FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kulke, MH Blaszkowsky, L Zhu, AX Florio, S Regan, E Ryan, DP Chan, JA AF Kulke, Matthew H. Blaszkowsky, Lawrence Zhu, Andrew X. Florio, Sarah Regan, Eileen Ryan, David P. Chan, Jennifer A. TI Phase I/II Study of Everolimus (RAD001) in Combination With Temozolomide (TMZ) in Patients With Advanced Pancreatic Neuroendocrine Tumors (NET) SO PANCREAS LA English DT Meeting Abstract C1 [Kulke, Matthew H.; Florio, Sarah; Regan, Eileen; Chan, Jennifer A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kulke, Matthew H.; Chan, Jennifer A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Blaszkowsky, Lawrence; Zhu, Andrew X.; Ryan, David P.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2011 VL 40 IS 2 BP 328 EP 328 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 719VN UT WOS:000287239700045 ER PT J AU Oberg, K Kulke, M Pavel, M Phan, A Hoosen, S St Peter, J Cherfi, A Yao, JC AF Oberg, Kjell Kulke, Matthew Pavel, Marianne Phan, Alexandria Hoosen, Sakina St Peter, Jessica Cherfi, Azzeddine Yao, James C. TI Evaluation of Chromogranin A and Neuron-Specific Enolase as Predictors of Response to Everolimus Therapy in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) SO PANCREAS LA English DT Meeting Abstract C1 [Oberg, Kjell] Uppsala Univ, Uppsala, Sweden. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pavel, Marianne] Charite, D-13353 Berlin, Germany. [Phan, Alexandria; Yao, James C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hoosen, Sakina; St Peter, Jessica] Novartis Pharmaceut, Novartis Oncol, E Hanover, NJ 07936 USA. [Cherfi, Azzeddine] Novartis Pharma Serv AG, Basel, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2011 VL 40 IS 2 BP 329 EP 330 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 719VN UT WOS:000287239700051 ER PT J AU Ter-Minassian, M Wang, ZX Asomaning, K Wu, MC Liu, CY Paulus, JK Liu, G Bradbury, PA Zhai, RH Su, L Frauenhoffer, CS Hooshmand, SM DeVivo, I Lin, XH Christiani, DC Kulke, MH AF Ter-Minassian, Monica Wang, Zhaoxi Asomaning, Kofi Wu, Michael C. Liu, Chen-Yu Paulus, Jessica K. Liu, Geoffrey Bradbury, Penelope A. Zhai, Rihong Su, Li Frauenhoffer, Christine S. Hooshmand, Susanne M. DeVivo, Immaculata Lin, Xihong Christiani, David C. Kulke, Matthew H. TI Genetic Associations With Sporadic Neuroendocrine Tumor Risk SO PANCREAS LA English DT Meeting Abstract C1 [Ter-Minassian, Monica; Wang, Zhaoxi; Asomaning, Kofi; Liu, Chen-Yu; Zhai, Rihong; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Paulus, Jessica K.; DeVivo, Immaculata; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wu, Michael C.; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Liu, Geoffrey; Bradbury, Penelope A.] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. [Ter-Minassian, Monica; Frauenhoffer, Christine S.; Hooshmand, Susanne M.; Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2011 VL 40 IS 2 BP 333 EP 334 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 719VN UT WOS:000287239700066 ER PT J AU Ter-Minassian, M Chan, JA Frauenhoffer, CS Hooshmand, SM Asomaning, K Lin, XH Christiani, DC Kulke, MH AF Ter-Minassian, Monica Chan, Jennifer A. Frauenhoffer, Christine S. Hooshmand, Susanne M. Asomaning, Kofi Lin, Xihong Christiani, David C. Kulke, Matthew H. TI Prospective Analysis of Clinical Outcomes and Prognostic Factors in Patients With Neuroendocrine Tumors (NETs) SO PANCREAS LA English DT Meeting Abstract C1 [Ter-Minassian, Monica; Asomaning, Kofi; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol EOME Program, Boston, MA 02115 USA. [Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ter-Minassian, Monica; Chan, Jennifer A.; Frauenhoffer, Christine S.; Hooshmand, Susanne M.; Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2011 VL 40 IS 2 BP 334 EP 334 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 719VN UT WOS:000287239700067 ER PT J AU Snarr, BS Rowley, CP Phan, SV Achanti, A Hendrix, GH AF Snarr, Brian S. Rowley, Christopher P. Phan, Stephanie V. Achanti, Anand Hendrix, Grady H. TI Prolonged Sinus Pauses with Hydromorphone in the Absence of Cardiac Conduction Disease SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE bradycardia; hydromorphone; opioid receptor; sinus pause; vagal response AB A 49-year-old male had open sigmoid colectomy with colorectal anastomosis for sigmoid diverticulitis. The patient was given patient-controlled analgesia (PCA) hydromorphone and subsequently developed bradycardia with prolonged sinus pauses up to 7.1 seconds. The pauses resolved shortly after the hydromorphone was discontinued. This is the first case report to our knowledge of reversible prolonged sinus pauses associated with the use of hydromorphone. Animal studies support a role for opioid signaling at the sinoatrial (SA) node. Hydromorphone is a potential cause of prolonged sinus pauses and should be taken into consideration when monitoring a patient on hydromorphone for pain control. C1 [Snarr, Brian S.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Snarr, BS (reprint author), Med Univ S Carolina, Dept Regenerat Med & Cell Biol, 173 Ashley Ave,Room BSB 648,POB 250508, Charleston, SC 29425 USA. EM snarr@musc.edu NR 7 TC 1 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD MAR PY 2011 VL 104 IS 3 BP 239 EP 240 DI 10.1097/SMJ.0b013e318206f6d3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 722ZE UT WOS:000287473400017 PM 21297541 ER PT J AU Pihlajamaki, M O'Keefe, K O'Brien, J Blacker, D Sperling, RA AF Pihlajamaki, Maija O'Keefe, Kelly O'Brien, Jackie Blacker, Deborah Sperling, Reisa A. TI Failure of repetition suppression and memory encoding in aging and Alzheimer's disease SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Aging; Alzheimer's disease; Functional magnetic resonance imaging; Medial temporal lobe; Memory; Repetition suppression ID MILD COGNITIVE IMPAIRMENT; MEDIAL TEMPORAL-LOBE; RECOGNITION MEMORY; HIPPOCAMPAL-FORMATION; PERIRHINAL CORTEX; NEURAL MECHANISMS; FAMILIARITY; FMRI; TEMPOROPOLAR; ACTIVATION AB The suppression of neural activity in the medial temporal lobe (MTL) has been suggested as a marker of successful recognition of familiarity in healthy subjects, but to be impaired in patients with Alzheimer's disease (AD). In this study, we investigated whether the ability to suppress MTL activity during repeated exposure to face-name pairs was related to the ability to successfully encode novel associations in 90 individuals ranging from healthy young and older subjects to mildly impaired elderly and AD patients. Activity in the anterior MTL during Repeated stimuli was inversely related to performance in post-scan associative recognition for the Novel face-name pairs. In a subset (n = 60) of subjects undergoing more detailed neuropsychological testing, greater MTL Repeated activity was correlated with worse word-list delayed recall performance. Failure of response suppression to familiar information may be a sensitive marker of MTL dysfunction and memory impairment in aging and prodromal AD. C1 [Pihlajamaki, Maija] Kuopio Univ Hosp, Dept Neurol, Kuopio 70211, Finland. [Pihlajamaki, Maija] Univ Eastern Finland, Inst Clin Med, Neurol Unit, Kuopio 70211, Finland. [Pihlajamaki, Maija; Sperling, Reisa A.] Harvard Univ, Sch Med, Memory Disorders Unit, Dept Neurol,Brigham & Womens Hosp, Boston, MA 02115 USA. [O'Keefe, Kelly; O'Brien, Jackie; Blacker, Deborah; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. RP Pihlajamaki, M (reprint author), Kuopio Univ Hosp, Dept Neurol, POB 1777, Kuopio 70211, Finland. EM Maija.Pihlajamaki@uef.fi FU Academy of Finland [108188, 214050]; Kuopio University Hospital EVO; National Institute of Aging [AG027435, AG04953, AG00513421] FX This study was supported by Academy of Finland grants # 108188 and # 214050, Kuopio University Hospital EVO grants, as well as National Institute of Aging grants AG027435, AG04953 and AG00513421. We thank the staff of the Massachusetts General Hospital Gerontology Research Unit and Brigham and Women's Hospital Memory Disorders Unit Clinical Research for assistance with subject recruitment, evaluation, and data management, as well as Mary Foley, Larry White, and the Athinoula A. Martinos Center staff for assistance with MRI data collection. We express special gratitude to the subjects who participated in this study. NR 37 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2011 VL 5 IS 1 BP 36 EP 44 DI 10.1007/s11682-010-9110-3 PG 9 WC Neuroimaging SC Neurosciences & Neurology GA 709TQ UT WOS:000286464700004 PM 21161449 ER PT J AU Roffman, JL Brohawn, DG Friedman, JS Dyckman, KA Thakkar, KN Agam, Y Vangel, MG Goff, DC Manoach, DS AF Roffman, Joshua L. Brohawn, David G. Friedman, Jesse S. Dyckman, Kara A. Thakkar, Katharine N. Agam, Yigal Vangel, Mark G. Goff, Donald C. Manoach, Dara S. TI MTHFR 677C > T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Schizophrenia; Functional MRI; Genetics; Executive function; Anterior cingulate cortex; Diffusion tensor imaging ID METHYLENETETRAHYDROFOLATE REDUCTASE DEFICIENCY; SURFACE-BASED ANALYSIS; WHITE-MATTER; CORTICAL SURFACE; C677T POLYMORPHISM; EXECUTIVE FUNCTION; COORDINATE SYSTEM; GENE POLYMORPHISM; CORTEX; BRAIN AB Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C > T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity. C1 [Roffman, Joshua L.