lesions. Using biotinylated suicide inhibitors we quantified increased activities of the Cathepsin B & Z in the polyps. More than 3/4 of the probe signal was localized in CD11b(+)Gr1(+) myeloid derived suppressor cells (MDSC) and CD11b(+)F4/80(+) macrophages infiltrating the lesions. Polyposis was attenuated through genetic ablation of cathepsin B, and suppressed by neutralization of TNF alpha in mice. In both cases, diminished probe signal was accounted for by loss of MDSC. Thus, in vivo NIR imaging of focal cathepsin activity reveals inflammatory reactions etiologically linked with cancer progression and is a suitable approach for monitoring response to therapy. C1 [Gounaris, Elias; Tung, Ching H.; Restaino, Clifford; Kohler, Rainer; Weissleder, Ralph; Khazaie, Khashayarsha] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Gounaris, Elias; Barrett, Terrence A.; Khazaie, Khashayarsha] Northwestern Univ, Robert Lurie Comprehensive Canc Ctr, Feinberg Sch Med, Div Gastroenterol, Chicago, IL USA. [Joyce, Johanna A.] Memorial Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY USA. [Plough, Hidde L.] MIT, Whitehead Inst, Cambridge, MA USA. [Tung, Ching H.] Weill Cornell Med Coll, Methodist Hosp Res Inst, Houston, TX USA. [Maehr, Rene] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA USA. [Maehr, Rene] Howard Hughes Med Inst, Cambridge, MA USA. RP Gounaris, E (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. EM khazaie@northwestern.edu RI Gounaris, Elias/B-3184-2011; OI Gounaris, Elias/0000-0001-8679-9711; Tung, Ching-Hsuan/0000-0001-6648-6195 FU NIH [R01 CA104547-03, R01-CA125162]; American Cancer Society [113422] FX Supported by NIH R01 CA104547-03 (KK), and American Cancer Society Research Scholar Grant, 113422 RSG (KK), NIH R01-CA125162 (JAJ). NR 32 TC 58 Z9 58 U1 1 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 AUG 13 PY 2008 VL 3 IS 8 AR e2916 DI 10.1371/journal.pone.0002916 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422FK UT WOS:000264412600004 PM 18698347 ER PT J AU O'Brien, CA Plotkin, LI Galli, C Goellner, JJ Gortazar, AR Allen, MR Robling, AG Bouxsein, M Schipani, E Turner, CH Jilka, RL Weinstein, RS Manolagas, SC Bellido, T AF O'Brien, Charles A. Plotkin, Lilian I. Galli, Carlo Goellner, Joseph J. Gortazar, Arancha R. Allen, Matthew R. Robling, Alexander G. Bouxsein, Mary Schipani, Ernestina Turner, Charles H. Jilka, Robert L. Weinstein, Robert S. Manolagas, Stavros C. Bellido, Teresita TI Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes SO PLOS ONE LA English DT Article ID OSTEOBLAST-DERIVED PTHRP; PARATHYROID-HORMONE; BETA-CATENIN; IN-VIVO; GENE-EXPRESSION; TRABECULAR BONE; PRIMARY HYPERPARATHYROIDISM; DIFFERENTIATED OSTEOBLASTS; OSTEOCLAST DIFFERENTIATION; PTH/PTHRP RECEPTOR AB Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and independent mechanisms, respectively. C1 [O'Brien, Charles A.; Plotkin, Lilian I.; Galli, Carlo; Goellner, Joseph J.; Gortazar, Arancha R.; Jilka, Robert L.; Weinstein, Robert S.; Manolagas, Stavros C.; Bellido, Teresita] Univ Arkansas Med Sci, Div Endocrinol, Ctr Osteoporosis & Metab Bone Dis, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. [Allen, Matthew R.; Robling, Alexander G.] Indiana Univ, Sch Med, Dept Anat & Cell Biol, Bloomington, IN 47405 USA. [Bouxsein, Mary] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Orthoped Surg, Orthoped Biomechan Lab, Boston, MA USA. [Schipani, Ernestina] Massachusetts Gen Hosp, Harvard Med Sch, Endocrine Unit, Boston, MA USA. [Turner, Charles H.] Indiana Univ, Sch Med, Dept Orthopaed Surg, Bloomington, IN 47405 USA. RP O'Brien, CA (reprint author), Univ Arkansas Med Sci, Div Endocrinol, Ctr Osteoporosis & Metab Bone Dis, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. EM caobrien@uams.edu; tbellido@iupui.edu RI Allen, Matthew/A-8799-2015 OI Allen, Matthew/0000-0002-1174-9004 FU National Institutes of Health [R01 DK076007, R01 AR049794, P01 AG13918, S10-RR023710]; Department of Veterans Affairs; University of Arkansas for Medical Sciences Tobacco Settlement funds FX This research was supported by the National Institutes of Health (R01 DK076007, R01 AR049794, P01 AG13918, and S10-RR023710), the Department of Veterans Affairs, and University of Arkansas for Medical Sciences Tobacco Settlement funds. NR 83 TC 185 Z9 188 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 13 PY 2008 VL 3 IS 8 AR e2942 DI 10.1371/journal.pone.0002942 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422FK UT WOS:000264412600028 PM 18698360 ER PT J AU Schuller, U Heine, VM Mao, J Kho, AT Dillon, AK Han, YG Huillard, E Sun, T Ligon, AH Qian, Y Ma, Q Alvarez-Buylla, A McMahon, AP Rowitch, DH Ligon, KL AF Schueller, Ulrich Heine, Vivi M. Mao, Junhao Kho, Alvin T. Dillon, Allison K. Han, Young-Goo Huillard, Emmanuelle Sun, Tao Ligon, Azra H. Qian, Ying Ma, Qiufu Alvarez-Buylla, Arturo McMahon, Andrew P. Rowitch, David H. Ligon, Keith L. TI Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma SO CANCER CELL LA English DT Article ID STEM-CELLS; SONIC HEDGEHOG; PRIMARY CILIA; HUMAN HOMOLOG; BRAIN-TUMORS; CEREBELLUM; EXPRESSION; PATHWAY; GENE; LEUKEMIA AB Whether the brain tumor medulloblastoma originates from stem cells or restricted progenitor cells is unclear. To investigate this, we activated oncogenic Hedgehog (Hh) signaling in multipotent and lineage-restricted central nervous system (CNS) progenitors. We observed that normal unipotent cerebellar granule neuron precursors (CGNPs) derive from hGFAP(+) and Olig2(+) rhombic lip progenitors. Hh activation in a spectrum of early-and late-stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hh signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. C1 [Schueller, Ulrich; Heine, Vivi M.; Dillon, Allison K.; Huillard, Emmanuelle; Sun, Tao; Rowitch, David H.; Ligon, Keith L.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ligon, Azra H.; Ligon, Keith L.] Harvard Univ, Sch Med, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Qian, Ying; Ma, Qiufu] Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Schueller, Ulrich] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany. [Heine, Vivi M.; Huillard, Emmanuelle; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Heine, Vivi M.; Han, Young-Goo; Huillard, Emmanuelle; Alvarez-Buylla, Arturo; Rowitch, David H.] Univ Calif San Francisco, Inst Regenerat Med, San Francisco, CA 94143 USA. [Alvarez-Buylla, Arturo; Rowitch, David H.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Mao, Junhao; McMahon, Andrew P.] Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA. [Kho, Alvin T.] Childrens Hosp Boston, Informat Program, Boston, MA 02115 USA. [Ligon, Keith L.] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Rowitch, DH (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM rowitchd@peds.ucsf.edu; keith_ligon@dfci.harvard.edu RI Heine, Vivi/F-1741-2011; OI Ligon, Keith/0000-0002-7733-600X; Han, Young-Goo/0000-0002-4008-294X FU Dr. Mildred-Scheel-Stiftung for Knebsforschung and by the Max-Eder-Nachwuchsgruppenprogramm of the Deutsche Krebshilfe; Charles King Trust/Medical Foundation; American Brain Tumor Association; NIH [NS047213, NS040828, NS033642, NS047527]; NS047527); the James S. McDonnell Foundation; he March of Dimes Foundation; Pediatric Brain Tumor Foundation of the United States FX The authors are grateful to R.J. Wechsler-Reya for sharing unpublished data; C.D. Stiles for comments; and J. Ling, S. Kaing, DA. Yuk, N. Vena, and E. Learner for expert technical assistance. U.S. was supported by a fellowship from the Dr. Mildred-Scheel-Stiftung for Knebsforschung and by the Max-Eder-Nachwuchsgruppenprogramm of the Deutsche Krebshilfe. V.M.H. thanks the Netherlands Organization for Scientific Research (NWO) for a TALENT stipend. J.M. was supported by a grant from the Charles King Trust/Medical Foundation. A.K.D., Y-G.H., and E.H. thank the American Brain Tumor Association for support. This work was supported by grants from the NIH to K.L.L. (NS047213), A.T.K. (NS040828), A.P.M. (NS033642), and D.H.R. (NS047527); the James S. McDonnell Foundation (to D.H.R.); the March of Dimes Foundation (to D.H.R and the Pediatric Brain Tumor Foundation of the United States (to A.A.-B. and D.H.R.). D.H.R. is a Howard Hughes Medical Institute Investigator. NR 59 TC 266 Z9 270 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 12 PY 2008 VL 14 IS 2 BP 123 EP 134 DI 10.1016/j.ccr.2008.07.005 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 339WN UT WOS:000258608100006 PM 18691547 ER PT J AU Majumder, PK Grisanzio, C O'Connell, F Barry, M Brito, JM Xu, Q Guney, I Berger, R Herman, P Bikoff, R Fedele, G Baek, WK Wang, S Ellwood-Yen, K Wu, H Sawyers, CL Signoretti, S Hahn, WC Loda, M Sellers, WR AF Majumder, Pradip K. Grisanzio, Chiara O'Connell, Fionnuala Barry, Marc Brito, Joseph M. Xu, Qing Guney, Isil Berger, Raanan Herman, Paula Bikoff, Rachel Fedele, Giuseppe Baek, Won-Ki Wang, Shunyou Ellwood-Yen, Katharine Wu, Hong Sawyers, Charles L. Signoretti, Sabina Hahn, William C. Loda, Massimo Sellers, William R. TI A prostatic intraepithelial neoplasia-dependent p27(Kip1) checkpoint induces senescence and inhibits cell proliferation and cancer progression SO CANCER CELL LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; TUMOR SUPPRESSION; EPITHELIAL-CELLS; BREAST-CANCER; NEEDLE-BIOPSY; MICE LACKING; E-CADHERIN; IN-VITRO; P27; EXPRESSION AB Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP. C1 [Majumder, Pradip K.; O'Connell, Fionnuala; Brito, Joseph M.; Xu, Qing; Guney, Isil; Berger, Raanan; Herman, Paula; Bikoff, Rachel; Fedele, Giuseppe; Baek, Won-Ki; Hahn, William C.; Loda, Massimo; Sellers, William R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Majumder, Pradip K.; Xu, Qing; Guney, Isil; Berger, Raanan; Herman, Paula; Bikoff, Rachel; Baek, Won-Ki; Hahn, William C.; Loda, Massimo; Sellers, William R.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Grisanzio, Chiara; O'Connell, Fionnuala; Barry, Marc; Fedele, Giuseppe; Loda, Massimo] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wang, Shunyou; Ellwood-Yen, Katharine; Wu, Hong] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA. [Hahn, William C.; Loda, Massimo] MIT, Borad Inst, Cambridge, MA 02142 USA. [Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP Loda, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM massimo_loda@dfci.harvard.edu; william.sellers@novartis.com RI Sawyers, Charles/G-5327-2016 FU Linda and Arthur Gelb Center for Translational Research; National Cancer Institute [K01 CA94223, PO1 CA89021]; Prostate Cancer Foundation; Damon Runyon Cancer Research Foundation; DF/HCC Prostate Cancer SPORE; Novartis Institutes for BioMedical Research FX We thank Erguen Sahin for the generous gift of mouse-specific CK19 antibody, Michelangelo Fiorentino for IHC analysis of p27Kip1 and HP1 in human PIN, and Heidi Lane of the Novartis Institutes for Biomedical Research (Oncology, Basel, Switzerland) for RAD001, We also thank Nandita Bhattacharya, Yeonju Shim, and Jennifer Kum for excellent technical support. This work was supported by the Linda and Arthur Gelb Center for Translational Research. National Cancer Institute grants K01 CA94223 (W.C.H.) and PO1 CA89021 (W.R.S.). the Prostate Cancer Foundation (R.B., W.C.H., M.L., and W.R.S.). the Damon Runyon Cancer Research Foundation (W.R.S.), and a Career Development Award from the DF/HCC Prostate Cancer SPORE (P.K.M). W.C.H., M.L., and W.R.S. receive research support from and are consultants for the Novartis Institutes for BioMedical Research. W.R.S. is an employee of the Novartis Institutes for BioMedical Research. P.K.M. and K.E.-Y, are employees of Merck Research Laboratories Boston. NR 46 TC 103 Z9 105 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 12 PY 2008 VL 14 IS 2 BP 146 EP 155 DI 10.1016/j.ccr.2008.06.002 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 339WN UT WOS:000258608100008 PM 18691549 ER PT J AU Hong, KH Lee, YJ Lee, E Park, SO Han, C Beppu, H Li, E Raizada, MK Bloch, KD Oh, SP AF Hong, Kwon-Ho Lee, Young Jae Lee, Eunji Park, Sung Ok Han, Chul Beppu, Hideyuki Li, En Raizada, Mohan K. Bloch, Kenneth D. Oh, S. Paul TI Genetic ablation of the Bmpr2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension SO CIRCULATION LA English DT Article DE endothelium; genetics; hypertension, pulmonary; receptors ID MORPHOGENETIC PROTEIN-RECEPTOR; HEREDITARY HEMORRHAGIC TELANGIECTASIA; SMOOTH-MUSCLE; II RECEPTOR; MICE; SUSCEPTIBILITY; PROLIFERATION; PATHOGENESIS; EXPRESSION; MUTATIONS AB Background-Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. PAH is now further subclassified as idiopathic PAH, familial PAH, and associated PAH varieties. Heterozygous mutations in BMPR2 can be detected in 50% to 70% of patients with familial PAH and 10% to 40% of patients with idiopathic PAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH. Methods and Results-The Bmpr2 gene was deleted in pulmonary endothelial cells using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure were observed in mice with heterozygous (21.7 to 44.1 mm Hg; median, 23.7 mm Hg) and homozygous (20.7 to 56.3 mm Hg; median, 27 mm Hg) conditional deletion of Bmpr2 in pulmonary endothelial cells compared with control mice (19.9 to 26.7 mm Hg; median, 23 mm Hg) at 2 to 7 months of age. A subset of mice with right ventricular systolic pressure >30 mm Hg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these mice with high right ventricular systolic pressure, the expression of proteins involved in the pathogenesis of PAH such as serotonin transporter and tenascin-C was elevated in distal arteries and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis. Conclusions-Conditional heterozygous or homozygous Bmpr2 deletion in pulmonary endothelial cells predisposes mice to develop PAH. C1 [Hong, Kwon-Ho; Lee, Young Jae; Lee, Eunji; Park, Sung Ok; Han, Chul; Raizada, Mohan K.; Oh, S. Paul] Univ Florida, Dept Physiol & Funct Genom, Shands Canc Ctr, Coll Med, Gainesville, FL 32610 USA. [Lee, Young Jae; Oh, S. Paul] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea. [Lee, Eunji; Beppu, Hideyuki; Bloch, Kenneth D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Beppu, Hideyuki; Bloch, Kenneth D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Charlestown, MA USA. RP Oh, SP (reprint author), Univ Florida, Dept Physiol & Funct Genom, Shands Canc Ctr, Coll Med, 1376 Mowry Rd,Room 456, Gainesville, FL 32610 USA. EM ohp@phys.med.ufl.edu FU NHLBI NIH HHS [HL74352, HL56921, HL64024, R01 HL056921, R01 HL064024, R01 HL064024-08, R01 HL074352] NR 28 TC 96 Z9 99 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 12 PY 2008 VL 118 IS 7 BP 722 EP 730 DI 10.1161/CIRCULATIONAHA.107.736801 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 336IA UT WOS:000258356300005 PM 18663089 ER PT J AU Yared, K Johri, AM Soni, AV Johnson, M Alkasab, T Cury, RC Hung, J Mamuya, W AF Yared, Kibar Johri, Amer M. Soni, Anand V. Johnson, Matthew Alkasab, Tarik Cury, Ricardo C. Hung, Judy Mamuya, Wilfred TI Cardiac sarcoidosis imitating arrhythmogenic right ventricular dysplasia SO CIRCULATION LA English DT Editorial Material C1 [Yared, Kibar; Johri, Amer M.; Hung, Judy] Harvard Univ, Cardiac Ultrasound Lab, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Soni, Anand V.; Cury, Ricardo C.] Harvard Univ, Dept Radiol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Johnson, Matthew] Harvard Univ, Dept Pathol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Alkasab, Tarik] Harvard Univ, Dept Nucl Med, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mamuya, Wilfred] Harvard Univ, Div Cardiol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yared, K (reprint author), Harvard Univ, Cardiac Ultrasound Lab, Sch Med, Massachusetts Gen Hosp, 55 Fruit St,Yawkey 5E, Boston, MA 02114 USA. EM kyared@partners.org OI Alkasab, Tarik/0000-0002-4433-9482 NR 4 TC 13 Z9 14 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 AUG 12 PY 2008 VL 118 IS 7 BP E113 EP E115 DI 10.1161/CIRCULATIONAHA.107.755215 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 336IA UT WOS:000258356300013 PM 18695196 ER PT J AU Padera, TP Jain, RK AF Padera, Timothy P. Jain, Rakesh K. TI VEGFR3: A new target for antiangiogenesis therapy? SO DEVELOPMENTAL CELL LA English DT Editorial Material ID TUMOR VASCULATURE; ANGIOGENESIS; RECEPTOR-3; CELLS C1 [Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu OI Padera, Timothy/0000-0002-3453-9384 FU NCI NIH HHS [P01 CA080124, R01 CA085140] NR 10 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 12 PY 2008 VL 15 IS 2 BP 178 EP 179 DI 10.1016/j.devcel.2008.07.014 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 338YS UT WOS:000258545900005 PM 18694556 ER PT J AU Blatt, JA Poole, JE Johnson, GW Callans, DJ Raitt, MH Reddy, RK Marchlinski, FE Yee, R Guarnieri, T Talajic, M Wilber, DJ Anderson, J Chung, K Wong, WS Mark, DB Lee, KL Bardy, GH AF Blatt, Joseph A. Poole, Jeanne E. Johnson, George W. Callans, David J. Raitt, Merritt H. Reddy, Ramakota K. Marchlinski, Francis E. Yee, Raymond Guarnieri, Thomas Talajic, Mario Wilber, David J. Anderson, Jill Chung, Kiyon Wong, Wai Shun Mark, Daniel B. Lee, Kerry L. Bardy, Gust H. CA SCD-HeFT Investigators TI No benefit from defibrillation threshold testing in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE sudden cardiac death; implantable cardioverter-defibrillator; defibrillation threshold testing; DFT testing ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; SYSTEM; MULTICENTER; EFFICACY; WAVEFORM; HUMANS; PULSES; TABLES AB Objectives This study investigated whether defibrillation threshold (DFT) testing during implantable cardioverter-defibrillator (ICD) implantation predicts clinical outcomes. Background Defibrillation testing is often performed during insertion of ICDs to confirm shock efficacy. There are no prospective data to suggest that this procedure improves outcomes when modern ICDs are implanted for primary prevention of sudden death. Methods The analysis included the 811 patients who were randomized to the ICD arm of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) and had the device implanted. The DFT testing protocol in SCD-HeFT was designed to limit shock testing in a primary prevention heart failure population. Results Baseline DFT data were available for 717 patients (88.4%). All 717 patients had a DFT of <= 30 J, the maximum output of the device in this study. The DFT was <= 20 J in 97.8% of patients. There was no survival difference between patients with a lower DFT (<= 10 J, n = 547) and a higher DFT (> 10 J, n = 170) (p = 0.41). First shock efficacy was 83.0% for the first clinical ventricular tachyarrhythmia event; there were no differences in shock efficacies when the cohort was subdivided by baseline DFT. Conclusions Low baseline DFTs were obtained in patients with stable, optimally treated heart failure during ICD implantation for primary prevention of sudden death. First shock efficacy for ventricular tachyarrhythmias was high regardless of baseline DFT testing results. Baseline DFT testing did not predict long-term mortality or shock efficacy in this study. C1 [Blatt, Joseph A.] Univ Washington, Dept Cardiol, Seattle, WA 98195 USA. [Johnson, George W.; Anderson, Jill; Bardy, Gust H.] Seattle Inst Cardiac Res, Seattle, WA USA. [Callans, David J.; Marchlinski, Francis E.] Univ Penn, Philadelphia, PA 19104 USA. [Raitt, Merritt H.] Portland VA Med Ctr, Portland, OR USA. [Yee, Raymond] Univ Western Ontario, London, ON, Canada. [Guarnieri, Thomas] Johns Hopkins Univ, Baltimore, MD USA. [Talajic, Mario] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Wilber, David J.] Loyola Univ Hlth Syst, Maywood, IL USA. [Chung, Kiyon] Everett Clin, Everett, WA USA. [Mark, Daniel B.; Lee, Kerry L.] Duke Univ, Sch Med, Durham, NC USA. [Wong, Wai Shun] Univ Michigan, Ann Arbor, MI 48109 USA. [Reddy, Ramakota K.] Oregon Cardiol PC, Eugene, OR USA. RP Blatt, JA (reprint author), Univ Washington, Dept Cardiol, Box 356422,1959 NE Pacific St, Seattle, WA 98195 USA. EM jablatt@u.washington.edu OI Mark, Daniel/0000-0001-6340-8087; Raitt, Merritt/0000-0001-5638-7732; Marchlinski, Francis/0000-0001-7962-9423 FU NHLBI NIH HHS [UO1 HL55496, UO1 HL55766, U01 HL55297, U01 HL055496] NR 27 TC 80 Z9 83 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 12 PY 2008 VL 52 IS 7 BP 551 EP 556 DI 10.1016/j.jacc.2008.04.051 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 336VV UT WOS:000258393800009 PM 18687249 ER PT J AU Boag, PR Atalay, A Robida, S Reinke, V Blackwell, TK AF Boag, Peter R. Atalay, Arzu Robida, Stacey Reinke, Valerie Blackwell, T. Keith TI Protection of specific maternal messenger RNAs by the P body protein CGH-1 (Dhh1/RCK) during Caenorhabditis elegans oogenesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PHYSIOLOGICAL GERMLINE APOPTOSIS; C-ELEGANS; GENE-EXPRESSION; TRANSLATIONAL REPRESSION; SACCHAROMYCES-CEREVISIAE; DROSOPHILA OOCYTES; STRESS GRANULES; BINDING-PROTEIN; LOCALIZATION; COMPLEX AB During oogenesis, numerous messenger RNAs (mRNAs) are maintained in a translationally silenced state. In eukaryotic cells, various translation inhibition and mRNA degradation mechanisms congregate in cytoplasmic processing bodies ( P bodies). The P body protein Dhh1 inhibits translation and promotes decapping-mediated mRNA decay together with Pat1 in yeast, and has been implicated in mRNA storage in metazoan oocytes. Here, we have investigated in Caenorhabditis elegans whether Dhh1 and Pat1 generally function together, and how they influence mRNA sequestration during oogenesis. We show that in somatic tissues, the Dhh1 orthologue (CGH-1) forms Pat1 (patr-1)-dependent P bodies that are involved in mRNA decapping. In contrast, during oogenesis, CGH-1 forms patr-1-independent mRNA storage bodies. CGH-1 then associates with translational regulators and a specific set of maternal mRNAs, and prevents those mRNAs from being degraded. Our results identify somatic and germ cell CGH-1 functions that are distinguished by the involvement of PATR-1, and reveal that during oogenesis, numerous translationally regulated mRNAs are specifically protected by a CGH-1 dependent mechanism. C1 [Boag, Peter R.; Atalay, Arzu; Robida, Stacey; Blackwell, T. Keith] Harvard Univ, Sch Med, Joslin Diabet Ctr, Harvard Stem Cell Inst, Boston, MA 02215 USA. [Boag, Peter R.; Atalay, Arzu; Blackwell, T. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Reinke, Valerie] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. RP Blackwell, TK (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Harvard Stem Cell Inst, Boston, MA 02215 USA. EM keith.blackwell@joslin.harvard.edu RI atalay, arzu/O-1601-2014 OI atalay, arzu/0000-0003-1309-5291 FU Myra R. Reinhard Family Foundation; Harvard Stem Cell Institute; National Institutes of Health [GM65682, GM63826] FX We thank the Caenorhabditis Genetics Center for strains and the National BioResource Project for the Nematode for patr-1 and dcap-2 deletions. We thank Paul Anderson, Carl Novina, and Karl Munger for insightful comments on the manuscript.; This work was supported by the Myra R. Reinhard Family Foundation (to P.R. Boag), a seed grant from the Harvard Stem Cell Institute (to T. Keith Blackwell), and grants from the National Institutes of Health (GM65682 to V. Reinke and GM63826 to T. Keith Blackwell). NR 73 TC 68 Z9 78 U1 1 U2 5 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 AUG 11 PY 2008 VL 182 IS 3 BP 543 EP 557 DI 10.1083/jcb.200801183 PG 15 WC Cell Biology SC Cell Biology GA 338SN UT WOS:000258529100014 PM 18695045 ER PT J AU Kim, IK Ji, F Morrison, MA Adams, S Zhang, Q Lane, AM Capone, A Dryja, TP Ott, J Miller, JW DeAngelis, MM AF Kim, Ivana K. Ji, Fei Morrison, Margaux A. Adams, Scott Zhang, Qingrun Lane, Anne Marie Capone, Antonio Dryja, Thaddeus P. Ott, Jurg Miller, Joan W. DeAngelis, Margaret M. TI Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration SO MOLECULAR VISION LA English DT Article ID C-REACTIVE PROTEIN; COMPLEMENT FACTOR-H; DISCORDANT SIB PAIRS; CARDIOVASCULAR-DISEASE; Y402H VARIANT; POLYMORPHISM; GENE; ASSOCIATION; HAPLOTYPE; MACULOPATHY AB Purpose: To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort. Methods: We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r(2)) between all CRP variants identified. Results: Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r(2)= 0.94). SNP rs3093068 was in LD but less so with rs3093059 (r(2)= 0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified. Conclusions: We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors. C1 [Kim, Ivana K.; Morrison, Margaux A.; Adams, Scott; Lane, Anne Marie; Dryja, Thaddeus P.; Miller, Joan W.; DeAngelis, Margaret M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Ji, Fei; Ott, Jurg] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. [Zhang, Qingrun; Ott, Jurg] Chinese Acad Sci, Beijing Inst Genom, Beijing, Peoples R China. [Capone, Antonio] William Beaumont Hosp, Royal Oak, MI 48072 USA. RP DeAngelis, MM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM margaret_deangelis@hms.harvard.edu RI DeAngelis, e/J-7863-2015 FU Ruth and Milton Steinbach Fund, New york, NY; Lincy Foundation, Beverly Hills; National Science Foundation of China, Beijing, China [30730057, 30700442]; National Institutes of Health, Bethesda [EY014458, EY14104, MH44292] FX This work was supported by grants from the Ruth and Milton Steinbach Fund, New York, NY; Lincy Foundation, Beverly Hills, CA; Massachusetts Lions, New Bedford, MA; Friends of the Massachusetts Eye and Ear Infirmary ( MEEI), Boston, MA; Genetics of Age- Related Macular Degeneration Fund, MEEI, Boston, MA; Research to Prevent Blindness, New York, NY; Marion W. and Edward F. Knight AMD Fund, Boston, MA; National Science Foundation of China, Beijing, China (30730057 and 30700442); and the National Institutes of Health, Bethesda, MD (EY014458, EY14104, and MH44292). NR 32 TC 27 Z9 27 U1 0 U2 0 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 AUG 11 PY 2008 VL 14 IS 177 BP 1487 EP 1495 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 344JT UT WOS:000258923600001 PM 18704199 ER PT J AU Finlay, E Shreve, S Casarett, D AF Finlay, Esme Shreve, Scott Casarett, David TI Nationwide veterans affairs quality measure for cancer: The family assessment of treatment at end of life SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID AFTER-DEATH INTERVIEWS; PALLIATIVE CARE; HOSPICE CARE; DATA SET; MEMBERS; PERCEPTIONS; CAREGIVERS; PATIENT; PAIN; SATISFACTION AB The Veterans Affairs (VA) health care system has created a national initiative to measure quality of care at the end of life. This article describes the first phase of this national initiative, the Family Assessment of Treatment at End of Life (FATE), in evaluating the quality of end-of-life care for veterans dying with cancer. In the initial phase, next of kin of patients from five VA Medical Centers were contacted 6 weeks after patients' deaths and invited to participate in a telephone interview, and surrogates for 262 cancer patients completed FATE interviews. Decedents were 98% male with an average age of 72 years. There was substantial variation among sites. Higher FATE scores, consistent with family reports of higher satisfaction with care, were associated with palliative care consultation and hospice referral and having a Do Not Resuscitate order at the time of death, whereas an intensive care unit death was associated with lower scores. Early experience with FATE suggests that it will be a helpful tool to characterize end-of-life cancer care and to identify targets for quality improvement. C1 [Casarett, David] Univ Penn, Ralston Penn Ctr, Div Hematol Oncol, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs VA Med Ctr, VA Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. Lebanon VA Med Ctr, Lebanon, NH USA. Off Geriatr & Extended Care, Washington, DC USA. RP Casarett, D (reprint author), Univ Penn, Ralston Penn Ctr, Div Hematol Oncol, 3615 Chestnut St,Rm 304, Philadelphia, PA 19104 USA. EM casarett@mail.med.upenn.edu NR 61 TC 38 Z9 38 U1 4 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 AUG 10 PY 2008 VL 26 IS 23 BP 3838 EP 3844 DI 10.1200/JCO.2008.16.8534 PG 7 WC Oncology SC Oncology GA 335ND UT WOS:000258296400004 PM 18688050 ER PT J AU Earle, CC Landrum, MB Souza, JM Neville, BA Weeks, JC Ayanian, JZ AF Earle, Craig C. Landrum, Mary Beth Souza, Jeffrey M. Neville, Bridget A. Weeks, Jane C. Ayanian, John Z. TI Aggressiveness of cancer care near the end of life: Is it a quality-of-care issue? 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 MEDICARE MANAGED CARE; HOSPICE USE; PALLIATIVE CARE; BREAST-CANCER; CHEMOTHERAPY; INDICATORS; PROGNOSIS; PATIENT; SERVICE; DEATH AB The purpose of this article is to review the literature and update analyses pertaining to the aggressiveness of cancer care near the end of life. Specifically, we will discuss trends and factors responsible for chemotherapy overuse very near death and underutilization of hospice services. Whether the concept of overly aggressive treatment represents a quality-of-care issue that is acceptable to all involved stakeholders is an open question. C1 Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. RP Earle, CC (reprint author), Sunnybrook Hlth Sci Ctr, Inst Clin Evaluat Sci, 2075 Bayview Ave,Room G-106, Toronto, ON M4N 3M5, Canada. EM craig.earle@ices.on.ca FU NCI NIH HHS [CA 91753-02] NR 39 TC 290 Z9 293 U1 2 U2 15 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 AUG 10 PY 2008 VL 26 IS 23 BP 3860 EP 3866 DI 10.1200/JCO.2007.15.8253 PG 7 WC Oncology SC Oncology GA 335ND UT WOS:000258296400007 PM 18688053 ER PT J AU Dy, SM Asch, SM Naeim, A Sanati, H Walling, A Lorenz, KA AF Dy, Sydney M. Asch, Steven M. Naeim, Arash Sanati, Homayoon Walling, Anne Lorenz, Karl A. TI Evidence-based standards for cancer pain management SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SPINAL-CORD COMPRESSION; BONE METASTASES; RANDOMIZED-TRIAL; PALLIATIVE CARE; SINGLE FRACTION; RADIOTHERAPY; METAANALYSIS; GUIDELINES; DIAGNOSIS; DISEASE AB High-quality management of cancer pain depends on evidence-based standards for screening, assessment, treatment, and follow-up for general cancer pain and specific pain syndromes. We developed a set of standards through an iterative process of structured literature review and development and refinement of topic areas and standards and subjected recommendations to rating by a multidisciplinary expert panel. Providers should routinely screen for the presence or absence and intensity of pain and should perform descriptive pain assessment for patients with a positive screen, including assessment for likely etiology and functional impairment. For treatment, providers should provide pain education, offer breakthrough opioids in patients receiving longacting formulations, offer bowel regimens in patients receiving opioids chronically, and ensure continuity of opioid doses across health care settings. Providers should also follow up on patients after treatment for pain. For metastatic bone pain, providers should offer single-fraction radiotherapy as an option when offering radiation, unless there is a contraindication. When spinal cord compression is suspected, providers should treat with corticosteroids and evaluate with wholespine magnetic resonance imaging scan or myelography as soon as possible but within 24 hours. Providers should initiate definitive treatment ( radiotherapy or surgical decompression) within 24 hours for diagnosed cord compression and should follow up on patients after treatment. These standards provide an initial framework for high-quality evidence-based management of general cancer pain and pain syndromes. C1 [Dy, Sydney M.] Johns Hopkins Univ, Baltimore, MD 21205 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RAND Hlth, Santa Monica, CA USA. Univ Calif Irvine, Irvine, CA USA. RP Dy, SM (reprint author), Johns Hopkins Univ, Room 609,624 N Broadway, Baltimore, MD 21205 USA. EM sdy@jhsph.edu NR 37 TC 62 Z9 66 U1 0 U2 5 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 AUG 10 PY 2008 VL 26 IS 23 BP 3879 EP 3885 DI 10.1200/JCO.2007.15.9517 PG 7 WC Oncology SC Oncology GA 335ND UT WOS:000258296400010 PM 18688056 ER PT J AU Dy, SM Lorenz, KA Naeim, A Sanati, H Walling, A Asch, SM AF Dy, Sydney M. Lorenz, Karl A. Naeim, Arash Sanati, Homayoon Walling, Anne Asch, Steven M. TI Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID TERMINALLY-ILL PATIENTS; QUALITY-OF-LIFE; CONTROLLED-TRIAL; PALLIATIVE CARE; CONSENSUS STATEMENT; SUPPORT GROUPS; METHYLPHENIDATE; PREVALENCE; MANAGEMENT; SYMPTOMS AB Purpose The experience of patients with cancer often involves symptoms of fatigue, anorexia, depression, and dyspnea. Methods We developed a set of standards through an iterative process of structured literature review and development and refinement of topic areas and standards and subjected recommendations to rating by a multidisciplinary expert panel. Results For fatigue, providers should screen patients at the initial visit, for newly identified advanced cancer, and at chemotherapy visits; assess for depression and insomnia in newly identified fatigue; and follow up after treatment for fatigue or a secondary cause. For anorexia, providers should screen at the initial visit for cancer affecting the oropharynx or gastrointestinal tract or advanced cancer, evaluate for associated symptoms, treat underlying causes, provide nutritional counseling for patients undergoing treatment that may affect nutritional intake, and follow up patients given appetite stimulants. For depression, providers should screen newly diagnosed patients, those started on chemotherapy or radiotherapy, those with newly identified advanced disease, and those expressing a desire for hastened death; document a treatment plan in diagnosed patients; and follow up response after treatment. For general dyspnea, providers should evaluate for causes of new or worsening dyspnea, treat or symptomatically manage underlying causes, follow up to evaluate treatment effectiveness, and offer opioids in advanced cancer when other treatments are unsuccessful. For dyspnea and malignant pleural effusions, providers should offer thoracentesis, follow up after thoracentesis, and offer pleurodesis or a drainage procedure for patients with reaccumulation and dyspnea. Conclusion These standards provide a framework for evidence-based screening, assessment, treatment, and follow-up for cancer-associated symptoms. C1 [Dy, Sydney M.] Johns Hopkins Univ, Baltimore, MD 21205 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RAND Hlth, Santa Monica, CA USA. Univ Calif Irvine, Irvine, CA USA. RP Dy, SM (reprint author), Johns Hopkins Univ, 624 N Broadway,Rm 609, Baltimore, MD 21205 USA. EM sdy@jhsph.edu NR 60 TC 58 Z9 59 U1 2 U2 11 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 AUG 10 PY 2008 VL 26 IS 23 BP 3886 EP 3895 DI 10.1200/JCO.2007.15.9525 PG 10 WC Oncology SC Oncology GA 335ND UT WOS:000258296400011 PM 18688057 ER PT J AU Walling, A Lorenz, KA Dy, SM Naeim, A Sanati, H Asch, SM Wenger, NS AF Walling, Anne Lorenz, Karl A. Dy, Sydney M. Naeim, Arash Sanati, Homayoon Asch, Steven M. Wenger, Neil S. TI Evidence-based recommendations for information and care planning in cancer care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID LIFE-SUSTAINING TREATMENT; BREAKING BAD-NEWS; TERMINALLY-ILL PATIENTS; PALLIATIVE-CARE; ADVANCE DIRECTIVES; PHYSICIAN ORDERS; DECISION-MAKING; TREATMENT PROGRAM; RANDOMIZED-TRIAL; END AB The practice of oncology is characterized by challenging communication tasks that make it difficult to ensure optimal physician-patient information sharing and care planning. Discussions of diagnosis, prognosis, and patient goals are essential processes that inform decisions. However, data suggest that there are deficiencies in this area. We conducted a systematic review to identify the evidence supporting high-quality clinical practices for information and care planning in the context of cancer care as part of the RAND Cancer Quality-Assessing Symptoms, Side Effects, and Indicators of Supportive Treatment Project. Domains of information and care planning that are important for high-quality cancer care include integration of palliation into cancer care, advance care planning, sentinel events as markers for the need to readdress a patient's goals of care, and continuity of care planning. The standards presented here for information and care planning