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Roffman, Joshua L.; Brohawn, David G.; Friedman, Jesse S.; Dyckman, Kara A.; Thakkar, Katharine N.; Agam, Yigal; Goff, Donald C.; Manoach, Dara S.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Roffman, Joshua L.; Brohawn, David G.; Friedman, Jesse S.; Dyckman, Kara A.; Thakkar, Katharine N.; Agam, Yigal; Vangel, Mark G.; Goff, Donald C.; Manoach, Dara S.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Vangel, Mark G.; Manoach, Dara S.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Roffman, JL (reprint author), Massachusetts Gen Hosp, 149 13th St,Room 2606, Charlestown, MA 02129 USA. EM jroffman@partners.org OI Thakkar, Katharine/0000-0002-0026-2030 FU National Institute for Mental Health [R01 MH67720]; NARSAD; Bank of America, Co-Trustee; Bushrod H. Campbell and Adah F. Hall Charity Fund; Howard Hughes Medical Institute Physician Scientist Early Career Award; Mental Illness Neuroscience Discovery (MIND) Institute [DOE DE-FG02-99ER62764]; National Center for Research Resources [P41RR14075]; Alden Trust; Charles A. King Trust FX This work was supported by the National Institute for Mental Health (R01 MH67720) and NARSAD Independent Investigator Award (to DSM); the Charles A. King Trust, Bank of America, Co-Trustee and the Bushrod H. Campbell and Adah F. Hall Charity Fund, Alden Trust, and Howard Hughes Medical Institute Physician Scientist Early Career Award (to JLR); the Mental Illness Neuroscience Discovery (MIND) Institute (DOE DE-FG02-99ER62764); and the National Center for Research Resources (P41RR14075). We thank Doug Greve for helpful discussions regarding the manuscript. None of the authors report any conflicts of interest. In memory of Jesse Friedman. NR 66 TC 12 Z9 13 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2011 VL 5 IS 1 BP 65 EP 75 DI 10.1007/s11682-010-9111-2 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 709TQ UT WOS:000286464700007 PM 21190096 ER PT J AU Favis, R Sun, Y van de Velde, H Broderick, E Levey, L Meyers, M Mulligan, G Harousseau, JL Richardson, PG Ricci, DS AF Favis, Reyna Sun, Yu van de Velde, Helgi Broderick, Erin Levey, Laura Meyers, Michael Mulligan, George Harousseau, Jean-Luc Richardson, Paul G. Ricci, Deborah S. TI Genetic variation associated with bortezomib-induced peripheral neuropathy SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE bortezomib; candidate gene association study; genetic variation; multiple myeloma; peripheral neuropathy ID ADVANCED MULTIPLE-MYELOMA; OF-THE-LITERATURE; NF-KAPPA-B; PROTEIN-INTERACTION; NEUROTOXICITY; REVERSIBILITY; COMPLEX; CANCER; DYNEIN; CELLS AB Objective To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN). Methods Two thousand and sixteen single-nucleotide polymorphisms (SNPs) were genotyped in 139 samples from myeloma patients treated with bortezomib-melphalan-prednisone in the VISTA phase 3 trial. Single-marker association analysis for PN onset and time/cumulative dose to PN onset using the Cox proportional hazards model and multiple covariates was performed under additive, dominant, and recessive genotypic models, followed by correction for multiplicity. Associations were also pursued in a cohort of 212 samples from patients treated with bortezomib-dexamethasone in the IFM 2005-01 phase 3 trial. Results In the VISTA cohort, after Bonferroni correction, two SNPs significantly associated with time to onset of PN [CTLA4 rs4553808, false discovery rate (FDR)=0.002] and time to onset of grade of at least 2 PN (PSMB1 rs1474642, FDR=0.014). Using FDR less than 0.05 as the threshold, two additional SNPs significantly associated with time to onset of grade of at least 2 (CTSS rs12568757, FDR=0.027) or grade of at least 3 PN (GJE1 rs11974610, FDR=0.041). DYNC1I1 rs916758 significantly associated (FDR=0.012) with cumulative dose to onset of grade of at least 2 PN. These associations were generally not detected in the IFM 2005-01 cohort, although CTLA4 rs4553808 showed the same trend in association with time to onset (P=0.138). In addition, in the IFM 2005-01 cohort, TCF4 rs1261134 significantly associated with onset of any neurologic event (FDR=0.048). Conclusion Genes associated with immune function (CTLA4, CTSS), reflexive coupling within Schwann cells (GJE1), drug binding (PSMB1), and neuron function (TCF4, DYNC1I1) associated with bortezomib-induced PN in this study. Pharmacogenetics and Genomics 21:121-129 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Favis, Reyna; Sun, Yu; Broderick, Erin; Levey, Laura; Meyers, Michael; Ricci, Deborah S.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ 08869 USA. [Mulligan, George] Millennium Pharmaceut Inc, Cambridge, MA USA. [Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [van de Velde, Helgi] Johnson & Johnson Pharmaceut Res & Dev, Beerse, Belgium. [Harousseau, Jean-Luc] Ctr Rene Gauducheau, F-44035 Nantes, France. RP Ricci, DS (reprint author), Johnson & Johnson Pharmaceut Res & Dev, 920 Route 202, Raritan, NJ 08869 USA. EM DRicci@its.jnj.com FU Johnson and Johnson Pharmaceutical Research & Development, L.L.C.; Millennium Pharmaceuticals, Inc. FX The authors would like to acknowledge the contribution of Dr Jesus San Miguel to the design and clinical data interpretation of the VISTA study and Professor Herve Avet-Loiseau for providing samples from the IFM 2005-01 study for this analysis. They would like to thank Andrew Jadwin and Eric Danzeisen for expert technical support during this study. This study is supported by Johnson and Johnson Pharmaceutical Research & Development, L.L.C. and Millennium Pharmaceuticals, Inc. NR 34 TC 30 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD MAR PY 2011 VL 21 IS 3 BP 121 EP 129 DI 10.1097/FPC.0b013e3283436b45 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 716MB UT WOS:000286971900003 PM 21228734 ER PT J AU Canavese, M Altruda, F Silengo, L Castiglioni, V Scanziani, E Radaelli, E AF Canavese, M. Altruda, F. Silengo, L. Castiglioni, V. Scanziani, E. Radaelli, E. TI Clinical, pathological and immunological features of psoriatic-like lesions affecting keratin 14-vascular endothelial growth factor transgenic mice SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE Angiogenesis; VEGF; Disease animal models; Psoriasis; Skin ID T-CELLS; MAST-CELLS; SKIN; EXPRESSION; ANGIOGENESIS; PATHOGENESIS; VEGF; IMMUNOPATHOGENESIS; INTERLEUKIN-17; INFLAMMATION AB Up-regulation of vascular endothelial growth factor (VEGF) plays a primary role in the pathogenesis of psoriasis. Transgenic mice over-expressing VEGF under the Keratin 14 (K14) promoter develop an inflammatory skin condition with many of the pathobiological features of human psoriasis. In this work, the development of spontaneous psoriatic-like dermatitis in K14-VEGF transgenic mice was monitored from week 6 to week 44 and skin lesions were characterized clinically (application of a clinical score system comparable to the human Psoriasis Area and Severity Index), microscopically (histopathology, leukocyte subset and neoangiogensis) and immunologically (evaluation of local and systemic cytokine/chemokine profiles). Based on PASI score system, three progressive clinical phases were identified: mild acute (8-14 weeks of age), moderate subacute (15-21 weeks of age) and severe chronic-active (22-44 weeks of age) dermatitis. Microscopically, skin lesions consisted of progressive proliferative psoriatic-like dermatitis dominated by dermo-epidermal infiltrates of CD3-positive lymphocytes, an increased number of mast cells and neoangiogenesis. Both local and systemic up-regulation of pro-inflammatory (IL-12, TNF-alpha, IL-6, MCP-1 and IL-8) and regulatory (IL-10) cytokines/chemokines was observed, mainly during the later stages of disease development. The results obtained in this study further confirm the central role of VEGF over-expression in the development of psoriatic-like dermatitis. Similarly to what is reported for human psoriasis, both the local and systemic immunologic profiles observed in K14-VEGF transgenic mice suggest that a combined Th1 and Th17 response may be implicated in lesion development. The identification of three progressive stages of disease, each with peculiar clinicopathological features, renders the K14-VEGF transgenic mouse a valuable model to study novel immunotherapies for psoriasis. C1 [Canavese, M.; Altruda, F.; Silengo, L.] Univ Turin, Dept Genet Biol & Biochem, I-10124 Turin, Italy. [Castiglioni, V.; Scanziani, E.; Radaelli, E.] Filarete Fdn, Mouse & Anim Pathol Lab, Milan, Italy. [Castiglioni, V.; Scanziani, E.; Radaelli, E.] Univ Milan, Fac Vet Med, Dept Vet Pathol Hyg & Publ Hlth, I-20122 Milan, Italy. RP Canavese, M (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 13th St Bldg 149, Charlestown, MA 01029 USA. EM miriamcanavese@yahoo.com FU MerckSerono International S.A. FX This work was supported by MerckSerono International S. A. We would like to thank Merck-Serono-RBM, Colleretto Giacosa, Torino, Italy as host Institute. Dr. PF Zaratin as Head of Immuno-pharmacology Department, Dr. CH Ladel, Dr. B. Greco and Dr. V. Ardissone for their scientific support and guidance. We also thank Dr. Pamela Ferro for organizing technical help in maintaining the line; Dr. Michele Ardizzone, Dr. Cristiano Marozzin and Dr. Raffaella Capobianco for their help in determining pathological diagnosis. We also thank Dr Giovanni Manarolla for the insightful comments. This work was supported by a Research Grant from MerckSerono International S. A. The funders supported study design, data collection and analysis, but they had no role in the decision to publish and preparation of the manuscript. NR 43 TC 7 Z9 7 U1 0 U2 4 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 EI 1699-5848 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD MAR PY 2011 VL 26 IS 3 BP 285 EP 296 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 702UK UT WOS:000285921200001 PM 21210341 ER PT J AU Crenshaw, K Shewchuk, RM Qu, HY Staton, LJ Bigby, JA Houston, TK Allison, J Estrada, CA AF Crenshaw, Katie Shewchuk, Richard M. Qu, Haiyan Staton, Lisa J. Bigby, Judy Ann Houston, Thomas K. Allison, Jeroan Estrada, Carlos A. TI What Should We Include in a Cultural Competence Curriculum? An Emerging Formative Evaluation Process to Foster Curriculum Development SO ACADEMIC MEDICINE LA English DT Article ID NOMINAL GROUP TECHNIQUE; WARD-ATTENDING ROUNDS; MEDICAL-EDUCATION; HEALTH-CARE; PERSPECTIVES; JUDGMENTS; TOOL; PERCEPTIONS; ATTRIBUTES; FACULTY AB Purpose To identify, prioritize, and organize components of a cultural competence curriculum to address disparities in cardiovascular disease. Method In 2006, four separate nominal group technique sessions were conducted with medical students, residents, community physicians, and academic physicians to generate and prioritize a list of concepts (i.e., ideas) to include in a curriculum. Afterward, 45 educators and researchers organized and prioritized the concepts using a card-sorting exercise. Multidimensional scaling (MDS) and hierarchical cluster analysis produced homogeneous groupings of related concepts and generated a cognitive map. The main outcome measures were the number of cultural competence concepts, their relative ranks, and the cognitive map. Results Thirty participants generated 61 concepts; 29 were identified by at least two participants. The cognitive map organized concepts into four clusters, interpreted as (1) patient's cultural background (e.g., information on cultures, habits, values), (2) provider and health care (e.g., clinical skills, awareness of one's bias, patient centeredness, professionalism), communication skills (e.g., history, stereotype avoidance, health disparities epidemiology), (3) cross-culture (e.g., idiomatic expressions, examples of effective communication), and (4) resources to manage cultural diversity (e.g., translator guides, instructions, community resources). The MDS two-dimensional solution demonstrated a good fit (stress = 0.07; R(2) = 0.97). Conclusions A novel, combined approach allowed stakeholders' inputs to identify and cognitively organize critical domains used to guide development of a cultural competence curriculum. Educators may use this approach to develop and organize educational content for their target audiences, especially in ill-defined areas like cultural competence. C1 [Estrada, Carlos A.] Univ Alabama, Div Gen Internal Med, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.] Birmingham Vet Affairs Med Ctr, REAP Ctr Surg Med Acute Care Res & Transit, Deep S Ctr Effectiveness, Birmingham, AL USA. [Estrada, Carlos A.] Vet Affairs Natl Qual Scholars Program, Birmingham, AL USA. [Crenshaw, Katie] Univ Alabama, Div Continuing Med Educ, Birmingham, AL USA. [Shewchuk, Richard M.; Qu, Haiyan] Univ Alabama, Sch Hlth Related Profess, Hlth Serv Adm, Birmingham, AL USA. [Staton, Lisa J.] Univ Tennessee, Coll Med Chattanooga, Chattanooga, TN USA. [Staton, Lisa J.] Dept Internal Med, Chattanooga, TN USA. [Bigby, Judy Ann] Commonwealth Massachusetts, Execut Off Hlth & Human Serv, Hlth & Human Serv, Boston, MA USA. [Houston, Thomas K.] Bedford VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Houston, Thomas K.] Univ Massachusetts, Sch Med, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Allison, Jeroan] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. RP Estrada, CA (reprint author), Univ Alabama, Div Gen Internal Med, Birmingham Vet Affairs Med Ctr, 732 Fac Off Tower,510 20th St S, Birmingham, AL USA. EM cestrada@uab.edu RI liu, jing/D-9482-2012; Houston, Thomas/F-2469-2013; OI Allison, Jeroan/0000-0003-4472-2112 FU National Heart, Lung, and Blood Institute as part of the National Consortium for Multicultural Education for Health Professionals [K07 HL081373-01] FX This study was funded by a National Heart, Lung, and Blood Institute (K07 HL081373-01) grant to Dr. Estrada as part of the National Consortium for Multicultural Education for Health Professionals. The funding source did not make any restrictions on the scope or reporting of the study. NR 46 TC 24 Z9 24 U1 5 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAR PY 2011 VL 86 IS 3 BP 333 EP 341 DI 10.1097/ACM.0b013e3182087314 PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 726AZ UT WOS:000287690700021 PM 21248602 ER PT J AU Huddle, TS AF Huddle, Thomas S. TI Perspective: Medical Professionalism and Medical Education Should Not Involve Commitments to Political Advocacy SO ACADEMIC MEDICINE LA English DT Article ID US PHYSICIANS; SCHOLARSHIP; IGNORANCE AB It is increasingly suggested that political advocacy is a core professional responsibility for physicians. The author argues that this is an error. Advocacy on behalf of societal goals, even those goals as unexceptionable as the betterment of human health, is inevitably political. Claims that political advocacy are a professional responsibility are mistaken, the author argues, because (1) civic virtues are outside the professional realm, (2) even if civic virtues were professionally obligatory, it is unclear that civic participation is necessary for such virtue, and (3) the profession of medicine ought not to require any particular political stance of its members. Claims that academic health centers should systematically foster advocacy are also deeply problematic. Although advocacy may coexist alongside the core university activities of research and education, insofar as it infects those activities, advocacy is likely to subvert them, as advocacy seeks change rather than knowledge. And official efforts on behalf of advocacy will undermine university aspirations to objectivity and neutrality. American society has conferred remarkable success and prosperity on its medical profession. Physicians are deserving of such success only insofar as they succeed in offering society excellence and dedication in professional work. Mandatory professional advocacy must displace such work but cannot substitute for it. The medical profession should steadfastly resist attempts to add advocacy to its essential professional commitments. C1 [Huddle, Thomas S.] UAB Sch Med, Div Gen Internal Med, Dept Med, Birmingham, AL 35294 USA. [Huddle, Thomas S.