in cancer care should be incorporated into care pathways and should become the expectation rather than the exception. C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RAND Hlth, Santa Monica, CA USA. Univ Calif Irvine, Irvine, CA USA. Johns Hopkins Univ, Baltimore, MD USA. RP Walling, A (reprint author), 911 Broxton Ave,3D, Los Angeles, CA 90024 USA. EM awalling@mednet.ucla.edu NR 81 TC 62 Z9 62 U1 5 U2 16 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 AUG 10 PY 2008 VL 26 IS 23 BP 3896 EP 3902 DI 10.1200/JCO.2007.15.9509 PG 7 WC Oncology SC Oncology GA 335ND UT WOS:000258296400012 PM 18688058 ER PT J AU Naeim, A Dy, SM Lorenz, KA Sanati, H Walling, A Asch, SM AF Naeim, Arash Dy, Sydney M. Lorenz, Karl A. Sanati, Homayoon Walling, Anne Asch, Steven M. TI Evidence-based recommendations for cancer nausea and vomiting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CHEMOTHERAPY-INDUCED NAUSEA; MODERATELY EMETOGENIC CHEMOTHERAPY; INOPERABLE BOWEL OBSTRUCTION; RANDOMIZED CONTROLLED-TRIAL; PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; ACUPUNCTURE-POINT STIMULATION; CISPLATIN-BASED CHEMOTHERAPY; RADIOTHERAPY-INDUCED EMESIS; NK1 ANTAGONIST APREPITANT; PLACEBO-CONTROLLED TRIALS AB The experience of patients living with cancer and being treated with chemotherapy often includes the symptoms of nausea and vomiting. To provide a framework for high-quality management of these symptoms, we developed a set of key targeted evidence-based standards through an iterative process of targeted systematic review, development, and refinement of topic areas and standards and consensus ratings by a multidisciplinary expert panel as part of the RAND Cancer Quality-Assessing Symptoms Side Effects and Indicators of Supportive Treatment Project. For nausea and vomiting, key clinical standards included screening at the initial outpatient and inpatient visit, prophylaxis for acute and delayed emesis in patients receiving moderate to highly emetic chemotherapy, and follow-up after treatment for nausea and vomiting symptoms. In addition, patients with cancer and small bowel obstruction were examined as a special subset of patients who present with nausea and vomiting. The standards presented here for preventing and managing nausea and vomiting in cancer care should be incorporated into care pathways and should become the expectation rather than the exception. C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RAND Hlth, Santa Monica, CA USA. Univ Calif Irvine, Irvine, CA USA. Johns Hopkins Univ, Baltimore, MD USA. RP Naeim, A (reprint author), 10945 LeConte Ave,Ste 2333, Los Angeles, CA 90095 USA. EM anaeim@mednet.ucla.edu NR 54 TC 51 Z9 54 U1 1 U2 7 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 AUG 10 PY 2008 VL 26 IS 23 BP 3903 EP 3910 DI 10.1200/JCO.2007.15.9533 PG 8 WC Oncology SC Oncology GA 335ND UT WOS:000258296400013 PM 18688059 ER PT J AU Martin, J Masri, J Bernath, A Nishimura, RN Gera, J AF Martin, Jheralyn Masri, Janine Bernath, Andrew Nishimura, Robert N. Gera, Joseph TI Hsp70 associates with Rictor and is required for mTORC2 formation and activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Hsp70; Rictor; mTORC2; kinase activity; heat shock ID HEAT-SHOCK-PROTEIN; PHOSPHATIDYLINOSITOL 3-KINASE; KINASE; PHOSPHORYLATION; BINDING; GROWTH; RECEPTOR; COMPLEX; STRESS; CANCER AB mTORC2 is a multiprotein kinase composed of mTOR, mLST8, PRR5, mSIN1 and Rictor. The complex is insensitive to rapamycin and has demonstrated functions controlling cell growth, motility, invasion and cytoskeletal assembly. mTORC2 is the major hydrophobic domain kinase which renders Akt fully active via phosphorylation on serine 473. We isolated Hsp70 as a putative Rictor interacting protein in a yeast two-hybrid assay and confirmed this interaction via co-immunoprecipitation and colocalization experiments. In cells expressing an antisense RNA targeting Hsp70, mTORC2 formation and activity were impaired. Moreover, in cells lacking Hsp70 expression, mTORC2 activity was inhibited following heat shock while controls demonstrated increased mTORC2 activity. These differential effects on mTORC2 activity were specific, in that mTORC1 did not demonstrate Hsp70-dependent alterations under these conditions. These data suggest that Hsp70 is a component of mTORC2 and is required for proper assembly and activity of the kinase both constitutively and following heat shock. Published by Elsevier Inc. C1 [Martin, Jheralyn; Masri, Janine; Bernath, Andrew; Nishimura, Robert N.; Gera, Joseph] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, Los Angeles, CA 91343 USA. [Nishimura, Robert N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90048 USA. [Gera, Joseph] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90048 USA. RP Gera, J (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, 16111 Plummer St 151,Bldg 1,Room C111A, Los Angeles, CA 91343 USA. EM gera@ucia.edu FU NCI NIH HHS [CA109312, R01 CA109312, R01 CA109312-04] NR 36 TC 37 Z9 39 U1 2 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 AUG 8 PY 2008 VL 372 IS 4 BP 578 EP 583 DI 10.1016/j.bbrc.2008.05.086 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 323BR UT WOS:000257419500013 PM 18505677 ER PT J AU Boxem, M Maliga, Z Klitgord, N Li, N Lemmens, I Mana, M de Lichtervelde, L Mul, JD van de Peut, D Devos, M Simonis, N Yildirim, MA Cokol, M Kao, HL de Smet, AS Wang, HD Schlaitz, AL Hao, T Milstein, S Fan, CY Tipsword, M Drew, K Galli, M Rhrissorrakrai, K Drechsel, D Koller, D Roth, FP Iakoucheva, LM Dunker, AK Bonneau, R Gunsalus, KC Hill, DE Piano, F Tavernier, J van den Heuvel, S Hyman, AA Vidal, M AF Boxem, Mike Maliga, Zoltan Klitgord, Niels Li, Na Lemmens, Irma Mana, Miyeko de Lichtervelde, Lorenzo Mul, Joram D. van de Peut, Diederik Devos, Maxime Simonis, Nicolas Yildirim, Muhammed A. Cokol, Murat Kao, Huey-Ling de Smet, Anne-Sophie Wang, Haidong Schlaitz, Anne-Lore Hao, Tong Milstein, Stuart Fan, Changyu Tipsword, Mike Drew, Kevin Galli, Matilde Rhrissorrakrai, Kahn Drechsel, David Koller, Daphne Roth, Frederick P. Iakoucheva, Lilia M. Dunker, A. Keith Bonneau, Richard Gunsalus, Kristin C. Hill, David E. Piano, Fabio Tavernier, Jan van den Heuvel, Sander Hyman, Anthony A. Vidal, Marc TI A protein domain-based interactome network for C-elegans early embryogenesis SO CELL LA English DT Article ID NUCLEAR-PORE COMPLEX; CAENORHABDITIS-ELEGANS; SACCHAROMYCES-CEREVISIAE; CENTROSOME MATURATION; 2-HYBRID SCREENS; INTERACTION MAP; GENOME; SCALE; RESOURCE; IDENTIFICATION AB Many protein-protein interactions are mediated through independently folding modular domains. Proteome-wide efforts to model protein-protein interaction or "interactome'' networks have largely ignored this modular organization of proteins. We developed an experimental strategy to efficiently identify interaction domains and generated a domain-based interactome network for proteins involved in C. elegans early-embryonic cell divisions. Minimal interacting regions were identified for over 200 proteins, providing important information on their domain organization. Furthermore, our approach increased the sensitivity of the two-hybrid system, resulting in amore complete interactome network. This interactome modeling strategy revealed insights into C. elegans centrosome function and is applicable to other biological processes in this and other organisms. C1 [Boxem, Mike; Klitgord, Niels; Li, Na; de Lichtervelde, Lorenzo; Mul, Joram D.; van de Peut, Diederik; Devos, Maxime; Simonis, Nicolas; Yildirim, Muhammed A.; Hao, Tong; Milstein, Stuart; Fan, Changyu; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. [Boxem, Mike; Klitgord, Niels; Li, Na; de Lichtervelde, Lorenzo; Mul, Joram D.; van de Peut, Diederik; Devos, Maxime; Simonis, Nicolas; Yildirim, Muhammed A.; Hao, Tong; Milstein, Stuart; Fan, Changyu; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Boxem, Mike; Klitgord, Niels; Li, Na; de Lichtervelde, Lorenzo; Mul, Joram D.; van de Peut, Diederik; Devos, Maxime; Simonis, Nicolas; Yildirim, Muhammed A.; Hao, Tong; Milstein, Stuart; Fan, Changyu; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Boxem, Mike] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Maliga, Zoltan; de Smet, Anne-Sophie; Tipsword, Mike; Drechsel, David; Hyman, Anthony A.] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany. [Lemmens, Irma; de Smet, Anne-Sophie; Tavernier, Jan] Univ Ghent VIB, Dept Med Prot Res, B-9000 Ghent, Belgium. [Lemmens, Irma; de Smet, Anne-Sophie; Tavernier, Jan] Univ Ghent, Fac Med & Hlth Sci, Dept Biochem, B-9000 Ghent, Belgium. [Cokol, Murat; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Mana, Miyeko; Kao, Huey-Ling; Drew, Kevin; Rhrissorrakrai, Kahn; Bonneau, Richard; Gunsalus, Kristin C.; Piano, Fabio] NYU, Ctr Genom & Syst Biol, Dept Biol, New York, NY 10003 USA. [Wang, Haidong; Koller, Daphne] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Galli, Matilde; van den Heuvel, Sander] Univ Utrecht, Fac Sci, Div Dev Biol, NL-3584 CH Utrecht, Netherlands. [Iakoucheva, Lilia M.] Rockefeller Univ, Lab Stat Genet, New York, NY 10065 USA. [Dunker, A. Keith] Indiana Univ, Sch Med & Informat, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. RP Boxem, M (reprint author), Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. EM mboxem@partners.org; hyman@mpi-cbg.de; marc_vidal@dfci.harvard.edu RI Klitgord, Niels/B-5121-2009; Boxem, Mike/B-8857-2011; van den Heuvel, Sander/B-8892-2011; Simonis, Nicolas/E-5124-2010; Hill, David/B-6617-2011; Roth, Frederick/H-6308-2011; Yildirim, Muhammed/J-3695-2014; Hyman, Anthony/B-3917-2017; OI Boxem, Mike/0000-0003-3966-4173; Yildirim, Muhammed/0000-0003-2826-1766; Hyman, Anthony/0000-0003-3664-154X; Iakoucheva, Lilia/0000-0002-4542-5219; Roth, Frederick/0000-0002-6628-649X FU Leukemia Research Foundation; W. M. Keck foundation; National Institutes of Health [R21RR023114, R01HG001715, R33CA105405, R33CA81658, R21CA113711, U54 CA011295, CA95281]; United States Army Medical Research Acquisition Activity [W23RYX-3275-N605]; New York State Foundation of Science, Technology; Academic Research [C040066]; National Science Foundation [MCB 0444818, BDI-0345474, IUAP-P6:28, UG-GOA12051401, FWO-G.0031.06] FX We are grateful to X. Xin and C. Boone for sharing of the cDNA library and yeast strains, to Joe Hargitai for unparalleled parallel computing support, to IBM's World Community Grid (http://www.wcgrid.org), and to M. Cusick for critical reading of the manuscript. Support was provided by the Leukemia Research Foundation to M. B., the W. M. Keck foundation to M. V., the FWO-V to I.L., National Institutes of Health grants R21RR023114 (M.B. P.I.), R01HG001715 ( M.V. P.I.), R33CA105405 (M.V. P.I.), R33CA81658 (M.V. P.I.), R21CA113711 (L.M.I. P.I.), U54 CA011295 (J. Nevins, PI; M.V. subcontract), and CA95281 (S.v.d.H.), United States Army Medical Research Acquisition Activity grant W23RYX-3275-N605 (K.C.G.), New York State Foundation of Science, Technology, and Academic Research grant C040066 (K.C.G.), National Science Foundation grants MCB 0444818 to L. M. I. and BDI-0345474 to D. K. and grants IUAP-P6:28, UG-GOA12051401, and FWO-G.0031.06 to J. T. M. V. is a "Chercheur Qualifie Honoraire'' from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium). NR 59 TC 116 Z9 119 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 8 PY 2008 VL 134 IS 3 BP 534 EP 545 DI 10.1016/j.cell.2008.07.009 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340SO UT WOS:000258665500025 PM 18692475 ER PT J AU Nirthanan, S Garcia, G Chiara, DC Husain, SS Cohen, JB AF Nirthanan, Selvanayagam Garcia, Galo, III Chiara, David C. Husain, S. Shaukat Cohen, Jonathan B. TI Identification of binding sites in the nicotinic acetylcholine receptor for TDBzl-etomidate, a photoreactive positive allosteric effector SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENERAL ANESTHETIC ETOMIDATE; LIPID-PROTEIN INTERFACE; GATED ION CHANNELS; NONCOMPETITIVE ANTAGONIST; MOLECULAR-MECHANISMS; SUBUNIT INTERFACES; AMINO-ACIDS; GABA(A); LIGAND; GALANTAMINE AB Etomidate, one of the most potent general anesthetics used clinically, acts at micromolar concentrations as an anesthetic and positive allosteric modulator of gamma-aminobutyric acid responses, whereas it inhibits muscle-type nicotinic acetylcholine receptors (nAChRs) at concentrations above 10 mu M. We report here that TDBzl-etomidate, a photoreactive etomidate analog, acts as a positive allosteric nAChR modulator rather than an inhibitor, and we identify its binding sites by photoaffinity labeling. TDBzl-etomidate (> 10 mu M) increased the submaximal response to acetylcholine (10 mu M) with a 2.5-fold increase at 60 mu M. At higher concentrations, it inhibited the binding of the noncompetitive antagonists [(3)H] tetracaine and [3H] phencyclidine to Torpedo nAChR-rich membranes (IC(50) values of 0.8 mM). nAChR-rich membranes were photolabeled with [3H] TDBzl-etomidate, and labeled amino acids were identified by Edman degradation. For nAChRs photolabeled in the absence of agonist (resting state), there was tetracaine-inhibitable photolabeling of amino acids in the ion channel at positions M2-9 (delta Leu-265) and M2-13 (alpha Val-255 and delta Val-269), whereas labeling of alpha M2-10 (alpha Ser-252) was not inhibited by tetracaine but was enhanced 10-fold by proadifen or phencyclidine. In addition, there was labeling in gamma M3 (gamma Met-299), a residue that contributes to the same pocket in the nAChR structure as alpha M2-10. The pharmacological specificity of labeling of residues, together with their locations in the nAChR structure, indicate that TDBzl-etomidate binds at two distinct sites: one within the lumen of the ion channel (labeling of M2-9 and -13), an inhibitory site, and another at the interface between the alpha and gamma subunits (labeling of alpha M2-10 and gamma Met-299) likely to be a site for positive allosteric modulation. C1 [Nirthanan, Selvanayagam; Garcia, Galo, III; Chiara, David C.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Husain, S. Shaukat] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 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 Howard Hughes Medical Institute; NIGMS NIH HHS [GM-58448, P01 GM058448] NR 48 TC 43 Z9 43 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 AUG 8 PY 2008 VL 283 IS 32 BP 22051 EP 22062 DI 10.1074/jbc.M801332200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 332WV UT WOS:000258114700024 PM 18524766 ER PT J AU Desai, R Kronengold, J Mei, J Forman, SA Kaczmarek, LK AF Desai, Rooma Kronengold, Jack Mei, Jianfeng Forman, Stuart A. Kaczmarek, Leonard K. TI Protein kinase C modulates inactivation of Kv3.3 channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THRESHOLD POTASSIUM CHANNEL; AUDITORY NEURONS; TRAPEZOID BODY; MEDIAL NUCLEUS; MOUSE-BRAIN; PHOSPHORYLATION; LOCALIZATION; SUBUNITS; CELLS; ORGANIZATION AB Modulation of some Kv3 family potassium channels by protein kinase C (PKC) regulates their amplitude and kinetics and adjusts firing patterns of auditory neurons in response to stimulation. Nevertheless, little is known about the modulation of Kv3.3, a channel that is widely expressed throughout the nervous system and is the dominant Kv3 family member in auditory brainstem. We have cloned the cDNA for the Kv3.3 channel from mouse brain and have expressed it in a mammalian cell line and in Xenopus oocytes to characterize its biophysical properties and modulation by PKC. Kv3.3 currents activate at positive voltages and undergo inactivation with time constants of 150-250 ms. Activators of PKC increased current amplitude and removed inactivation of Kv3.3 currents, and a specific PKC pseudosubstrate inhibitor peptide prevented the effects of the activators. Elimination of the first 78 amino acids of the N terminus of Kv3.3 produced noninactivating currents suggesting that PKC modulates N-type inactivation, potentially by phosphorylation of sites in this region. To identify potential phosphorylation sites, we investigated the response of channels in which serines in this N-terminal domain were subjected to mutagenesis. Our results suggest that serines at positions 3 and 9 are potential PKC phosphorylation sites. Computer simulations of model neurons suggest that phosphorylation of Kv3.3 by PKC may allow neurons to maintain action potential height during stimulation at high frequencies, and may therefore contribute to stimulus-induced changes in the intrinsic excitability of neurons such as those of the auditory brainstem. C1 [Desai, Rooma; Kronengold, Jack; Mei, Jianfeng; Kaczmarek, Leonard K.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Kaczmarek, Leonard K.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Desai, Rooma; Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Kaczmarek, LK (reprint author), Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA. EM leonard.kaczmarek@yale.edu FU NIDCD NIH HHS [DC-01919] NR 39 TC 17 Z9 17 U1 0 U2 0 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 AUG 8 PY 2008 VL 283 IS 32 BP 22283 EP 22294 DI 10.1074/jbc.M801663200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 332WV UT WOS:000258114700047 PM 18539595 ER PT J AU Prasad, R Giri, S Singh, AK Singh, I AF Prasad, Ratna Giri, Shailendra Singh, Avtar K. Singh, Inderjit TI 15-deoxy-delta12,14-prostaglandin J2 attenuates endothelial-monocyte interaction: implication for inflammatory diseases SO JOURNAL OF INFLAMMATION-LONDON LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; NF-KAPPA-B; CELL ADHESION MOLECULES; NITRIC-OXIDE SYNTHASE; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); PPAR-GAMMA; CYCLOPENTENONE PROSTAGLANDINS; TRANSCRIPTIONAL REGULATION; MULTIPLE-SCLEROSIS AB Background: The Infiltration of leukocytes across the brain endothelium is a hallmark of various neuroinflammatory disorders. Under inflammatory conditions, there is increased expression of specific cell adhesion molecules (CAMs) on activated vascular endothelial cells which increases the adhesion and infiltration of leukocytes. TNF alpha is one of the major proinflammatory cytokines that causes endothelial dysfunction by various mechanisms including activation of transcription factor NF-kappa B, a key transcription factor that regulates expression of CAMs. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear hormone superfamily of ligand-activated transcriptional factors. 15-deoxy-delta 12, 14-prostaglandin J2 (15d-PGJ2) is a well recognized natural ligand of PPAR gamma and possesses anti-inflammatory properties both in vitro and in vivo. This study aims to elucidate the mechanism of 15-PGJ2 on the adhesion of mononuclear cells to activated endothelial cells. Methods: To delineate the signaling pathway of 15d-PGJ2 mediated effects, we employed an in vitro adhesion assay model of endothelial-monocyte interaction. Expression of CAMs was examined using flow cytometry and real time PCR techniques. To define the mechanism of 15d-PGJ2, we explored the role of NF-kappa B by EMSA (Electrophoretic Mobility Shift Assay) gels, NF-kappa B reporter and p65-transcriptional activities by transient transfection in the brain-derived endothelial cell line (bEND.3). Results: Using an in vitro adhesion assay model, we demonstrate that 15d-PGJ2 inhibits TNF alpha induced monocyte adhesion to endothelial cells, which is mediated by downregulation of endothelial cell adhesion molecules in a PPAR gamma independent manner. 15d-PGJ2 modulated the adhesion process by inhibiting the TNF alpha induced IKK-NF-kappa B pathway as evident from EMSA, NF-kappa B reporter and p65 mediated transcriptional activity results in bEND.3 cells. Conclusion: These findings suggest that 15d-PGJ2 inhibits inflammation at multiple steps and thus is a potential therapeutic target for various inflammatory diseases. C1 [Prasad, Ratna; Giri, Shailendra; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph Johnson Vet Affairs Med Ctr, Dept Pathol & Lab Med, Charleston, SC 29425 USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. EM prasadr@musc.edu; giris@musc.edu; avtar.singh@va.gov; singhi@musc.edu FU NIH [NS-40144, NS-22576, NS-34741, NS-37766, NS-40810]; State of South Carolina Spinal Cord Injury Research Fund Board [SCIRF 0406, SCIRF 0506]; National Center for Research Resources [C06 RR018823, C06 RR015455] FX RP and SG are equal contributors for this work. We would like to thank Drs. Anne G. Gilg and Ramandeep Rattan for editing manuscript and Ms Joyce Bryan for procurement of chemicals used in this study. These studies were supported by grants (NS-40144, NS-22576, NS-34741, NS-37766, and NS-40810) from the NIH and (SCIRF 0406 and SCIRF 0506) from State of South Carolina Spinal Cord Injury Research Fund Board. This work was supported by the NIH (NS-22576, NS-34741, NS-37766 and NS-40810) and from the Extramural Research Facilities Program of the National Center for Research Resources (Grants C06 RR018823 and No C06 RR015455). NR 57 TC 11 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-9255 J9 J INFLAMM-LOND JI J. Inflamm.-Lond. PD AUG 8 PY 2008 VL 5 AR 14 DI 10.1186/1476-9255-5-14 PG 10 WC Immunology SC Immunology GA 507FC UT WOS:000270836200001 PM 18691416 ER PT J AU Zhang, HM Casasnovas, JM Jin, M Liu, JH Gahmberg, CG Springer, TA Wang, JH AF Zhang, Hongmin Casasnovas, Jose M. Jin, Moonsoo Liu, Jin-huan Gahmberg, Carl G. Springer, Timothy A. Wang, Jia-huai TI An unusual allosteric mobility of the C-terminal helix of a high-affinity alpha(L) integrin I domain variant bound to ICAM-5 SO MOLECULAR CELL LA English DT Article ID NEURONAL ADHESION MOLECULE; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; CONFORMATIONAL REGULATION; CELL-SURFACE; TELENCEPHALIN; RECOGNITION; GLYCOPROTEIN; COMPLEX AB Integrins are cell surface receptors that transduce signals bidirectionally across the plasma membrane. The key event of integrin signaling is the allosteric regulation between its ligand-binding site and the C-terminal helix (alpha 7) of integrin's inserted (1) domain. A significant axial movement of the alpha 7 helix is associated with the open, active conformation of integrins. We describe the crystal structure of an engineered high-affinity I domain from the integrin alpha(L)beta(2) (LFA-1) alpha subunit in complex with the N-terminal two domains of ICAM-5, an adhesion molecule expressed in telencephalic neurons. The finding that the a7 helix swings out and inserts into a neighboring I domain in an upside-down orientation in the crystals implies an intrinsically unusual mobility of this helix. This remarkable feature allows the alpha 7 helix to trigger integrin's large-scale conformational changes with little energy penalty. It serves as a mechanistic example of how a weakly bound adhesion molecule works in signaling. C1 [Zhang, Hongmin; Liu, Jin-huan; Wang, Jia-huai] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhang, Hongmin; Liu, Jin-huan; Wang, Jia-huai] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Hongmin; Liu, Jin-huan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wang, Jia-huai] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Wang, Jia-huai] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Casasnovas, Jose M.] CSIC, Ctr Nacl Biotecnol, E-28049 Madrid, Spain. [Jin, Moonsoo; Springer, Timothy A.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Jin, Moonsoo; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Gahmberg, Carl G.] Univ Helsinki, Div Biochem, FIN-00014 Helsinki, Finland. RP Wang, JH (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM jwang@red.dfci.harvard.edu RI Zhang, Hongmin/C-4503-2009; Jin, Moonsoo/D-6128-2011; Casasnovas, Jose/L-6299-2014 OI Zhang, Hongmin/0000-0001-6357-4106; Casasnovas, Jose/0000-0002-2873-6410 FU NIH; Academy of Finland; Sigrid Juselius Foundation; MEC of Spain [BFU2005-05972] FX We thank staff members at Advanced Photon Source for beam time help. This work was supported by grants from the NIH to J.-h.W. and T.A.S., the Academy of Finland and the Sigrid Juselius Foundation to C.G.G., and the MEC of Spain (BFU2005-05972) to J.M.C. NR 26 TC 24 Z9 26 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 8 PY 2008 VL 31 IS 3 BP 432 EP 437 DI 10.1016/j.molcel.2008.06.022 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 339CU UT WOS:000258556500016 PM 18691975 ER PT J AU Lee, JK Won, JS Singh, AK Singh, I AF Lee, Jin-Koo Won, Je-Seong Singh, Avtar K. Singh, Inderjit TI Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death SO NEUROSCIENCE LETTERS LA English DT Article DE atorvastatin; excitotoxicity; inflammation; hippocampus; kainic acid; lovastatin and seizure ID NITRIC-OXIDE SYNTHASE; TRAUMATIC BRAIN-INJURY; INDUCED STATUS-EPILEPTICUS; COA REDUCTASE INHIBITOR; TEMPORAL-LOBE EPILEPSY; SPINAL-CORD-INJURY; MULTIPLE-SCLEROSIS; LEWIS RATS; NEUROLOGIC DISEASES; ALZHEIMERS-DISEASE AB Statins are inhibitors of HMG-CoA reductase that have been recently recognized as anti-inflammatory and neuroprotective drugs. Herein, we investigated anti-excitotoxic and anti-seizure effects of statins by using kainic acid (KA)-rat seizure model, an animal model for temporal lobe epilepsy and excitotoxic neurodegeneration. We observed that pre-treatment with Lipitor (atorvastatin) efficiently reduced KA-induced seizure activities, hippocampal neuron death, monocyte infiltration and proinflammatory gene expression. In addition, we also observed that lovastatin treatment attenuated KA- or glutamate-induced excitotoxicity of cultured hippocampal neurons. These observations suggest a potential for use of statin treatment in modulation of seizures and other neurological diseases associated with excitotoxicity. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Lee, Jin-Koo; Won, Je-Seong; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Won, Je-Seong; Singh, Avtar K.] Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Lee, Jin-Koo] Hallym Univ, Inst Nat Med, Chunchon, South Korea. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave,505 Childrens Res Bldg, Charleston, SC 29425 USA. EM singhi@musc.edu FU NINDS NIH HHS [NS-22576, NS-34741, NS-37766, NS-40144, R01 NS022576, R01 NS022576-17, R01 NS034741, R01 NS034741-12, R01 NS037766, R01 NS037766-10, R01 NS040144, R37 NS022576] NR 44 TC 55 Z9 58 U1 0 U2 3 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 AUG 8 PY 2008 VL 440 IS 3 BP 260 EP 264 DI 10.1016/j.neulet.2008.05.112 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 331MP UT WOS:000258016600014 PM 18583044 ER PT J AU Larsson, J Ohishi, M Garrison, B Aspling, M Janzen, V Adams, GB Curto, M McClatchey, AI Schipani, E Scadden, DT AF Larsson, Jonas Ohishi, Masanobu Garrison, Brian Aspling, Marie Janzen, Viktor Adams, Gregor B. Curto, Marcello McClatchey, Andrea I. Schipani, Ernestina Scadden, David T. TI Nf2/merlin regulates hematopoietic stem cell behavior by altering microenvironmental architecture SO CELL STEM CELL LA English DT Article ID NF2 TUMOR-SUPPRESSOR; VASCULAR-PERMEABILITY FACTOR; PROGENITOR CELLS; MICE; ANGIOPOIETIN-1; ANGIOGENESIS; NICHE; TUMORIGENESIS; DEFICIENCY; MUTATION AB Stem cell population size is highly regulated across species and tissue types, and alterations are associated with premature tissue failure or cancer. We assessed whether the tumor suppressor and mediator of cell contact inhibition Nf2/merlin plays a role in governing the hematopoietic stem cell pool by stem cell-autonomous or niche-determined processes. Hematopoietic stem cells in Nf2-deficient mice were increased in number and demonstrated a marked shift in location to the circulation. These changes were entirely dependent on changes in the microenvironment, with a marked increase in trabecular bone and marrow vascularity associated with increased VEGF, but without cell-autonomous alterations in stem cell characteristics. Nf2/merlin is critical for maintaining normal structure and function of the hematopoietic stem cell niche. It limits both bone and vascular components, and our model suggests that it thereby constrains stem cell number and position. C1 [Larsson, Jonas; Garrison, Brian; Aspling, Marie; Janzen, Viktor; Adams, Gregor B.; Scadden, David T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Larsson, Jonas; Garrison, Brian; Janzen, Viktor; Adams, Gregor B.; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Ohishi, Masanobu; Schipani, Ernestina] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 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, Boston, MA 02114 USA. EM scadden.david@mgh.harvard.edu FU National Institutes of Health [HL44851, HL081030, CA113733]; Department of Defense [W81XWH-05-1-0189]; EMBO FX The authors would like to thank Marco Giovannini for providing the Nf2 floxed mice. This work was supported by National Institutes of Health Grants (HL44851, HL081030) to D.T.S. and (CA113733) to A.I.M., a Department of Defense Grant (W81XWH-05-1-0189) to A.I.M., and an EMBO postdoctoral grant to J.L. NR 23 TC 26 Z9 27 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD AUG 7 PY 2008 VL 3 IS 2 BP 221 EP 227 DI 10.1016/j.stem.2008.06.005 PG 7 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 338QT UT WOS:000258523300016 PM 18682243 ER PT J AU Roizen, M Rodriguez, S Bauer, G Medin, G Bevilacqua, S Varni, JW Dussel, V AF Roizen, Mariana Rodriguez, Susana Bauer, Gabriela Medin, Gabriela Bevilacqua, Silvina Varni, James W. Dussel, Veronica TI Initial validation of the Argentinean Spanish version of the PedsQL (TM) 4.0 Generic Core Scales in children and adolescents with chronic diseases: acceptability and comprehensibility in low-income settings SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article ID QUALITY-OF-LIFE; ASSESSMENT QUESTIONNAIRE CHAQ; CROSS-CULTURAL ADAPTATION; POPULATION HEALTH MEASURE; SCHOOL-CHILDREN; INVENTORY(TM) PEDSQL(TM); PSYCHOMETRIC EVALUATION; SELF-REPORT; RELIABILITY; VALIDITY AB Background: To validate the Argentinean Spanish version of the PedsQL (TM) 4.0 Generic Core Scales in Argentinean children and adolescents with chronic conditions and to assess the impact of socio-demographic characteristics on the instrument's comprehensibility and acceptability. Reliability, and known-groups, and convergent validity were tested. Methods: Consecutive sample of 287 children with chronic conditions and 105 healthy children, ages 2-18, and their parents. Chronically ill children were: (1) attending outpatient clinics and (2) had one of the following diagnoses: stem cell transplant, chronic obstructive pulmonary disease, HIV/AIDS, cancer, end stage renal disease, complex congenital cardiopathy. Patients and adult proxies completed the PedsQL (TM) 4.0 and an overall health status assessment. Physicians were asked to rate degree of health status impairment. Results: The PedsQL (TM) 4.0 was feasible (only 9 children, all 5 to 7 year-olds, could not complete the instrument), easy to administer, completed without, or with minimal, help by most children and parents, and required a brief administration time (average 5-6 minutes). People living below the poverty line and/or low literacy needed more help to complete the instrument. Cronbach Alpha's internal consistency values for the total and subscale scores exceeded 0.70 for self-reports of children over 8 years-old and parent-reports of children over 5 years of age. Reliability of proxy-reports of 2-4 year-olds was low but improved when school items were excluded. Internal consistency for 5-7 year-olds was low (alpha range = 0.28-0.76). Construct validity was good. Child self-report and parent proxy-report PedsQL (TM) 4.0 scores were moderately but significantly correlated (rho = 0.39, p < 0.0001) and both significantly correlated with physician's assessment of health impairment and with child self-reported overall health status. The PedsQL (TM) 4.0 discriminated between healthy and chronically ill children (72.72 and 66.87, for healthy and ill children, respectively, p = 0.01), between different chronic health conditions, and children from lower socioeconomic status. Conclusion: Results suggest that the Argentinean Spanish PedsQL (TM) 4.0 is suitable for research purposes in the public health setting for children over 8 years old and parents of children over 5 years old. People with low income and low literacy need help to complete the instrument. Steps to expand the use of the Argentinean Spanish PedsQL T 4.0 include an alternative approach to scoring for the 2-4 year-olds, further understanding of how to increase reliability for the 5-7 yearolds self-report, and confirmation of other aspects of validity. C1 [Dussel, Veronica] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Dussel, Veronica] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Roizen, Mariana; Rodriguez, Susana; Bauer, Gabriela; Bevilacqua, Silvina] Hosp Pediat Prof Dr Juan P Garrahan, Comm Qual Life, RA-1414 Buenos Aires, DF, Argentina. [Rodriguez, Susana] Hosp Pediat Prof Dr Juan P Garrahan, Dept Res, RA-1414 Buenos Aires, DF, Argentina. [Rodriguez, Susana; Bauer, Gabriela] Hosp Pediat Prof Dr Juan P Garrahan, Dept Neonatol, RA-1414 Buenos Aires, DF, Argentina. [Bauer, Gabriela] Hosp Pediat Prof Dr Juan P Garrahan, Dept Pulmonol, RA-1414 Buenos Aires, DF, Argentina. [Bevilacqua, Silvina] Hosp Pediat Prof Dr Juan P Garrahan, Palliat Care Team, RA-1414 Buenos Aires, DF, Argentina. [Medin, Gabriela] Hosp Gen Gregorio Maranon, Madrid, Spain. [Varni, James W.] Texas A&M Univ, Dept Pediat, Coll Med, College Stn, TX USA. [Varni, James W.] Texas A&M Univ, Dept Landscape Architecture & Urban Planni, Coll Architecture, College Stn, TX USA. [Dussel, Veronica] Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. RP Dussel, V (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 44 Binney St SM-215, Boston, MA 02115 USA. EM mroizen@gmail.com; susiro@ciudad.com.ar; gababauer@gmail.com; Gabriela.medin@gmail.com; silbevi@netverk.com.ar; jvarni@archmail.tamu.edu; veronica_dussel@dfci.harvard.edu FU Buenos Aires Secretary of Heath (Decreto Ndegrees 2.244); Agency for Health Research and Quality [T32HP10018] FX We express our appreciation to the children, parents, and physicians that participated in this study, to Dr. Sonia Iorcansky for her mentoring (MR), and to the members of the Committee on Quality of Life at Hospital de Pediatria Garrahan Drs. Julia Redondo, Carlos Figueroa, Alejandra Bordato, Mar a Magdalena Contreras, Virginia Fano, Lidia Fraquelli, Graciela Massanti, Isabel Maza, Luis Novali, Marcela Palladino, Mercedes Pico, Luc a Salvia, Griselda Splivalo, and Rodolfo Verna for their input during the study design and help with its implementation.; MR is the recipient of a fellowship from the Buenos Aires Secretary of Heath (Decreto N degrees 2.244). VD is the recipient of a fellowship from the Agency for Health Research and Quality (T32HP10018). NR 48 TC 19 Z9 22 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD AUG 7 PY 2008 VL 6 AR 59 DI 10.1186/1477-7525-6-59 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 351DP UT WOS:000259405000001 PM 18687134 ER PT J AU Tanzi, RE Bertram, L AF Tanzi, Rudolph E. Bertram, Lars TI Alzheimer's disease - The latest suspect SO NATURE LA English DT Editorial Material ID PRESENILIN; ASSOCIATION; RISK; GENE C1 [Tanzi, Rudolph E.; Bertram, Lars] Massachusetts Gen Hosp, Genet & Aging Res Unit, MIND, Dept Neurol, Charlestown, MA 02129 USA. RP Tanzi, RE (reprint author), Massachusetts Gen Hosp, Genet & Aging Res Unit, MIND, Dept Neurol, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X NR 11 TC 23 Z9 24 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 7 PY 2008 VL 454 IS 7205 BP 706 EP 708 DI 10.1038/454706a PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334NH UT WOS:000258228000030 PM 18685694 ER PT J AU Jones, PA Archer, TK Baylin, SB Beck, S Berger, S Bernstein, BE Carpten, JD Clark, SJ Costello, JF Doerge, RW Esteller, M Feinberg, AP Gingeras, TR Greally, JM Henikoff, S Herman, JG Jackson-Grusby, L Jenuwein, T Jirtle, RL Kim, YJ Laird, PW Lim, B Martienssen, R Polyak, K Stunnenberg, H Tlsty, TD Tycko, B Ushijima, T Zhu, JD Pirrotta, V Allis, CD Elgin, SC Rine, J Wu, C AF Jones, Peter A. Archer, Trevor K. Baylin, Stephen B. Beck, Stephan Berger, Shelley Bernstein, Bradley E. Carpten, John D. Clark, Susan J. Costello, Joseph F. Doerge, Rebecca W. Esteller, Manel Feinberg, Andrew P. Gingeras, Thomas R. Greally, John M. Henikoff, Steven Herman, James G. Jackson-Grusby, Laurie Jenuwein, Thomas Jirtle, Randy L. Kim, Young-Joon Laird, Peter W. Lim, Bing Martienssen, Robert Polyak, Kornelia Stunnenberg, Henk Tlsty, Thea Dorothy Tycko, Benjamin Ushijima, Toshikazu Zhu, Jingde Pirrotta, Vincenzo Allis, C. David Elgin, Sarah C. Rine, Jasper Wu, Carl CA Amer Assoc Canc Res Human Epigenom European Union Network Excellence TI Moving AHEAD with an international human epigenome project SO NATURE LA English DT Editorial Material ID DNA METHYLATION; HUMAN GENOME; ARABIDOPSIS-THALIANA; CELLS; TRANSCRIPTION; PLURIPOTENT C1 [Jones, Peter A.; Laird, Peter W.