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Huddle, TS (reprint author), UAB Sch Med, Div Gen Internal Med, Dept Med, 1530 3rd Ave S,FOT 720, Birmingham, AL 35294 USA. EM thuddle@uab.edu RI liu, jing/D-9482-2012 NR 22 TC 33 Z9 33 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAR PY 2011 VL 86 IS 3 BP 378 EP 383 DI 10.1097/ACM.0b013e3182086efe PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 726AZ UT WOS:000287690700028 PM 21248605 ER PT J AU Cai, WL Lee, EY Vij, A Mahmood, SA Yoshida, H AF Cai, Wenli Lee, Edward Y. Vij, Abhinav Mahmood, Soran A. Yoshida, Hiroyuki TI MDCT for Computerized Volumetry of Pneumothoraces in Pediatric Patients SO ACADEMIC RADIOLOGY LA English DT Article DE Computerized volumetry method; multidetector computed tomography (MDCT); pneumothorax; quantification of pneumothorax; pediatric patients ID BLUNT CHEST TRAUMA; SEVERELY INJURED PATIENTS; TUBE THORACOSTOMY; OCCULT PNEUMOTHORACES; TOMOGRAPHY; COMPLICATIONS; MANAGEMENT; CT; AGREEMENT; SIZE AB Rationale and Objectives: Our purpose in this study was to develop an automated computer-aided volumetry (CAV) scheme for quantifying pneumothorax in multidetector computed tomography (MDCT) images for pediatric patients and to investigate the imaging parameters that may affect its accuracy. Materials and Methods: Fifty-eight consecutive pediatric patients (mean age 12 6 years) with pneumothorax who underwent MDCT for evaluation were collected retrospectively for this study. All cases were imaged by a 16-or 64-MDCT scanner with weight-based kilovoltage, low-dose tube current, 1.0-1.5 pitch, 0.6-5.0 mm slice thickness, and a B70f (sharp) or B31f (soft) reconstruction kernel. Sixty-three pneumothoraces >= 1 mL were visually identified in the left (n = 30) and right (n = 33) lungs. Each identified pneumothorax was contoured manually on an Amira workstation V4.1.1 (Mercury Computer Systems, Chelmsford, MA) by two radiologists in consensus. The computerized volumes of the pneumothoraces were determined by application of our CAV scheme. The accuracy of our automated CAV scheme was evaluated by comparison between computerized volumetry and manual volumetry, for the total volume of pneumothoraces in the left and right lungs. Results: The mean difference between the computerized volumetry and the manual volumetry for all 63 pneumothoraces >= 1 mL was 8.2%. For pneumothoraces >= 10 mL, >= 50 mL, and >= 200 mL, the mean differences were 7.7% (n = 57), 7.3% (n = 33), and 6.4% (n = 13), respectively. The correlation coefficient was 0.99 between the computerized volume and the manual volume of pneumothoraces. Bland-Altman analysis showed that computerized volumetry has a mean difference of -5.1% compared to manual volumetry. For all pneumothoraces >= 10 mL, the mean differences for slice thickness <= 1.25 mm, = 1.5 mm, and = 5.0 mm were 6.1% (n = 28), 3.5% (n = 10), and 12.2% (n = 19), respectively. For the two reconstruction kernels, B70f and B31f, the mean differences were 6.3% (n = 42, B70f) and 11.7% (n = 15, B31f11, respectively. Conclusion: Our automated CAV scheme provides an accurate measurement of pneumothorax volume in MDCT images of pediatric patients. For accurate volumetric quantification of pneumothorax in children in MDCT images by use of the automated CAV scheme, we recommended reconstruction parameters based on a slice thickness <= 1.5 mm and the reconstruction kernel B70f. C1 [Cai, Wenli; Vij, Abhinav; Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cai, Wenli; Vij, Abhinav; Yoshida, Hiroyuki] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lee, Edward Y.; Mahmood, Soran A.] Childrens Hosp Boston, Dept Radiol, Boston, MA 02115 USA. [Lee, Edward Y.; Mahmood, Soran A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cai, WL (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,400C, Boston, MA 02114 USA. EM Cai.Wenli@mgh.harvard.edu FU Harvard Clinical and Translational Science Center, from the National Center for Research Resources [1 UL1 RR025758-01] FX From the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 25 New Chardon Street, 400C, Boston, MA 02114 (W.C., A.V., H.Y.); Department of Radiology, Children's Hospital Boston and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115 S.A.M). Received August 10, 2010; accepted November 1, 201(). This research was conducted with the support of Grant Number 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. Address correspondence to: W.C. e-mail: Cai.Wenli@mgh.harvard.edu NR 26 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2011 VL 18 IS 3 BP 315 EP 323 DI 10.1016/j.acra.2010.11.008 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 725BR UT WOS:000287620700008 PM 21216160 ER PT J AU Feuchtner, GM Spoeck, A Lessick, J Dichtl, W Plass, A Leschka, S Mueller, S Klauser, A Scheffel, H Wolf, F Jaschke, W Alkadhi, H AF Feuchtner, Gudrun M. Spoeck, Alexander Lessick, Jonathan Dichtl, Wolfgang Plass, Andre Leschka, Sebastian Mueller, Silvana Klauser, Andrea Scheffel, Hans Wolf, Florian Jaschke, Werner Alkadhi, Hatem TI Quantification of Aortic Regurgitant Fraction and Volume with Multi-detector Computed Tomography: Comparison with Echocardiography SO ACADEMIC RADIOLOGY LA English DT Article DE Multislice computed tomography; aortic regurgitation; automated 3-D volume segmentation; aortic regurgitant volume ID CORONARY-ARTERY-DISEASE; LEFT-VENTRICULAR FUNCTION; CARDIOVASCULAR-MAGNETIC-RESONANCE; DIAGNOSTIC PERFORMANCE; VALVE-REPLACEMENT; GLOBAL LEFT; ANGIOGRAPHY; CT; CARDIOLOGY; COMMITTEE AB Rationale and Objectives: Evaluate quantification of the aortic regurgitant fraction and volume with computed tomography (CT). Materials and Methods: Fifty-three patients with aortic regurgitation (AR) and 29 controls were examined with 64-multi-detector CT coronary angiography and transthoracic echocardiography CITE). A dedicated software algorithm employing three-dimensional segmentation of left ventricle (LV) and right ventricle (RV) volumes and LV mass was applied. AR volume and fraction was calculated based on RV and LV stroke volumes (SV) and compared with echocardiography. The aortic regurgitant orifice area (ROA) was measured by CT. Results: A good correlation of the AR fraction and AR volume determined by CT compared to echocardiography was found for mild, moderate, and severe AR with 14.2% +/- 9, 28.8% +/- 8, and 57.9% +/- 9 (r = 0.95, P < .001) for AR fraction, and 15.7 mL +/- 11.33 mL +/- 14, and 98.9 mL +/- 36 for AR volume (r = 0.92, P < .0001), respectively. CT correctly classified severity of AR in 93% of patients based of AR-fraction, and in 89% based on AR volume. The sensitivity and specificity of CT were 98% and specificity 90.3%. The specificity improved to 97%, if the ROA by CT was added as diagnostic criterion. Conclusion: Aortic regurgitation fraction and volume can be accurately quantified from CT coronary angiography datasets. These parameters can assist clinical management, e.g. in case of pending cardiac surgery decision. C1 [Feuchtner, Gudrun M.; Spoeck, Alexander; Klauser, Andrea] Innsbruck Med Univ, Dept Radiol 2, A-6020 Innsbruck, Austria. [Dichtl, Wolfgang; Mueller, Silvana; Jaschke, Werner] Innsbruck Med Univ, Dept Cardiol, A-6020 Innsbruck, Austria. [Feuchtner, Gudrun M.; Leschka, Sebastian; Scheffel, Hans; Alkadhi, Hatem] Univ Zurich Hosp, Inst Diagnost Radiol, Zurich, Switzerland. [Lessick, Jonathan] Rambam Med Ctr, Dept Cardiol, Haifa, Israel. [Plass, Andre] Univ Zurich Hosp, Cardiovasc Surg Clin, Zurich, Switzerland. [Wolf, Florian] Vienna Med Univ, Dept Radiol, Vienna, Austria. [Jaschke, Werner; Alkadhi, Hatem] Massachusetts Gen Hosp, Cardiac MR CT PET Program, Boston, MA 02114 USA. RP Feuchtner, GM (reprint author), Innsbruck Med Univ, Dept Radiol 2, Anichstr 35, A-6020 Innsbruck, Austria. EM Gudrun.Feuchtner@i-med.ac.at OI Dichtl, Wolfgang/0000-0002-0421-2110; Lessick, Jonathan/0000-0003-4430-712X FU Philips Medical Systems FX From the Departments of Radiology II (G.M.F., A.S., AK.) and Cardiology (W.D., S.M., W.J), Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria; Institute of Diagnostic Radiology, University Hospital Zurich, Switzerland (G.M.F., S.L., H.S., HA.); Rambam Medical Center, Department of Cardiology, Haifa, Israel (J.L.); Clinic for Cardiovascular Surgery, University Hospital Zurich, Switzerland (A.P.); Department of Radiology, Vienna Medical University, Vienna, Austria (F.W.); Cardiac MR/CT/PET Program, Massachusetts General Hospital, Boston, MA (H.A., W.J). Received September 20, 2010; accepted November 3, 2010. J. Lessick receives salary support from Philips Medical Systems. Address correspondence to: G.M.F. e-mail: Gudrun.Feuchtner@i-med.ac.at NR 37 TC 7 Z9 7 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 MAR PY 2011 VL 18 IS 3 BP 334 EP 342 DI 10.1016/j.acra.2010.11.006 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 725BR UT WOS:000287620700010 PM 21295735 ER PT J AU Deng, XM Yang, QK Kwiatkowski, N Sim, T McDermott, U Settleman, JE Lee, JD Gray, NS AF Deng, Xianming Yang, Qingkai Kwiatkowski, Nicholas Sim, Taebo McDermott, Ultan Settleman, Jeffrey E. Lee, Jiing-Dwan Gray, Nathanael S. TI Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1 SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE MAPK; BMK1; ERK5 ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION; IN-VIVO; PATHWAY; EXPRESSION; CANCER; POLO-LIKE-KINASE-1; IDENTIFICATION; BI-2536; CELLS AB Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by 11, 18, and 21. For example, 11 possesses a dissociation constant (K(d)) for BMK1 of 19 nM, a cellular IC(50) for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 +/- 0.04 mu M, and an Ambit KINOMEscan selectivity score (Ss) of 0.035. Inhibitors 18 and I 21 are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts. C1 [Deng, Xianming; Kwiatkowski, Nicholas; Sim, Taebo; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yang, Qingkai; Lee, Jiing-Dwan] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Deng, Xianming; Kwiatkowski, Nicholas; Sim, Taebo; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [McDermott, Ultan; Settleman, Jeffrey E.] Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Charlestown, MA 02129 USA. [McDermott, Ultan; Settleman, Jeffrey E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA. EM jdlee@scripps.edu; Nathanael_Gray@dfci.harvard.edu OI Yang, Qingkai/0000-0001-6628-5393; McDermott, Ultan/0000-0001-9032-4700 FU NIH [P41 GM079575-03, CA079871, CA114059]; University of California [19XT-0084]; Sanger Research Centre FX This work was supported by NIH Grant P41 GM079575-03 (N.S.G.), NIH Grants CA079871 and CA114059 (J.-D.L.), funds from the Tobacco-Related Disease, Research Program of the University of California, 19XT-0084 (J.-D.L.), and the Sanger Research Centre (U.M.). NR 21 TC 22 Z9 22 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD MAR PY 2011 VL 2 IS 3 BP 195 EP 200 DI 10.1021/ml100304b PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 735GN UT WOS:000288401500002 ER PT J AU Medina, JL Vujanovic, AA Smits, JAJ Irons, JG Zvolensky, MJ Bonn-Miller, MO AF Medina, Johnna L. Vujanovic, Anka A. Smits, Jasper A. J. Irons, Jessica G. Zvolensky, Michael J. Bonn-Miller, Marcel O. TI Exercise and coping-oriented alcohol use among a trauma-exposed sample SO ADDICTIVE BEHAVIORS LA English DT Article DE Trauma; Exercise; Alcohol; Coping; Anxiety ID POSTTRAUMATIC-STRESS-DISORDER; SEXUAL ASSAULT SURVIVORS; ANXIETY SENSITIVITY; PHYSICAL-ACTIVITY; AEROBIC EXERCISE; USE MOTIVES; DRINKING; ABUSE; PTSD; INTERVENTIONS AB The present investigation examined the relation between exercise intensity and alcohol use coping motives among trauma-exposed adults. Participants were 114 adults (58 women; M(age) = 22.31 years, SD = 8.89) who reported exposure to at least one traumatic event (American Psychiatric Association, 2000) and alcohol use in the past 30 days. Partially consistent with expectation, engagement in vigorous-intensity activities (>= 6 resting metabolic rate [MET] score) demonstrated a significant, incremental (negative) association with alcohol use coping motives. This incremental association was observed after accounting for current alcohol consumption, non-criterion alcohol use motives, anxiety sensitivity, posttraumatic stress symptom severity, as well as engagement in light- and moderate-intensity activities (<6 resting MET score). Results are discussed in terms of better understanding the association between vigorous-intensity aerobic exercise and coping-oriented alcohol use among trauma-exposed individuals. Published by Elsevier Ltd. C1 [Bonn-Miller, Marcel O.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk Div 152, Menlo Pk, CA 94025 USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA 94025 USA. [Vujanovic, Anka A.] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Smits, Jasper A. J.] So Methodist Univ, Dept Psychol, Dallas, TX 75275 USA. [Irons, Jessica G.] James Madison Univ, Dept Psychol, Harrisonburg, VA USA. [Zvolensky, Michael J.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. RP Bonn-Miller, MO (reprint author), VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk Div 152, 795 Willow Rd, Menlo Pk, CA 94025 USA. EM Marcel.Bonn-Miller@va.gov RI Smits, Jasper/A-4350-2008; OI Smits, Jasper/0000-0001-7128-9807; Smits, Jasper/0000-0003-1633-9693 FU Veterans Affairs (VA) Clinical Science Research and Development (CSRD); National Institute on Drug Abuse (NIDA) [1 R01 DA027533, 1 R03 DA016566-01A2] FX This work was supported, in part, by a Veterans Affairs (VA) Clinical Science Research and Development (CSR&D) Career Development Award - 2, granted to Dr. Bonn-Miller. This work was also supported by the National Institute on Drug Abuse (NIDA) research grants (1 R01 DA027533 and 1 R03 DA016566-01A2) awarded to Dr. Zvolensky and by the NIDA research grant R01DA027533 awarded to Dr. Smits. Neither VA nor NIDA had a role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. The views expressed here are those of the authors and do not necessarily represent those of the Department of Veterans Affairs. NR 38 TC 8 Z9 8 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2011 VL 36 IS 3 BP 274 EP 277 DI 10.1016/j.addbeh.2010.11.008 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 722GD UT WOS:000287419200020 PM 21111538 ER PT J AU Bergwitz, C Juppner, H AF Bergwitz, Clemens Jueppner, Harald TI Phosphate Sensing SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Human phosphate homeostasis; Bacterial phosphate sensor; Yeast phosphate sensor; Metazoan phosphate sensor ID PARATHYROID-HORMONE SECRETION; CHRONIC KIDNEY-DISEASE; FAMILIAL TUMORAL CALCINOSIS; MESSENGER-RIBONUCLEIC-ACID; FRIZZLED-RELATED PROTEIN-4; FIBROBLAST-GROWTH-FACTOR; CELL-LINE ST2; SACCHAROMYCES-CEREVISIAE; INORGANIC-PHOSPHATE; VITAMIN-D AB Human phosphate homeostasis is regulated at the level of intestinal absorption of phosphate from the diet, release of phosphate through bone resorption, and renal phosphate excretion, and involves the actions of parathyroid hormone, 1,25-dihydroxy-vitamin