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Archer, Trevor K.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Baylin, Stephen B.; Herman, James G.] Johns Hopkins Univ, Baltimore, MD 21231 USA. [Beck, Stephan] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Berger, Shelley] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Carpten, John D.] TGen, Phoenix, AZ 85004 USA. [Clark, Susan J.] Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Costello, Joseph F.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Doerge, Rebecca W.] Purdue Univ, W Lafayette, IN 47907 USA. [Esteller, Manel] Spanish Natl Canc Ctr, Madrid, Spain. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Oncol & Mol Biol, Baltimore, MD 21205 USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Genet, Baltimore, MD 21205 USA. [Gingeras, Thomas R.] Affymetrix, Santa Clara, CA 95051 USA. [Greally, John M.] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Henikoff, Steven] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Jackson-Grusby, Laurie] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Jenuwein, Thomas] Res Inst Mol Pathol, A-1030 Vienna, Austria. [Jirtle, Randy L.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Kim, Young-Joon] Yonsei Univ, Seoul 120719, South Korea. [Lim, Bing] Genome Inst Singapore, Singapore 138672, Singapore. [Martienssen, Robert] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Polyak, Kornelia] Dana Farber Canc Inst, Boston, MA 02115 USA. [Stunnenberg, Henk] Radboud Univ Nijmegen, NL-6525 ED Nijmegen, Netherlands. [Tlsty, Thea Dorothy] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Tycko, Benjamin] Columbia Univ, New York, NY 10032 USA. [Ushijima, Toshikazu] Natl Canc Ctr, Tokyo 1040045, Japan. [Zhu, Jingde] Shanghai Canc Inst, Shanghai 200032, Peoples R China. [Pirrotta, Vincenzo] Rutgers State Univ, Piscataway, NJ 08854 USA. [Allis, C. David] Rockefeller Univ, New York, NY 10021 USA. [Elgin, Sarah C.] Washington Univ, St Louis, MO 63130 USA. [Rine, Jasper] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Wu, Carl] NCI, Bethesda, MD 20892 USA. RP Jones, PA (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. EM jones_p@ccnt.hsc.usc.edu RI Clark, Susan/B-2272-2008; Clark, Stewart/A-3462-2012; Stunnenberg, Hendrik/D-6875-2012; Laird, Peter/G-8683-2012; Esteller, Manel/L-5956-2014; OI Greally, John/0000-0001-6069-7960; Clark, Susan/0000-0001-5925-5030; Esteller, Manel/0000-0003-4490-6093; Gingeras, Thomas/0000-0001-9106-3573 NR 16 TC 104 Z9 111 U1 2 U2 27 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 AUG 7 PY 2008 VL 454 IS 7205 BP 711 EP 715 DI 10.1038/454711a PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334NH UT WOS:000258228000034 ER PT J AU Meissner, A Mikkelsen, TS Gu, HC Wernig, M Hanna, J Sivachenko, A Zhang, XL Bernstein, BE Nusbaum, C Jaffe, DB Gnirke, A Jaenisch, R Lander, ES AF Meissner, Alexander Mikkelsen, Tarjei S. Gu, Hongcang Wernig, Marius Hanna, Jacob Sivachenko, Andrey Zhang, Xiaolan Bernstein, Bradley E. Nusbaum, Chad Jaffe, David B. Gnirke, Andreas Jaenisch, Rudolf Lander, Eric S. TI Genome-scale DNA methylation maps of pluripotent and differentiated cells SO NATURE LA English DT Article ID EMBRYONIC STEM-CELLS; DISTINCT; CANCER; GENES; HYPERMETHYLATION; SIGNATURES; PROMOTERS; PATTERNS; DISPLAY AB DNA methylation is essential for normal development(1-3) and has been implicated in many pathologies including cancer(4,5). Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing(6) and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine. C1 [Meissner, Alexander; Wernig, Marius; Hanna, Jacob; Jaenisch, Rudolf; Lander, Eric S.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Meissner, Alexander; Mikkelsen, Tarjei S.; Gu, Hongcang; Sivachenko, Andrey; Zhang, Xiaolan; Bernstein, Bradley E.; Nusbaum, Chad; Jaffe, David B.; Gnirke, Andreas; Lander, Eric S.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Mikkelsen, Tarjei S.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Canc Res Ctr, Charlestown, MA 02129 USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Jaenisch, Rudolf; Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. RP Jaenisch, R (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM jaenisch@wi.mit.edu; lander@broad.mit.edu RI Mikkelsen, Tarjei/A-1306-2007; HANNA, JACOB/K-1339-2012 OI Mikkelsen, Tarjei/0000-0002-8133-3135; HANNA, JACOB/0000-0003-2042-9974 FU NHGRI NIH HHS [U54 HG003067, R01 HG004401, R01 HG004401-02, U54 HG003067-04, U54 HG003067-06] NR 30 TC 1317 Z9 1345 U1 28 U2 207 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 7 PY 2008 VL 454 IS 7205 BP 766 EP U91 DI 10.1038/nature07107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334NH UT WOS:000258228000045 PM 18600261 ER PT J AU Jia, SD Liu, ZN Zhang, S Liu, PX Zhang, L Lee, SH Zhang, J Signoretti, S Loda, M Roberts, TM Zhao, JJ AF Jia, Shidong Liu, Zhenning Zhang, Sen Liu, Pixu Zhang, Lei Lee, Sang Hyun Zhang, Jing Signoretti, Sabina Loda, Massimo Roberts, Thomas M. Zhao, Jean J. TI Essential roles of PI(3)K-p110 beta in cell growth, metabolism and tumorigenesis SO NATURE LA English DT Article ID TUMOR-SUPPRESSOR GENE; PHOSPHOINOSITIDE 3-KINASE; PHOSPHATIDYLINOSITOL 3-KINASES; LYSOPHOSPHATIDIC ACID; EMBRYONIC LETHALITY; P110-ALPHA SUBUNIT; CATALYTIC SUBUNIT; PROSTATE-CANCER; PI 3-KINASE; BETA-GAMMA AB On activation by receptors, the ubiquitously expressed class IA isoforms (p110 alpha and p110 beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades(1-5). Recent studies have demonstrated specific functions for p110 alpha in growth factor and insulin signalling(6-8). To probe for distinct functions of p110 beta, we constructed conditional knockout mice. Here we show that ablation of p110 beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110 beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110 beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110 beta-null cells with a wild-type or kinase-dead allele of p110 beta demonstrated that p110 beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110 beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110 beta (also known as Pik3cb), but not that of p110 alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110 beta, and strongly indicate the kinase-dependent functions of p110 beta as a promising target in cancer therapy. C1 [Jia, Shidong; Liu, Zhenning; Zhang, Sen; Liu, Pixu; Zhang, Lei; Lee, Sang Hyun; Zhang, Jing; Roberts, Thomas M.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Signoretti, Sabina; Loda, Massimo] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jia, Shidong; Liu, Zhenning; Zhang, Sen; Liu, Pixu; Zhang, Lei; Lee, Sang Hyun; Zhang, Jing; Signoretti, Sabina; Loda, Massimo; Roberts, Thomas M.; Zhao, Jean J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM thomas_roberts@dfci.harvard.edu; jean_zhao@dfci.harvard.edu FU NCI NIH HHS [R01 CA030002-27, P01 CA050661, P01 CA050661-200001, P01 CA089021, P01 CA089021-06A1, P50 CA089393, P50 CA089393-08S1, P50 CA090381, P50 CA090381-05, R01 CA030002, R01 CA134502, R01 CA134502-01] NR 34 TC 372 Z9 393 U1 3 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 7 PY 2008 VL 454 IS 7205 BP 776 EP U102 DI 10.1038/nature07091 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334NH UT WOS:000258228000047 PM 18594509 ER PT J AU Gutierrez, OM Mannstadt, M Isakova, T Rauh-Hain, JA Tamez, H Shah, A Smith, K Lee, H Thadhani, R Juppner, H Wolf, M AF Gutierrez, Orlando M. Mannstadt, Michael Isakova, Tamara Rauh-Hain, Jose Alejandro Tamez, Hector Shah, Anand Smith, Kelsey Lee, Hang Thadhani, Ravi Juppner, Harald Wolf, Myles TI Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHRONIC KIDNEY-DISEASE; FIBROBLAST GROWTH FACTOR-23; DOMINANT HYPOPHOSPHATEMIC RICKETS; STAGE RENAL-DISEASE; VITAMIN-D; MAINTENANCE HEMODIALYSIS; MINERAL METABOLISM; VASCULAR CALCIFICATION; ONCOGENIC OSTEOMALACIA; DIALYSIS PATIENTS AB Background: Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown. Methods: We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality. Results: Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]). Conclusions: Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease. C1 [Gutierrez, Orlando M.; Isakova, Tamara; Rauh-Hain, Jose Alejandro; Tamez, Hector; Shah, Anand; Smith, Kelsey; Thadhani, Ravi; Wolf, Myles] Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. [Mannstadt, Michael; Juppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wolf, M (reprint author), Univ Miami, Div Nephrol & Hypertens, Miller Sch Med, 1120 NW 14th St, Miami, FL 33136 USA. EM mwolf2@med.miami.edu FU NCRR NIH HHS [K23RR017376, K23 RR017376, K30RR02229207]; NIDDK NIH HHS [K08 DK081669, R01 DK076116, R01DK076116, R21 DK071674, R21DK071674, R37 DK046718, R37 DK046718-17] NR 39 TC 799 Z9 845 U1 2 U2 23 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 AUG 7 PY 2008 VL 359 IS 6 BP 584 EP 592 DI 10.1056/NEJMoa0706130 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 334IY UT WOS:000258216700006 PM 18687639 ER PT J AU Li, S Liu, C Li, N Hao, T Han, T Hill, DE Vidal, M Lin, JD AF Li, Sinning Liu, Chang Li, Na Hao, Tong Han, Ting Hill, David E. Vidal, Marc Lin, Jiandie D. TI Genome-wide coactivation analysis of PGC-1 alpha identifies BAF60a as a regulator of hepatic lipid metabolism SO CELL METABOLISM LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; CHROMATIN-REMODELING COMPLEX; OPEN READING FRAMES; MITOCHONDRIAL BIOGENESIS; ENERGY-METABOLISM; NUCLEAR RECEPTORS; TRANSCRIPTIONAL COACTIVATORS; GAMMA COACTIVATOR-1; SWI/SNF COMPLEXES; RESPONSE ELEMENT AB Impaired mitochondrial function has been implicated in the pathogenesis of type 2 diabetes, heart failure, and neurodegeneration as well as during aging. Studies with the PGC-1 transcriptional coactivators have demonstrated that these factors are central components of the regulatory network that controls mitochondrial function in mammalian cells. Here we describe a genome-wide coactivation assay to globally identify transcription factors and cofactors; in this pathway. These analyses revealed a molecular signature of the PGC-1 alpha transcriptional network and identified BAF60a (SMARCD1) as a molecular link between the SWI/SNF chromatin-remodeling complexes and hepatic lipid metabolism. Adenoviral-mediated expression of BAF60a stimulates fatty acid beta-oxidation in cultured hepatocytes and ameliorates hepatic steatosis in vivo. PGC-1 alpha mediates the recruitment of BAF60a to PPAR alpha-bincling sites, leading to transcriptional activation of peroxisomal and mitochondrial fat-oxidation genes. These results define a role for the SWI/SNF complexes in the regulation of lipid homeostasis. C1 [Li, Sinning; Liu, Chang; Han, Ting; Lin, Jiandie D.] Univ Michigan, Med Ctr, Inst Life Sci, Ann Arbor, MI 48109 USA. [Li, Sinning; Liu, Chang; Han, Ting; Lin, Jiandie D.] Univ Michigan, Med Ctr, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Li, Na; Hao, Tong; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. [Li, Na; Hao, Tong; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Li, Na; Hao, Tong; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Lin, JD (reprint author), Univ Michigan, Med Ctr, Inst Life Sci, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM jdlin@umich.edu RI Hill, David/B-6617-2011 FU NIDDK NIH HHS [DK065584, DK077086, K01 DK065584, K01 DK065584-04, K01 DK065584-05, R01 DK077086, R01 DK077086-01A1, R01 DK077086-02] NR 57 TC 67 Z9 68 U1 0 U2 7 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 AUG 6 PY 2008 VL 8 IS 2 BP 105 EP 117 DI 10.1016/j.cmet.2008.06.013 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 335AH UT WOS:000258262700004 PM 18680712 ER PT J AU Lo, J You, SM Canavan, B Liebau, J Beltrani, G Koutkia, P Hemphill, L Lee, H Grinspoon, S AF Lo, Janet You, Sung Min Canavan, Bridget Liebau, James Beltrani, Greg Koutkia, Polyxeni Hemphill, Linda Lee, Hang Grinspoon, Steven TI Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the Endocrine-Society CY JUN 15-18, 2008 CL San Francisco, CA SP Endocrine Soc ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTIMA-MEDIA THICKNESS; SEVERE GH DEFICIENCY; INFECTED PATIENTS; BODY-COMPOSITION; ADIPOSE-TISSUE; INSULIN SENSITIVITY; ADULTS; MEN; LIPODYSTROPHY AB Context Antiretroviral therapy can be associated with visceral adiposity and metabolic complications, increasing cardiovascular risk, and reduced growth hormone ( GH) secretion may be a contributing factor. Objective To investigate the effects of low- dose physiological GH administrationon body composition, glucose, and cardiovascular parameters in patients with human immunodeficiency virus ( HIV) having abdominal fat accumulation and relative GH deficiency. Design, Setting, and Patients A randomized, double- blind, placebo- controlled trial of 56 patients with HIV, abdominal fat accumulation, and reduced GH secretion ( peak GH < 7.5 ng/mL) conducted at a US academic medical center between November 2003 and October 2007. Intervention Patients were randomly assigned to receive either subcutaneous GH or matching placebo titrated to the upper quartile of normal insulin like growth factor 1 ( IGF- 1) range for 18 months. Starting dose was 2 mu g/kg/d and increased to maximum dose of 6 mu g/kg/d ( average dose, 0.33 mg/d). Main Outcome Measures Change in body composition assessed by computed tomographic scan and dual- energy x- ray absorptiometry. Secondary outcomes included glucose, IGF- 1, blood pressure ( BP), and lipids. Treatment effect was the difference in the change between GH and placebo groups, using all available data. Results Fifty- five patients ( 26 with GH and 29 with placebo) were included in the safety analyses and 52 patients ( 25 with GH and 27 with placebo) were included in the efficacy analyses. Visceral adipose tissue area ( treatment effect [ last- value- carried-forward analysis {n= 56}, - 19 cm(2); 95% confidence interval {CI}, - 37 to - 0.3 cm(2)], - 19 cm(2); 95% CI, - 38 to - 0.5 cm(2); P=. 049); trunk fat (- 0.8 kg; 95% CI, - 1.5 to - 0.04 kg; P=. 04); diastolic BP (- 7 mm Hg; 95% CI, - 11 to - 2 mm Hg; P=. 006); and triglycerides (- 7 mg/ dL, P=. 002) improved but 2- hour glucose levels on glucose tolerance testing increased in the GH group vs the placebo group ( treatment effect, 22 mg/ dL; 95% CI, 6- 37 mg/ dL; P=. 009). The IGF- 1 levels increased ( treatment effect, 129 ng/ mL; 95% CI, 95- 164 ng/ mL; P <. 001). Adverse events were not increased for GH vs placebo ( 23%; 95% CI, 9%- 44% vs 28%; 95% CI, 13%- 47%; P=. 70). Conclusions In HIV- associated abdominal fat accumulation and relative GH deficiency, low- dose GH received for 18 months resulted in significantly reduced visceral fat and truncal obesity, triglycerides, and diastolic BP, but 2- hour glucose levels on glucose tolerance testing were increased. Trial Registration clinicaltrials. gov Identifier: NCT00100698. C1 [Lo, Janet; You, Sung Min; Canavan, Bridget; Liebau, James; Beltrani, Greg; Koutkia, Polyxeni; Grinspoon, Steven] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Hemphill, Linda] Boston Heart Fdn, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [M01 RR01066-25S1, M01 RR001066, M01 RR001066-270437]; NHLBI NIH HHS [F32 HL088991, F32 HL088991-01]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-13, R01 DK063639, R01 DK063639-01, R01 DK63639] NR 45 TC 47 Z9 49 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 6 PY 2008 VL 300 IS 5 BP 509 EP 519 DI 10.1001/jama.300.5.509 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 333YG UT WOS:000258188900012 PM 18677023 ER PT J AU Jungmann, R Liedl, T Sobey, TL Shih, W Simmel, FC AF Jungmann, Ralf Liedl, Tim Sobey, Thomas L. Shih, William Simmel, Friedrich C. TI Isothermal assembly of DNA origami structures using denaturing agents SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID FORMAMIDE; STABILITY AB DNA origami is one the most promising recent developments in DNA self-assembly. It allows for the construction of arbitrary nanoscale patterns and objects by folding a long viral scaffold strand using a large number os short "staple" strands. Assembly is usually accomplished by thermal annealing of DNA molecules is buffer solution. We here demonstrate that both 2D and 3D origami structures can be assembled isothermally by annealing the DNA strands in denaturing buffer, followed by a controlled reduction of denaturant concentration. This opens up origami assembly for the integration of temperature-sensitive components. C1 [Jungmann, Ralf; Sobey, Thomas L.; Simmel, Friedrich C.] Tech Univ Munich, Phys Dept E14, D-85748 Garching, Germany. [Liedl, Tim; Shih, William] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Simmel, FC (reprint author), Tech Univ Munich, Phys Dept E14, James Franck Str 1, D-85748 Garching, Germany. EM simmel@ph.tum.de RI Simmel, Friedrich/G-3281-2010; Liedl, Tim/O-7539-2014; Jungmann, Ralf/A-6357-2015 OI Simmel, Friedrich/0000-0003-3829-3446; Liedl, Tim/0000-0002-0040-0173; Jungmann, Ralf/0000-0003-4607-3312 NR 16 TC 59 Z9 61 U1 3 U2 38 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 AUG 6 PY 2008 VL 130 IS 31 BP 10062 EP + DI 10.1021/ja8030196 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 332JZ UT WOS:000258080600014 PM 18613687 ER PT J AU Emmons, K AF Emmons, Karen TI Smoking among childhood cancer survivors: We can do better SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID DISADVANTAGE; PREDICTORS; CESSATION; POLICY C1 [Emmons, Karen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Emmons, Karen] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Emmons, K (reprint author), Dana Farber Canc Inst, 44 Binney St,LW 703, Boston, MA 02115 USA. EM karen_m_emmons@dfci.harvard.edu NR 17 TC 6 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 6 PY 2008 VL 100 IS 15 BP 1048 EP 1049 DI 10.1093/jnci/djn242 PG 2 WC Oncology SC Oncology GA 335YE UT WOS:000258330700005 PM 18664648 ER PT J AU Patel, N Hoang, D Miller, N Ansaloni, S Huang, QH Rogers, JT Lee, JC Saunders, AJ AF Patel, Neha Hoang, David Miller, Nathan Ansaloni, Sara Huang, Qihong Rogers, Jack T. Lee, Jeremy C. Saunders, Aleister J. TI MicroRNAs can regulate human APP levels SO MOLECULAR NEURODEGENERATION LA English DT Article ID PROTEIN MESSENGER-RNA; ALZHEIMERS-DISEASE; PRECURSOR; EXPRESSION; INTERLEUKIN-1; GROWTH; REGION; GENE AB A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs. C1 [Patel, Neha; Hoang, David; Miller, Nathan; Ansaloni, Sara; Saunders, Aleister J.] Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. [Huang, Qihong] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Rogers, Jack T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurochem Lab, Boston, MA USA. [Lee, Jeremy C.] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Saunders, Aleister J.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA. [Saunders, Aleister J.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. RP Saunders, AJ (reprint author), Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. EM npp22@drexel.edu; dth92@drexel.edu; nfm25@drexel.edu; sa355@drexel.edu; qhuang@wistar.org; jtrogers@rics.bwh.harvard.edu; jeremy@biology.ucsc.edu; aleister.saunders@drexel.edu FU NIH [R21NS48227]; Commonwealth of Pennsylvania; Drexel University; [RO3-DA022201] FX We would like to thank members of Saunders lab and Trinna Cuellar for comments on the manuscript. We would also like to thank Trinna Cuellar and Michael T. McManus for helpful discussions (RO3-DA022201). This work was funded by the NIH (AJS: R21NS48227), Commonwealth of Pennsylvania (AJS), and Drexel University (AJS). NR 22 TC 85 Z9 94 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 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD AUG 6 PY 2008 VL 3 AR 10 DI 10.1186/1750-1326-3-10 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 439NG UT WOS:000265633200001 PM 18684319 ER PT J AU Gong, XM Lin, T Sun, ZH Na, M Zuo, HC Xie, ZP AF Gong, Xiaoming Lin, Tong Sun, Zhaohui Na, Min Zuo, Huancong Xie, Zuoping TI Oligl is downregulated in oligodendrocyte progenitor cell differentiation SO NEUROREPORT LA English DT Article DE differentiation; mouse oligodendrocyte progenitors; Oligl; oligodendrocyte progenitor cells; transcription ID MULTIPLE-SCLEROSIS; STEM-CELLS; PROTEINS; LESIONS; ASTROCYTES; EXPRESSION; CULTURES; NEURONS; GROWTH; CORTEX AB Oligl is a transcription factor that is essential for oligodendrogenesis. It is important to understand the upstream regulation of Oligi expression because of its critical role in remyelination repair. A mouse oligodendrocyte progenitor cell (OPC) differentiation model was established to explore Oligl transcriptional activity during OPC differentiation. Using an Oligl promoter-luciferase reporter plasmid, we found that Oligl transcription is dramatically decreased during OPC differentiation in response to 0.5% fetal bovine serum. Oligl protein expression is also remarkably decreased as revealed by immunostaining and western blotting. Thus, Oligl is downregulated during OPC differentiation, suggesting that Oligl is not actively required in differentiated oligodendrocytes. C1 [Gong, Xiaoming; Sun, Zhaohui; Na, Min; Zuo, Huancong] Tsinghua Univ, Coll Med, Beijing 100084, Peoples R China. [Xie, Zuoping] Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Dept Biol Sci & Biotechnol, Beijing 100084, Peoples R China. [Lin, Tong] Massachusetts Gen Hosp, MassGen Inst Neuroclegenerat Dis, CNS Signaling Lab, Charlestown, MA USA. RP Zuo, HC (reprint author), Tsinghua Univ, Coll Med, Beijing 100084, Peoples R China. EM zuohc@mail.tsinghua.edu.cn; zuopingx@mail.tsinghua.edu.cn NR 25 TC 4 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 6 PY 2008 VL 19 IS 12 BP 1203 EP 1207 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 331PA UT WOS:000258022900007 PM 18628665 ER PT J AU Hao, JJ Daleo, MA Murphy, CK Yu, PB Ho, JN Hu, JY Peterson, RT Hatzopoulos, AK Hong, CC AF Hao, Jijun Daleo, Marie A. Murphy, Clare K. Yu, Paul B. Ho, Joshua N. Hu, Jianyong Peterson, Randall T. Hatzopoulos, Antonis K. Hong, Charles C. TI Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells SO PLOS ONE LA English DT Article AB Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine. C1 [Hao, Jijun; Daleo, Marie A.; Murphy, Clare K.; Ho, Joshua N.; Hu, Jianyong; Hatzopoulos, Antonis K.; Hong, Charles C.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Hong, Charles C.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN USA. [Yu, Paul B.; Peterson, Randall T.] Harvard Univ, Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Hu, Jianyong; Hatzopoulos, Antonis K.] Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN USA. RP Hao, JJ (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. EM charles.c.hong@vanderbilt.edu RI Hatzopoulos, Antonis/D-2049-2010; Hong, Charles/C-9989-2010; OI Yu, Paul/0000-0003-2145-4944 FU NIH [HL081535, HL083958]; GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease FX This work was supported by NIH grants HL081535 (CCH) and HL083958 (AKH), and a grant from the GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease (CCH). NR 30 TC 130 Z9 135 U1 2 U2 17 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 AUG 6 PY 2008 VL 3 IS 8 AR e2904 DI 10.1371/journal.pone.0002904 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 421NW UT WOS:000264366600060 PM 18682835 ER PT J AU Krishnamoorthy, S AF Krishnamoorthy, Srinivasan TI Receptor Tyrosine Kinase (RTK) Mediated Tyrosine Phosphor- Proteome from Drosophila S2 (ErbB1) Cells Reveals Novel Signaling Networks SO PLOS ONE LA English DT Article AB Protein phosphorylation mediates many critical cellular responses and is essential for many biological functions during development. About one-third of cellular proteins are phosphorylated, representing the phosphor-proteome, and phosphorylation can alter a protein's function, activity, localization and stability. Tyrosine phosphorylation events mediated by aberrant activation of Receptor Tyrosine Kinase (RTK) pathways have been proven to be involved in the development of several diseases including cancer. To understand the systems biology of RTK activation, we have developed a phosphor-proteome focused on tyrosine phosphorylation events under insulin and EGF signaling pathways using the PhosphoScan (R) technique coupled with high-throughput mass spectrometry analysis. Comparative proteomic analyses of all these tyrosine phosphorylation events revealed that around 70% of these pY events are conserved in human orthologs and paralogs. A careful analysis of published in vivo tyrosine phosphorylation events from literature and patents revealed that around 38% of pY events from Drosophila proteins conserved on 185 human proteins are confirmed in vivo tyrosine phosphorylation events. Hence the data are validated partially based on available reports, and the credibility of the remaining 62% of novel conserved sites that are unpublished so far is very high but requires further follow-up studies. The novel pY events found in this study that are conserved on human proteins could potentially lead to the discovery of drug targets and biomarkers for the detection of various cancers and neurodegenerative diseases. C1 [Krishnamoorthy, Srinivasan] Harvard Univ, Sch Med, Dept Surg, Pediat Surg Res Labs,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Krishnamoorthy, S (reprint author), Harvard Univ, Sch Med, Dept Surg, Pediat Surg Res Labs,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM ksrini10@gmail.com FU NIH [R01 GM-61707, P01-HD-39942, Project2] FX The funding for supplies and chemicals used in this study was from grants from NIH R01 GM-61707 and P01-HD-39942, Project2. The author did not receive any salary for this work. NR 19 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 6 PY 2008 VL 3 IS 8 AR e2877 DI 10.1371/journal.pone.0002877 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 421NW UT WOS:000264366600033 PM 18682802 ER PT J AU Bowman, BR Lee, SM Wang, SY Verdine, GL AF Bowman, Brian R. Lee, Seongmin Wang, Shuyu Verdine, Gregory L. TI Structure of the E-coli DNA glycosylase AlkA bound to the ends of duplex DNA: A system for the structure determination of lesion-containing DNA SO STRUCTURE LA English DT Article ID N-TERMINAL FRAGMENT; G-A MISPAIRS; CRYSTAL-STRUCTURE; BASE-EXCISION; 3-METHYLADENINE DNA; REPAIR ENZYME; DAMAGED DNA; SACCHAROMYCES-CEREVISIAE; PSEUDO-16-MER DNA; ENDONUCLEASE-VIII AB The constant attack on DNA by endogenous and exogenous agents gives rise to nucleolbase modifications that cause mutations, which can lead to cancer. Visualizing the effects of these lesions on the structure of duplex DNA is key to understanding their biologic consequences. The most definitive method of obtaining such structures, X-ray crystallography, i's troublesome to employ owing to the difficulty of obtaining diffraction-quality crystals of DNA. Here, we present a crystallization system that uses a protein, the DNA glycosylase AlkA, as a scaffold to mediate the crystallization of lesion-containing duplex DNA. We demonstrate the use of this system to facilitate the rapid structure determination of DNA containing the lesion 8-oxoguanine in several different sequence contexts, and also deoxyinosine and 1,N 6_ ethenoadenine, each stabilized as the corresponding 2'-flouro analog. The structures of 8-oxoguanine provide a correct atomic-level view of this important endogenous lesion in DNA. C1 [Bowman, Brian R.; Lee, Seongmin; Wang, Shuyu; Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. RP Verdine, GL (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM gregory_verdine@harvard.edu FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH1 1357]; National Institutes of Health [CA100742 to G.L.V]; Ruth Kirschstein National Research Service Award fellowship [F32 GM077935-01]; Microbial Sciences Institute FX We thank the staff at the SBC-CAT and NE-CAT at the Advance Photon Source for assistance during data collection, and Hariharan Jayaram, Danaya Pakoti-prapha, Marie Spong, Charisse Crenshaw, and members of the G.L.V. laboratory for useful discussions. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH1 1357. This work was supported by a grant from the National Institutes of Health (CA100742 to G.L.V). B.R.B. is the recipient of a Ruth Kirschstein National Research Service Award fellowship (F32 GM077935-01). S.W. is the recipient of an undergraduate research fellowship from the Microbial Sciences Institute. Figures were computed by using PyMOL (DeLano Scientific LLC, 2008) as a renderer. All representations of the DNA and DNA lesion base pairs were made by using chains G and H of the PDB file. NR 64 TC 20 Z9 21 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 6 PY 2008 VL 16 IS 8 BP 1166 EP 1174 DI 10.1016/j.str.2008.04.012 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 337JA UT WOS:000258431200005 PM 18682218 ER PT J AU Walensky, RP Arbelaez, C Reichmann, WM Walls, RM Katz, JN Block, BL Dooley, M Hetland, A Kimmel, S Solomon, JD Losina, E AF Walensky, Rochelle P. Arbelaez, Christian Reichmann, William M. Walls, Ron M. Katz, Jeffrey N. Block, Brian L. Dooley, Matthew Hetland, Adam Kimmel, Simeon Solomon, Jessica D. Losina, Elena TI Revising expectations from rapid HIV tests in the emergency department SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASE; PREVENTION GUIDELINES; SEVERITY INDEX; UNITED-STATES; IMPLEMENTATION; OUTCOMES AB Background: Expanded HIV screening efforts in the United States have increased the use of rapid HIV tests in emergency departments. The reported sensitivity and specificity of rapid HIV tests exceed 99%. Objective: To assess whether a reactive rapid oral HIV test result correctly identifies adults with HIV infection in the emergency department. Design: Diagnostic test performance assessment within the framework of a randomized, clinical trial. Setting: Brigham and Women's Hospital emergency department (Boston, Massachusetts) from 7 February to 1 October 2007. Patients: 849 adults with valid rapid oral HIV test results. Intervention: Rapid HIV testing with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania). Patients with reactive rapid test results were offered enzyme-linked immunoassay, Western blot, and plasma HIV-1 RNA testing for confirmation. Measurements: Specificity and positive likelihood ratio. Results: 39 patients had reactive results (4.6% [95% CI, 3.2% to 6.0%]). On confirmation, 5 patients were HIV-infected (prevalence, 0.6% [CI, 0.1% to 1.1%]) and 26 were non-HIV-infected (8 patients declined confirmation). The estimated rapid test specificity was 96.9% (CI, 95.7% to 98.1%). Sensitivity analyses of the true HIV status of unconfirmed cases and test sensitivity resulted in a positive likelihood ratio of 8 to 32. Western blot alone as a confirmation test provided conclusive HIV status in only 50.0% (CI, 30.8% to 69.2%) of patients at first follow-up. The addition of HIV-1 RNA testing to the confirmation protocol improved this rate to 96.2% (CI, 88.8% to 100.0%). Limitation: Test sensitivity cannot be assessed because nonreactive OraQuick test results were not confirmed. Conclusion: Although patients with a reactive oral OraQuick HIV screening test in the emergency department had an 8- to 32-fold increased odds of HIV infection compared with the pretest odds, the specificity of the test was lower than anticipated. C1 [Walensky, Rochelle P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. Partners AIDS Res, Boston, MA USA. RP Walensky, RP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM rwalensky@partners.org FU NIAMS NIH HHS [K24 AR002123, K24 AR002123-08]; NIMH NIH HHS [R01 MH065869, R01 MH073445, R01 MH65869] NR 22 TC 60 Z9 60 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 AUG 5 PY 2008 VL 149 IS 3 BP 153 EP 160 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 336CW UT WOS:000258342900001 PM 18678842 ER PT J AU Burgio, KL Kraus, SR Menefee, S Borello-France, D Corton, M Johnson, HW Mallett, V Norton, P FitzGerald, MP Dandreo, KJ Richter, HE Rozanski, T Albo, M Zyczynski, HM Lemack, GE Chai, TC Khandwala, S Baker, J Brubaker, L Stoddard, AM Goode, PS Nielsen-Omeis, B Nager, CW Kenton, K Tennstedt, SL Kusek, JW Chang, TD Nyberg, LM Steers, W AF Burgio, Kathryn L. Kraus, Stephen R. Menefee, Shawn Borello-France, Diane Corton, Marlene Johnson, Harry W. Mallett, Veronica Norton, Peggy FitzGerald, Mary P. Dandreo, Kimberly J. Richter, Holly E. Rozanski, Thomas Albo, Michael Zyczynski, Halina M. Lemack, Gary E. Chai, Toby C. Khandwala, Salil Baker, Jan Brubaker, Linda Stoddard, Anne M. Goode, Patricia S. Nielsen-Omeis, Betsy Nager, Charles W. Kenton, Kimberly Tennstedt, Sharon L. Kusek, John W. Chang, T. Debuene Nyberg, Leroy M. Steers, William CA Urinary Incontinence Treatment Net TI Behavioral therapy to enable women with urge incontinence to discontinue drug treatment SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; URINARY-INCONTINENCE; OLDER WOMEN; OVERACTIVE BLADDER; CLINICAL-TRIALS; TOLTERODINE; IMPACT AB Background: Women with urge urinary incontinence are commonly treated with antimuscarinic medications, but many discontinue therapy. Objective: To determine whether combining antimuscarinic drug therapy with supervised behavioral training, compared with drug therapy alone, improves the ability of women with urge incontinence to achieve clinically important reductions in incontinence episodes and to sustain these improvements after discontinuing drug therapy. Design: 2-stage, multicenter, randomized clinical trial conducted from July 2004 to January 2006. Setting: 9 university-affiliated outpatient clinics. Patients: 307 women with urge-predominant incontinence. Intervention: 10 weeks of open-label, extended-release tolterodine alone (n = 153) or combined with behavioral training (n = 154), followed by discontinuation of therapy and follow-up at 8 months. Measurements: The primary outcome, measured at 8 months, was no receipt of drugs or other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes. Secondary outcomes were reduction in incontinence, self-reported satisfaction and improvement, and scores on validated questionnaires measuring symptom distress and bother and health-related quality of life. Study staff who performed outcome evaluations, but not participants and interventionists, were blinded to group assignment. Results: 237 participants completed the trial. According to life-table estimates, the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups (41% in both groups; difference, 0 percentage points [95% CI, -12 to 12 percentage points]). A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks (69% vs. 58%; difference, 11 percentage points [CI, -0.3 to 22.1 percentage points]). Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Questionnaire (both P <0.001) at both time points for patient satisfaction and perceived improvement but not health-related quality of life. Adverse events were uncommon (12 events in 6 participants [3 in each group]). Limitations: Behavioral therapy components (daily bladder diary and recommendations for fluid management) in the group receiving drug therapy alone may have attenuated between-group differences. Assigned treatment was completed by 68% of participants, whereas 8-month outcome status was assessed on 77%. Conclusion: The addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence. Combination therapy has a beneficial effect on patient satisfaction, perceived improvement, and reduction of other bladder symptoms. C1 [Burgio, Kathryn L.] Univ Alabama, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. Dept Vet Affairs, Birmingham, AL USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. Duquesne Univ, Pittsburgh, PA 15219 USA. SW Texas State Univ, Dallas, TX USA. Univ Maryland, Baltimore, MD 21201 USA. Oakwood Hosp, Dearborn, MI USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. New England Res Inst, Watertown, MA 02172 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Burgio, KL (reprint author), Univ Alabama, Birmingham Vet Affairs Med Ctr, 11G 700 S 19th St, Birmingham, AL 35233 USA. EM kburgio@aging.uab.edu FU NIDDK NIH HHS [U01 DK060397, U01 DK058225, U01 DK058231, U01 DK058234, U01 DK060379, U01 DK58229, U01 DK60380, U01 DK60395, U01 DK60401, U01 DK58234, U01 DK58225, U01 DK060393, U01 DK60379, U01 DK60397, U01 DK58231, U01 DK060380, U01 DK058229, U01 DK060395, U01 DK060401, U01 DK60393] NR 25 TC 62 Z9 63 U1 1 U2 3 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 AUG 5 PY 2008 VL 149 IS 3 BP 161 EP 169 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 336CW UT WOS:000258342900002 PM 18678843 ER PT J AU Prunier, F Kawase, Y Gianni, D Scapin, C Danik, SB Ellinor, PT Hajjar, RJ del Monte, F AF Prunier, Fabrice Kawase, Yoshiaki Gianni, Davide Scapin, Cristina Danik, Stephan B. Ellinor, Patric T. Hajjar, Roger J. del Monte, Federica TI Prevention of ventricular arrhythmias with sarcoplasmic reticulum Ca2+ ATPase pump overexpression in a porcine model of ischemia reperfusion SO CIRCULATION LA English DT Article DE arrhythmia; calcium; gene therapy; infarction; ischemia; reperfusion; sarcoplasmic reticulum ID CORONARY-ARTERY OCCLUSION; T-WAVE ALTERNANS; MECHANISMS; CA2+-ATPASE; VULNERABILITY; FIBRILLATION; PROTECTION; DURATION; MYOCYTES; HEART AB Background - Ventricular arrhythmias are life- threatening complications of heart failure and myocardial ischemia. Increased diastolic Ca2+ overload occurring in ischemia leads to afterdepolarizations and aftercontractions that are responsible for cellular electric instability. We inquired whether sarcoplasmic reticulum Ca2+ ATPase pump ( SERCA2a) overexpression could reduce ischemic ventricular arrhythmias by modulating Ca2+ overload. Methods and Results - SERCA2a overexpression in pig hearts was achieved by intracoronary gene delivery of adenovirus in the 3 main coronary arteries. Homogeneous distribution of the gene was obtained through the left ventricle. After gene delivery, the left anterior descending coronary artery was occluded for 30 minutes to induce myocardial ischemia followed by reperfusion. We compared this model with a model of permanent coronary artery occlusion. Twenty- four hour ECG Holter recordings showed that SERCA2a overexpression significantly reduced the number of episodes of ventricular tachycardia after reperfusion, whereas no significant difference was found in the occurrence of sustained or nonsustained ventricular tachycardia and ventricular fibrillation in pigs undergoing permanent occlusion. Conclusions - We show that Ca2+ cycling modulation using SERCA2a overexpression reduces ventricular arrhythmias after ischemia- reperfusion. Strategies that modulate postischemic Ca2+ overload may have clinical promise for the treatment of ventricular arrhythmias. C1 [Prunier, Fabrice; Gianni, Davide; Scapin, Cristina; Ellinor, Patric T.; del Monte, Federica] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Danik, Stephan B.; Ellinor, Patric T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Kawase, Yoshiaki; Hajjar, Roger J.] Mt Sinai Med Ctr, Dept Gene & Cell Med, New York, NY 10029 USA. [Scapin, Cristina] Univ Padua, Dipartimento Sci Biomed Sperimentali, Padua, Italy. RP del Monte, F (reprint author), Ctr Life Sci, 3 Blackfan Cir,Rm 911, Boston, MA 02215 USA. EM fdelmont@bidmc.harvard.edu RI SCAPIN, CRISTINA/K-7595-2016 OI SCAPIN, CRISTINA/0000-0002-4187-982X FU NHLBI NIH HHS [R01 HL083156, R01 HL093183, R01 HL088434] NR 27 TC 60 Z9 69 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 AUG 5 PY 2008 VL 118 IS 6 BP 614 EP 624 DI 10.1161/CIRCULATIONAHA.108.770883 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 333ZR UT WOS:000258192600003 PM 18645052 ER PT J AU Allada, R Siegel, JM AF Allada, Ravi Siegel, Jerome M. TI Unearthing the phylogenetic roots of sleep SO CURRENT BIOLOGY LA English DT Review ID IN-VIVO MICRODIALYSIS; SLOW-WAVE SLEEP; LIZARD CTENOSAURA-PECTINATA; BRAIN GENE-EXPRESSION; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; CIRCADIAN CLOCK; LOCOMOTOR-ACTIVITY; AROUSAL THRESHOLD; MAMMALIAN SLEEP AB Why we sleep remains one of the enduring unanswered questions in biology. At its core, sleep can be defined behaviorally as a homeostatically regulated state of reduced movement and sensory responsiveness. The cornerstone of sleep studies in terrestrial mammals, including humans, has been the measurement of coordinated changes in brain activity during sleep measured using the electroencephalogram (EEG). Yet among a diverse set of animals, these EEG sleep traits can vary widely and, in some cases, are absent, raising questions as to whether they define a universal, or even essential, feature of sleep. Over the past decade, behaviorally defined sleep-like states have been identified in a series of genetic model organisms, including fish, flies and worms. Genetic analyses in these systems are revealing a remarkable conservation in the underlying mechanisms controlling sleep behavior. Taken together, these studies suggest an ancient origin for sleep and raise the possibility that model organism genetics may reveal the molecular mechanisms that guide sleep and wake. C1 [Allada, Ravi] Northwestern Univ, Dept Neurobiol & Physiol, 2205 Tech Dr 2-160, Evanston, IL 60208 USA. [Siegel, Jerome M.] Univ Calif Los Angeles, Sch Med, Dept Psychiat, VA GLAHS Sepulveda, North Hills, CA 91343 USA. [Siegel, Jerome M.] Univ Calif Los Angeles, Sch Med, Brain Res Inst, North Hills, CA 91343 USA. RP Allada, R (reprint author), Northwestern Univ, Dept Neurobiol & Physiol, 2205 Tech Dr 2-160, Evanston, IL 60208 USA. EM r-allada@northwestern.edu; jsiegel@ucla.edu FU NIMH NIH HHS [R01 MH064109, R01 MH067870, R01 MH067870-05, R01MH067870, R01MH64109]; NINDS NIH HHS [1R01-NS42947, R01 NS042947, R01 NS052903, R01 NS052903-03, R01 NS059042, R01 NS059042-01A2, R01NS052903] NR 150 TC 85 Z9 85 U1 3 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD AUG 5 PY 2008 VL 18 IS 15 BP R670 EP R679 DI 10.1016/j.cub.2008.06.033 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 335AI UT WOS:000258262800020 PM 18682212 ER PT J AU Korosoglou, G Weiss, RG Kedziorek, DA Walczak, P Gilson, WD Schar, M Sosnovik, DE Kraitchman, DL Boston, RC Bulte, JWM Weissleder, R Stuber, M AF Korosoglou, Grigorios Weiss, Robert G. Kedziorek, Dorota A. Walczak, Piotr Gilson, Wesley D. Schaer, Michael Sosnovik, David E. Kraitchman, Dara L. Boston, Raymond C. Bulte, Jeff W. M. Weissleder, Ralph Stuber, Matthias TI Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using "positive contrast" magnetic resonance imaging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atherosclerosis; vulnerable plaque; superparamagnetic nanoparticles; molecular imaging; inversion recovery with ON-resonant water suppression (IRON) positive contrast; magnetic resonance imaging ID ULTRASMALL SUPERPARAMAGNETIC PARTICLES; IRON-OXIDE; IN-VIVO; CELLS; MRI; NANOPARTICLES; ANGIOGRAPHY; METASTASES; TRACKING; STENOSIS AB Objectives This study was designed to identify macrophage-rich atherosclerotic plaque noninvasively by imaging the tissue uptake of long-circulating superparamagnetic nanoparticles with a positive contrast off-resonance imaging sequence (inversion recovery with ON-resonant water suppression [IRON]). Background The sudden rupture of macrophage-rich atherosclerotic plaques can trigger the formation of an occlusive thrombus in coronary vessels, resulting in acute myocardial infarction. Therefore, a noninvasive technique that can identify macrophage-rich plaques and thereby assist with risk stratification of patients with atherosclerosis would be of great potential clinical utility. Methods Experiments were conducted on a clinical 3-T magnetic resonance imaging (MRI) scanner in 7 heritable hyperlipidemic and 4 control rabbits. Monocrystalline iron-oxide nanoparticles (MION)-47 were administrated intravenously (2 doses of 250 mu mol Fe/kg), and animals underwent serial IRON-MRI before injection of the nanoparticles and serially after 1, 3, and 6 days. Results After administration of MION-47, a striking signal enhancement was found in areas of plaque only in hyperlipidemic rabbits. The magnitude of enhancement on magnetic resonance images had a high correlation with the number of macrophages determined by histology (p < 0.001) and allowed for the detection of macrophage-rich plaque with high accuracy (area under the curve: 0.92, SE: 0.04, 95% confidence interval: 0.84 to 0.96, p < 0.001). No significant signal enhancement was measured in remote areas without plaque by histology and in control rabbits without atherosclerosis. Conclusions Using IRON-MRI in conjunction with superparamagnetic nanoparticles is a promising approach for the noninvasive evaluation of macrophage-rich, vulnerable plaques. C1 [Korosoglou, Grigorios] Univ Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany. [Korosoglou, Grigorios; Weiss, Robert G.; Kedziorek, Dorota A.; Walczak, Piotr; Gilson, Wesley D.; Schaer, Michael; Kraitchman, Dara L.; Bulte, Jeff W. M.; Stuber, Matthias] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Div Cardiol, Baltimore, MD USA. [Weiss, Robert G.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD USA. [Schaer, Michael] Philips Med Syst, Cleveland, OH USA. [Sosnovik, David E.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. [Boston, Raymond C.] Univ Penn, Sch Vet Med, Kennett Sq, PA 19348 USA. RP Korosoglou, G (reprint author), Univ Heidelberg, Dept Cardiol, Neuenheimer Feld 410, D-69120 Heidelberg, Germany. EM grigorios_korosoglou@med.uni-heidelberg.de RI Walczak, Piotr/B-8707-2008; Stuber, Matthias/B-2949-2010; Bulte, Jeff/A-3240-2008; Schar, Michael/C-8087-2015; OI Stuber, Matthias/0000-0001-9843-2028; Bulte, Jeff/0000-0003-1202-1610; Schar, Michael/0000-0002-7044-9941; Walczak, Piotr/0000-0002-3733-3322 FU NCI NIH HHS [R24 CA092782-06, R24 CA092782, R24 CA092782-01, R24 CA092782-02, R24 CA092782-03, R24 CA092782-04, R24 CA092782-05, R24 CA92782]; NHLBI NIH HHS [R01 HL061912, R01 HL061912-02, R01 HL061912-03, R01 HL061912-04, R01 HL061912-05, R01 HL061912-06, R01 HL061912-07, R01 HL061912-08, R01 HL061912-09, R01 HL073223, R01 HL073223-04, R01 HL084186, R01 HL084186-01, R01 HL084186-02, R01 HL084186-03, R01 HL61912]; NIBIB NIH HHS [1 K08 EB004922-01, K08 EB004922] NR 27 TC 81 Z9 85 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 AUG 5 PY 2008 VL 52 IS 6 BP 483 EP 491 DI 10.1016/j.jacc.2008.03.063 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 331RW UT WOS:000258031300012 PM 18672170 ER PT J AU Adams, DR Toner, M Langer, R AF Adams, Dana R. Toner, Mehmet Langer, Robert TI Microflow and crack formation patterns in drying sessile droplets of liposomes suspended in trehalose solutions SO LANGMUIR LA English DT Article ID MAMMALIAN-CELLS; INTRACELLULAR TREHALOSE; DESICCATION; DROPS; VITRIFICATION; PRESERVATION; EVAPORATION; BILAYERS; FILMS; RING AB Anhydrobiotic preservation potentially provides a means of long-term storage of mammalian cells in carbohydrate glasses under ambient conditions. During desiccation, sessile droplets of glass-forming carbohydrate solutions exhibit complex phenomena, including fluid flow, droplet deformation, and crack formation, all of which may alter the cell preservation efficacy. Cell-sized liposomes were employed as a model system to explore these phenomena in diffusively dried sessile droplets of trehalose solutions. Two factors were identified that strongly influenced the features of the desiccated droplets: the underlying surface and the liposomes themselves. In particular, the surface altered the droplet shape as well as the microflow pattern and, in turn, the moisture conditions encountered by the liposomes during desiccation. A ring deposit formed when the droplets were dried on polystyrene, as would be expected owing to the capillary flow that generally occurs in pinned droplets. In contrast, when dried on the more hydrophilic glass slide, the resulting droplets were thinner, and the liposomes accumulated near their centers, which was an unexpected result likely owing to the glass-forming nature of trehalose solutions. As might be anticipated given the variations in liposome distribution, the choice of surface also influenced crack formation upon continued drying. In addition to providing a preferential path for drying, such cracks are relevant because they could inflict mechanical damage on cells. The liposomes themselves had an even more profound effect on crack formation; indeed, whereas cracks were found in all droplets containing liposomes, in their absence few of the droplets cracked at all, regardless of the surface type. These complex drying dynamics merit further investigation in the development of anhydrobiotic preservation protocols, particularly with regard to the role therein of surface hydrophobicity and the cells themselves. C1 [Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Adams, Dana R.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Toner, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM mtoner@hms.harvard.edu FU NCI NIH HHS [U54-CA119349]; NIDDK NIH HHS [DK46270] NR 59 TC 7 Z9 7 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 5 PY 2008 VL 24 IS 15 BP 7688 EP 7697 DI 10.1021/la703835w PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 331TC UT WOS:000258034500012 PM 18613701 ER PT J AU Stegh, AH Kesari, S Mahoney, JE Jenq, HT Forloney, KL Protopopov, A Louis, DN Chin, L DePinho, RA AF Stegh, Alexander H. Kesari, Santosh Mahoney, John E. Jenq, Harry T. Forloney, Kristin L. Protopopov, Alexei Louis, David N. Chin, Lynda DePinho, Ronald A. TI Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE heat shock protein; apoptosis/necrosis balance; glial cells ID ALPHA-B-CRYSTALLIN; LIGAND-INDUCED APOPTOSIS; OXIDATIVE STRESS; MALIGNANT GLIOMAS; DROSOPHILA HSP27; BRAIN-TUMORS; CELL-DEATH; BCL-X; EXPRESSION; ACTIVATION AB Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein alpha-basic-crystallin (alpha B-crystallin/HspB5), a link reinforced by robust alpha B-crystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of alpha B-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced alpha B-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of alpha B-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous alpha B-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, alpha B-crystallin selectively binds procaspase-3 and its cleavage intermediates in vitro and in vivo. Thus, alpha B-crystallin is a Bcl2L12-induced oncoprotein that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties. C1 [Stegh, Alexander H.; Kesari, Santosh; Forloney, Kristin L.; Protopopov, Alexei; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mahoney, John E.; Protopopov, Alexei; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Inst Innovat Canc Sci, Belfer Fdn, Ctr Appl Canc Sci, Boston, MA 02115 USA. [Kesari, Santosh] Brigham & Womens Hosp, Ctr Neurooncol, Boston, MA 02115 USA. [Kesari, Santosh] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Jenq, Harry T.] Harvard Univ, Sch Med, Div Hlth Sci & Technol, Boston, MA 02114 USA. [Louis, David N.] MIT, Dept Pathol, Boston, MA 02114 USA. [Louis, David N.] MIT, Ctr Canc, Boston, MA 02114 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu RI Kesari, Santosh/E-8461-2013 FU NCI NIH HHS [K08CA124804, K08 CA124804, K99 CA129172, K99CA129172, P01 CA095616, P01 CA95616, R01 CA057683, R01 CA099041, R01 CA57683] NR 31 TC 83 Z9 88 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2008 VL 105 IS 31 BP 10703 EP 10708 DI 10.1073/pnas.0712034105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335RT UT WOS:000258308500017 PM 18669646 ER PT J AU Savas, JN Makusky, A Ottosen, S Baillat, D Then, F Krainc, D Shiekhattar, R Markey, SP Tanese, N AF Savas, Jeffrey N. Makusky, Anthony Ottosen, Soren Baillat, David Then, Florian Krainc, Dimitri Shiekhattar, Ramin Markey, Sanford P. Tanese, Naoko TI Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microRNA; poly-glutamine; RNA interference; post-transcriptional gene silencing; neuronal RNA granule ID MICRORNA-DEPENDENT LOCALIZATION; STRESS GRANULES; PROCESSING BODIES; PATHOGENESIS; DEGENERATION; INTERACTS; PATHWAYS; CLEAVAGE; REVEALS; REPEATS AB Huntington's disease is a dominant autosomal neurodegenerative disorder caused by an expansion of polyglutamines in the huntingtin (Htt) protein, whose cellular function remains controversial. To gain insight into Htt function, we purified epitope-tagged Htt and identified Argonaute as associated proteins. Colocalization studies demonstrated Htt and Agog to be present in P bodies, and depletion of Htt showed compromised RNA-mediated gene silencing. Mouse striatal cells expressing mutant Htt showed fewer P bodies and reduced reporter gene silencing activity compared with wild-type counterparts. These data suggest that the previously reported transcriptional deregulation in HD may be attributed in part to mutant Htt's role in post-transcriptional processes. C1 [Savas, Jeffrey N.; Ottosen, Soren; Tanese, Naoko] NYU, Inst Canc, Dept Microbiol, New York, NY 10016 USA. [Savas, Jeffrey N.] NYU, Natl Inst Hlth, Grad Partnership Program Struct Biol, Sch Med, New York, NY 10016 USA. [Makusky, Anthony; Markey, Sanford P.] NIMH, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. [Baillat, David; Shiekhattar, Ramin] Ctr Regulacio Genom, Barcelona 08003, Spain. [Then, Florian; Krainc, Dimitri] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat,Med Sch, Charlestown, MA 02129 USA. RP Tanese, N (reprint author), NYU, Inst Canc, Dept Microbiol, 550 1St Ave, New York, NY 10016 USA. EM naoko.tanese@med.nyu.edu OI Tanese, Naoko/0000-0002-1946-3211 FU Intramural NIH HHS; NCRR NIH HHS [S10 RR017970]; NIMH NIH HHS [Z01 MH000274]; NINDS NIH HHS [R01NS050352, R01 NS050352] NR 42 TC 79 Z9 81 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 AUG 5 PY 2008 VL 105 IS 31 BP 10820 EP 10825 DI 10.1073/pnas.0800658105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335RT UT WOS:000258308500037 PM 18669659 ER PT J AU Sasaki, Y Calado, DP Derudder, E Zhang, B Shimizu, Y Mackay, F Nishikawa, S Rajewsky, K Schmidt-Supprian, M AF Sasaki, Yoshiteru Calado, Dinis P. Derudder, Emmanuel Zhang, Baochun Shimizu, Yuri Mackay, Fabienne Nishikawa, Shin-ichi Rajewsky, Klaus Schmidt-Supprian, Marc TI NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF : BAFF-R-mediated survival signals in B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE I kappa B kinase; NF-kappa B; hyperplasia; p100 processing; knockin ID NF-KAPPA-B; FACTOR-RECEPTOR; MULTIPLE-MYELOMA; ACTIVATION; PATHWAY; KINASE; FAMILY; TRAF2; TNF; NF-KAPPA-B1 AB BAFF-R-dependent activation of the alternative NF-kappa B pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes amplifies alternative NF-kappa B activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia of BAFF-R-independent B cells. NIK controls alternative NF-kappa B signaling by increasing the protein levels of its negative regulator TRAF3 in a dose-dependent fashion. This mechanism keeps NIK protein levels below detection even when they cause B cell hyperplasia, so that contributions of NIK to B cell pathologies can easily be overlooked. C1 [Sasaki, Yoshiteru; Calado, Dinis P.; Derudder, Emmanuel; Zhang, Baochun; Rajewsky, Klaus; Schmidt-Supprian, Marc] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Sasaki, Yoshiteru; Shimizu, Yuri; Nishikawa, Shin-ichi] RIKEN, Ctr Dev Biol, Lab Stem Cell Biol, Kobe, Hyogo 6500047, Japan. [Mackay, Fabienne] Garvan Inst Med Res, Autoimmun Res Unit, Darlinghurst, NSW 2010, Australia. [Schmidt-Supprian, Marc] Max Planck Inst Biochem, D-82152 Martinsried, Germany. RP Sasaki, Y (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 200 Longwood Ave, Boston, MA 02115 USA. EM yoshisasaki@cdb.riken.jp; rajewsky@cbr.med.harvard.edu; supprian@biochem.mpg.de RI Schmidt-Supprian, Marc/F-5893-2011; Mackay, Fabienne/B-7440-2008; OI Schmidt-Supprian, Marc/0000-0002-8543-6166; Mackay, Fabienne/0000-0002-6074-2693; Zhang, Baochun/0000-0003-1759-1161 FU NCI NIH HHS [CA92625, P01 CA092625]; NIAID NIH HHS [AI054636, AI057947, R01 AI057947, R37 AI054636] NR 30 TC 63 Z9 66 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 AUG 5 PY 2008 VL 105 IS 31 BP 10883 EP 10888 DI 10.1073/pnas.0805186105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335RT UT WOS:000258308500048 PM 18663224 ER PT J AU Gridi-Papp, M Feng, AS Shen, JX Yu, ZL Rosowski, JJ Narins, PM AF Gridi-Papp, Marcos Feng, Albert S. Shen, Jun-Xian Yu, Zu-Lin Rosowski, John J. Narins, Peter M. TI Active control of ultrasonic hearing in frogs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE audition; Eustachian tube; middle ear; tuning; eardrum ID BULLFROG RANA-CATESBEIANA; MIDDLE-EAR MUSCLES; AMOLOPS-TORMOTUS; CHINESE FROG AB Vertebrates can modulate the sound levels entering their inner ears in the face of intense external sound or during their own vocalizations. Middle ear muscle contractions restrain the motion of the middle ear ossicles, attenuating the transmission of low-frequency sound and thereby protecting the hair cells in the inner ear. Here we show that the Chinese concave-eared torrent frog, Odorrana tormota, can tune its ears dynamically by closing its normally open Eustachian tubes. Contrary to the belief that the middle ear in frogs permanently communicates with the mouth, O. tormota can close this connection by contraction of the submaxillary and petrohyoid muscles, drastically reducing the air volume behind the eardrums. Mathematical modeling and laser Doppler vibrometry revealed that the reduction of this air volume increases the middle ear impedance, resulting in an up to 20 dB gain in eardrum vibration at high frequencies (10-32 kHz) and 26 dB attenuation at low frequencies (3-10 kHz). Eustachian tube closure was observed in the field during calling and swallowing. Besides a potential role in protecting the inner ear from intense low-frequency sound and high buccal air pressure during calling, this previously unrecognized vertebrate mechanism may unmask the high-frequency calls of this species from the low-frequency stream noise which dominates the environment. This mechanism also protects the thin tympanic membranes from injury during swallowing of live arthropod prey. C1 [Gridi-Papp, Marcos; Narins, Peter M.] Univ Calif Los Angeles, Dept Physiol Sci, Los Angeles, CA 90095 USA. [Narins, Peter M.] Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 90095 USA. [Feng, Albert S.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Feng, Albert S.] Univ Illinois, Beckman Inst, Urbana, IL 61801 USA. [Shen, Jun-Xian; Yu, Zu-Lin] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China. [Rosowski, John J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab, Boston, MA 02114 USA. [Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Rosowski, John J.] Harvard Univ, MIT, Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. RP Gridi-Papp, M (reprint author), Univ Calif Los Angeles, Dept Physiol Sci, 621 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM mgpapp@ucla.edu RI YU, ZULIN/D-7979-2012 FU NIDCD NIH HHS [R01 DC000194, R01 DC000222, R01 DC004998, R01DC00194, R01DC00222, R01DC04998, R01 DC000194-24] NR 25 TC 11 Z9 12 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 AUG 5 PY 2008 VL 105 IS 31 BP 11014 EP 11019 DI 10.1073/pnas.0802210105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335RT UT WOS:000258308500070 PM 18658240 ER PT J AU Xiong, W Hupert, N Hollingsworth, EB O'Brien, ME Fast, J Rodriguez, WR AF Xiong, Wei Hupert, Nathaniel Hollingsworth, Eric B. O'Brien, Megan E. Fast, Jessica Rodriguez, William R. TI Can modeling of HIV treatment processes improve outcomes? Capitalizing on an operations research approach to the global pandemic SO BMC HEALTH SERVICES RESEARCH LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Medical-Decision-Making CY OCT 15-18, 2006 CL Boston, MA SP Soc Med Decis Making ID MIDDLE-INCOME COUNTRIES; ANTIRETROVIRAL DRUGS; PREVENTION RESOURCES; CARE SERVICES; SCALE; IMPLEMENTATION; CHALLENGES; SETTINGS; CAPACITY; SYSTEMS AB Background: Mathematical modeling has been applied to a range of policy-level decisions on resource allocation for HIV care and treatment. We describe the application of classic operations research (OR) techniques to address logistical and resource management challenges in HIV treatment scale-up activities in resource-limited countries. Methods: We review and categorize several of the major logistical and operational problems encountered over the last decade in the global scale-up of HIV care and antiretroviral treatment for people with AIDS. While there are unique features of HIV care and treatment that pose significant challenges to effective modeling and service improvement, we identify several analogous OR-based solutions that have been developed in the service, industrial, and health sectors. Results: HIV treatment scale-up includes many processes that are amenable to mathematical and simulation modeling, including forecasting future demand for services; locating and sizing facilities for maximal efficiency; and determining optimal staffing levels at clinical centers. Optimization of clinical and logistical processes through modeling may improve outcomes, but successful OR-based interventions will require contextualization of response strategies, including appreciation of both existing health care systems and limitations in local health workforces. Conclusion: The modeling techniques developed in the engineering field of operations research have wide potential application to the variety of logistical problems encountered in HIV treatment scale-up in resource-limited settings. Increasing the number of cross-disciplinary collaborations between engineering and public health will help speed the appropriate development and application of these tools. C1 [Xiong, Wei; Hupert, Nathaniel; Hollingsworth, Eric B.] Cornell Univ, Weill Med Coll, Dept Publ Hlth, New York, NY 10021 USA. [Hupert, Nathaniel] Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. [Hupert, Nathaniel] New York Presbyterian Hosp, New York, NY USA. [O'Brien, Megan E.; Fast, Jessica] Clinton Fdn HIV AIDS Initiat CHAI, Quincy, MA USA. [Rodriguez, William R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Global Hlth Delivery Project, Boston, MA 02115 USA. [Rodriguez, William R.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. RP Hupert, N (reprint author), Cornell Univ, Weill Med Coll, Dept Publ Hlth, New York, NY 10021 USA. EM wmz2001@med.cornell.edu; nah2005@med.cornell.edu; ebh2001@med.cornell.edu; mobrien@clintonfoundation.org; jfast@clintonfoundation.org; wrodriguez@partners.org NR 40 TC 5 Z9 5 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD AUG 4 PY 2008 VL 8 AR 166 DI 10.1186/1472-6963-8-166 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 348NL UT WOS:000259217100001 PM 18680594 ER PT J AU Streeck, H Li, B Poon, AFY Schneidewind, A Gladden, AD Power, KA Daskalakis, D Bazner, S Zuniga, R Brander, C Rosenberg, ES Frost, SDW Altfeld, M Allen, TM AF Streeck, Hendrik Li, Bin Poon, Art F. Y. Schneidewind, Arne Gladden, Adrianne D. Power, Karen A. Daskalakis, Demetre Bazner, Suzane Zuniga, Rosario Brander, Christian Rosenberg, Eric S. Frost, Simon D. W. Altfeld, Marcus Allen, Todd M. TI Immune-driven recombination and loss of control after HIV superinfection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID T-LYMPHOCYTE RESPONSE; CTL ESCAPE MUTATION; CELL RESPONSES; VIRUS; INFECTION; REPLICATION; VIREMIA; GAG; TRANSMISSION; PROGRESSION AB After acute HIV infection, CD8(+) T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27(+) subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8(+) T cell responses revealed that each of these recombination sites (similar to 50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8(+) T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV. C1 [Streeck, Hendrik; Li, Bin; Schneidewind, Arne; Gladden, Adrianne D.; Power, Karen A.; Bazner, Suzane; Brander, Christian; Rosenberg, Eric S.; Altfeld, Marcus; Allen, Todd M.] Harvard Univ, Sch Med, Partners AIDS Res Ctr, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Poon, Art F. Y.; Frost, Simon D. W.] Univ Calif San Diego, Univ Calif San Diego Antiviral Res Ctr, San Diego, CA 92103 USA. [Daskalakis, Demetre] NYU, Sch Med, New York, NY 10021 USA. [Zuniga, Rosario] Asociac Civil IMPACTA Salud & Educ, Lima 17, Peru. RP Allen, TM (reprint author), Harvard Univ, Sch Med, Partners AIDS Res Ctr, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM tallen2@partners.org RI Frost, Simon/F-3648-2010; Allen, Todd/F-5473-2011; OI Frost, Simon/0000-0002-5207-9879; Brander, Christian/0000-0002-0548-5778; Poon, Art/0000-0003-3779-154X FU National Institutes of Health [R01-AI054178, U01-AI052403, R01-205672, AI47745, AI57167, N01-AI-30024] FX We would like to thank Sergei Kosakovsky, Yaoyu E. Wang, and Nicole Frahm for their assistance.; This study was supported by National Institutes of Health grants R01-AI054178 (T. M. Allen), U01-AI052403 (T. M. Allen and M. Altfeld), R01-205672 (M. Altfeld), AI47745 and AI57167 (S. D. W. Frost), and N01-AI-30024 (C. Brander and R. Zuniga).; The authors have no conflicting financial interests. NR 28 TC 52 Z9 53 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 AUG 4 PY 2008 VL 205 IS 8 BP 1789 EP 1796 DI 10.1084/jem.20080281 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 338SH UT WOS:000258528500009 PM 18625749 ER PT J AU Munoz-Fontela, C Macip, S Martinez-Sobrido, L Brown, L Ashour, J Garcia-Sastre, A Lee, SW Aaronson, SA AF Munoz-Fontela, Cesar Macip, Salvador Martinez-Sobrido, Luis Brown, Lauren Ashour, Joseph Garcia-Sastre, Adolfo Lee, Sam W. Aaronson, Stuart A. TI Transcriptional role of p53 in interferon-mediated antiviral immunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID LACKING FUNCTIONAL P53; NEGATIVE REGULATOR; POSITIVE FEEDBACK; TUMOR SUPPRESSION; DNA-DAMAGE; VIRUS; CELLS; GENE; SENESCENCE; DEFENSE AB Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424: 516-523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene. C1 [Munoz-Fontela, Cesar; Macip, Salvador; Aaronson, Stuart A.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. [Martinez-Sobrido, Luis; Ashour, Joseph; Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. [Martinez-Sobrido, Luis; Brown, Lauren; Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Emerging Pathogens Inst, New York, NY 10029 USA. [Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Dept Med, Div Infect Dis, New York, NY 10029 USA. [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. RP Aaronson, SA (reprint author), Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. EM Stuart.Aaronson@mssm.edu RI Macip, Salvador/K-5985-2014; OI Garcia-Sastre, Adolfo/0000-0002-6551-1827; Munoz-Fontela, Cesar/0000-0002-7725-2586 FU Spanish Ministry of Education and Science; National Cancer Institute [T32CA78207]; National Institutes of Health [CA80058, CA85214]; National Institute of Allergy and Infectious Disease-funded Center to Investigate Viral Immunity and Antagonism [U19AI62623]; [CA127247]; [CA097216] FX We thank E. Rodriguez, G. Akiri, A. Mahale, and L. Grumolato for helpful comments and discussions about the manuscript; R. Cadagan, S. Yao, and R. Qiao for excellent technical support; and S. Woo, J. Manfredi, and T. Ouchi for providing us with reagents. We specially thank B. Beitzel for providing us with the 293T HISG54-RFP/CAT reporter cells.; C. Munoz-Fontela is a recipient of a postdoctoral fellowship from the Spanish Ministry of Education and Science. S. Macip is a recipient of a postdoctoral fellowship from the National Cancer Institute (T32CA78207). This work was supported by National Institutes of Health grants CA80058 and CA85214 (to S. A. Aaronson), and CA127247 and CA097216 (to S. W. Lee). L. Martinez-Sobrido and A. Garcia-Sastre were supported by grant U19AI62623 from the National Institute of Allergy and Infectious Disease-funded Center to Investigate Viral Immunity and Antagonism.; The authors have no conflicting financial interests. NR 36 TC 80 Z9 88 U1 0 U2 6 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 AUG 4 PY 2008 VL 205 IS 8 BP 1929 EP 1938 DI 10.1084/jem.20080383 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 338SH UT WOS:000258528500021 PM 18663127 ER PT J AU Kojic, N Huang, A Chung, E Tschumperlin, D So, PTC AF Kojic, Nikola Huang, Austin Chung, Euiheon Tschumperlin, Daniel So, Peter T. C. TI Quantification of three-dimensional dynamics of intercellular geometry under mechanical loading using a weighted directional adaptive-threshold method SO OPTICS EXPRESS LA English DT Article ID MECHANOTRANSDUCTION AB Capturing and quantifying dynamic changes in three-dimensional cellular geometries on fast time scales is a challenge because of mechanical limitations of imaging systems as well as of the inherent tradeoffs between temporal resolution and image quality. We have combined a custom highspeed two-photon microscopy approach with a novel image segmentation method, the weighted directional adaptive-threshold (WDAT), to quantify the dimensions of intercellular spaces of cells under compressive stress on timescales previously inaccessible. The adaptation of a high-speed two-photon microscope addressed the need to capture events occurring on short timescales, while the WDAT method was developed to address artifacts of standard intensity-based analysis methods when applied to this system. Our novel approach is demonstrated by the enhanced temporal analysis of the three-dimensional cellular and extracellular deformations that accompany compressive loading of airway epithelial cells. (C) 2008 Optical Society of America. C1 [So, Peter T. C.] MIT, Cambridge, MA 02139 USA. [Kojic, Nikola; Huang, Austin] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Chung, Euiheon] Massachusetts Gen Hosp, Steele Lab, Dept Radiat Oncol, Boston, MA 02114 USA. [Tschumperlin, Daniel] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP So, PTC (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ptso@mit.edu OI Chung, Euiheon/0000-0002-3326-6927 FU NHLBI NIH HHS [HL-082856, R01 HL082856, R01 HL082856-03] NR 11 TC 2 Z9 2 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 4 PY 2008 VL 16 IS 16 BP 12403 EP 12414 DI 10.1364/OE.16.012403 PG 12 WC Optics SC Optics GA 336MS UT WOS:000258368600081 PM 18679517 ER PT J AU Vanderweil, SG Tsai, CL Pelletier, AJ Espinola, JA Sullivan, AF Blumenthal, D Camargo, CA AF Vanderweil, Stefan G. Tsai, Chu-Lin Pelletier, Andrea J. Espinola, Janice A. Sullivan, Ashley F. Blumenthal, David Camargo, Carlos A. TI Inappropriate use of antibiotics for acute asthma in United States emergency departments SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE asthma; antibiotics; emergency medicine; National Emergency Department Safety Study (NEDSS); National Hospital Ambulatory Medical Care Survey (NHAMCS) AB Objectives: The aim was to examine the use of antibiotics to treat asthma patients in U.S. emergency departments (EDs). The authors sought to investigate inappropriate antibiotic prescriptions by identifying the frequency and predictors of antibiotics prescribed for asthma exacerbations using data from two sources, the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Emergency Department Safety Study (NEDSS). Methods: The authors used data from NHAMCS and NEDSS to identify the proportion of ED visits for asthma exacerbations that resulted in the prescription of an antibiotic. NHAMCS provided national data from 1993 through 2004, while NEDSS provided data from 63 primarily academic EDs from 2003 through 2006. Univariate analysis and multivariate logistic regression modeling were used to identify variables associated with antibiotic administration. Results: Analysis of NHAMCS data revealed that 22% (95% confidence interval [CI] = 20% to 24%) of acute asthma visits resulted in an antibiotic prescription from 1993 through 2004, with no significant change in prescribing frequency over the 12-year period. NEDSS data from 2003 through 2006 showed that 18% (95% CI = 17% to 19%) of acute asthma cases in academic EDs received an antibiotic. Multivariate modeling of NHAMCS data revealed that African American patients (odds ratio [OR] = 0.8; 95% CI = 0.6 to 0.97) and patients in urban EDs (OR = 0.5; 95% CI = 0.4 to 0.7) were less likely to receive antibiotics for asthma exacerbations than white patients and patients in nonurban EDs, respectively. NHAMCS analysis also found that patients in the South were more likely to receive antibiotics than those in the Northeast (OR = 1.4; 95% CI = 1.1 to 1.9). A NEDSS multivariate model found a similar difference, with African Americans (OR = 0.6; 95% CI = 0.4 to 0.8) and Hispanics (OR = 0.6; 95% CI = 0.4 to 0.8) being less likely than whites to receive an antibiotic. Conclusions: ED treatment of acute asthma with unnecessary antibiotics is likely to contribute to bacterial antibiotic resistance. Interventions are needed to reduce inappropriate antibiotic prescriptions and to address disparities in asthma care. C1 [Vanderweil, Stefan G.; Tsai, Chu-Lin; Pelletier, Andrea J.; Espinola, Janice A.; Sullivan, Ashley F.; Blumenthal, David] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Blumenthal, David; Camargo, Carlos A.