D, and fibroblast growth factor 23 to maintain circulating phosphate levels within a narrow normal range, which is essential for numerous cellular functions, for the growth of tissues and for bone mineralization. Prokaryotic and single cellular eukaryotic organisms such as bacteria and yeast "sense" ambient phosphate with a multi-protein complex located in their plasma membrane, which modulates the expression of genes important for phosphate uptake and metabolism (pho pathway). Database searches based on amino acid sequence conservation alone have been unable to identify metazoan orthologs of the bacterial and yeast phosphate sensors. Thus, little is known about how human and other metazoan cells sense inorganic phosphate to regulate the effects of phosphate on cell metabolism ("metabolic" sensing) or to regulate the levels of extracellular phosphate through feedback system(s) ("endocrine" sensing). Whether the "metabolic" and the "endocrine" sensor use the same or different signal transduction cascades is unknown. This article will review the bacterial and yeast phosphate sensors, and then discuss what is currently known about the metabolic and endocrine effects of phosphate in multicellular organisms and human beings. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved. C1 [Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St, Boston, MA 02114 USA. EM cbergwitz@partners.org FU NIDDK NIH HHS [K08 DK078361, K08 DK078361-04, R03 DK089127] NR 166 TC 33 Z9 34 U1 0 U2 25 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD MAR PY 2011 VL 18 IS 2 BP 132 EP 144 DI 10.1053/j.ackd.2011.01.004 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 741BW UT WOS:000288839100012 PM 21406298 ER PT J AU Hanlon, JT Sloane, RJ Pieper, CF Schmader, KE AF Hanlon, Joseph T. Sloane, Richard J. Pieper, Carl F. Schmader, Kenneth E. TI Association of adverse drug reactions with drug-drug and drug-disease interactions in frail older outpatients SO AGE AND AGEING LA English DT Article ID MEDICATION; APPROPRIATENESS; MANAGEMENT; EVENTS; ADULTS C1 [Hanlon, Joseph T.] Univ Pittsburgh, Dept Geriatr Med, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Sloane, Richard J.; Pieper, Carl F.; Schmader, Kenneth E.] Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Durham, NC USA. [Pieper, Carl F.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Dept Geriatr Med, Durham, NC USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. RP Hanlon, JT (reprint author), Univ Pittsburgh, Dept Geriatr Med, Kaufman Med Bldg Suite 514,3471 5th Ave, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu FU National Institutes of Health [R01-AG-15432]; Veterans Affairs Cooperative Study Program 006; National Institute of Aging [P30AG024827, T32 AG021885, 3U01 AG012553 K07AG033174, R01AG034056, 2R56AG027017]; National Institute of Mental Health [R34 MH082682]; National Institute of Nursing Research [R01 NR010135]; Agency for Healthcare Research and Quality [R01 HS017695, R01HS018721]; VA Health Services Research [IIR-06-062] FX This study was not funded by outside sources. The original GEM Drug Study [8] was supported by the National Institutes of Health [R01-AG-15432] and the Veterans Affairs Cooperative Study Program 006. J.T.H. was supported by the following: National Institute of Aging grants (P30AG024827, T32 AG021885, 3U01 AG012553 K07AG033174, R01AG034056, 2R56AG027017), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01 NR010135), an Agency for Healthcare Research and Quality grants (R01 HS017695 and R01HS018721) and a VA Health Services Research grant (IIR-06-062). NR 16 TC 15 Z9 16 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAR PY 2011 VL 40 IS 2 BP 274 EP 277 DI 10.1093/ageing/afq158 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 723DA UT WOS:000287485200025 PM 21177281 ER PT J AU Hardy, H Kumar, V Doros, G Farmer, E Drainoni, ML Rybin, D Myung, D Jackson, J Backman, E Stanic, A Skolnik, PR AF Hardy, Helene Kumar, Vikram Doros, Gheorghe Farmer, Eric Drainoni, Mari-Lynn Rybin, Denis Myung, Dan Jackson, Jonathan Backman, Elke Stanic, Anela Skolnik, Paul R. TI Randomized Controlled Trial of a Personalized Cellular Phone Reminder System to Enhance Adherence to Antiretroviral Therapy SO AIDS PATIENT CARE AND STDS LA English DT Article ID IMPROVE ADHERENCE; MESSAGING SYSTEM; OUTCOMES; INTERVENTION; INFECTION; FAILURE; SUPPORT; PATIENT; HEALTH; ADULTS AB Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 +/- 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue. C1 [Hardy, Helene; Backman, Elke; Stanic, Anela; Skolnik, Paul R.] Boston Univ, Med Ctr, Ctr HIV AIDS Care & Res, Boston, MA USA. [Kumar, Vikram; Myung, Dan; Jackson, Jonathan] Dimagi, Cambridge, MA USA. [Doros, Gheorghe; Rybin, Denis] Boston Univ, Biostat Consulting Grp, Boston, MA 02215 USA. [Farmer, Eric] Dept Pharm, LifeCare Program Clarian Hlth, Indianapolis, IN USA. [Drainoni, Mari-Lynn] Boston Univ, Sch Publ Hlth, Ctr Hlth Qual Outcomes & Econ Res, Dept Hlth Policy & Management, Boston, MA USA. [Backman, Elke] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. RP Hardy, H (reprint author), Bristol Myers Squibb Co, US Pharmaceut Med Affairs Virol Res & Dev, 777 Scudders Mill Rd, Plainsboro, NJ 08536 USA. EM hhardy34@gmail.com RI Emchi, Karma/Q-1952-2016; OI Rybin, Denis/0000-0002-3657-4829 FU National Institute of Mental Health [1R43MH080655-01A1] FX The authors want to thank the patients who participated to this research project, Verizon Wireless for generously providing the cellular phones utilized by the patients during this study, the National Institute of Mental Health who provided the funding for the SBIR (1R43MH080655-01A1) NR 26 TC 73 Z9 75 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD MAR PY 2011 VL 25 IS 3 BP 153 EP 161 DI 10.1089/apc.2010.0006 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 730VI UT WOS:000288062800004 PM 21323532 ER PT J AU Kelly, JF Stout, RL Magill, M Tonigan, JS Pagano, ME AF Kelly, John F. Stout, Robert L. Magill, Molly Tonigan, J. Scott Pagano, Maria E. TI Spirituality in Recovery: A Lagged Mediational Analysis of Alcoholics Anonymous' Principal Theoretical Mechanism of Behavior Change SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcoholics Anonymous; Spirituality; Self-Help Groups; Alcoholism; Alcohol Dependence ID SELF-HELP GROUPS; SUBSTANCE-ABUSE PATIENTS; PROJECT MATCH; 12-STEP INVOLVEMENT; ADDICTION TREATMENT; DRINKING OUTCOMES; SOCIAL NETWORKS; REDUCE DEMAND; HEALTH; PROGRAMS AB Background: Evidence indicates Alcoholics Anonymous (AA) can play a valuable role in recovery from alcohol use disorder. While AA itself purports it aids recovery through "spiritual" practices and beliefs, this claim remains contentious and has been only rarely formally investigated. Using a lagged, mediational analysis, with a large, clinical sample of adults with alcohol use disorder, this study examined the relationships among AA, spirituality/religiousness, and alcohol use, and tested whether the observed relation between AA and better alcohol outcomes can be explained by spiritual changes. Method: Adults (N = 1,726) participating in a randomized controlled trial of psychosocial treatments for alcohol use disorder (Project MATCH) were assessed at treatment intake, and 3, 6, 9, 12, and 15 months on their AA attendance, spiritual/religious practices, and alcohol use outcomes using validated measures. General linear modeling (GLM) and controlled lagged mediational analyses were utilized to test for mediational effects. Results: Controlling for a variety of confounding variables, attending AA was associated with increases in spiritual practices, especially for those initially low on this measure at treatment intake. Results revealed AA was also consistently associated with better subsequent alcohol outcomes, which was partially mediated by increases in spirituality. This mediational effect was demonstrated across both outpatient and aftercare samples and both alcohol outcomes (proportion of abstinent days; drinks per drinking day). Conclusions: Findings suggest that AA leads to better alcohol use outcomes, in part, by enhancing individuals' spiritual practices and provides support for AA's own emphasis on increasing spiritual practices to facilitate recovery from alcohol use disorder. C1 [Kelly, John F.] Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, Boston, MA 02114 USA. [Kelly, John F.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stout, Robert L.] Decis Sci Inst PIRE, Providence, RI USA. [Magill, Molly] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Tonigan, J. Scott] Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM USA. [Pagano, Maria E.] Case Western Reserve Univ, Sch Med, Dept Psychiat, WO Walker Ctr,Div Child Psychiat, Cleveland, OH 44106 USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, 60 Staniford St,Suite 120, Boston, MA 02114 USA. EM jkelly11@partners.org FU US National Institute on Alcohol Abuse and Alcoholism [R21 AA016762] FX This research was supported by a grant from the US National Institute on Alcohol Abuse and Alcoholism (R21 AA016762; Mechanisms and Moderators of Behavior Change in Alcoholics Anonymous). NR 77 TC 38 Z9 39 U1 5 U2 26 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 MAR PY 2011 VL 35 IS 3 BP 454 EP 463 DI 10.1111/j.1530-0277.2010.01362.x PG 10 WC Substance Abuse SC Substance Abuse GA 731XF UT WOS:000288143100009 PM 21158876 ER PT J AU Harrington, MB Kraft, M Grande, LJ Rudolph, JL AF Harrington, Mary Beth Kraft, Malissa Grande, Laura J. Rudolph, James L. TI INDEPENDENT ASSOCIATION BETWEEN PREOPERATIVE COGNITIVE STATUS AND DISCHARGE LOCATION AFTER CARDIAC SURGERY SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID CORONARY-ARTERY-BYPASS; CLOCK DRAWING TEST; GRAFT-SURGERY; ALZHEIMERS-DISEASE; EXECUTIVE FUNCTION; RANDOMIZED TRIAL; IMPAIRMENT; DELIRIUM; OUTCOMES; INTERVENTION AB Background Among cardiac surgery patients, those with impaired cognitive status before surgery may have longer postoperative stays than do patients with normal status and may require additional care upon discharge. Objectives To determine if preoperative scores on a screening measure for cognitive status (the Clock-in-the-Box), were associated with postoperative length of stay and discharge to a location other than home in patients who had cardiac surgery. Methods A total of 181 consecutive patients scheduled for cardiac surgery at a single site were administered the Clock-in-the-Box as part of the preoperative evaluation. Scores on the Clock-in-the-Box tool, demographic and operative information, postoperative length of stay, and discharge location were collected retrospectively from medical records. Results The mean age of the patients was 68.1 years (SD, 0.7), and 99% were men. Mean postoperative length of stay was 10.5 days (SD, 8.2), and 35 patients (19%) were discharged to a facility. Scores on the Clock-in-the-Box assessment were not associated with postoperative length of stay. Increasing age, living alone before surgery, and duration of cardiopulmonary bypass were associated with discharge to a facility and were used as covariates in adjusted analyses. After adjustment, better preoperative cognitive status reduced the risk of being discharged to a facility (adjusted relative risk, 0.93; 95% confidence interval, 0.89-0.98) after cardiac surgery. Conclusions Cognitive screening before cardiac surgery can identify patients with impaired cognitive status who are less likely than patients with normal cognitive status to return home after cardiac surgery. (American Journal of Critical Care. 2011;20:129-137) C1 [Harrington, Mary Beth; Rudolph, James L.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Kraft, Malissa; Grande, Laura J.] VA Boston Healthcare Syst, Dept Psychol, Boston, MA USA. [Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rudolph, James L.] Harvard Univ, Sch Med, Boston, MA USA. RP Rudolph, JL (reprint author), VABHS GRECC, JP-182,150 S Huntington Ave, Boston, MA 02130 USA. EM jrudolph@partners.org FU VA Rehabilitation Research career development award; National Institutes of Health [AG023480, AG08812, AG029861] FX Dr Rudolph was funded by a VA Rehabilitation Research career development award. Additional support was provided by grants AG023480, AG08812, and AG029861 from the National Institutes of Health. NR 52 TC 6 Z9 6 U1 2 U2 5 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 EI 1937-710X J9 AM J CRIT CARE JI Am. J. Crit. Care PD MAR 1 PY 2011 VL 20 IS 2 BP 129 EP 137 DI 10.4037/ajcc2011275 PG 9 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 728AO UT WOS:000287846100006 PM 21362717 ER PT J AU Lin, JC Karno, MP Grella, CE Warda, U Liao, DH Hu, PF Moore, AA AF Lin, James C. Karno, Mitchell P. Grella, Christine E. Warda, Umme Liao, Diana H. Hu, Peifung Moore, Alison A. TI Alcohol, Tobacco, and Nonmedical Drug Use Disorders in US Adults Aged 65 Years and Older: Data From the 2001-2002 National Epidemiologic Survey of Alcohol and Related Conditions SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Substance use disorder; alcohol; tobacco; nonmedical drug use ID AT-RISK DRINKERS; DSM-IV ALCOHOL; UNITED-STATES; SUBSTANCE USE; NICOTINE DEPENDENCE; COOCCURRING ALCOHOL; PREVALENCE; COMORBIDITY; ABUSE; DISABILITY AB Objectives: To examine the prevalence, sociodemographic, and health-related correlates of substance use disorders, including alcohol, tobacco, and nonmedical drug use among adults aged 65 years and older. Design: The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, a cross-sectional survey of a population-based sample. Setting: The United States. Participants: Eight thousand two hundred five adults aged 65 years and older. Measurements: Prevalence of lifetime and past 12-month Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, determined alcohol, tobacco, and nonmedical drug use disorders. Results: Prevalence of any substance use disorder was 21.1% during the lifetime and 5.4% in the past 12 months. Lifetime and past 12-month alcohol use disorders were 16.1% and 1.5%; tobacco use disorders were 8.7% and 4.0%; and nonmedical drug use disorders were 0.6% and 0.2%, respectively. Younger age was associated with greater odds of any lifetime or past 12-month substance use disorders. Men and those who were divorced or separated had greater odds of both lifetime alcohol and tobacco use disorders. Very good or excellent self-rated health was associated with lower odds of lifetime and past 12-month tobacco use disorders. Younger age and being divorced or separated were associated with greater odds of lifetime nonmedical drug use disorder. Conclusions: More than one in five older adults ever had a substance use disorder, and more than 1 in 20 had a disorder in the past 12 months, primarily involving alcohol or tobacco. Older adults have increased comorbidities and use of medications, which can increase risks associated with substance use. (Am J Geriatr Psychiatry 2011; 19:292-299) C1 [Lin, James C.] VA Greater Los Angeles Healthcare Syst, Dept Geriatr Med, Special Fellowship Adv Geriatr, Los Angeles, CA USA. [Lin, James C.; Liao, Diana H.; Hu, Peifung; Moore, Alison A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lin, James C.] Cheng Ching Hosp, Dept Med, Taichung, Taiwan. [Karno, Mitchell P.; Grella, Christine E.; Warda, Umme; Moore, Alison A.