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Blumenthal, David; Camargo, Carlos A.] Partners Hlth Syst, Boston, MA USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM ccamargo@partners.org OI TSAI, CHU-LIN/0000-0003-4639-1513 FU Agency for Healthcare Research and Quality (Rockville, MD) [R01 HS-13099] FX The National Emergency Department Safety Study was supported by Grant R01 HS-13099 from the Agency for Healthcare Research and Quality (Rockville, MD). NR 28 TC 25 Z9 26 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD AUG PY 2008 VL 15 IS 8 BP 736 EP 743 DI 10.1111/j.1553-2712.2008.00167.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 337XP UT WOS:000258469100006 PM 18627585 ER PT J AU Ginde, AA Foianini, A Renner, DM Valley, M Camargo, CA AF Ginde, Adit A. Foianini, Anthony Renner, Daniel M. Valley, Morgan Camargo, Carlos A., Jr. TI Availability and quality of computed tomography and magnetic resonance imaging equipment in US emergency departments SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Academic-Emergency-Medicine (SAEM) CY MAY 29-JUN 02, 2008 CL Washington, DC SP Soc Acad Emergency Med DE imaging; access to care; emergency medicine; rural; healthcare quality ID RECOMMENDATIONS AB Objectives: The objective was to determine the availability and quality of computed tomography (CT) and magnetic resonance imaging (MRI) equipment in U.S. emergency departments (EDs). The authors hypothesized that smaller, rural EDs have less availability and lower-quality equipment. Methods: This was a random selection of 262 (5%) U.S. EDs from the 2005 National Emergency Department Inventories (NEDI)-USA (http://www.emnet-usa.org). The authors telephoned radiology technicians about the presence of CT and MRI equipment, availability for ED imaging, and number of slices for the available CT scanners. The analysis was stratified by site characteristics. Results: The authors collected data from 260 institutions (99% response). In this random sample of EDs, the median annual patient visit volume was 19,872 (interquartile range = 6,788 to 35,757), 28% (95% confidence interval [CI] = 22% to 33%) were rural, and 27% (95% CI = 21% to 32%) participated in the Critical Access Hospital program. CT scanners were present in 249 (96%) institutions, and of these, 235 (94%) had 24/7 access for ED patients. CT scanner resolution varied: 28% had 1-4 slice, 33% had 5-16 slice, and 39% had a more than 16 slice. On-site MRI was available for 171 (66%) institutions, and mobile MRI for 53 (20%). Smaller, rural, and critical access hospitals had lower CT and MRI availability and less access to higher-resolution CT scanners. Conclusions: Although access to CT imaging was high (> 90%), CT resolution and access to MRI were variable. Based on observed differences, the availability and quality of imaging equipment may vary by ED size and location. C1 [Ginde, Adit A.; Foianini, Anthony; Renner, Daniel M.; Valley, Morgan] Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ginde, AA (reprint author), Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO USA. EM adit.ginde@uchsc.edu RI Siry, Bonnie/D-7189-2017 NR 10 TC 43 Z9 43 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD AUG PY 2008 VL 15 IS 8 BP 780 EP 783 DI 10.1111/j.1553-2712.2008.00192.x PG 4 WC Emergency Medicine SC Emergency Medicine GA 337XP UT WOS:000258469100015 PM 18783491 ER PT J AU Singh, AK Sahani, DV Blake, MA Joshi, MC Wargo, JA Castillo, CFD AF Singh, Anand K. Sahani, Dushyant V. Blake, Michael A. Joshi, Mukta C. Wargo, Jennifer A. Castillo, Carlos Fernandez-del TI Assessment of pancreatic tumor resectability with multidetector computed tomography: Semiautomated console-generated images versus dedicated workstation-generated images SO ACADEMIC RADIOLOGY LA English DT Article DE multidetector-CT; pancreatic tumor; resectability; 3D imaging; workflow ID ROW HELICAL CT; SPIRAL CT; VASCULAR INVOLVEMENT; ADENOCARCINOMA; ANGIOGRAPHY; REFORMATIONS; CANCER; CARCINOMA; DIAGNOSIS; INVASION AB Rationale and Objectives. The purpose of this retrospective study was to compare the maximum intensity projection (MIP) images generated at a multidetector computed tomography (MDCT) scanner console using advanced tools at a three-dimensional (3D) workstation for assessment of pancreatic tumor resectability. Materials and Methods. Institutional review board approval and informed consent wavier were obtained for this retrospective study. The intraoperative findings were used as reference standard. Two radiologists assessed console NlEPs that were created using computed tomographic (CT) data sets of 30 patients (17 men and 13 women; age range, 35-79 years; mean age, 58 years) operated for pancreatic tumors. Semi-automated NIEP images were created on a separate MDCT console. Two blinded radiologist (R1, R2) and surgeons (S1, S2) evaluated the image data independently for vascular involvement and tumor resectability. The image quality and diagnostic confidence for MIN were graded on a 5-point scale (1 = poor, 2 = suboptimal, 3 intermediate, 4 = good; 5 = excellent) and comparison was made with 3D workstation image scores. Results. The findings revealed greater than 90% sensitivity, specificity, and accuracy for detecting involvement of peripancreatic vessels by pancreatic tumor with an excellent interobserver agreement (kappa = 0.87-1.00). The findings of console-generated MIPs were same as the findings of 3D workstation images. The mean of image quality and diagnostic confidence grading for console MIPs by assessors were 4.4 and 4.2, respectively. The average time to generate simple MIPs at the console was 3.4 minutes (range, 2.3-4.4) compared to 26 minutes (range, 18-33) to create images at the 3D workstation. Conclusion. Serni-automated MIN generated from an MDCT scanner console is an excellent alternative to 3D workstation images for assessing resectability of pancreatic tumor based on vascular involvement. Console MIN can be quickly generated during the time of scan and thus can improve CT workflow. C1 [Singh, Anand K.; Sahani, Dushyant V.; Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wargo, Jennifer A.; Castillo, Carlos Fernandez-del] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Joshi, Mukta C.] GE Healthcare, FCT Engn, Belmont, MA USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM dsahani@partners.org NR 25 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 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2008 VL 15 IS 8 BP 1058 EP 1068 DI 10.1016/j.acra.2008.03.005 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 331JQ UT WOS:000258008900012 PM 18620126 ER PT J AU Tondo, L Lepri, B Baldessarini, RJ AF Tondo, L. Lepri, B. Baldessarini, R. J. TI Suicidal status during antidepressant treatment in 789 Sardinian patients with major affective disorder SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE antidepressants; bipolar disorders; depression rating scale; major depression; suicidality ID SEROTONIN REUPTAKE INHIBITORS; RANDOMIZED CONTROLLED-TRIALS; BIPOLAR-I DISORDER; LITHIUM MAINTENANCE TREATMENT; CONTROLLED 18-MONTH TRIAL; COMMON MENTAL-DISORDERS; CLINICAL-TRIALS; UNIPOLAR DEPRESSION; UNITED-STATES; RISK-FACTORS AB Objective: Relationships between antidepressant treatment and suicidality remain uncertain in major depressive disorder (MDD), and rarely evaluated in bipolar disorder (BPD). Method: We evaluated changes in suicidality ratings (Hamilton Depression Rating Scale item-3) at the start and after 3.59 +/- 2.57 months of sustained antidepressant treatment in a systematically assessed clinical sample (n = 789) of 605 patients with MDD, 103 patients with BPD-II and 81 patients with BPD-I (based on DSM-IV; 68.1% women; aged 44.3 +/- 16.1 years), comparing suicidal vs. non-suicidal and recovered vs. unrecovered initially suicidal patients. Results: Suicidal patients (103/789, 16.5%; BPD/MDD risk: 2.2) were more depressed and were ill longer. During treatment, 81.5% of suicidal patients became non-suicidal; 0.46% of 656 initially non-suicidal patients reported new suicidal thoughts, with no new attempts. Becoming non-suicidal was associated with greater depression severity and greater improvement. Conclusion: Suicidal ideation was prevalent in patients with depressed major affective disorder, but most of the initially suicidal patients became non-suicidal with antidepressant treatment, independent of diagnosis, treatment type or dose. C1 [Tondo, L.; Baldessarini, R. J.] Massachusetts Gen Hosp, McLean Div, Boston, MA 02114 USA. [Tondo, L.; Baldessarini, R. J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tondo, L.; Baldessarini, R. J.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Tondo, L.; Lepri, B.] Univ Cagliari, Dept Psychol, Cagliari, Sardinia, Italy. [Tondo, L.; Lepri, B.] Lucio Bini Mood Disorders Res Ctr, Cagliari, Sardinia, Italy. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr, 115 Mill St, Elmont, MA 02478 USA. EM rjb@mclean.org FU NIMH NIH HHS [MH-073779] NR 70 TC 30 Z9 30 U1 1 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 AUG PY 2008 VL 118 IS 2 BP 106 EP 115 DI 10.1111/j.1600-0447.2008.01178.x PG 10 WC Psychiatry SC Psychiatry GA 323VC UT WOS:000257475500005 PM 18397362 ER PT J AU Douaihy, A Hilsabeck, RC Azzam, P Jain, A Daley, DC AF Douaihy, Antoine Hilsabeck, Robin C. Azzam, Pierre Jain, Abhishek Daley, Dennis C. TI Neuropsychiatric aspects of coinfection with HIV and hepatitis C virus SO AIDS READER LA English DT Review DE HIV/AIDS; hepatitis C; coinfection; neuropsychiatric disorder ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; INTERFERON-ALPHA TREATMENT; SUBSTANCE USE DISORDERS; QUALITY-OF-LIFE; COGNITIVE IMPAIRMENT; DRUG-USERS; PSYCHIATRIC-DISORDERS; LIVER-DISEASE; NEUROPSYCHOLOGICAL IMPAIRMENT AB The increasing health care crisis of coinfection with hepatitis C virus (HCV) and HIV has recently attracted the attention of research in the areas of psychiatric and neurocognitive complications related to coinfection. The preliminary data suggest that HIV/HCV coinfection has neurocognitive and psychiatric effects. This review summarizes the findings of what is known about the neurocognitive and psychiatric aspects of HIV/HCV coinfection and discusses the clinical implications and challenges in working with coinfected persons. An integrated, flexible, and interdisciplinary team approach model for treating patients who are coinfected is presented with specific recommendations for clinicians working with this population. C1 [Douaihy, Antoine; Daley, Dennis C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Hilsabeck, Robin C.] Texas Hlth Sci Ctr, San Antonio, TX USA. [Hilsabeck, Robin C.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Azzam, Pierre; Jain, Abhishek] Univ Pittsburgh, Grad Med Educ Prog, Dept Psychiat, Pittsburgh, PA 15260 USA. [Azzam, Pierre; Jain, Abhishek] Western Psychiat Inst & Clin, Pittsburgh, PA USA. RP Douaihy, A (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. FU National Institute of Neurological Disorders and Stroke (NINDS) [K23NS051244]; National Institute on Drug Abuse [U10 DA020036] FX This project was supported in part by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS051244) and in part by a grant from the National Institute on Drug Abuse (U10 DA020036). The content is solely the responsibility of the authors and does not represent the official view of the NINDS or the NTH. NR 115 TC 6 Z9 6 U1 3 U2 4 PU CLIGGOTT PUBLISHING CO PI DARIEN PA 330 BOSTON POST RD, DARIEN, CT 06820 USA SN 1053-0894 J9 AIDS READ JI Aids Read. PD AUG PY 2008 VL 18 IS 8 BP 425 EP + PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 342LY UT WOS:000258786800005 PM 18770900 ER PT J AU Kelly, JF Brown, SA Abrantes, A Kahler, CW Myers, M AF Kelly, John F. Brown, Sandra A. Abrantes, Ana Kahler, Christopher W. Myers, Mark TI Social recovery model: An 8-year investigation of adolescent 12-step group involvement following inpatient treatment SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE mutual-help groups; self-help; Alcoholics Anonymous; Narcotics Anonymous; adolescents ID SELF-HELP GROUPS; SUBSTANCE-ABUSE PATIENTS; INTENSIVE OUTPATIENT TREATMENT; COCAINE-DEPENDENT PATIENTS; MULTIVARIATE PROCESS MODEL; GROUP ATTENDANCE; CONTINUING CARE; ALCOHOL-ABUSE; USE DISORDERS; USE OUTCOMES AB Background: Despite widespread use of 12-step treatment approaches and referrals to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) by youth providers, little is known about the significance of these organizations in youth addiction recovery. Furthermore, existing evidence is based mostly on short-term follow-up and is limited methodologically. Methods: Adolescent inpatients (n = 160: mean age = 16 40% female) were followed at 6-months, and at 1, 2, 4, 6, and 8 years posttreatment. Time-lagged, generalized estimating equations modeled treatment outcome in relation to AA/NA attendance controlling for static and time-varying covariates. Robust regression (locally weighted scatterplot smoothing) explored dose-response thresholds of AA/NA attendance on outcome. Results: The AA/NA attendance was common and intensive early posttreatment, but declined sharply and steadily over the 8-year period. Patients with greater addiction severity and those who believed that they could not use substances in moderation were more likely to attend. Despite declining attendance, the effects related to AA/NA remained significant and consistent. Greater early participation was associated with better long-term outcomes. Conclusions: Even though many youth discontinue AA/NA over time, attendees appear to benefit, and more severely substance-involved youth attend most. Successful early posttreatment engagement of youth in abstinence-supportive social contexts, such as AA/NA, may have long-term implications for alcohol and drug involvement into young adulthood. C1 [Kelly, John F.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Brown, Sandra A.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Myers, Mark] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Abrantes, Ana; Kahler, Christopher W.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Abrantes, Ana] Butler Hosp, Providence, RI 02906 USA. [Kahler, Christopher W.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, 60 Staniford St,Suite 120, Boston, MA 02114 USA. EM jkelly11@partners.org OI Myers, Mark/0000-0003-4044-2914 FU NIAAA NIH HHS [5R01AA007033-09, R01 AA015526, R01AA015526-02] NR 84 TC 41 Z9 41 U1 4 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2008 VL 32 IS 8 BP 1468 EP 1478 DI 10.1111/j.1530-0277.2008.00712.x PG 11 WC Substance Abuse SC Substance Abuse GA 335YM UT WOS:000258331500015 PM 18557829 ER PT J AU Weiss, JJ Bhatti, L Dieterich, DT Edlin, BR Fishbein, DA Goetz, MB Yu, K Wagner, GJ AF Weiss, J. J. Bhatti, L. Dieterich, D. T. Edlin, B. R. Fishbein, D. A. Goetz, M. B. Yu, K. Wagner, G. J. TI Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ALPHA-2A PLUS RIBAVIRIN; HIV-INFECTED PATIENTS; PEGINTERFERON ALPHA-2A; ANTIRETROVIRAL THERAPY; VIRUS-INFECTION; TRIAL; CARE AB Background Prior research on adherence to hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence. Aim To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings. Methods One hundred and eighty patients on treatment for hepatitis C (23% co-infected with HIV) completed a cross-sectional survey at the site of their hepatitis C care. Results Seven per cent of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load. Conclusions Self-reported dose non-adherence to hepatitis C treatment occurs frequently. Further studies of dose non-adherence (assessed by method other than self-report) and its relationship to HCV virological outcome are warranted. C1 [Weiss, J. J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Bhatti, L.] AIDS Healthcare Fdn, Los Angeles, CA USA. [Dieterich, D. T.; Fishbein, D. A.] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Edlin, B. R.] Cornell Univ, Weill Med Coll, Ctr Study Hepatitis C, New York, NY 10021 USA. [Goetz, M. B.] VA Greater Los Angeles Healthcare Syst, Dept Med, Infect Dis Sect, Los Angeles, CA USA. [Goetz, M. B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Yu, K.] W LA Kaiser Permanente, Dept Infect Dis, Los Angeles, CA USA. [Wagner, G. J.] RAND Corp, Hlth Unit, Santa Monica, CA USA. RP Weiss, JJ (reprint author), Mt Sinai Sch Med, Dept Psychiat, 1 Gustave L Levy Pl,Box 1228, New York, NY 10029 USA. EM Jeffrey.Weiss@msnyuhealth.org OI Goetz, Matthew/0000-0003-4542-992X FU NIMH NIH HHS [K23 MH071177, K23 MH071177-04, K23MH071177] NR 20 TC 24 Z9 24 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD AUG 1 PY 2008 VL 28 IS 3 BP 289 EP 293 DI 10.1111/j.1365-2036.2008.03718.x PG 5 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 327GP UT WOS:000257717900003 PM 19086329 ER PT J AU Jarcho, JM Chang, L Berman, SM Suyenobu, B Naliboff, BD Lieberman, MD Ameen, VZ Mandelkern, MA Mayer, EA AF Jarcho, J. M. Chang, L. Berman, S. M. Suyenobu, B. Naliboff, B. D. Lieberman, M. D. Ameen, V. Z. Mandelkern, M. A. Mayer, E. A. TI Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT(3) receptor antagonist: a pilot study SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FUNCTIONAL G1 DISORDERS; DIARRHEA-PREDOMINANT; CEREBRAL ACTIVATION; BRAIN RESPONSES; VISCERAL PAIN; ALOSETRON; AMYGDALA; STIMULATION; PATHWAYS; PLACEBO AB Background Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50-70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT(3)R antagonist alosetron is correlated with reduced amygdala activity. Aim To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron. Methods Basal psychological distress and neural activity ((15)O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment. Results Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. Conclusions Irritable bowel disease symptom improvement with 5-HT(3)R antagonist alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome. C1 [Jarcho, J. M.; Chang, L.; Berman, S. M.; Suyenobu, B.; Naliboff, B. D.; Lieberman, M. D.; Mandelkern, M. A.; Mayer, E. A.] Univ Calif Los Angeles, Ctr Neurovisceral Sci & Womens Hlth, VAGLAHS, Los Angeles, CA 90073 USA. [Jarcho, J. M.; Lieberman, M. D.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90073 USA. [Chang, L.; Berman, S. M.; Suyenobu, B.; Mayer, E. A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. [Berman, S. M.; Naliboff, B. D.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90073 USA. [Naliboff, B. D.; Mandelkern, M. A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ameen, V. Z.] GlaxoSmithKline Inc, Res & Dev, Clin Pharmacol & Discovery Med, Res Triangle Pk, NC USA. [Mandelkern, M. A.] UCI, Dept Phys & Radiol Sci, Irvine, CA USA. [Mayer, E. A.] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90073 USA. [Mayer, E. A.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90073 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, Ctr Neurovisceral Sci & Womens Hlth, VAGLAHS, Bldg 115,Room 22,11310 Wilshire Blvd, Los Angeles, CA 90073 USA. EM emayer@ucla.edu OI Jarcho, Johanna/0000-0001-9075-6968 FU NCCIH NIH HHS [R24 AT002681-04, R24 AT002681]; NIDDK NIH HHS [R01 DK 48351, R01 DK048351-08, R01 DK048351]; NIMH NIH HHS [T32 MH015750, T32 MH015750-25, MH15750] NR 49 TC 20 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD AUG 1 PY 2008 VL 28 IS 3 BP 344 EP 352 DI 10.1111/j.1365-2036.2008.03721.x PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 327GP UT WOS:000257717900009 PM 19086332 ER PT J AU Daugherty, SL Peterson, PN Magid, DJ Ho, PM Bondy, J Hokanson, JE Ross, CA Rumsfeld, JS Masoudi, FA AF Daugherty, Stacie L. Peterson, Pamela N. Magid, David J. Ho, P. Michael Bondy, Jessica Hokanson, John E. Ross, Colleen A. Rumsfeld, John S. Masoudi, Frederick A. TI The relationship between gender and clinical management after exercise stress testing SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY-DISEASE; AMERICAN-HEART-ASSOCIATION; SEX-DIFFERENCES; PROGNOSTIC VALUE; TREADMILL; WOMEN; CAPACITY; ANGIOGRAPHY; COMMITTEE; MORTALITY AB Background Controversy remains regarding whether gender differences exist in clinical management after exercise treadmill testing (ETT). Methods We studied 7,506 patients (49.8% women) without documented coronary heart disease referred for ETT from July 2001 to June 2004 in a community-based setting. We assessed the relationship between gender and subsequent diagnostic testing (secondary stress testing or coronary angiography) within 6 months after ETT. Secondary outcomes included subsequent stress testing, coronary angiography, and new cardiology visits in the 6-month interval. Multivariable analyses assessed the relationship between gender and these outcomes adjusting for demographic, clinical, and stress test characteristics. In subsequent analyses, patients were stratified by Duke Treadmill Scores (Duke University, Durham, NC). Results Compared with men, women referred for ETT were older, had a higher prevalence of some cardiac risk factors, achieved lower peak workloads, and, more often, experienced chest pain or ST-segment changes. After accounting for differences in clinical and ETT parameters, gender was not associated with any subsequent diagnostic testing in the 6 months after ETT (OR 1.0, 95% CI 0.85-1.18). In secondary analyses, women were less likely to undergo angiography (OR 0.63, 95% CI 0.47-0.83) with a trend toward more subsequent stress testing. Stratified analyses revealed less subsequent testing in high-to-intermediate Duke Treadmill Score women compared with men (OR 0.61, 95% CI 0.48-0.79). Women and men were equally likely to die (hazards ratio 0.93, 95% CI 0.61-1.44) in the adjusted survival analysis. Conclusions Overall, women and men equally underwent subsequent diagnostic testing after ETT. Although women were less likely to undergo angiography and higher-risk women were less likely to undergo subsequent testing, adverse events were not higher in women. Given these findings, assumptions regarding gender disparities in clinical management after ETT should be reevaluated in other settings. C1 [Daugherty, Stacie L.; Peterson, Pamela N.; Ho, P. Michael; Rumsfeld, John S.; Masoudi, Frederick A.] Univ Colorado Denver, Div Cardiol, Aurora, CO 80045 USA. [Peterson, Pamela N.; Masoudi, Frederick A.] Denver Hlth Med Ctr, Div Cardiol, Denver, CO USA. [Magid, David J.; Bondy, Jessica; Hokanson, John E.] Univ Colorado Denver, Dept Prevent Med & Biometr, Aurora, CO 80045 USA. [Magid, David J.; Ross, Colleen A.; Rumsfeld, John S.; Masoudi, Frederick A.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Ho, P. Michael; Rumsfeld, John S.] Denver VA Med Ctr, Div Cardiol, Denver, CO USA. RP Daugherty, SL (reprint author), Univ Colorado Denver, Div Cardiol, 12631 E 17th Ave,B130,POB 6511, Aurora, CO 80045 USA. EM stacie.daugherty@uchsc.edu FU CV Therapeutics, Inc FX This study was funded in part by CV Therapeutics, Inc. The sponsor did not play a role in the design and conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, and approval of the manuscript. NR 27 TC 7 Z9 7 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 AUG PY 2008 VL 156 IS 2 BP 301 EP 307 DI 10.1016/j.ahj.2008.03.022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 335ZF UT WOS:000258333400016 PM 18657660 ER PT J AU Sanchez-Ledesma, M Cruz-Gonzalez, I Sanchez, PL Martin-Moreiras, J Jneid, H Rengifo-Moreno, P Cubeddu, RJ Inglessis, I Maree, AO Palacios, IF AF Sanchez-Ledesma, Maria Cruz-Gonzalez, Ignacio Sanchez, Pedro L. Martin-Moreiras, Javier Jneid, Hani Rengifo-Moreno, Pablo Cubeddu, Roberto J. Inglessis, Ignacio Maree, Andrew O. Palacios, Igor F. TI Impact of concomitant aortic regurgitation on percutaneous mitral valvuloplasty: Immediate results, short-term, and long-term outcome SO AMERICAN HEART JOURNAL LA English DT Article ID BALLOON VALVOTOMY; HEART-DISEASE; VALVE DISEASE; STENOSIS; COMMISSUROTOMY; MANAGEMENT; VARIABLES; CATHETER AB Background The aim of the study is to examine the effect of concomitant aortic regurgitation (AR) on percutaneous mitral valvuloplasty (PMV) procedural success, short-term, and long-term clinical outcome. No large-scale study has explored the impact of coexistent AR on PMV procedural success and outcome. Methods Demographic, echocardiographic, and procedure-related variables were recorded in 644 consecutive patients undergoing 676 PMV at a single center. Mortality, aortic valve surgery (replacement or repair) (AVR), mitral valve surgery (MVR), and redo PMV were recorded during follow-up. Results of the 676 procedures performed, 361 (53.4%) had no AR, 287 (42.5%) mild AR, and 28 (4.1 %) moderate AR. There were no differences between groups in the preprocedure characteristics, procedural success, or in the incidence of inhospital adverse events. At a median follow-up of 4.11 years, there was no difference in the overall survival rate (P = .22), MVR rate (P = .69), or redo PMV incidence (P = .33). The rate of AVR. was higher in the moderate AR group (0.9% vs 1.9% vs 13%, P = .003). Mean time to AVR was 4.5 years and did not differ significantly between patients with no AR, mild AR, or moderate AR (2.9 +/- 2.1 vs 5.7 +/- 3.6 vs 4.1 +/- 2.5 years, P = .46). Conclusions Concomitant AR at the time of PMV does not influence procedural success and is not associated with inferior outcome. A minority of patients with MS and moderate AR who undergo PMV will require subsequent AVR on long-term follow-up. Thus, patients with rheumatic MS and mild to moderate AR remain good candidates for PMV. C1 [Palacios, Igor F.] Harvard Univ, Cardiac Catheterizat Lab, Div Cardiol, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Sanchez, Pedro L.] Hosp Univ Gregorio Maranon, Serv Cardiol, Madrid, Spain. [Martin-Moreiras, Javier] Hosp Univ Salamanca, Serv Cardiol, Salamanca, Spain. RP Palacios, IF (reprint author), Harvard Univ, Cardiac Catheterizat Lab, Div Cardiol, Massachusetts Gen Hosp,Med Sch, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM ipalacios@partners.org RI 2008, Ibsal/A-1268-2012; OI Sanchez, Pedro L/0000-0002-4288-345X FU Spanish Society of Cardiology, Hemodynamic section (Madrid, Spain); Medtronic Iberia S.A. (Madrid, Spain); University Hospital of Salamanca (Salamanca, Spain); RECAVA; Instituto de Salud Carlos III; Spanish Ministry of Health (Madrid, Spain) FX Dr Cruz-Gonzalez would like to acknowledge the support of the Spanish Society of Cardiology, Hemodynamic section (Madrid, Spain) and Medtronic Iberia S.A. (Madrid, Spain). Dr Cruz-Gonzalez and Dr Sanchez-Ledesma would also like to acknowledge the support of the University Hospital of Salamanca (Salamanca, Spain). The authors would like to acknowledge the support of the cardiovascular network RECAVA, Instituto de Salud Carlos III, Spanish Ministry of Health (Madrid, Spain). NR 21 TC 3 Z9 3 U1 0 U2 0 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 AUG PY 2008 VL 156 IS 2 BP 361 EP 366 DI 10.1016/j.ahj.2008.03.009 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 335ZF UT WOS:000258333400025 PM 18657669 ER PT J AU LoConte, NK Gleason, CE Gunter-Hunt, G Carlsson, CM Siebers, M AF LoConte, Noelle K. Gleason, Carey E. Gunter-Hunt, Gail Carlsson, Cynthia M. Siebers, Michael TI Standardized note template improves screening of firearm access and driving among veterans with dementia SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE firearms; driving; dementia; screening; computerized medical records ID MOTOR-VEHICLE CRASHES; ALZHEIMERS-DISEASE; CARE; AFFAIRS; CLINICIAN; CESSATION; RISK; GUN AB Little is known about screening used in clinical practice to assess driving and firearm safety among patients with dementia. A case-controlled study was performed, including 22 patients with dementia seen in a geriatric evaluation and management clinic and 22 matched patients with dementia seen in a memory assessment clinic. Data about prevalence of firearm use and driving were obtained. In geriatric evaluation and management clinic, 57.9% of patients had dementia, compared with 71.0% in memory assessment clinic, and more patients were diagnosed with Alzheimer dementia in memory assessment clinic (P = .005). In geriatric evaluation and management clinic, 65% of patients had driving screening compared with 100% in memory assessment clinic (P = .07). Four percent in geriatric evaluation and management clinic were screened for firearm access versus 100% in memory assessment clinic (P < .001). In memory assessment clinic, 31.8% had firearms access and 50% were driving. Many patients continued to drive and have access to firearms. The use of templates for the progress note was effective in increasing the screening rate. C1 [LoConte, Noelle K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Hematol Oncol Sect, Madison, WI USA. [Gleason, Carey E.; Carlsson, Cynthia M.; Siebers, Michael] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Sect Geriatr & Gerontol, Madison, WI USA. [Gleason, Carey E.; Gunter-Hunt, Gail; Carlsson, Cynthia M.; Siebers, Michael] Univ Wisconsin, William S Middleton Mem Vet Hosp, Ctr Geriatr Res Educ & Clin, Madison, WI USA. [Gunter-Hunt, Gail] Univ Wisconsin, Sch Social Work, Madison, WI 53706 USA. RP LoConte, NK (reprint author), 600 Highland Ave,CSC K4-548, Madison, WI 53792 USA. EM ns3@medicine.wisc.edu FU NCI NIH HHS [K12 CA087718] NR 30 TC 5 Z9 6 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD AUG-SEP PY 2008 VL 23 IS 4 BP 313 EP 318 DI 10.1177/1533317508317061 PG 6 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA 346DS UT WOS:000259049200002 PM 18453646 ER PT J AU Conlin, PR AF Conlin, Paul R. TI Genes and environment in blood pressure control - salt intake again shows its importance SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID ANGIOTENSINOGEN GENE; HUMAN HYPERTENSION; ASSOCIATION C1 [Conlin, Paul R.] VA Boston Healthcare Syst, Med Serv, Boston, MA 02132 USA. [Conlin, Paul R.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Conlin, Paul R.] Harvard Univ, Sch Med, Boston, MA USA. RP Conlin, PR (reprint author), VA Boston Healthcare Syst, Med Serv, 1400 VFW Pkwy, W Rox Bury, MA 02132 USA. EM paul.conlin@va.gov FU NHLBI NIH HHS [R01 HL77234] NR 11 TC 1 Z9 1 U1 0 U2 0 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 AUG 1 PY 2008 VL 88 IS 2 BP 255 EP 256 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 346FY UT WOS:000259055300002 PM 18689358 ER PT J AU Rehman, S Lloyd-Jones, DM Martinez-Rumayor, A Januzzi, JL AF Rehman, Shafiq Lloyd-Jones, Donald M. Martinez-Rumayor, Abelardo Januzzi, James L., Jr. TI Inflammatory markers, amino-terminal pro-brain natriuretic peptide, and mortality risk in dyspneic patients SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE inflammatory markers; amino-terminal pro-brain natriuretic peptide; C-reactive protein; mortality; dyspnea ID C-REACTIVE PROTEIN; CONGESTIVE-HEART-FAILURE; OBSTRUCTIVE PULMONARY-DISEASE; PROGNOSTIC VALUE; ISCHEMIC CARDIOMYOPATHY; EMERGENCY-DEPARTMENT; PREDICTOR; THERAPY; PATHOGENESIS; CYTOKINES AB Dyspnea is a common emergency department (ED) complaint, and it may be associated with significant mortality risk. We studied 599 dyspneic subjects enrolled in an ED. At 1 year, the role of inflammatory markers (including C-reactive protein [CRP]) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) as independent predictors of mortality was assessed. By 1 year, 91 subjects (15.2%) had died. Among patients who died, the median CRP concentration at admission was significantly higher than in survivors: 47.2 mg/L (449.5 nmol/L; interquartile range [IQR], 10.2-101.9 mg/L [97.1-970.5 nmol/L]) vs 7.25 mg/L (69.5 nmol/L; IQR, 2.2-29.6 mg/L [21.0-281.9 nmol/L]; P < .001). For 1-year mortality, CRP had an area under the receiver operating characteristic curve of 0.76 (95% confidence interval [CI], 0.69-0.80; P < .001). In multivariable analysis, a CRP concentration greater than 14 mg/L was a strong predictor of mortality at 1 year (hazard ratio, 2.47; 95% CI, 1.51-4.02; P < .001). In multivariable models, CRP and NT-proBNP demonstrated independent and additive prognostic value. Among dyspneic patients, CRP levels are significantly associated with mortality at 1 year and show additive value to natriuretic peptide testing for prognosis. C1 [Rehman, Shafiq; Martinez-Rumayor, Abelardo; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Rehman, Shafiq; Martinez-Rumayor, Abelardo; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lloyd-Jones, Donald M.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Lloyd-Jones, Donald M.] Northwestern Univ, Div Cardiol, Bluhm Cardiovasc Inst, Chicago, IL 60611 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,Yawkey 5984, Boston, MA 02114 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 30 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2008 VL 130 IS 2 BP 305 EP 311 DI 10.1303/L7BP57F7UF7YNYKX PG 7 WC Pathology SC Pathology GA 328YG UT WOS:000257833500021 PM 18628102 ER PT J AU Gupta, N Bostrom, AG Kirschner, BS Cohen, SA Abramson, O Ferry, GD Gold, BD Winter, HS Baldassano, RN Smith, T Heyman, MB AF Gupta, Neera Bostrom, Alan G. Kirschner, Barbara S. Cohen, Stanley A. Abramson, Oren Ferry, George D. Gold, Benjamin D. Winter, Harland S. Baldassano, Robert N. Smith, Terry Heyman, Melvin B. TI Presentation and disease course in early-compared to later-onset pediatric Cohn's disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; CHILDHOOD; MORTALITY; CHILDREN; YOUNGER; AGE AB BACKGROUND: The relationship between the age at diagnosis and disease course is poorly defined in children with Crohn's disease (CD). We examined the presentation and course of disease in patients 0-5 compared to 6-17 yr of age at diagnosis. METHODS: We analyzed uniform data from 989 consecutive CD patients collected between January 2000 and November 2003, and stored in the Pediatric IBD Consortium Registry. The statistical tests account for the length of follow-up of each patient. RESULTS: In total, 98 patients (9.9%) were of 0-5 yr of age at diagnosis. The mean follow-up time was 5.6 +/- 5.0 yr in the younger group and 3.3 +/- 2.8 yr in the older group (P < 0.001). Race/ethnicity differed by the age group (P = 0.015); a larger proportion of the younger group was Asian/Pacific Islander or Hispanic, and a larger proportion of the older group was African American. The initial classification as ulcerative colitis or indeterminate colitis was more common among the 0-5 yr of age group (P < 0.001). The 6-17 yr of age patients presented with more abdominal pain (P < 0.001), weight loss (P = 0.001) or fever (P = 0.07), while the 0-5 yr of age patients presented with more rectal bleeding (P = 0.008). The 6-17 yr of age patients were more likely to be treated with antibiotics (P < 0.001), 6-mercaptopurine/azathioprine (P < 0.001), infliximab (P = 0.001), or corticosteroids (P = 0.0006). The 6-17 yr of age patients had a higher cumulative incidence of treatment with 5-aminosalicylates (P = 0.009) or methotrexate (P = 0.04). The risk for developing an abscess (P = 0.001), a fistula (P = 0.02), a stricture (P = 0.05), or a perianal fissure (P =0.06) was greater in the 6-17 yr of age patients. CONCLUSIONS: The 6-17 yr of age patients with CD appear to have a more complicated disease course compared to 0-5 yr of age children. The 0-5 yr of age group may represent a unique disease phenotype and benefit from different approaches to management. Long-term prospective studies are required to validate these findings. C1 [Gupta, Neera; Heyman, Melvin B.] Univ Calif San Francisco, Childrens Hosp, San Francisco, CA 94143 USA. [Bostrom, Alan G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kirschner, Barbara S.] Univ Chicago, Comer Childrens Hosp, Chicago, IL 60637 USA. [Cohen, Stanley A.; Gold, Benjamin D.] Childrens Healthcare Atlanta, Childrens Ctr Digest Healthcare, Atlanta, GA USA. [Abramson, Oren] Kaiser Permanente No Calif, Oakland, CA USA. [Ferry, George D.; Smith, Terry] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Cohen, Stanley A.; Gold, Benjamin D.] Emory Univ, Sch Med, Atlanta, GA USA. [Winter, Harland S.] MassGen Hosp Children, Boston, MA USA. [Baldassano, Robert N.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Gupta, N (reprint author), Univ Calif San Francisco, Childrens Hosp, 500 Parnassus Ave,MU-4 East,Box 0136, San Francisco, CA 94143 USA. FU NIDDK NIH HHS [DK007762, DK060617, DK077734, DK53708, K23 DK077734, K24 DK060617, K24 DK060617-03, R01 DK053708, T32 DK007762, T32 DK007762-27] NR 17 TC 46 Z9 46 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 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2008 VL 103 IS 8 BP 2092 EP 2098 DI 10.1111/j.1572-0241.2008.02000.x PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 335GG UT WOS:000258278200030 PM 18796101 ER PT J AU Barton, C Sklenicka, J Sayegh, P Yaffe, K AF Barton, Cynthia Sklenicka, Julie Sayegh, Philip Yaffe, Kristine TI Contraindicated medication use among patients in a memory disorders clinic SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article; Proceedings Paper CT 58th Annual Meeting of the American-Academy-of-Neurology CY APR 01-08, 2006 CL San Diego, CA SP Amer Acad Neurol DE dementia; medications; Alzheimer's disease ID COGNITIVE IMPAIRMENT; OLDER-ADULTS; CHOLINESTERASE-INHIBITORS; ANTICHOLINERGIC DRUGS; OVERACTIVE BLADDER; CONSENSUS PANEL; ELDERLY-PEOPLE; INAPPROPRIATE; DEMENTIA; CRITERIA AB Background: Inappropriate or contraindicated use of medications in elderly patients is common and associated with poor outcomes. An important risk factor for adverse drug events is the increased sensitivity to drug effects on the central nervous system (CNS). There is a high rate of use of CNS-active drugs in patients with cognitive impairment, despite the fact that these medications may worsen cognition and be a possible "reversible" cause of memory loss. Objectives: The goals of this study were to establish the prevalence of these contraindicated medications in a Population of elderly patients referred to a memory disorders clinic for evaluation and to determine if those individuals receiving contraindicated medications had specific characteristics. This included determining how many patients were concurrently being prescribed a cholinesterase inhibitor. Methods: The review included new patients consecutively evaluated for cognitive complaints in a memory disorders clinic between June 2003 and August 2004. Each patient underwent a comprehensive evaluation by a multi-disciplinary team during a 3-hour clinic appointment. A thorough history of cognitive deficits and associated symptoms was obtained by the physician, who also performed a comprehensive neurologic examination. All patients underwent neuropsychologic testing with an extensive cognitive battery. In addition, patients' electronic medical records were reviewed to determine a list of prescribed and over-the-counter medications at the time of the initial referral. Contraindicated medications were identified using the updated Beers criteria of medications that should be avoided in older patients with cognitive impairment or that have high CNS adverse effects. Results: A total of 100 patients (91 men, 9 women; mean [SD] age, 7-5.8 [9.7] years; 73% white) were included in the study. Eighty-six patients were determined at the time of evaluation to have some kind of cognitive impairment. They were mildly impaired, with a mean (SD) Mini-Mental State Examination score of 22.9 (5.1), based oil a scale of 0 to 30. Twenty-two patients were taking >= 1 contraindicated medication that could potentially affect their cognition; the most frequently prescribed were benzodiazepines, oxybutynin, amitriptyline, fluoxetine, and diphenhydramine. Twenty-eight of the 100 patients were being treated with a cholinesterase inhibitor at the time of their evaluation; of these, 4 (14%) were also taking >= 1 medication with anticholinergic properties. Conclusions: Despite research evidence and recommendations to avoid these CNS-active medications because of their adverse effects, they continue to be prescribed in elderly patients with cognitive impairments. Further research is needed to determine strategies that will help reduce their administration in this population. C1 [Barton, Cynthia; Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Sklenicka, Julie] USN, Ctr Med, San Diego, CA 92152 USA. [Sayegh, Philip] Univ So Calif, Dept Psychol, Clin Sci Program, Los Angeles, CA 90089 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Barton, C (reprint author), Univ Calif San Francisco, Dept Neurol, Box 127,4150 Clement St, San Francisco, CA 94121 USA. EM cbarton@memory.ucsf.edu NR 27 TC 21 Z9 21 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 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD AUG PY 2008 VL 6 IS 3 BP 147 EP 152 DI 10.1016/j.amjopharm.2008.08.002 PG 6 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 344US UT WOS:000258953400002 PM 18775389 ER PT J AU Kasckow, J Patterson, T Fellows, I Golshan, S Solorzano, E Mohamed, S AF Kasckow, John Patterson, Thomas Fellows, Ian Golshan, Shahrokh Solorzano, Ellen Mohamed, Somaia TI Functioning in middle aged and older patients with schizophrenia and depressive symptoms: Relationship to psychopathology SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE schizophrenia; functioning; psychopathology; negative symptoms AB Background: Depressive symptoms are common in middle aged and older patients with schizophrenia. The authors hypothesized that worse functioning in these patients would be associated with worse psychopathology. Methods: Outpatients with schizophrenia were >= 40 years old with subsyndromal depression and Hamilton Depression Rating Scale Scores of >= 8. Exclusions were dementia, two months of either mania or major depression or 1 month active substance abuse/dependence. The authors administered performance based functional assessments, the Positive and Negative Syndrome Scale of Schizophrenia [PANSS], and Calgary Depression Rating Scale. Results: PANSS (-) scores were negatively correlated with the UCSD Performance Skills Based Assessment, Social Skills Performance Assessment and Medication Management Ability Assessment total error (MMAA) scores. Digit symbol scores served as a moderator of the relationship between MMAA and PANSS (-) scores. Conclusions: Negative symptoms were associated with functioning. The relationship between negative symptoms and medication errors seem to weaken in subjects with quicker processing speed. C1 VA Pittsburgh Hlth Care System, MIRECC & Behav Hlth Serv, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. San Diego Hlth Care System, San Diego, CA USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Kasckow, J (reprint author), VA Pittsburgh Hlth Care System, MIRECC & Behav Hlth Serv, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM jkasckow@pol.net FU NIMH NIH HHS [R01 MH063798-06, R01 MH063798, MH6398-05, R01 MH063931-05, R01 MH063931] NR 9 TC 7 Z9 7 U1 0 U2 0 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 AUG PY 2008 VL 16 IS 8 BP 660 EP 663 DI 10.1097/JGP.0b013e31816ff746 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 332QD UT WOS:000258097300006 PM 18669944 ER PT J AU Kiely, DK Prigerson, H Mitchell, SL AF Kiely, Dan K. Prigerson, Holly Mitchell, Susan L. TI Health care proxy grief symptoms before the death of nursing home residents with advanced dementia SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE grief; depression; advanced dementia; nursing homes; health care proxy ID BEREAVEMENT-RELATED DEPRESSION; OF-LIFE CARE; STAGE ALZHEIMERS-DISEASE; COMPLICATED GRIEF; TRAUMATIC GRIEF; DISORDER DISTINCT; MENTAL-HEALTH; ANXIETY; SCALES; CAREGIVERS AB Objectives: The loss experienced by family members of dementia patients before their actual death is known as "predeath grief." This study's objectives were to identify and describe factors associated predeath grief symptoms among health care proxies (HCPs) of nursing home (NH) residents with advanced dementia, and distinguish grief symptoms from those of depression. Design: Cross-sectional. Setting: Twenty-one Boston-area NHs. Participants: Three hundred fifteen NH residents with advanced dementia and their HCPs. Measurements: Factor analysis was used to distinguish predeath grief and depression symptoms. Multivariate regression analyses identified factors associated with greater predeath grief measured on a 10-item summary scale of grief symptoms. Independent variables included sociodemographic information and health status of HCPs and residents, and depressive symptoms, physician communication, preparedness for death, and satisfaction with care of HCPs. Results: Predeath grief symptoms were distinct from depressive symptoms. The mean predeath grief scores was 15.0 +/- 5.6 (range, 10-49), suggesting relatively low levels of overall grief. Yearning (i.e., separation distress) was the most frequently experienced grief symptom (sometimes, 27%; often, 18%; or always, 15%). Variables associated with greater predeath grief included HCPs whose primary language was not English, HCPs who lived with a resident before institutionalization, more depressive symptoms of HCPs, less satisfaction with care of HCPs, and younger resident age. Conclusions: Family members of NH residents with advanced dementia experience predeath grief symptoms, particularly separation distress. Predeath grief symptoms are associated with, but distinct from, those of depression. Several factors identified HCPs at higher risk for predeath grief and who may benefit from early interventions to reduce suffering. C1 [Kiely, Dan K.; Mitchell, Susan L.] Hebrew Senior Life, Inst Aging Res, Boston, MA 02131 USA. [Prigerson, Holly] Dana Farber Canc Inst, Ctr Psychosocial Oncol & Palliat Care Res, Boston, MA 02115 USA. [Mitchell, Susan L.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Kiely, DK (reprint author), Hebrew Senior Life, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM kiely@hrca.harvard.edu FU NIA NIH HHS [K24 AG033640, P50 AG05134, R01 AG024091, R01 AG024091-03, P50 AG005134] NR 40 TC 28 Z9 28 U1 1 U2 13 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 AUG PY 2008 VL 16 IS 8 BP 664 EP 673 DI 10.1097/JGP.0b013e3181784143 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 332QD UT WOS:000258097300007 PM 18669945 ER PT J AU Zivin, K McCammon, RJ Davis, MM Halasyamani, LK Kales, HC AF Zivin, Kara McCammon, Ryan J. Davis, Matthew M. Halasyamani, Lakshmi K. Kales, Helen C. TI Increases in Medicare prescription drug plan costs attributable to psychotropic medications SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE prescription medication; medicare prescription drug plan; depression; bipolar disorder' psychosis; dementia ID LATE-LIFE DEPRESSION; BENEFICIARIES; NONADHERENCE; COMORBIDITY; PRESSURES; ADULTS AB Objective: Older patients may regard some medications, particularly psychotropic medications, as discretionary compared with what they perceive as more "essential" nonpsychiatric medications. Patients' concerns about psychotropic medication costs under Medicare Part D may reinforce these impressions. Design: The authors examined which Medicare prescription drug plans (PDPs) would be least expensive for beneficiaries considering the costs of 1) all medications; and 2) only nonpsychiatric medications. Setting: The authors collected data from the PDP online comparison tool provided by the Centers for Medicare and Medicaid Services (CMS). Participants: Hypothetical Medicare beneficiaries. Measurements: The authors examined four clinical scenarios from older outpatients with both chronic medical and psychiatric conditions (including psychosis, bipolar disorder, depression, and dementia with behavioral disturbances). Results: The authors examined data from all 160 plans available in CMS PDP regions in May 2007. There were frequent discrepancies in the least expensive PDPs within region, depending on considering the costs of all medications, or just nonpsychiatric medications. In the clinical scenarios, patients selecting a PDP based on nonpsychiatric medications alone would pick an unnecessarily more expensive plan 74%-100% of the time (when they took any brand name medication), suggesting that excluding psychiatric medications from PDP choices may be excessively costly. However, brand name psychotropic medications significantly increased the costs of the least expensive plans. The latter finding might persuade patients to avoid taking needed psychiatric medication due to cost. Conclusion: This research highlights the complexity that patients with psychiatric and cognitive disorders face when choosing a Medicare PDP. Policymakers and clinicians should be aware of the tradeoffs that beneficiaries with psychiatric disorders face when making PDP plan choices. C1 [Zivin, Kara; Kales, Helen C.] US Dept Vet Affairs, HSR&D, Ctr Excellence, SMITREC, Ann Arbor, MI USA. [Zivin, Kara; McCammon, Ryan J.; Kales, Helen C.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Davis, Matthew M.; Halasyamani, Lakshmi K.] Univ Michigan, Sch Med, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Davis, Matthew M.] Univ Michigan, Sch Med, Div Gen Pediat, Child Hlth Evaluat & Res Unit, Ann Arbor, MI 48109 USA. [Davis, Matthew M.] Univ Michigan, Gerald R Ford Sch Publ Policy, Ann Arbor, MI 48109 USA. [Halasyamani, Lakshmi K.] St Joseph Mercy Hosp, Dept Internal Med, Ann Arbor, MI 48104 USA. RP Zivin, K (reprint author), Univ Michigan, Sch Med, Dept Psychiat, 4250 Plymouth Rd,Box 5765, Ann Arbor, MI 48109 USA. EM kzivin@umich.edu NR 17 TC 3 Z9 3 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD AUG PY 2008 VL 16 IS 8 BP 674 EP 685 DI 10.1097/JGP.0b013e3181794591 PG 12 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 332QD UT WOS:000258097300008 PM 18669946 ER PT J AU Smith, AK Ladner, D McCarthy, EP AF Smith, Alexander K. Ladner, Daniela McCarthy, Ellen P. TI Racial/ethnic disparities in liver transplant surgery and hospice use: Parallels, differences, and unanswered questions SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE hospice; liver transplant; race; ethnicity; disparities ID OF-LIFE CARE; MEDICARE MANAGED CARE; RACIAL DISPARITIES; CANCER-PATIENTS; RENAL-TRANSPLANTATION; NATIONAL HOSPICE; PALLIATIVE CARE; WHITE PATIENTS; TERMINAL CARE; END AB Despite well-documented racial/ethnic disparities in liver transplantation and hospice enrollment, reasons for these disparities are unclear. This study was conducted to elucidate what is known and unknown about the underlying causes of racial/ethnic disparities in liver transplantation and hospice enrollment. The root causes of inequities in access to liver transplantation and hospice are as yet poorly understood. Potential contributors to differences include differences in preferences, mistrust of the health care system, geographic factors such as neighborhood, health care system factors such as access to care and managed care versus fee-for-service insurance status, and social factors Such as the availability of a full time caregiver. Although the goals of care are different, by examining hospice and transplant surgery side by side in the larger context of health disparities, a number of potentially promising avenues for future research have been uncovered. C1 [Smith, Alexander K.; McCarthy, Ellen P.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Smith, Alexander K.] Dana Farber Canc Inst, Div Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Ladner, Daniela] Stanford Univ, Med Ctr, Dept Surg, Div Transplantat, Palo Alto, CA 94304 USA. RP Smith, AK (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM asmith7@bidmc.harvard.edu FU National Research Service Award [5 T32 HP11001-19] FX Dr Smith is supported by an institutional National Research Service Award, #5 T32 HP11001-19. NR 51 TC 4 Z9 4 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD AUG-SEP PY 2008 VL 25 IS 4 BP 285 EP 291 DI 10.1177/1049909108315914 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 341ZU UT WOS:000258755200006 PM 18463409 ER PT J AU Newsome, BB McClellan, WM Allison, JJ Eggers, PW Chen, SC Collins, AJ Kiefe, CI Coffey, CS Warnock, DG AF Newsome, Britt B. McClellan, William M. Allison, Jeroan J. Eggers, Paul W. Chen, Shu-Cheng Collins, Allan J. Kiefe, Catarina I. Coffey, Christopher S. Warnock, David G. TI Racial differences in the competing risks of mortality and ESRD after acute myocardial infarction SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE African American; chronic kidney disease; end-stage renal disease; health disparities; Medicare ID STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; NUTRITION EXAMINATION SURVEY; GLOMERULAR-FILTRATION-RATE; 3RD NATIONAL-HEALTH; POTENTIAL EXPLANATORY FACTORS; QUALITY-OF-CARE; UNITED-STATES; MEDICARE BENEFICIARIES; SERUM CREATININE AB Background: The prevalence of earlier stage chronic kidney disease is lower for African Americans than whites in the United States. This is counterintuitive given the known 4-fold greater incidence of end-stage renal disease (ESRD) in African Americans. We describe racial differences in the rate of progression to ESRD and address the competing risk of mortality. Study Design: Retrospective analysis of Cooperative Cardiovascular Project data. Setting & Participants: 127,736 Medicare beneficiaries 65 years and older admitted to 4,545 hospitals with acute myocardial infarction between February 1994 and June 1995, with follow-up data for ESRD and mortality through June 2004. Predictors: African American versus white race, estimated glomerular filtration rate (eGFR), and their interaction; other characteristics at hospital admission. Outcomes & Measurements: Time to ESRD using Cox proportional hazards models. Results: Mean age was 77.1 years, with 8,278 African Americans (6.5%) and 49.9% women. Mean baseline eGFRs were 61.4 +/- 31.4 and 57.0 +/- 25.6 mL/min/1.73 m(2) (P < 0.001) for African Americans and whites, respectively. Of 2,161 patients (1.7%) progressing to ESRD (incidence, 3.75/1,000 person-years), 14.9% were African American. The adjusted hazard ratio for ESRD (African Americans versus whites) was 1.90 (95% confidence interval, 1.78 to 2.03); African Americans were at significantly increased risk of incident ESRD at each baseline eGFR stage (P for interaction < 0.001). Racial differences in incident ESRD were not accounted for by differences in mortality. Limitations: Retrospective analysis, residual bias from unmeasured factors, baseline eGFR determined from serum creatinine levels at the time of acute hospitalization. Conclusions: Within a nationally representative sample of Medicare patients with acute myocardial infarction, African Americans had an increased 10-year risk of ESRD regardless of baseline kidney function that was not accounted for by differences in pre-ESRD mortality. C1 [Newsome, Britt B.; Allison, Jeroan J.; Kiefe, Catarina I.] Univ Alabama, Ctr Outcomes Effectiveness Res & Educ, Birmingham, AL USA. [Newsome, Britt B.; Allison, Jeroan J.; Kiefe, Catarina I.] Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Newsome, Britt B.; Warnock, David G.] Univ Alabama, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. [McClellan, William M.] Emory Univ, Sch Med, Div Renal, Dept Med, Atlanta, GA 30322 USA. [Allison, Jeroan J.] Univ Alabama, Dept Med, Div Gen Internal Med, Birmingham, AL 35294 USA. [Eggers, Paul W.; Chen, Shu-Cheng; Collins, Allan J.] US Renal Data System, Bethesda, MD USA. [Kiefe, Catarina I.] Univ Alabama, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Coffey, Christopher S.] Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. RP Newsome, BB (reprint author), 1530 3rd Ave S,MT 40JE2, Birmingham, AL 35294 USA. EM bnewsome@uab.edu OI Allison, Jeroan/0000-0003-4472-2112 FU AHRQ HHS [HS013852]; NHLBI NIH HHS [R01 HL070786, R01 HL70786]; None [HS013852] NR 38 TC 14 Z9 14 U1 1 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2008 VL 52 IS 2 BP 251 EP 261 DI 10.1053/j.ajkd.2008.03.019 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 330LR UT WOS:000257943400010 PM 18468746 ER PT J AU Jhamb, M Weisbord, SD Steel, JL Unruh, M AF Jhamb, Manisha Weisbord, Steven D. Steel, Jennifer L. Unruh, Mark TI Fatigue in patients receiving maintenance dialysis: A review of definitions, measures, and contributing factors SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Review DE fatigue; end-stage renal disease; quality of life; psychometrics; cytokines; postdialysis fatigue ID QUALITY-OF-LIFE; STAGE RENAL-DISEASE; ECOLOGICAL MOMENTARY ASSESSMENT; CHRONIC KIDNEY-DISEASE; C-REACTIVE PROTEIN; RANDOMIZED CONTROLLED-TRIAL; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; HEMODIALYSIS-PATIENTS; PERITONEAL-DIALYSIS AB Fatigue is a debilitating symptom or side effect experienced by many patients on long-term dialysis therapy. Fatigue has a considerable effect on patient health-related quality of life and is viewed as being more important than survival by some patients. Renal providers face many challenges when attempting to reduce fatigue in dialysis patients. The lack of a reliable, valid, and sensitive fatigue scale complicates the accurate identification of this symptom. Symptoms of daytime sleepiness and depression overlap with fatigue, making it difficult to target specific therapies. Moreover, many chronic health conditions common in the long-term dialysis population may lead to the development of fatigue and contribute to the day-to-day and diurnal variation in fatigue in patients. Key to improving the assessment and treatment of fatigue is improving our understanding of potential mediators, as well as potential therapies. Cytokines have emerged as an important mediator of fatigue and have been studied extensively in patients with cancer-related fatigue. In addition, although erythropoietin-stimulating agents have been shown to mitigate fatigue, the recent controversy regarding erythropoietin-stimulating agent dosing in patients with chronic kidney disease suggests that erythropoietin-stimulating agent therapy may not serve as the sole therapy to improve fatigue in this population. In conclusion, fatigue is an important and often underrecognized symptom in the dialysis population. Possible interventions for minimizing fatigue in patients on long-term dialysis therapy should aim at improving health care provider awareness, developing improved methods of measurement, understanding the pathogenesis better, and managing known contributing factors. C1 [Unruh, Mark] Univ Pittsburgh, Med Ctr, Renal Electrolyte Div, Pittsburgh, PA 15261 USA. [Jhamb, Manisha] Western Penn Med Ctr, Pittsburgh, PA USA. [Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Weisbord, Steven D.] Univ Pittsburgh, Renal Electrolyte Div, Med Ctr, Pittsburgh, PA USA. [Steel, Jennifer L.] Univ Pittsburgh, Sch Med, Dept Surg, Liver Canc Ctr,Starzl Transplantat Inst, Pittsburgh, PA USA. RP Unruh, M (reprint author), Univ Pittsburgh, Med Ctr, Renal Electrolyte Div, 3550 Terrace St,A915 Scaife Hall, Pittsburgh, PA 15261 USA. EM unruh@pitt.edu RI Jhamb, Manisha/E-4169-2013 FU NIDDK NIH HHS [DK66006, DK77785, K23 DK066006, K23 DK066006-04, R01 DK077785, R01 DK077785-01] NR 131 TC 68 Z9 76 U1 2 U2 11 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 AUG PY 2008 VL 52 IS 2 BP 353 EP 365 DI 10.1053/j.ajkd.2008.05.005 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 330LR UT WOS:000257943400021 PM 18572290 ER PT J AU Masoud, M Masoud, I Kent, RL Gowharji, N Cohen, LE AF Masoud, Mohamed Masoud, Ibrahim Kent, Ralph L., Jr. Gowharji, Nour Cohen, Laurie E. TI Assessing skeletal maturity by using blood spot insulin-like growth factor I (IGF-I) testing SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID MANDIBULAR CONDYLAR CARTILAGE; LONGITUDINAL BONE-GROWTH; FILTER-PAPER; CHONDROCYTE DIFFERENTIATION; CERVICAL-VERTEBRAE; HEALTHY-CHILDREN; MATURATION; HORMONE; SOMATOMEDIN; EXPRESSION AB Introduction: Accurate determination of skeletal maturity and remaining growth is crucial to many orthodontic, orthognathic, and dental-implant timing decisions. Cervical vertebral stages and hand-wrist radiographs are currently used to identify peak mandibular bone growth. These are highly subjective techniques that not only involve radiographic exposure but also lack the ability to determine the intensity of the growth spurt and the end of growth. Insulin-like growth factor I (IGF-I) is a circulating growth hormone-dependent factor whose level correlates with sexual maturity; it is used to diagnose growth hormone deficiency and excess. We hypothesized that IGF-I levels would also correlate with cervical skeletal maturity and would be highest at the cervical stages that correspond to the greatest amount of facial growth. Methods: We measured mean blood spot IGF-I levels in a cross-sectional study of 83 patients (44 female, 39 male) on recall to begin orthodontic treatment, in active treatment, or in posttreatment follow-up. Results: Mean blood spot IGF-I levels were significantly higher in the late pubertal stages than in the prepubertal, early pubertal, and postpubertal stages. Linear correlation showed that IGF-I levels had a significant positive correlation with cervical skeletal maturity from the prepubertal to the late pubertal stages, and a significant negative correlation from the late pubertal to the postpubertal stages. In the postpubertal stage, IGF-I levels had a negative linear correlation with increasing time since the onset of puberty and with chronological age. Conclusions: Blood spot IGF-I could be used as a skeletal maturity indicator and might be useful in detecting residual mandibular growth in young adults. C1 [Masoud, Mohamed] Harvard Univ, Sch Dent Med, Dept Orthodont, Boston, MA 02115 USA. [Masoud, Mohamed] King Abdulaziz Univ, Div Orthodont, Jeddah 21413, Saudi Arabia. [Kent, Ralph L., Jr.] Forsyth Inst, Dept Biostat, Boston, MA USA. [Gowharji, Nour] Tufts Sch Dent Med, Boston, MA USA. [Cohen, Laurie E.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Masoud, M (reprint author), Harvard Univ, Sch Dent Med, Dept Orthodont, 188 Longwood Ave,REB 402, Boston, MA 02115 USA. EM masoudortho@gmail.com NR 72 TC 16 Z9 19 U1 3 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 EI 1097-6752 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD AUG PY 2008 VL 134 IS 2 BP 209 EP 216 DI 10.1016/j.ajodo.2006.09.063 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 332SS UT WOS:000258104000016 PM 18675202 ER PT J AU Akbay, EA Contreras, CM Perera, SA Sullivan, JP Broaddus, RR Schorge, JO Ashfaq, R Saboorian, H Wong, KK Castrillon, DH AF Akbay, Esra A. Contreras, Cristina M. Perera, Samanthi A. Sullivan, James P. Broaddus, Russell R. Schorge, John O. Ashfaq, Raheela Saboorian, Hossein Wong, Kwok-Kin Castrillon, Diego H. TI Differential roles of telomere attrition in type I and II endometrial carcinogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID DNA MISMATCH REPAIR; MOLECULAR-GENETIC-PATHWAYS; UTERINE CORPUS; CHROMOSOME-ABNORMALITIES; PROBLEMATIC ASPECTS; CELL-LINE; CARCINOMA; CANCER; P53; LENGTH AB Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers. C1 [Akbay, Esra A.; Contreras, Cristina M.; Ashfaq, Raheela; Castrillon, Diego H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Akbay, Esra A.; Contreras, Cristina M.; Sullivan, James P.; Schorge, John O.; Ashfaq, Raheela; Castrillon, Diego H.] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Sullivan, James P.; Schorge, John O.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Schorge, John O.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Div Gynecol Oncol, Dallas, TX 75390 USA. [Broaddus, Russell R.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Perera, Samanthi A.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Saboorian, Hossein] Caris Diagnost, Irving, TX USA. RP Castrillon, DH (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pathol, 6000 Harry Hines Blvd, Dallas, TX 75390 USA. EM diego.castrillon@utsouthwestern.edu OI wong, kwok kin/0000-0001-6323-235X NR 51 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2008 VL 173 IS 2 BP 536 EP 544 DI 10.2353/ajpath.2008.071179 PG 9 WC Pathology SC Pathology GA 331LJ UT WOS:000258013400023 PM 18599611 ER PT J AU Popescu, G Park, Y Lue, N Best-Popescu, C Deflores, L Dasari, RR Feld, MS Badizadegan, K AF Popescu, Gabriel Park, YoungKeun Lue, Niyom Best-Popescu, Catherine Deflores, Lauren Dasari, Ramachandra R. Feld, Michael S. Badizadegan, Kamran TI Optical imaging of cell mass and growth dynamics SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE phase microscopy; interferometric microscopy; cell growth ID PHASE MICROSCOPY; DIFFRACTION PHASE; LIVING CELLS; HIGH GLUCOSE; CONTRAST; INTERFEROMETER; MICRORHEOLOGY; SUBWAVELENGTH; HYPERTROPHY; BEHAVIOR AB Using novel interferometric quantitative phase microscopy methods, we demonstrate that the surface integral of the optical phase associated with live cells is invariant to cell water content. Thus, we provide an entirely noninvasive method to measure the nonaqueous content or " dry mass" of living cells. Given the extremely high stability of the interferometric microscope and the femtogram sensitivity of the method to changes in cellular dry mass, this new technique is not only ideal for quantifying cell growth but also reveals spatially resolved cellular and subcellular dynamics of living cells over many decades in a temporal scale. Specifically, we present quantitative histograms of individual cell mass characterizing the hypertrophic effect of high glucose in a mesangial cell model. In addition, we show that in an epithelial cell model observed for long periods of time, the mean squared displacement data reveal specific information about cellular and subcellular dynamics at various characteristic length and time scales. Overall, this study shows that interferometeric quantitative phase microscopy represents a noninvasive optical assay for monitoring cell growth, characterizing cellular motility, and investigating the subcellular motions of living cells. C1 [Badizadegan, Kamran] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Popescu, Gabriel; Park, YoungKeun; Lue, Niyom; Deflores, Lauren; Dasari, Ramachandra R.; Feld, Michael S.; Badizadegan, Kamran] Massachusetts Inst Technol, George R Harrison Spect Lab, Cambridge, MA USA. [Best-Popescu, Catherine] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Hlth Sci & Technol, Boston, MA 02115 USA. RP Badizadegan, K (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WRN219, Boston, MA 02114 USA. EM kbadizadegan@partners.org RI Park, YongKeun/B-9017-2009 FU National Center for Research Resources Research [P41-RR-02594] FX This work was supported by National Center for Research Resources Research Grant P41-RR-02594 and by Hamamatsu Photonics. NR 41 TC 151 Z9 151 U1 3 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 2008 VL 295 IS 2 BP C538 EP C544 DI 10.1152/ajpcell.00121.2008 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 345JI UT WOS:000258992200028 PM 18562484 ER PT J AU Jiang, Q Ko, WKW Lerner, EA Chan, KM Wong, AOL AF Jiang, Quan Ko, Wendy K. W. Lerner, Ethan A. Chan, K. M. Wong, Anderson O. L. TI Grass carp somatolactin: I. Evidence for PACAP induction of somatolactin-alpha and -beta gene expression via activation of pituitary PAC-I receptors SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE pituitary adenylate cyclase-activating polypeptide; grass carp pituitary cells ID HORMONE/PROLACTIN/SOMATOLACTIN FAMILY HORMONES; TROUT ONCORHYNCHUS-MYKISS; FISH GROWTH-HORMONE; ADENYLATE-CYCLASE; POLYPEPTIDE PACAP; RAINBOW-TROUT; (GH)-RELEASING FACTOR; REPRODUCTIVE STATUS; MOLECULAR-CLONING; ANGUILLA-ANGUILLA AB Somatolactin (SL), the latest member of the growth hormone/prolactin family, is a novel pituitary hormone with diverse functions. At present, SL can be identified only in fish but not in tetrapods and its regulation at the pituitary level has not been fully characterized. Using grass carp as a model, we examined the direct effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on SL secretion and synthesis at the pituitary cell level. As a first step, the structural identity of grass carp SL, SL alpha and SL beta, was established by 5 '/3 '-rapid amplification of cDNA ends. These two SL isoforms are single-copy genes and are expressed in two separate populations of pituitary cells located in the pars intermedia. In the carp pituitary, PACAP nerve fibers were detected in the nerve tracts of the neurohypophysis and extended into the vicinity of pituitary cells forming the pars intermedia. In primary cultures of grass carp pituitary cells, PACAP was effective in stimulating SL release, cellular SL content, and total SL production. The increase in SL production also occurred with parallel rises in SL alpha and SL beta mRNA levels. With the use of a combination of molecular and pharmacological approaches, PACAP-induced SL release and SL gene expression were shown to be mediated by pituitary PAC-I receptors. These findings, as a whole, suggest that PACAP may serve as a hypophysiotropic factor in fish stimulating SL secretion and synthesis at the pituitary level. Apparently, PACAP-induced SL production is mediated by upregulation of SL alpha and SL beta gene expression through activation of PAC-I receptors. C1 [Wong, Anderson O. L.] Univ Hong Kong, Div Endocrinol, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. [Lerner, Ethan A.] Massachusetts Gen Hosp, Dept Dermatol, Charlestown, MA USA. [Chan, K. M.] Chinese Univ Hong Kong, Dept Biochem, Shatin, Hong Kong, Peoples R China. RP Wong, AOL (reprint author), Univ Hong Kong, Div Endocrinol, Sch Biol Sci, 4S-12 Kadoorie Biol Sci Bldg,Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. EM olwong@hkucc.hku.hk RI Wong, Anderson/A-2735-2010 NR 54 TC 26 Z9 26 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2008 VL 295 IS 2 BP E463 EP E476 DI 10.1152/ajpendo.90385.2008 PG 14 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 333DS UT WOS:000258133200030 PM 18523122 ER PT J AU Misra, M Bredella, MA Tsai, P Mendes, N Miller, KK Klibanski, A AF Misra, Madhusmita Bredella, Miriam A. Tsai, Patrika Mendes, Nara Miller, Karen K. Klibanski, Anne TI Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE obesity; body composition; homeostasis model assessment of insulin resistance; lipids ID PLACEBO-CONTROLLED TRIAL; BODY-COMPOSITION; OBESE ADOLESCENTS; CUSHINGS-SYNDROME; FAT DISTRIBUTION; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR RISK; METABOLIC PROFILE; GLUCOSE-TOLERANCE; ANOREXIA-NERVOSA AB Although body composition, insulin sensitivity, and lipids are markedly altered in overweight adolescents, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. We hypothesized that low-peak GH on the GH-releasing hormone (GHRH)-arginine stimulation test and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance, and lipids. We examined the following parameters in 15 overweight and 15 bone age-matched control 12- to 18-yr-old girls: 1) body composition using dual-energy X-ray absorptiometry and MR [visceral and subcutaneous adipose tissue at L-4-L-5 and soleus intramyocellular lipid (H-1-MR spectroscopy)], 2) peak GH on the GHRH-arginine stimulation test, 3) mean overnight GH and cortisol, 4) 24-h urinary free cortisol (UFC), 5) fasting lipids, and 6) an oral glucose tolerance test. Stepwise regression was the major tool employed to determine relationships between measured parameters. Log peak GH on the GHRH-arginine test was lower (P = 0.03) and log UFC was higher (P = 0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with subcutaneous adipose tissue and, with body mass index standard deviation score, accounted for 92% of its variability, whereas log peak GH and body mass index standard deviation score accounted for 88% of visceral adipose tissue variability and log peak GH for 34% of the intramyocellular lipid variability. Log mean cortisol was independently associated with log homeostasis model assessment of insulin resistance, LDL, and HDL and explained 49-59% of the variability. Our data indicate that lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance, and lipids. C1 [Misra, Madhusmita; Tsai, Patrika; Mendes, Nara; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Misra, Madhusmita] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. [Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bul 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/E-4682-2013; Mendes Estella, Nara/A-1469-2015 FU NCRR NIH HHS [M01 RR 01066, K23 RR 018851]; NIDDK NIH HHS [P30 DK040561-13, P30 DK040561, F32 DK 072816] NR 44 TC 64 Z9 65 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2008 VL 295 IS 2 BP E385 EP E392 DI 10.1152/ajpendo.00052.2008 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 333DS UT WOS:000258133200020 PM 18544645 ER PT J AU Adams, JW Wang, JM Davis, JR Liaw, C Gaidarov, I Gatlin, J Dalton, ND Gu, Y Ross, J Behan, D Chien, K Connolly, D AF Adams, John W. Wang, Jianming Davis, James R. Liaw, Chen Gaidarov, Ibragim Gatlin, Joel Dalton, Nancy D. Gu, Yusu Ross, John, Jr. Behan, Dominic Chien, Ken Connolly, Daniel TI Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE heart failure; hypertrophy; orphan receptor ID MESSENGER-RNA; CARDIAC MYOCYTES; PERTUSSIS-TOXIN; GENE-EXPRESSION; HEART-FAILURE; HYPERTROPHY; APOPTOSIS; RAT; INFARCTION; ADENOSINE AB G protein-coupled receptors (GPCRs) play an essential role in the regulation of cardiovascular function. Therapeutic modulation of GPCRs has proven to be beneficial in the treatment of human heart disease. Myocardial "orphan" GPCRs, for which the natural ligand is unknown, represent potential novel therapeutic targets for the treatment of heart disease. Here, we describe the expression pattern, signaling pathways, and possible physiological role of the orphan GPR22. GPR22 mRNA analysis revealed a highly restricted expression pattern, with remarkably abundant and selective expression in the brain and heart of humans and rodents. In the heart, GPR22 mRNA was determined to be expressed in all chambers and was comparable with transcript levels of the beta(1)-adrenergic receptor as assessed by Taqman PCR. GPR22 protein expression in cardiac myocytes and coronary arteries was demonstrated in the rat heart by immunohistochemistry. When transfected into HEK-293 cells, GPR22 coupled constitutively to G(i)/G(o), resulting in the inhibition of adenyl cyclase. No constitutive coupling to G(s) or G(q) was observed. Myocardial mRNA expression of GPR22 was dramatically reduced following aortic banding in mice, suggesting a possible role in response to the stress associated with increased afterload. The absence of detectable GPR22 mRNA expression in the hearts of GPR22(-/-) mice had no apparent effect on normal heart structure or function; however, these mice displayed increased susceptibility to functional decompensation following aortic banding. Thus, we described, for the first time, the expression pattern and signaling for GPR22 and identified a protective role for GPR22 in response to hemodynamic stress resulting from increased afterload. C1 [Adams, John W.] Arena Pharmaceut Inc, Cardiovasc Biol, San Diego, CA 92121 USA. [Wang, Jianming; Dalton, Nancy D.; Gu, Yusu; Ross, John, Jr.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Chien, Ken] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Adams, JW (reprint author), Arena Pharmaceut Inc, Cardiovasc Biol, 6166 Nancy Ridge Dr, San Diego, CA 92121 USA. EM jadams@arenapharm.com NR 40 TC 16 Z9 17 U1 2 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2008 VL 295 IS 2 BP H509 EP H521 DI 10.1152/ajpheart.00368.2008 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 334XE UT WOS:000258254200010 PM 18539757 ER PT J AU Song, YL Coleman, L Shi, J Beppu, H Sato, K Walsh, K Loscalzo, J Zhang, YY AF Song, Yanli Coleman, Laura Shi, Jianru Beppu, Hideyuki Sato, Kaori Walsh, Kenneth Loscalzo, Joseph Zhang, Ying-Yi TI Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE heterozygous bone morphogenetic protein receptor-2 knockout mice ID BONE MORPHOGENETIC PROTEIN; NF-KAPPA-B; GROWTH-FACTOR; MONOCROTALINE PNEUMOTOXICITY; GERMLINE MUTATIONS; TUMOR ANGIOGENESIS; SIGNALING PATHWAY; II RECEPTOR; CELLS; GENE AB Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2(+/-)) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2(+/)-mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT + Ad5LO). After the challenge (1 wk), BMPR2(+/-) mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wildtype mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2(+/-) lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20-40% of original levels at 1 wk after the challenge in both BMPR2(+/-) and wild-type mice and largely recovered in wild-type (50-80%) but not BMPR2(+/-) lungs (30-50%) at 3 wk after the challenge. Macrophage inflammatory protein-1 alpha and fractalkine receptor expression doubled in BMPR2(+/-) compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-beta receptors, in the challenged BMPR2(+/-) and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2(+/-) lungs than the wild-type lungs. These data show that BMPR2(+/-) mice are more sensitive to MCT + Ad5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension. C1 [Song, Yanli; Coleman, Laura; Shi, Jianru; Loscalzo, Joseph; Zhang, Ying-Yi] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Beppu, Hideyuki] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02115 USA. [Sato, Kaori; Walsh, Kenneth] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. RP Zhang, YY (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, 77 Ave Louis Pasteur,NRB 630, Boston, MA 02115 USA. EM yyzhang@rics.bwh.harvard.edu FU NHLBI NIH HHS [R01 HL061795, HL-58976, HL-61795, N01 HV-28178, N01 HV028178, P01 HL-81587, P01 HL081587, R01 HL058976] NR 53 TC 50 Z9 51 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2008 VL 295 IS 2 BP H677 EP H690 DI 10.1152/ajpheart.91519.2007 PG 14 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 334XE UT WOS:000258254200027 PM 18552156 ER PT J AU Figlewicz, DP Bennett, JL Aliakbari, S Zavosh, A Sipols, AJ AF Figlewicz, Dianne P. Bennett, Jennifer L. Aliakbari, Sepideh Zavosh, Aryana Sipols, Alfred J. TI Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE food reward; ventral tegmental area; arcuate nucleus ID FOOD-MOTIVATED BEHAVIOR; VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; FEEDING-BEHAVIOR; INTRAVENTRICULAR INSULIN; ADIPOSITY SIGNALS; PARAVENTRICULAR NUCLEUS; REWARD CIRCUITRY; NEUROPEPTIDE-Y; C-FOS AB Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and mu opioid-stimulated sucrose feeding-when administered into several insulin-receptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75 +/- 5% of paired control). However, although the mu opioid DAMGO, [D-Ala2, N-MePhe4, Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) mu opioid-stimulated sucrose feeding: sucrose intake was 53 +/- 8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner. C1 [Figlewicz, Dianne P.] VA Puget Sound Hlth Care Syst 151, Seattle, WA USA. [Figlewicz, Dianne P.; Bennett, Jennifer L.; Zavosh, Aryana] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Sipols, Alfred J.] Latvian State Univ, Fac Med, LV-1063 Riga, Latvia. RP Figlewicz, DP (reprint author), VA Puget Sound Hlth Care Syst, 1660 So Columbian Way, Seattle, WA 98108 USA. EM latte@u.washington.edu FU NIDDK NIH HHS [R01 DK040963] NR 46 TC 61 Z9 61 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD AUG 1 PY 2008 VL 295 IS 2 BP R388 EP R394 DI 10.1152/ajpregu.90334.2008 PG 7 WC Physiology SC Physiology GA 335WB UT WOS:000258322700003 PM 18525010 ER PT J AU Jaureguiberry, G Carpenter, TO Forman, S Juppner, H Bergwitz, C AF Jaureguiberry, Graciana Carpenter, Thomas O. Forman, Stuart Jueppner, Harald Bergwitz, Clemens TI A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE SLC34A3; rickets; hypercalciuria; nephrolithiasis ID P-I COTRANSPORTER; PARATHYROID-HORMONE; EXPRESSION AB The present study describes two novel compound heterozygous mutations, c. 410C>T(p. T137M) (T137M) on the maternal and g. 4225_50del on the paternal allele of SLC34A3, in a previously reported male with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and recurrent kidney stones (Chen C, Carpenter T, Steg N, Baron R, Anast C. Pediatrics 84: 276-280, 1989). For functional analysis in vitro, we generated expression plasmids encoding enhanced green fluorescence protein (EGFP) concatenated to the NH(2) terminus of wild-type or mutant human type IIc Na-P(i) cotransporter (NaPi-IIc), i.e., EGFP-hNaPi-IIc, EGFP-[M137] hNaPi-IIc, or EGFP[Stop446] hNaPi-IIc. The V446Stop mutant showed complete loss of expression and function when assayed for apical patch expression in opossum kidney (OK) cells and sodium-dependent (33)P uptake into Xenopus laevis oocytes. Conversely, EGFP-[M137] hNaPi-IIc was inserted into apical patches of OK cells and into oocyte membranes. However, when quantified by confocal microscopy, surface fluorescence was reduced to 40% compared with wild-type. After correction for surface expression, the rate of 33P uptake by oocytes mediated by EGFP-[M137] hNaPi-IIc was decreased by an additional 60%. The resulting overall reduction of function of this NaPi-IIc mutant to 16%, taken together with complete loss of expression and function of g. 4225_50del(V446Stop), thus appears to be sufficient to explain the phenotype in our patient. Furthermore, the stoichiometric ratio of (22)Na and (33)P uptake was increased to 7.1 +/- 3.65 for EGFP[M137] hNaPi-IIc compared with wild-type. Two-electrode studies indicate that EGFP-[M137] hNaPi-IIc is nonelectrogenic but displayed a significant phosphate-independent inward-rectified sodium current, which appears to be insensitive to phosphonoformic acid. M137 thus may uncouple sodium-phosphate cotransport, suggesting that this amino acid residue has an important functional role in human NaPi-IIc. C1 [Jaureguiberry, Graciana; Jueppner, Harald; Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Forman, Stuart] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. [Carpenter, Thomas O.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT USA. [Carpenter, Thomas O.] Yale Univ, Sch Med, Endocrine Unit, New Haven, CT USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 1038 Thier Bldg,50 Blossom St, Boston, MA 02114 USA. EM cbergwitz@partners.org FU NICHD NIH HHS [K24-HD-01288]; NIDDK NIH HHS [K08 DK078361, P01-DK-11794, R03 DK089127] NR 35 TC 39 Z9 40 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG 1 PY 2008 VL 295 IS 2 BP F371 EP F379 DI 10.1152/ajprenal.00090.2008 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 333BR UT WOS:000258127500007 PM 18480181 ER PT J AU Lee, UJ Gustilo-Ashby, AM Daneshgari, F Kuang, M Vurbic, D Lin, DL Flask, CA Li, TS Damaser, MS AF Lee, Una J. Gustilo-Ashby, A. Marcus Daneshgari, Firouz Kuang, Mei Vurbic, Drina Lin, Dan Li Flask, Chris A. Li, Tiansen Damaser, Margot S. TI Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE lysyl oxidase-like 1 knockout; elastin; pelvic organ prolapse; urinary incontinence; urodynamics ID STRESS URINARY-INCONTINENCE; LEAK POINT PRESSURE; ORGAN PROLAPSE; CARDINAL LIGAMENTS; WOMEN; PROTEIN; DISORDERS; BLADDER; RAT AB Female pelvic floor dysfunction (FPFD) is a complex group of conditions that include urinary incontinence and pelvic organ prolapse (POP). In humans, elastin homeostasis has been implicated in the pathophysiology of FPFD. Lysyl oxidase-like 1 knockout (LOXL1-KO) mice demonstrate abnormal elastic fiber homeostasis and develop FPFD after parturition. We compared the lower urogenital tract (LUT) anatomy and function in LOXL1-KO mice with and without POP. LUT anatomy was assessed in LOXL1-KO mice over 28 wk. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7-Tesla magnetic resonance imaging (MRI) scanner. LUT function was assessed using conscious cystometry and leak point pressure (LPP) testing. Quantitative histological analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 wk of age, 50% of parous LOXL1-KO mice developed POP. LOXL1-KO mice with POP had greater variability in the size and location of the bladder on MRI compared with mice without POP. Parity and POP were associated with lower LPP. Elastin clusters were significantly increased in the EUS of LOXL1-KO mice with POP. Because parity triggers POP in LOXL1-KO mice, LOXL1-KO mice with POP have variable internal pelvic anatomy, and both parity and POP are associated with a decrease in LPP, we conclude that LOXL1 LUT anatomical and functional phenotype resembles FPFD in humans. The increase in elastin clusters in the urethra of LOXL1-KO mice with POP suggests that elastin disorganization may lead to functional abnormalities. We conclude that LOXL1 warrants further investigation in the pathphysiology of FPFD. C1 [Daneshgari, Firouz; Lin, Dan Li; Damaser, Margot S.] Cleveland Clin, Dept Biomed Engn, Cleveland, OH 44195 USA. [Lee, Una J.; Daneshgari, Firouz; Kuang, Mei; Damaser, Margot S.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44195 USA. [Gustilo-Ashby, A. Marcus] Cleveland Clin, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, Cleveland, OH 44195 USA. [Vurbic, Drina; Lin, Dan Li; Damaser, Margot S.] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Flask, Chris A.] Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. [Li, Tiansen] Massachusetts Eye & Ear Infirm, Dept Ophthalmol Neurosci, Boston, MA 02114 USA. RP Damaser, MS (reprint author), Cleveland Clin, Dept Biomed Engn, Lerner Res Inst ND20,9500 Euclid Ave, Cleveland, OH 44195 USA. EM damasem@ccf.org NR 26 TC 24 Z9 26 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG 1 PY 2008 VL 295 IS 2 BP F545 EP F555 DI 10.1152/ajprenal.00063.2008 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 333BR UT WOS:000258127500026 PM 18495804 ER PT J AU Freed, GL Almquist, JR Birkhead, GS Dekker, C Feinberg, M Fergie, J Gordon, LK Hinman, AR Humiston, SG Johnson, C Klein, JO Koslap-Petraco, MB Lovell, C Parnell, T Pavia, A Riley, LE Young, AE AF Freed, Gary L. Almquist, Jon R. Birkhead, Guthrie S. Dekker, Cornelia Feinberg, Mark Fergie, Jaime Gordon, Lance K. Hinman, Alan R. Humiston, Sharon G. Johnson, Calvin Klein, Jerome O. Koslap-Petraco, Mary Beth Lovell, Charles, Jr. Parnell, Trish Pavia, Andrew Riley, Laura E. Young, Adele E. CA Natl Vaccine Advisory Comm TI Mandates for adolescent immunizations - Recommendations from the National Vaccine Advisory Committee SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID HUMAN-PAPILLOMAVIRUS VACCINE; NONMEDICAL EXEMPTIONS; STATE POLICIES; COVERAGE; HEALTH; REQUIREMENTS; SAFETY; IMPACT; LAWS; ATTITUDES C1 [Freed, Gary L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Birkhead, Guthrie S.] New York State Dept Hlth, Albany, NY 12237 USA. [Dekker, Cornelia] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Feinberg, Mark] Merck & Co Inc, Whitehouse Stn, NJ USA. [Johnson, Calvin] Penn Dept Hlth, Harrisburg, PA 17108 USA. [Klein, Jerome O.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Koslap-Petraco, Mary Beth] Dept Hlth Serv Suffolk Cty, New York, NY USA. [Pavia, Andrew] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Riley, Laura E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Young, Adele E.] George Mason Univ, Fairfax, VA 22030 USA. RP Freed, GL (reprint author), Univ Michigan, 300 N Ingalls Bldg,6EO8, Ann Arbor, MI 48109 USA. EM gfreed@med.umich.edu NR 45 TC 12 Z9 12 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2008 VL 35 IS 2 BP 145 EP 151 DI 10.1016/j.amepre.2008.03.033 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 329TO UT WOS:000257893700009 ER PT J AU Freed, GL Almquist, JR Birkhead, GS Dekker, C Feinberg, M Fergie, J Gordon, LK Hinman, AR Humiston, SG Johnson, C Mein, JO Koslap-Petraco, MB Lovell, C Parnell, T Pavia, A Riley, LE Young, AE AF Freed, Gary L. Almquist, Jon R. Birkhead, Guthrie S. Dekker, Cornelia Feinberg, Mark Fergie, Jaime Gordon, Lance K. Hinman, Alan R. Humiston, Sharon G. Johnson, Calvin Mein, Jerome O. Koslap-Petraco, Mary Beth Lovell, Charles, Jr. Parnell, Trish Pavia, Andrew Riley, Laura E. Young, Adele E. CA Natl Vaccine Advisory Comm TI The promise and challenge of adolescent immunization SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID HEALTH-CARE; RECOMMENDATIONS; ADHERENCE; VACCINES; SERVICES; VISIT; LAWS C1 [Freed, Gary L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Birkhead, Guthrie S.] New York State Dept Hlth, Albany, NY 12237 USA. [Dekker, Cornelia] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Feinberg, Mark] Merck & Co Inc, Whitehouse Stn, NJ USA. [Johnson, Calvin] Penn Dept Hlth, Harrisburg, PA 17108 USA. [Mein, Jerome O.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Koslap-Petraco, Mary Beth] Dept Hlth Serv Suffolk Cty, New York, NY USA. [Pavia, Andrew] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Riley, Laura E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Young, Adele E.] George Mason Univ, Fairfax, VA 22030 USA. RP Freed, GL (reprint author), Univ Michigan, 300 N Ingalls Bldg,6EO8, Ann Arbor, MI 48109 USA. EM gfreed@med.umich.edu NR 23 TC 23 Z9 23 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2008 VL 35 IS 2 BP 152 EP 157 DI 10.1016/j.amepre.2008.03.034 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 329TO UT WOS:000257893700010 ER PT J AU Emmons, KM Viswanath, K Colditz, GA AF Emmons, Karen M. Viswanath, Kasisomayajula Colditz, Graham A. TI The role of transdisciplinary collaboration in translating and disseminating health research - Lessons learned and exemplars of success SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CANCER-RISK INDEX; PRIMARY-CARE; INTERVENTIONS; COMMUNICATION; ENVIRONMENTS; PREVENTION; DECISIONS AB In the past few decades, significant advances have been made related to understanding, preventing, and treating chronic disease. Given these many advances across multiple disciplines, it is unclear why the potential for yielding substantial reduction in disease has not been achieved overall and across various subgroups. Socioeconomic and racial/ethnic disparities in a wide range of disease outcomes persist, and a number of studies highlight the importance of further improving behavioral risk-factor prevalence on a population level. The goal of this paper is to explore the role of transdisciplinary collaboration in the translation of research related to these vexing public health problems, and, in particular, to explore factors that appear to facilitate effective and sustainable translation. Transdisciplinary collaboration also has great potential to speed the rate of adoption of evidence-based practices. Examples of transdisciplinary collaborations in academic and community settings are provided, along with factors that may influence the long-term outcomes of transdisciplinary efforts. C1 [Emmons, Karen M.; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Emmons, Karen M.; Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. RP Emmons, KM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,LW703, Boston, MA 02115 USA. EM karen_m_emmons@dfci.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 NR 30 TC 27 Z9 27 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2008 VL 35 IS 2 SU S BP S204 EP S210 DI 10.1016/j.amepre.2008.05.009 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 329TQ UT WOS:000257893900015 PM 18619401 ER PT J AU Goff, DC AF Goff, Donald C. TI New insights into clinical response in schizophrenia: From dopamine D-2 receptor occupancy to patients' quality of life SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID ARIPIPRAZOLE; PERFORMANCE; SYMPTOMS C1 Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. RP Goff, DC (reprint author), Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. EM goff@psych.mgh.harvard.edu RI Sia, Michelle/A-1756-2010 NR 12 TC 5 Z9 5 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2008 VL 165 IS 8 BP 940 EP 943 DI 10.1176/appi.ajp.2008.08050673 PG 4 WC Psychiatry SC Psychiatry GA 332WL UT WOS:000258113700003 PM 18676595 ER PT J AU Mathalon, DH Ford, JM AF Mathalon, Daniel H. Ford, Judith M. TI Divergent approaches converge on frontal lobe dysfunction in schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID ABNORMALITIES C1 [Mathalon, Daniel H.] San Francisco VA Med Ctr, Mental Hlth Serv 116d, San Francisco, CA 94121 USA. RP Mathalon, DH (reprint author), San Francisco VA Med Ctr, Mental Hlth Serv 116d, 4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu OI Mathalon, Daniel/0000-0001-6090-4974 FU NIMH NIH HHS [R01 MH076989, R01 MH076989-02] NR 12 TC 9 Z9 9 U1 2 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2008 VL 165 IS 8 BP 944 EP 948 DI 10.1176/appi.ajp.2008.08050735 PG 5 WC Psychiatry SC Psychiatry GA 332WL UT WOS:000258113700004 PM 18676596 ER PT J AU Roffman, JL AF Roffman, Joshua L. TI Eight ball SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Psychiat Neurosci Res Program, Charlestown, MA 02129 USA. RP Roffman, JL (reprint author), Massachusetts Gen Hosp, Psychiat Neurosci Res Program, Rm 2656,Bldg 149,149 13th St, Charlestown, MA 02129 USA. EM jroffman@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2008 VL 165 IS 8 BP 956 EP 957 DI 10.1176/appi.ajp.2008.07121950 PG 2 WC Psychiatry SC Psychiatry GA 332WL UT WOS:000258113700007 PM 18676599 ER PT J AU Rottnek, M Riggio, S Byne, W Sano, M Margolis, RL Walker, RH AF Rottnek, Matthew Riggio, Silvana Byne, William Sano, Mary Margolis, Russell L. Walker, Ruth H. TI Schizophrenia in a patient with spinocerebellar ataxia 2: Coincidence of two disorders or a Neurodegenerative disease presenting with psychosis? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID COGNITIVE-AFFECTIVE SYNDROME; ATAXIA; IMPAIRMENT; DYSMETRIA; CORTEX C1 James J Peters Vet Affairs Med Center, Dept Neurol, New York, NY USA. James J Peters Vet Affairs Med Center, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Dept Neurol, New York, NY USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA. RP Walker, RH (reprint author), James J Peters Vet Affairs Med Ctr, Dept Neurol 127, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM ruth.walker@mssm.edu NR 21 TC 11 Z9 12 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2008 VL 165 IS 8 BP 964 EP 967 DI 10.1176/appi.ajp.2008.08020285 PG 4 WC Psychiatry SC Psychiatry GA 332WL UT WOS:000258113700009 PM 18676601 ER PT J AU Freedman, R Olincy, A Buchanan, RW Harris, JG Gold, JM Johnson, L Allensworth, D Guzman-Bonilla, A Clement, B Ball, MP Kutnick, J Pender, V Martin, LF Stevens, KE Wagner, BD Zerbe, GO Soti, F Kem, WR AF Freedman, Robert Olincy, Ann Buchanan, Robert W. Harris, Josette G. Gold, James M. Johnson, Lynn Allensworth, Diana Guzman-Bonilla, Alejandrina Clement, Bettye Ball, M. Patricia Kutnick, Jay Pender, Vicki Martin, Laura F. Stevens, Karen E. Wagner, Brandie D. Zerbe, Gary O. Soti, Ferenc Kem, William R. TI Initial phase 2 trial of a nicotinic agonist in schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CONSENSUS COGNITIVE BATTERY; ALPHA-BUNGAROTOXIN; NEGATIVE SYMPTOMS; DOUBLE-BLIND; CLOZAPINE; RECEPTORS; RELIABILITY; SMOKING; DEFICIT; GTS-21 AB Objective: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia. Method: Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers. Results: There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A. Conclusion: DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined. C1 Denver VA Med Ctr, Dept Psychiat, Denver, CO USA. Denver VA Med Ctr, Dept Prevent Med & Biometr, Denver, CO USA. Univ Maryland, Psychiat Res Ctr, College Pk, MD 20742 USA. Baltimore VA Med Ctr, Dept Psychiat, Baltimore, MD USA. Univ Florida, Dept Pharmacol & Therapeut, Gainesville, FL USA. RP Freedman, R (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Psychiat C249 32, Denver, CO 80262 USA. EM Robert.Freedman@UCHSC.edu OI Wagner, brandie/0000-0002-2745-0103 FU NIMH NIH HHS [P50 MH068582, MH-061412, MH-068582, R01 MH061412] NR 39 TC 272 Z9 276 U1 2 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2008 VL 165 IS 8 BP 1040 EP 1047 DI 10.1176/appi.ajp.2008.07071135 PG 8 WC Psychiatry SC Psychiatry GA 332WL UT WOS:000258113700019 PM 18381905 ER PT J AU Dang, PA Kalra, MK Blake, MA Schultz, TJ Halpern, EF Dreyer, KJ AF Dang, Pragya A. Kalra, Mannudeep K. Blake, Michael A. Schultz, Thomas J. Halpern, Elkan F. Dreyer, Keith J. TI Extraction of recommendation features in radiology with natural language processing: Exploratory study SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE radiology practice; recommendations; recommended imaging techniques AB OBJECTIVE. The purposes of this study were to validate a natural language processing program for extraction of recommendation features, such as recommended time frames and imaging technique, from electronic radiology reports and to assess patterns of recommendation features in a large database of radiology reports. MATERIALS AND METHODS. This study was performed on a radiology reports database covering the years 1995-2004. From this database, 120 reports with and without recommendations were selected and randomized. Two radiologists independently classified these reports according to presence of recommendations, time frame, and imaging technique suggested for follow-up or repeated examinations. The natural language processing program then was used to classify the reports according to the same criteria used by the radiologists. The accuracy of classification of recommendation features was determined. The program then was used to determine the patterns of recommendation features for different patients and imaging features in the entire database of 4,211,503 reports. RESULTS. The natural language processing program had an accuracy of 93.2% (82/88) for identifying the imaging technique recommended by the radiologists for further evaluation. Categorization of recommended time frames in the reports with the 88 recommendations obtained with the program resulted in 83 (94.3%) accurate classifications and five (5.7%) inaccurate classifications. Recommendations of CT were most common (27.9%, 105,076 of 376,918 reports) followed by those for MRI (17.8%). In most (85.4%, 322,074/376,918) of the reports with imaging recommendations, however, radiologists did not specify the time frame. CONCLUSION. Accurate determination of recommended imaging techniques and time frames in a large database of radiology reports is possible with a natural language processing program. Most imaging recommendations are for high-cost but more accurate radiologic studies. C1 [Dang, Pragya A.; Kalra, Mannudeep K.; Blake, Michael A.; Schultz, Thomas J.; Halpern, Elkan F.; Dreyer, Keith J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Dreyer, KJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,Ste 400E, Boston, MA 02114 USA. EM kdreyer@partners.org NR 14 TC 15 Z9 15 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 313 EP 320 DI 10.2214/AJR.07.3508 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800002 PM 18647895 ER PT J AU Hargaden, GC Yeh, ED Georgian-Smith, D Moore, RH Rafferty, EA Halpern, EF McKee, GT AF Hargaden, Gormlaith C. Yeh, Eren D. Georgian-Smith, Dianne Moore, Richard H. Rafferty, Elizabeth A. Halpern, Elkan F. McKee, Grace T. TI Analysis of the mammographic and sonographic features of pseudoangiomatous stromal hyperplasia SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE breast; mammography; pseudoangiomatous stromal hyperplasia; sonography ID MAMMARY STROMA; BREAST; TUMOR AB OBJECTIVE. The purpose of this study was to describe the imaging findings in 149 patients with pseudoangiomatous stromal hyperplasia (PASH) who had undergone at least 4 years of clinical follow-up for detection of subsequent malignancy. CONCLUSION. PASH is a common entity that presents with benign imaging features without evidence of subsequent malignant potential. At our institution, in the absence of suspicious features a diagnosis of PASH at core biopsy is considered sufficient, and surgical excision has been obviated. C1 [Hargaden, Gormlaith C.; Yeh, Eren D.; Georgian-Smith, Dianne; Moore, Richard H.; Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Dept Radiol, Div Breast Imaging, Avon Comprehens Breast Ctr, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [McKee, Grace T.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hargaden, GC (reprint author), Mater Misericordiae Univ Hosp, 36 Eccles St, Dublin 7, Ireland. EM gormlaith.hargaden@breastcheck.ie NR 10 TC 16 Z9 17 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 359 EP 363 DI 10.2214/AJR.07.2479 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800009 PM 18647902 ER PT J AU Cronin, CG Lohan, DG Blake, MA Roche, C McCarthy, P Murphy, JM AF Cronin, Carmel G. Lohan, Derek G. Blake, Michael A. Roche, Clare McCarthy, Peter Murphy, Joseph M. TI Retroperitoneal fibrosis: A review of clinical features and imaging findings SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE fibrosis; malignant retroperitoneal disease; retroperitoneal fibrosis ID SMALL-BOWEL OBSTRUCTION; CHRONIC PERIAORTITIS; ANKYLOSING-SPONDYLITIS; CT; TOMOGRAPHY; ASSOCIATION; DIAGNOSIS; CHILDREN; SPECTRUM AB OBJECTIVE. Retroperitoneal fibrosis is a rare collagen vascular disorder of unclear cause. Both benign and malignant associations have been described, rendering differentiation of these entities of paramount importance because sinister pathology alters the diagnosis. Thus, a high level of diligence is required in the investigation of this condition, particularly in patients with concomitant systemic conditions. CONCLUSION. Familiarity with the realm of imaging manifestations of retroperitoneal fibrosis is vital to ensure correct diagnosis and optimal treatment. C1 [Cronin, Carmel G.; Lohan, Derek G.; Roche, Clare; McCarthy, Peter; Murphy, Joseph M.] Univ Coll Hosp, Dept Radiol, Galway, Ireland. [Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Cronin, CG (reprint author), Univ Coll Hosp, Dept Radiol, Newcastle Rd, Galway, Ireland. EM carmelcronin2000@hotmail.com NR 56 TC 55 Z9 63 U1 1 U2 6 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 423 EP 431 DI 10.2214/AJR.07.3629 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800019 PM 18647912 ER PT J AU Dodd, JD Rieber, J Pomerantsev, E Chaithiraphan, V Achenbach, S Moreiras, JM Abbara, S Hoffmann, U Brady, TJ Cury, RC AF Dodd, Jonathan D. Rieber, Johannes Pomerantsev, Eugene Chaithiraphan, Vithaya Achenbach, Stephan Moreiras, Javier M. Abbara, Suhny Hoffmann, Udo Brady, Thomas J. Cury, Ricardo C. TI Quantification of nonculprit coronary lesions: Comparison of cardiac 64-MDCT and invasive coronary angiography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE coronary angiography; coronary stenosis; CT; myocardial infarction; nonculprit coronary lesion ID MULTISLICE COMPUTED-TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; INTRAVASCULAR ULTRASOUND; ARTERY-DISEASE; ATHEROSCLEROTIC PLAQUE; NONINVASIVE ASSESSMENT; DIAGNOSTIC-ACCURACY; STABLE ANGINA; STENOSES; INFLAMMATION AB OBJECTIVE. The purpose of our study was to evaluate the accuracy of cardiac 64-MDCT to quantify the grade of stenosis of nonculprit lesions. SUBJECTS AND METHODS. Twenty-nine consecutive patients (23 men and six women; mean age, 62 +/- 10 years) presenting with acute coronary syndrome (ACS) had nonculprit coronary lesions of >= 30% stenosis quantified on quantitative coronary angiography (QCA). Five 64-MDCT postprocessing techniques (maximum intensity projection [MIP], multiplanar reformat [MPR], cross-sectional area [CSA], and diameter and area derived from semiquantitative coronary software) were used to grade lesions. Two separate groups of two independent readers analyzed QCA and cardiac CT images using a 17-segment model. Coronary angiography was the reference standard. RESULTS. Nonculprit lesions were identified in 46 analyzable coronary segments. Sub-grouping lesions on the basis of reference vessel diameter resulted in strong correlations for quantifying nonculprit lesions in vessels > 3 mm (R = 0.78-0.91, p < 0.01) but poor correlations for nonculprit lesions in vessels <= 3 mm (R = 0.1-0.07). Sub-grouping lesions on the basis of plaque type resulted in poor correlations for calcified plaques (R = 0.01-0.30) but moderate to strong correlations for mixed (R = 0.58-0.75, p < 0.01) and noncalcified (R = 0.44-0.61, p < 0.01) plaques. The best overall correlation among all CT techniques with QCA was CSA (R = 0.56, p < 0.01). Interobserver agreement (kappa values) for MPR, MIP, coronary software diameter and area were 0.6, 0.7, 0.62, and 0.57, respectively. CONCLUSION. In patients presenting with ACS, 64-MDCT provided an accurate grade of stenosis for nonculprit coronary lesions in proximal coronary segments. Calcified plaques and lesions in coronary segments = 3 mm diameter remained difficult to accurately quantify. C1 [Dodd, Jonathan D.] St Vincents Univ Hosp, Dept Radiol, Dublin 4, Ireland. [Rieber, Johannes; Chaithiraphan, Vithaya; Abbara, Suhny; Hoffmann, Udo; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Cardiac MRI PET CT Program, Boston, MA 02114 USA. [Rieber, Johannes; Pomerantsev, Eugene; Chaithiraphan, Vithaya; Moreiras, Javier M.; Abbara, Suhny; Hoffmann, Udo; Brady, Thomas J.; Cury, Ricardo C.] Harvard Univ, Sch Med, Boston, MA USA. [Pomerantsev, Eugene; Moreiras, Javier M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Achenbach, Stephan] Univ Hosp Erlangen, Dept Med 2, Erlangen, Germany. RP Dodd, JD (reprint author), St Vincents Univ Hosp, Dept Radiol, Elm Pk, Dublin 4, Ireland. EM j.dodd@st-vincents.ie NR 25 TC 15 Z9 17 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 432 EP 438 DI 10.2214/AJR.07.3315 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800020 PM 18647913 ER PT J AU Ladapo, JA Hoffmann, U Bamberg, F Nagurney, JT Cutler, DM Weinstein, MC Gazelle, GS AF Ladapo, Joseph A. Hoffmann, Udo Bamberg, Fabian Nagurney, John T. Cutler, David M. Weinstein, Milton C. Gazelle, G. Scott TI Cost-effectiveness of coronary MDCT in the triage of patients with acute chest pain SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE acute chest pain; cardiac CT; cost-effectiveness; health policy; noninvasive angiography ID ACUTE CARDIAC ISCHEMIA; ELEVATION MYOCARDIAL-INFARCTION; ARTERY-DISEASE; EMERGENCY-DEPARTMENT; COMPUTED-TOMOGRAPHY; LOW-RISK; DIAGNOSTIC-ACCURACY; AMERICAN-COLLEGE; RANDOMIZED-TRIAL; BYPASS-SURGERY AB OBJECTIVE. Patients at low risk for acute coronary syndrome (ACS) who present to the emergency department complaining of acute chest pain place a substantial economic burden on the U. S. health care system. Noninvasive 64-MDCT coronary angiography may facilitate their triage, and we evaluated its cost-effectiveness. MATERIALS AND METHODS. A microsimulation model was developed to compare costs and health effects of performing CT coronary angiography and either discharging, stress testing, or referring emergency department patients for invasive coronary angiography, depending on their severity of atherosclerosis, compared with a standard-of-care (SOC) algorithm that based management on biomarkers and stress tests alone. RESULTS. Using CT coronary angiography to triage 55-year-old men with acute chest pain increased emergency department and hospital costs by $110 and raised total health care costs by $200. In 55-year-old women, the technology was cost-saving; emergency department and hospital costs decreased by $410, and total health care costs decreased by $380. Compared with the SOC, CT coronary angiography-based triage extended life expectancy by 10 days in men and by 6 days in women. This translated into corresponding improvements of 0.03 quality-adjusted life years (QALYs) and 0.01 QALYs, respectively. The incremental cost-effectiveness ratio for CT coronary angiography was $6,400 per QALY in men; in women, CT coronary angiography was cost-saving. Cost-effectiveness ratios were sensitive to several parameters but generally remained in the range of what is typically considered cost-effective. CONCLUSION. CT coronary angiography-based triage for patients with low-risk chest pain is modestly more effective than the SOC. It is also cost-saving in women and associated with low cost-effectiveness ratios in men. C1 [Ladapo, Joseph A.] Harvard PhD Program Hlth Policy, Cambridge, MA 02138 USA. [Hoffmann, Udo; Bamberg, Fabian; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Gazelle, G. Scott] Harvard Univ, Sch Med, Boston, MA USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Cutler, David M.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Cutler, David M.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Weinstein, Milton C.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Ladapo, JA (reprint author), Harvard PhD Program Hlth Policy, 14 Story St,4th Floor, Cambridge, MA 02138 USA. EM joseph.ladapo@gmail.com OI Ladapo, Joseph/0000-0002-8518-4800 NR 49 TC 70 Z9 70 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 455 EP 463 DI 10.2214/AJR.07.3611 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800024 PM 18647917 ER PT J AU Roedl, JB Colen, RR King, K Fischman, AJ Mueller, PR Blake, MA AF Roedl, Johannes B. Colen, Rivka R. King, Kevin Fischman, Alan J. Mueller, Peter R. Blake, Michael A. TI Visual PET/CT scoring for nonspecific F-18-FDG uptake in the differentiation of early malignant and benign esophageal lesions SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE esophagus; F-18-FDG; nonspecific uptake; PET; PET/CT ID POSITRON-EMISSION-TOMOGRAPHY; CARCINOMA; VARIANTS; PITFALLS; CT AB OBJECTIVE. The purpose of our study was to evaluate a visual PET/CT scoring system for the differentiation of benign and early malignant esophageal uptake. MATERIALS AND METHODS. Thirty-six consecutive patients with precancerous or early malignant esophageal lesions including Barrett's esophagus, Tis, T1, and T2 adenocarcinomas were eligible. Findings of these patients were compared with 66 patients who had reported increased esophageal F-18-FDG uptake due to benign esophageal disorders. Lesions were evaluated with scores using the following characteristics in PET/CT: FDG uptake intensity (low = 0, moderate = 1, high = 2), FDG uptake eccentricity (concentric = 0, eccentric = 1), FDG uptake focality (diffuse = 0, segmental = 1, focal = 2), esophageal thickness on the CT component (normal = 0, thickening = 1, mass = 2), and location (distal third of the esophagus = 0, middle third of the esophagus = 1, proximal third of the esophagus = 2). RESULTS. Early malignant lesions had higher scores in FDG uptake intensity (p = 0.003; chi-square), eccentricity (p < 0.001), and focality (p < 0.001) compared with benign lesions. No significant difference was seen in esophageal thickness on CT (p = 0.168) and in location of the lesion (p = 0.291). Binary logistic regression analysis with a stepwise forward inclusion of all score components including the maximum standardized uptake value (SUV) of the lesions revealed that a total score combining eccentricity and focality scores has the highest accuracy of predicting early malignant disease. Using a threshold of equal or higher than 2 in the combined total focality-eccentricity score, the sensitivity was 83.3% and specificity was 68.2% for predicting early malignant disease. CONCLUSION. Focality and eccentricity of FDG uptake prove to be valuable PET/CT characteristics for the differentiation of nonspecific FDG uptake in the esophagus. C1 [Roedl, Johannes B.; Colen, Rivka R.; King, Kevin; Mueller, Peter R.; Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. [Roedl, Johannes B.; Colen, Rivka R.; King, Kevin; Mueller, Peter R.; Blake, Michael A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Roedl, Johannes B.; Colen, Rivka R.; Fischman, Alan J.] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. RP Roedl, JB (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, 55 Fruit St, Boston, MA 02114 USA. EM johannes.roedl@gmail.com NR 14 TC 12 Z9 14 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2008 VL 191 IS 2 BP 515 EP 521 DI 10.2214/AJR.07.3320 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329FH UT WOS:000257851800032 PM 18647925 ER PT J AU Gray, SH Vick, CC Graham, LA Finan, KR Neumayer, LA Hawn, MT AF Gray, Stephen H. Vick, Catherine C. Graham, Laura A. Finan, Kelly R. Neumayer, Leigh A. Hawn, Mary T. TI Variation in mesh placement for ventral hernia repair: an opportunity for process improvement? SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE incisional hernia repair; variation; quality ID ABDOMINAL-WALL HERNIAS; OF-VETERANS-AFFAIRS; INCISIONAL HERNIA; RISK-FACTORS; SURGICAL CARE; RECURRENCE; COMPLICATIONS; OUTCOMES; HERNIORRHAPHY; INFECTION AB BACKGROUND: Incisional hernia repair (IHR) with mesh has been associated with decreased hernia recurrence. We analyzed variation in mesh use for IHR. METHODS: A cohort undergoing IHR from 16 Veterans' Administration (VA) Hospitals was identified. Patient-specific variables were obtained from National Surgical Quality Improvement Program (NSQIP) data. Operative variables were obtained from physician-abstracted operative notes. Univariate and multivariable logistic regression analyses were used to model mesh implantation predictors. RESULTS: A total of 1,123 IHR cases were analyzed; Mesh was implanted in 69.6% (n = 781). Regression models demonstrated repair at a high performing facility was associated with a nearly 4-fold increase in mesh utilization. Other significant predictors include repair of recurrent hernia, chronic steroid use, and multiple fascial defects. CONCLUSIONS: There is variation in the rate of mesh placement for IHR by VA facility, even after accounting for key explanatory variables. Patterns of mesh placement in IHR appear to be based on practice style. (c) 2008 Published by Elsevier Inc. C1 [Gray, Stephen H.; Vick, Catherine C.; Graham, Laura A.; Finan, Kelly R.; Hawn, Mary T.] Birmingham Vet Affairs VA Med Ctr, Deep S Ctr Effectiveness Res, Birmingham, AL USA. [Gray, Stephen H.; Vick, Catherine C.; Finan, Kelly R.; Hawn, Mary T.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Gray, Stephen H.] Univ Alabama, Dept Med, Hlth Serv & Outcomes Res Training Program, Birmingham, AL 35294 USA. [Neumayer, Leigh A.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Neumayer, Leigh A.] Univ Utah, VA Med Ctr, Salt Lake City, UT USA. RP Hawn, MT (reprint author), Birmingham Vet Affairs VA Med Ctr, Deep S Ctr Effectiveness Res, Birmingham, AL USA. EM mhawn@uab.edu OI Gray, Stephen/0000-0002-5702-7226 FU AHRQ HHS [5 T32 HS013852, HS013852]; None [HS013852] NR 36 TC 13 Z9 13 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 0002-9610 J9 AM J SURG JI Am. J. Surg. PD AUG PY 2008 VL 196 IS 2 BP 201 EP 206 DI 10.1016/j.amjsurg.2007.09.041 PG 6 WC Surgery SC Surgery GA 334VB UT WOS:000258248200010 PM 18513688 ER PT J AU Wang, WL Abramson, JH Ganguly, A Rosenberg, AE AF Wang, Wei-Lien Abramson, Jerome H. Ganguly, Aniruddha Rosenberg, Andrew E. TI The surgical pathology of notochordal remnants in adult intervertebral disks - A report of 3 cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE notochordal remnant; adult intervertebral disk; benign notochordal cell tumor; chordoma ID NUCLEUS PULPOSUS; CELL TUMORS; CLASSIC CHORDOMAS; FETAL NOTOCHORD; ULTRASTRUCTURE; DISCS; SPINE AB The notochord plays a critical role in organizing and directing vertebral development. In humans, most notochordal cells are eventually sequestered into the nucleus pulposus and disappear within the first decade of life. Although notochordal remnants and related lesions have been described in the axial skeleton of adults, their presence in intervertebral disks is rare. We describe herein 3 cases of incidental notochordal remnants identified in surgically removed adult intervertebral disks. Their histologic features were reminiscent of notochordal vestiges in the fetus. However, they raised the differential diagnosis of benign notochordal cell tumor and chordoma. Notochordal rests can be a source of diagnostic confusion and should be distinguished from notochordal neoplasms because they do not necessitate resection or other forms of therapy. C1 [Wang, Wei-Lien; Ganguly, Aniruddha; Rosenberg, Andrew E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Abramson, Jerome H.] Erlanger Med Ctr, Dept Pathol, Chattanooga, TN USA. RP Rosenberg, AE (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN 219,55 Fruit St, Boston, MA 02114 USA. EM arosenberg@partners.org NR 35 TC 9 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2008 VL 32 IS 8 BP 1123 EP 1129 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 332AP UT WOS:000258054300002 PM 18545146 ER PT J AU Oble, DA Mino-Kenudson, M Goldsmith, J Hodi, FS Seliem, RM Dranoff, G Mihm, M Hasserjian, R Lauwers, GY AF Oble, Darryl A. Mino-Kenudson, Mari Goldsmith, Jeffrey Hodi, F. Stephen Seliem, Rania M. Dranoff, Glenn Mihm, Martin Hasserjian, Robert Lauwers, Gregory Y. TI alpha-CTLA-4 mAb-associated panenteritis - A histologic and immunohistochemical analysis SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE cytotoxic T lymphocyte antigen-4; monoclonal antibody; autoimmune enteropathy; iatrogenic; immunotherapy; diarrhea ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; MONOCLONAL-ANTIBODY THERAPY; PHASE-I TRIAL; METASTATIC MELANOMA; TUMOR-IMMUNOTHERAPY; CTLA-4 BLOCKADE; AUTOIMMUNITY; CANCER; REGRESSION; RESPONSES AB Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3(+), C134(+), and CD8(+)) and of CD4(+)CD25(+) regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity. C1 [Oble, Darryl A.; Mino-Kenudson, Mari; Seliem, Rania M.; Dranoff, Glenn; Mihm, Martin; Hasserjian, Robert; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Goldsmith, Jeffrey] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 2, Boston, MA 02114 USA. EM glauwers@partners.org NR 31 TC 33 Z9 33 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2008 VL 32 IS 8 BP 1130 EP 1137 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 332AP UT WOS:000258054300003 PM 18545145 ER PT J AU Mark, EJ Meng, FQ Kradin, RL Mathisen, DJ Matsubara, O AF Mark, Eugene J. Meng, Fanqing Kradin, Richard L. Mathisen, Douglas J. Matsubara, Osamu TI Idiopathic tracheal stenosis - A clinicopathologic study of 63 cases and comparison of the pathology with chondromalacia SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE idiopathic tracheal stenosis; chondromalacia; trachea ID SUBGLOTTIC STENOSIS; MANAGEMENT; DIAGNOSIS AB Tracheal stenosis in adults usually is the result of mechanical injuries either from direct trauma or intubation. Rarely do cases develop in patients without such a precedent history, and there are few reports of the pathology of idiopathic tracheal stenosis (ITS). We reviewed clinicopathologically, 63 tracheal resections for tracheal stenosis in patients who had no antecedent explanation for their stenosis. We contrasted these 63 cases with 34 cases of tracheal stenosis owing to chondromalacia (CM) after mechanical injury. All 63 cases occurred in females, with a mean age of 49 years. The most common symptom was dyspnea on exertion. The average duration of symptoms was greater than 2 years. One-third of the patients gave a history of gastroesophageal reflux. All but one of the cases occurred in the subglottic region and/or upper one-third of the trachea. Pathologically, most cases showed extensive keloidal fibrosis and dilation of mucus glands, a finding that was not obvious in most cases of CM. ITS has relatively normal cartilage with smooth inner and outer perichondrium, whereas CM has extensive degeneration of cartilage with irregular border of inner perichondrium observable at shirt sleeve magnification. Immunohistochemical staining for estrogen receptor and progesterone receptor was positive in fibroblasts cells in most cases. ITS is a rare disease and restricted to females. It may represent some form of fibromatosis. ITS can be distinguished histologically from CM in tracheal resection specimens in most cases. C1 [Mark, Eugene J.; Meng, Fanqing; Kradin, Richard L.; Mathisen, Douglas J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mark, Eugene J.; Meng, Fanqing; Kradin, Richard L.; Mathisen, Douglas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meng, Fanqing] Nanjing Drum Tower Hosp, Nanjing, Peoples R China. [Meng, Fanqing] Nanjing Univ, Sch Med, Nanjing 210008, Peoples R China. [Matsubara, Osamu] Natl Def Med Coll, Dept Pathol, Saitama, Japan. RP Mark, EJ (reprint author), Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM emark@partners.org NR 18 TC 22 Z9 23 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2008 VL 32 IS 8 BP 1138 EP 1143 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 332AP UT WOS:000258054300004 PM 18545144 ER PT J AU Ulbright, TM Young, RH AF Ulbright, Thomas M. Young, Robert H. TI Seminoma with conspicuous signet ring cells: A rare, previously uncharacterized morphologic variant SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE seminoma; signet ring cells; testicular neoplasms ID DIFFERENTIAL-DIAGNOSIS; CLINICOPATHOLOGICAL ANALYSIS; IMMUNOHISTOCHEMICAL ANALYSIS; ADIPOCYTIC DIFFERENTIATION; METASTATIC ADENOCARCINOMA; UROTHELIAL CARCINOMA; SINUS HISTIOCYTOSIS; MALIGNANT-MELANOMA; TUBULAR SEMINOMA; TUMORS AB We report 2 seminomas with conspicuous numbers of signet ring cells. The tumors occurred in men, 24 and 69 years of age, who presented with testicular masses; I seminoma was a component of a mixed germ cell tumor and the other was pure. The signet ring cells occurred in a multifocal fashion in areas of otherwise typical seminoma and comprised approximately 70% and 10%, respectively, of the tumors. They had large, translucent to clear cytoplasmic vacuoles that compressed the nuclei to a peripheral crescent. In I case, the vacuoles contained numerous refractile, nonpolarizable globular deposits that were shown to be glycogen on the basis of periodic acid-Schiff stain positivity that was abolished by pretreatment with diastase; in the second case, they mostly appeared "empty" and lacked periodic acid-Schiff positivity. The signet ring cells were mucicarmine, cytokeratin (AE1/3) and alpha-fetoprotein negative, but positive for OCT3/4 and CD 117, the latter 2 being expected for seminoma cells. A review of 30 randomly selected seminomas identified very rare, inconspicuous signet ring cells in 43%. The presence of prominent signet ring cells in seminoma may cause confusion as it has not been described previously in detail, and a variety of neoplasms, particularly metastasis, may be considered. The description of this phenomenon expands the known morphologic spectrum of the most common testicular neoplasm. C1 [Ulbright, Thomas M.] Indiana Univ, Sch Med, Dept Pathol, Indianapolis, IN USA. [Young, Robert H.] Harvard Univ, Sch Med, James Homer Wright Pathol Labs, Massachusetts Gen Hosp, Boston, MA USA. RP Ulbright, TM (reprint author), Clarian Pathol Lab, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. EM tulbrigh@iupui.edu NR 68 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2008 VL 32 IS 8 BP 1175 EP 1181 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 332AP UT WOS:000258054300008 PM 18580681 ER PT J AU Sachs, DH Kawai, T Colvin, RB Fishman, JA Sykes, M Cosimi, AB AF Sachs, D. H. Kawai, T. Colvin, R. B. Fishman, J. A. Sykes, M. Cosimi, A. B. TI Response to 'Tolerance versus immunosuppression: A perspective' SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID TRANSPLANTATION; SPECIFICITY; CHIMERAS C1 [Sachs, D. H.; Sykes, M.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Kawai, T.; Fishman, J. A.; Cosimi, A. B.] Massachusetts Gen Hosp, Transplant Unit, Boston, MA 02114 USA. [Colvin, R. B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. EM David.Sachs@TBRC.mgh.harvard.edu NR 7 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2008 VL 8 IS 8 BP 1573 EP 1574 DI 10.1111/j.1600-6143.2008.02344.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 333WH UT WOS:000258183800002 PM 18694470 ER PT J AU Markmann, JF Kaufman, DB Ricordi, C Schwab, PM Stock, PG AF Markmann, J. F. Kaufman, D. B. Ricordi, C. Schwab, P. M. Stock, P. G. TI Financial issues constraining the use of pancreata recovered for islet transplantation: A white paper SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE organ acquisition costs; pancreata; pancreatic islets; transplantation AB Islet transplantation is a very promising therapy for select patients with type 1 diabetes. Continued clinical investigation is required to define the long-term safety and efficacy outcomes before the procedure will be accepted as a standard of care even for those with the most severe manifestations of diabetes. Threatening successful accomplishment of these and other innovative studies designed to advance the field are the complex financial cost accounting issues that pose undue burden on organ procurement organizations and transplant centers trying to manage the costs of the pancreata from deceased donors needed to isolate islets. Compounding the problem is the recent ruling by CMS regarding 'intent to transplant' (CMS-1543-R Dec. 21, 2006: Allocation of Donor Acquisition Costs Incurred by Organ Procurement Organizations) that does not account for the clinical need to complete the manufacturing process for islets before suitability and transplant intent of the pancreata involved can be determined. We provide a consensus document supported by a diverse group of stakeholders in islet transplantation to suggest actions to address this problem. C1 [Markmann, J. F.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kaufman, D. B.] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Ricordi, C.] Univ Miami, Diabet Res Inst, Miami, FL USA. [Schwab, P. M.] Assoc Organ Procurement Org, Mclean, VA USA. [Stock, P. G.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM JMarkmann@partners.org OI Ricordi, Camillo/0000-0001-8092-7153 NR 9 TC 6 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2008 VL 8 IS 8 BP 1588 EP 1592 DI 10.1111/j.1600-6143.2008.02305.x PG 5 WC Surgery; Transplantation SC Surgery; Transplantation GA 333WH UT WOS:000258183800006 PM 18557722 ER PT J AU Smith, RN Kawai, T Boskovic, S Nadazdin, O Sachs, DH Cosimi, AB Colvin, RB AF Smith, R. N. Kawai, T. Boskovic, S. Nadazdin, O. Sachs, D. H. Cosimi, A. B. Colvin, R. B. TI Four stages and lack of stable accommodation in chronic alloantibody-mediated renal allograft rejection in cynomolgus monkeys SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE allograft; antibody; chronic; kidney; monkey; rejection ID ACUTE HUMORAL REJECTION; CAPILLARY C4D DEPOSITION; LONG-TERM SURVIVAL; TRANSPLANT GLOMERULOPATHY; KIDNEY-TRANSPLANTATION; ENDOTHELIAL-CELLS; NONHUMAN-PRIMATES; PROTOCOL BIOPSIES; PERITUBULAR CAPILLARIES; MIXED CHIMERISM AB The etiology of immunologically mediated chronic renal allograft failure is unclear. One cause is thought to be alloantibodies. Previously in Cynomolgus monkeys, we observed a relationship among donor-specific alloantibodies (DSA), C4d staining, allograft glomerulopathy, allograft arteriopathy and progressive renal failure. To define the natural history of chronic antibody-mediated rejection and its effect on renal allograft survival, we now extend this report to include 417 specimens from 143 Cynomolgus monkeys with renal allografts. A subset of animals with long-term renal allografts made DSA (48%), were C4d positive (29%), developed transplant glomerulopathy (TG) (22%) and chronic allograft arteriopathy (CAA) (19%). These four features were highly correlated and associated with statistically significant shortened allograft survival. Acute cellular rejection, either Banff type 1 or 2, did not correlate with alloantibodies, C4d deposition or TG. However, endarteritis (Banff type 2) correlated with later CAA. Sequential analysis identified four progressive stages of chronic antibody-mediated rejection: (1) DSA, (2) deposition of C4d, (3) TG and (4) rising creatinine/renal failure. These new findings provide strong evidence that chronic antibody-mediated rejection develops without enduring stable accommodation, progresses through four defined clinical pathological stages and shortens renal allograft survival. C1 [Smith, R. N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Smith, RN (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM smith.rex@mgh.harvard.edu FU NHLBI NIH HHS [HL18646, P01 HL018646, P01 HL018646-21A19001, P01 HL018646-229001, P01 HL018646-22S19001, P01 HL018646-239001, P01 HL018646-249001, P01 HL018646-259001, P01 HL018646-31A16609] NR 91 TC 58 Z9 62 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2008 VL 8 IS 8 BP 1662 EP 1672 DI 10.1111/j.1600-6143.2008.02303.x PG 11 WC Surgery; Transplantation SC Surgery; Transplantation GA 333WH UT WOS:000258183800014 PM 18557724 ER PT J AU Cabral, CB Bullock, KH Bischoff, DJ Tompkins, RG Yu, YM Kelleher, JK AF Cabral, Carolina B. Bullock, Kevin H. Bischoff, David J. Tompkins, Ronald G. Yu, Yong M. Kelleher, Joanne K. TI Estimating glutathione synthesis with deuterated water: A model for peptide biosynthesis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE glutathione; deuterated water; models; isotopomers; mass spectrometry; LC/MS ID CHROMATOGRAPHY-MASS-SPECTROMETRY; AMINO-ACIDS; RATES; METABOLISM; HOMEOSTASIS; (H2O)-H-2; TURNOVER; BLOOD; LIVER AB Glutathione (GSH), an intracellular tripeptide that combats oxidative stress, must be continually replaced due to loss through conjugation and destruction. Previous methods, estimating the synthesis of GSH in vivo, used constant infusions of labeled amino acid precursors. We developed a new method based on incorporation of (2)H from Orally supplied (2)H(2)O into stable C-H bonds on the tripeptide. The incorporation of (2)H(2)O into GSH was studied in rabbits over a 2-week period. The method estimated N, the maximum number of C-H bonds in GSH that equilibrate with (2)H(2)O as amino acids. GSH was analyzed by liquid chromatography/mass spectrometry after derivatization to yield GSH-N-ethylmaleimide (GSNEM). A model, which simulated the expected abundance at each mass isotopomer for the GSNEM ion at various values for N, was used to find the best fit to the data. The plateau labeling fit best a model with N = 6 of a possible 10 C-H bonds. Thus, the amino acid precursors do not completely equilibrate With (2)H(2)O prior to GSH synthesis. Advantages of this new method include replacing costly amino acid infusions with the oral administration of (2)H(2)O and a statistical basis for estimating N. (C) 2008 Elsevier Inc. All rights reserved. C1 [Cabral, Carolina B.; Tompkins, Ronald G.; Yu, Yong M.; Kelleher, Joanne K.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Bullock, Kevin H.; Bischoff, David J.; Tompkins, Ronald G.; Yu, Yong M.; Kelleher, Joanne K.] Shriners Hosp Children, Boston, MA 02114 USA. RP Kelleher, JK (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM jkkelleher@partners.org FU NIDDK NIH HHS [P30 DK040561-13, P30 DK040561]; NIEHS NIH HHS [R01 ES013925, R01ES013925]; NIGMS NIH HHS [P50 GM021700] NR 18 TC 11 Z9 11 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 2008 VL 379 IS 1 BP 40 EP 44 DI 10.1016/j.ab.2008.04.042 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 319YA UT WOS:000257199700007 PM 18486587 ER PT J AU Schiavo, S Ebbel, E Sharma, S Matson, W Kristal, BS Hersch, S Vouros, P AF Schiavo, Susan Ebbel, Erika Sharma, Swati Matson, Wayne Kristal, Bruce S. Hersch, Steven Vouros, Paul TI Metabolite identification using a nanoelectrospray LC-EC-array-MS integrated system SO ANALYTICAL CHEMISTRY LA English DT Article ID SODIUM PHENYLBUTYRATE; ELECTROCHEMISTRY/MASS SPECTROMETRY; LIQUID-CHROMATOGRAPHY; UREA; 4-PHENYLBUTYRATE AB A novel approach to the parallel coupling of normal-bore high-performance liquid chromatography (LC) with electrochemical-array detection (EC-array) and nanoelectrospray mass spectrometry (MS), based on the use of a nanosplitting interface, is described where both detectors are utilized at their optimal detection mode for parallel configuration. The dual detection platform was shown to maintain frill chromatographic integrity with retention times and peak widths at half-height between the EC-array and MS displaying high reproducibility with relative standard deviations of <2%. Detection compatibility between the two detectors at the part per billion level injected on-column was demonstrated using selected metabolites representative of the diversity typically encountered in physiological systems. Metabolites were detected with equal efficiency whether neat or in serum, demonstrating the system's ability to handle biological samples with limited sample cleanup and reduced concern for biological matrix effects. Direct quantification of known analytes from the EC-array signal using Faraday's law can eliminate the need for isotopically labeled internal standards. The system was successfully applied to the detection and characterization of metabolites of phenylbutyrate from serum samples of Huntington's disease patients in an example that illustrates the complementarity of the dual detection nanoelectrospray LC-EC-array-MS system. C1 [Schiavo, Susan; Vouros, Paul] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Schiavo, Susan; Vouros, Paul] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Ebbel, Erika] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sharma, Swati; Matson, Wayne] Bedford VA Med Ctr, Dept Syst Biochem, Bedford, MA 01430 USA. [Kristal, Bruce S.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Hersch, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Vouros, P (reprint author), Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. EM p.vouros@neu.edu FU NCI NIH HHS [R01 CA102536, CA102536]; NIDDK NIH HHS [P30 DK040561-13, 4R33DK070326-02, 3R33DK070326-02S1, R33 DK070326, P30 DK040561]; NINDS NIH HHS [NS058793, P01 NS058793-01A1, P01 NS058793, P01 NS058793-01A19001, NS04524] NR 35 TC 15 Z9 15 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD AUG 1 PY 2008 VL 80 IS 15 BP 5912 EP 5923 DI 10.1021/ac800507y PG 12 WC Chemistry, Analytical SC Chemistry GA 332PX UT WOS:000258096700038 PM 18576668 ER PT J AU Leissner, KB Mahmood, F Aragam, JR Amouzgar, A Ortega, R AF Leissner, Kay B. Mahmood, Feroze Aragam, Jayashri R. Amouzgar, Abolhassan Ortega, Rafael TI Catecholamine-induced cardiomyopathy and pheochromocytoma SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID HEART C1 [Leissner, Kay B.] VA Boston Healthcare Serv, Anesthesiol Serv, Dept Anesthesiol & Crit Care, Boston, MA 02132 USA. [Leissner, Kay B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mahmood, Feroze] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02215 USA. [Aragam, Jayashri R.] VA Boston Healthcare Syst, Dept Cardiol, Boston, MA USA. [Amouzgar, Abolhassan; Ortega, Rafael] Boston Univ, Med Ctr, Sch Med, Dept Anesthesiol, Boston, MA 02118 USA. RP Leissner, KB (reprint author), VA Boston Healthcare Serv, Anesthesiol Serv, Dept Anesthesiol & Crit Care, 1400 VFW Pkwy, Boston, MA 02132 USA. EM kbleissner@yahoo.com RI Mahmood, Feroze/B-1383-2008; OI Mahmood, Feroze/0000-0002-7071-0476; Ortega, Rafael/0000-0002-8212-3471 NR 6 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2008 VL 107 IS 2 BP 410 EP 412 DI 10.1213/ane.0b013e31817e65d0 PG 3 WC Anesthesiology SC Anesthesiology GA 333QV UT WOS:000258168300013 PM 18633017 ER PT J AU Eger, EJ Tang, M Liao, M Laster, MJ Solt, K Flood, P Jenkins, A Raines, D Hendrickx, JF Shafer, SL Yasumasa, T Sonner, JM AF Eger, Edmond J., II Tang, Michael Liao, Mark Laster, Michael J. Solt, Ken Flood, Pamela Jenkins, Andrew Raines, Douglas Hendrickx, Jan F. Shafer, Steven L. Yasumasa, Tanifuji Sonner, James M. TI Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats SO ANESTHESIA AND ANALGESIA LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; D-ASPARTATE RECEPTOR; NITROUS-OXIDE; GLYCINE RECEPTORS; CONCENTRATION MAC; GENERAL-ANESTHETICS; ISOFLURANE; HALOTHANE; XENON; SEVOFLURANE AB BACKGROUND: We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC) one acting strongly at MAC] on specific receptors /channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By "divergently," we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and gamma-aminobutvric acid type A, glycine, N-methyl-D-aspartic acid, and acetylcholine receptors. W also studied the additivity of cyclopropane-benzene because the N-methyl-D-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result with in 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation. C1 [Eger, Edmond J., II; Tang, Michael; Liao, Mark; Laster, Michael J.; Sonner, James M.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Solt, Ken; Raines, Douglas] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Solt, Ken; Raines, Douglas] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Flood, Pamela] Columbia Univ, Dept Anesthesiol, New York, NY USA. [Jenkins, Andrew] Emory Univ, Dept Anesthesiol, Atlanta, GA 30322 USA. [Hendrickx, Jan F.; Shafer, Steven L.] Stanford Univ, Dept Anesthesia, Stanford, CA 94305 USA. [Shafer, Steven L.] UCSF, Dept Biopharmaceut Sci, San Francisco, CA USA. [Yasumasa, Tanifuji] Jekei Univ Sch Med, Dept Anesthesiol, Tokyo, Japan. RP Eger, EJ (reprint author), Univ Calif San Francisco, Dept Anesthesia, S-455, San Francisco, CA 94143 USA. EM egere@anesthesia.ucsf.edu RI Jenkins, Andrew/E-1180-2011; OI Shafer, Steven/0000-0002-0289-7793; Solt, Ken/0000-0001-5328-2062 FU NIGMS NIH HHS [1P01GM47818] NR 46 TC 20 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2008 VL 107 IS 2 BP 479 EP 485 DI 10.1213/01.ane.0000295805.70887.65 PG 7 WC Anesthesiology SC Anesthesiology GA 333QV UT WOS:000258168300022 PM 18633026 ER PT J AU Jenkins, A Lobo, IA Gong, D Trudell, JR Solt, K Harris, RA Eger, EI AF Jenkins, Andrew Lobo, Ingrid A. Gong, Diane Trudell, James R. Solt, Ken Harris, R. Adron Eger, Edmond I., II TI General anesthetics have additive actions on three ligand gated ion channels SO ANESTHESIA AND ANALGESIA LA English DT Article ID D-ASPARTATE RECEPTORS; GLYCINE RECEPTORS; INHALED ANESTHETICS; GABA(A) RECEPTOR; MODULATION; MECHANISMS; SUBUNIT AB BACKGROUND: The purpose of this study was to determine whether pairs of compounds, including general anesthetics, could simultaneously modulate receptor function in a synergistic manner, thus demonstrating the existence of multiple intraprotein anesthetic binding sites. METHODS: Using standard electrophysiologic methods, we measured the effects of at least one combination of benzene, isoflurane (ISO), halothane (HAL), chloroform, flunitrazepam, zinc, and pentobarbital on at least one of the following ligand gated ion channels: N-methyl-D-aspartate receptors, glycine receptors and gamma-aminobutyric acid type A receptors. RESULTS: All drug-drug-receptor combinations were found to exhibit additive, not synergistic modulation. ISO with benzene additively depressed N-methyl-D-aspartate receptors function. ISO with HAL additively enhanced glycine receptors function, as did ISO with zinc. ISO with HAL additively enhanced gamma-aminobutyric acid type A receptors function as did all of the following: HAL with chloroform, pentobarbital with ISO, and flunitrazepam with ISO. CONCLUSION: The simultaneous allosteric modulation of ligand gated ion channels by general anesthetics is entirely additive. Where pairs of general anesthetic drugs interact synergistically to produce general anesthesia, they must do so on systems more complex than a single receptor. C1 [Jenkins, Andrew] Emory Univ, Sch Med, Dept Anesthesiol, Atlanta, GA 30322 USA. [Lobo, Ingrid A.; Gong, Diane; Harris, R. Adron] Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Neurobiol Sect, Austin, TX 78712 USA. [Lobo, Ingrid A.; Gong, Diane; Harris, R. Adron] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Trudell, James R.] Stanford Univ, Dept Anesthesiol, Stanford, CA 94305 USA. [Solt, Ken] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Solt, Ken] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Eger, Edmond I., II] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. RP Jenkins, A (reprint author), Emory Univ, Sch Med, Dept Anesthesiol, 1462 Clifton Rd NE,Suite 420, Atlanta, GA 30322 USA. EM ajenki2@emory.edu RI Jenkins, Andrew/E-1180-2011; OI Solt, Ken/0000-0001-5328-2062 FU NIGMS NIH HHS [R01 GM073959-03, P01 GM047818, GM073959, R01 GM073959, P01 GM047818-140004, GM04718] NR 26 TC 14 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2008 VL 107 IS 2 BP 486 EP 493 DI 10.1213/ane.0b013e31817b70c1 PG 8 WC Anesthesiology SC Anesthesiology GA 333QV UT WOS:000258168300023 PM 18633027 ER PT J AU Fitzsimons, MG Baker, KH Lowenstein, E Zapol, WM AF Fitzsimons, Michael G. Baker, Keith H. Lowenstein, Edward Zapol, Warren M. TI Random drug testing to reduce the incidence of addiction in anesthesia residents: Preliminary results from one program SO ANESTHESIA AND ANALGESIA LA English DT Article ID IMPAIRED PHYSICIANS; URINE; ABUSE; IMMUNOASSAYS; INTERFERENCE; PROPOFOL; EXPOSURE AB Substance abuse occurs in approximately 1%-2% of anesthesia residents and nearly 80% of programs have had one or more resident (s) with such a problem. Education and control efforts have failed to reduce the frequency of substance abuse. Anesthesia providers have a professional obligation to be drug-free for the well being of their patients. We have instituted a program of preplacement and random urine testing of residents in anesthesiology in an attempt to decrease the incidence of substance abuse. We demonstrate that such a program is feasible, despite logistic and cultural obstacles. Larger multi-institutional studies will be required to determine whether instituting a program of random urine testing decreases the incidence of substance abuse in anesthesiology residents. C1 [Fitzsimons, Michael G.; Baker, Keith H.; Lowenstein, Edward; Zapol, Warren M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Fitzsimons, MG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM mfitzsimons@partners.org NR 25 TC 20 Z9 21 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2008 VL 107 IS 2 BP 630 EP 635 DI 10.1213/ane.0b013e318176fefa PG 6 WC Anesthesiology SC Anesthesiology GA 333QV UT WOS:000258168300040 PM 18633044 ER PT J AU Rathmell, JP AF Rathmell, James P. TI The promise of an effective treatment for sacroiliac-related low back pain SO ANESTHESIOLOGY LA English DT Editorial Material ID JOINT PAIN; RADIOFREQUENCY NEUROTOMY; DENERVATION; DIAGNOSIS C1 [Rathmell, James P.] Massachusetts Gen Hosp, Ctr Pain Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Rathmell, James P.] Harvard Univ, Sch Med, Boston, MA USA. RP Rathmell, JP (reprint author), Massachusetts Gen Hosp, Ctr Pain Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM jrathmell@partners.org NR 15 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2008 VL 109 IS 2 BP 167 EP 168 PG 2 WC Anesthesiology SC Anesthesiology GA 330KK UT WOS:000257939600002 PM 18648223 ER PT J AU He, XM Fowler, A Menze, M Hand, S Toner, M AF He, Xiaoming Fowler, Alex Menze, Michael Hand, Steve Toner, Mehmet TI Desiccation kinetics and biothermodynamics of glass forming trehalose solutions in thin films SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE trehalose; lyopreservation; desiccation; free volume theory; diffusion coefficient; viscosity; glass transition ID WATER REPLACEMENT HYPOTHESIS; PRESERVING DRY BIOMATERIALS; MAMMALIAN-CELLS; INTRACELLULAR TREHALOSE; VAPOR ABSORPTION; SOLVENT SYSTEMS; ANHYDROBIOSIS; TARDIGRADES; POLYMER; VITRIFICATION AB In this study, the desiccation kinetics of aqueous trehalose solutions were investigated numerically by solving the coupled heat and mass transfer problem with a moving interface using the finite element method. The free volume models for vapor pressure and mutual diffusion coefficient were incorporated into the model to account for the effect of glass transition on the heat and mass transport process that ultimately determines the desiccation kinetics. It was found that the temperature in the film could drop significantly upon the initiation of drying due to the absorption of latent heat associated with water evaporation although the spatial distribution of temperature in the solution is very homogeneous. On the contrary, the spatial distribution of water content in the solution is non-homogeneous, particularly at the solution-vapor interface where an extremely thin layer of skin with extremely low molecular mobility usually forms during drying. The solution film can be dried to similar to 6-10 wt.% residual water within minutes for thin films; but drying times depends strongly on the initial film thickness, initial solution concentration, temperature, and convective coefficient. Desiccation to below 6 wt.% residual water is very slow due to the retarded water mobility in the extremely thin skin where the solution is in the glassy state. Since the water mobility in a trehalose solution or glass with 6-10% residual water is still high enough to allow degradative