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Integrated Subst Abuse Programs, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. RP Lin, JC (reprint author), 11301 Wilshire Ave,Bldg 220, Los Angeles, CA 90073 USA. EM jlin1207@ucla.edu FU National Institute on Drug Abuse [R01DA020944]; National Institute on Alcoholism and Alcohol Abuse [K24AA15957]; National Institute on Aging [P30AG028748]; VA FX This work was supported by National Institute on Drug Abuse (R01DA020944), the National Institute on Alcoholism and Alcohol Abuse (K24AA15957), the National Institute on Aging (P30AG028748), and VA Special Fellowship in Advanced Geriatrics. NR 48 TC 29 Z9 29 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 BP 292 EP 299 DI 10.1097/JGP.0b013e3181e898b4 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 725QE UT WOS:000287659900013 PM 20808122 ER PT J AU Perry, TW Pugh, MJV Waterer, GW Nakashima, B Orihuela, CJ Copeland, LA Restrepo, MI Anzueto, A Mortensen, EM AF Perry, Theodore W. Pugh, Mary Jo V. Waterer, Grant W. Nakashima, Brandy Orihuela, Carlos J. Copeland, Laurel A. Restrepo, Marcos I. Anzueto, Antonio Mortensen, Eric M. TI Incidence of Cardiovascular Events After Hospital Admission for Pneumonia SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiac arrhythmia; Cardiovascular disease; Congestive heart failure; Myocardial infarction; Pneumonia ID COMMUNITY-ACQUIRED PNEUMONIA; ACUTE MYOCARDIAL-INFARCTION; RECENT RESPIRATORY-INFECTION; DISEASE; RISK; ASSOCIATION; INFLUENZA; OUTCOMES; COMPLICATION; EXPRESSION AB OBJECTIVE: Several studies have suggested an increased risk of cardiovascular events, primarily acute myocardial infarction, around the time of hospital admission for pneumonia. Therefore, we examined cardiovascular events, including myocardial infarction, congestive heart failure, unstable angina, stroke, and serious cardiac arrhythmias, within 90 days after hospitalization for pneumonia. METHODS: By using data from the administrative databases of the Department of Veterans Affairs, we examined a cohort of subjects hospitalized with pneumonia between October 2001 and September 2007. Subjects were at least 65 years of age. We examined the incidence of myocardial infarction, congestive heart failure, cardiac arrhythmias, unstable angina, and stroke by International Classification of Diseases, Ninth Revision codes, excluding those with a diagnosis before the admission for pneumonia. RESULTS: The cohort comprised 50,119 subjects with a mean age of 77.5 years (standard deviation 6.7 years), 98% of whom were male. The 90-day incidence of cardiovascular events was 1.5% for myocardial infarction, 10.2% for congestive heart failure, 9.5% for arrhythmia, 0.8% for unstable angina, and 0.2% for stroke. The majority of events occurred during the hospitalization for pneumonia. CONCLUSION: A clinically important number of subjects in this cohort had a cardiovascular event within 90 days of hospital admission, suggesting that such events may have an important role in post-pneumonia mortality. Additional research is needed to determine whether interventions may reduce the number of cardiovascular events after pneumonia. Published by Elsevier Inc. . The American Journal of Medicine (2011) 124, 244-251 C1 [Perry, Theodore W.; Nakashima, Brandy; Copeland, Laurel A.; Restrepo, Marcos I.; Anzueto, Antonio; Mortensen, Eric M.] VERDICT S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Div Gen Internal Med, Dept Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Orihuela, Carlos J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Waterer, Grant W.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Waterer, Grant W.] Northwestern Univ, Evanston, IL USA. RP Mortensen, EM (reprint author), VERDICT Res Program 11C6, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM mortensene@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU National Institute of Nursing Research [R01NR010828]; Department of Veteran Affairs Veterans Integrated Service Network [17]; National Health Institutes [KL2 RR025766] FX The project described was supported by Grant R01NR010828 from the National Institute of Nursing Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. Dr Restrepo is supported by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and National Health Institutes Grant KL2 RR025766. The funding agencies had no role in conducting the study or in the preparation, review, or approval of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 37 TC 35 Z9 37 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2011 VL 124 IS 3 BP 244 EP 251 DI 10.1016/j.amjmed.2010.11.014 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 732QM UT WOS:000288203700020 PM 21396508 ER PT J AU Kayama, M Nakazawa, T Thanos, A Morizane, Y Murakami, Y Theodoropoulou, S Abe, T Vavvas, D Miller, JW AF Kayama, Maki Nakazawa, Toru Thanos, Aristomenis Morizane, Yuki Murakami, Yusuke Theodoropoulou, Sofia Abe, Toshiaki Vavvas, Demetrios Miller, Joan W. TI Heat Shock Protein 70 (HSP70) Is Critical for the Photoreceptor Stress Response after Retinal Detachment via Modulating Anti-Apoptotic Akt Kinase SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HEAT-SHOCK PROTEINS; EXPERIMENTAL GLAUCOMA; EXPERIMENTAL-MODEL; SIGNALING PATHWAY; CELL-SURVIVAL; UP-REGULATION; IN-VIVO; ACTIVATION; RAT; GERANYLGERANYLACETONE AB Photoreceptor apoptosis is a major cause of vision loss in many ocular diseases. Significant progress has been made to elucidate the molecular pathways involved in this process, yet little is known about proteins counteracting these apoptotic pathways. It is established that heat shock proteins (HSPs) function as molecular helper proteins (chaperones) by preventing protein aggregation and facilitating refolding of dysfunctional proteins, critical to the survival of all organisms. Here, we investigated the role of HSP70 on photoreceptor survival after experimental retinal detachment (RD) in mice and rats. We found that HSP70 was up-regulated after RD and associated with phosphorylated Akt, thereby preventing its dephosphorylation and further activation of cell death pathways. Administration of quercetin, which inhibits HSP70 and suppresses Akt phosphorylation significantly increased photoreceptor apoptosis. Similarly, RD-induced photoreceptor apoptosis was augmented in mice carrying hypomorphic mutations of the genes encoding HSP70. On the other hand, administration of geranylgeranylacetone, which induces an increase in HSP70 significantly decreased photoreceptor apoptosis after RD through prolonged activation of Ala pathway. Thus, HSP70 may be a favorable potential target to increase photoreceptor cell survival after RD. (Am J Pathol 2011, 178:1080-1091; DOI: 10.1016/j.ajpath.2010.11.072) C1 [Kayama, Maki; Nakazawa, Toru; Thanos, Aristomenis; Morizane, Yuki; Murakami, Yusuke; Theodoropoulou, Sofia; Vavvas, Demetrios; Miller, Joan W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Nakazawa, Toru] Tohoku Grad Univ, Sch Med, Dept Ophthalmol, Sendai, Miyagi, Japan. [Abe, Toshiaki] Tohoku Univ, Grad Sch Med, Div Clin Cell Therapy, Sendai, Miyagi 980, Japan. RP Miller, JW (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab, 243 Charles St, Boston, MA 02114 USA. EM ntoru@oph.med.tohoku.ac.jp; joan_miller@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU Ministry of Education, Science, and Technology of Japan [21659395, 22689045]; Uehara Memorial Research Foundation; Takeda Research Foundation; Imai Glaucoma Research Foundation; Bausch & Lomb Vitreoretinal Fellowship; National Eye Institute [EY014104] FX Supported by Grants-in-Aid from the Ministry of Education, Science, and Technology of Japan (21659395 and 22689045 to T.N.), Uehara Memorial Research Foundation, Takeda Research Foundation and Imai Glaucoma Research Foundation (T.N.), a Bausch & Lomb Vitreoretinal Fellowship (M.K. and Y.M.), and National Eye Institute grant EY014104 (MEEI Core Grant). NR 45 TC 29 Z9 31 U1 0 U2 4 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 MAR PY 2011 VL 178 IS 3 BP 1080 EP 1091 DI 10.1016/j.ajpath.2010.11.072 PG 12 WC Pathology SC Pathology GA 732LD UT WOS:000288185600016 PM 21356360 ER PT J AU Bunni, MA Kramarenko, II Walker, L Raymond, JR Garnovskaya, MN AF Bunni, Marlene A. Kramarenko, Inga I. Walker, Linda Raymond, John R. Garnovskaya, Maria N. TI Role of integrins in angiotensin II-induced proliferation of vascular smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE G protein-coupled receptors; signal transduction; extracellular signal-regulated protein kinase 1 and 2 ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION; RECEPTOR ANTAGONIST; ADHESION RECEPTORS; FOCAL ADHESIONS; BALLOON INJURY; EGF RECEPTOR; ALPHA(V)BETA(3); HYPERTROPHY; EXPRESSION AB Bunni MA, Kramarenko II, Walker L, Raymond JR, Garnovskaya MN. Role of integrins in angiotensin II-induced proliferation of vascular smooth muscle cells. Am J Physiol Cell Physiol 300: C647-C656, 2011. First published December 9, 2010; doi: 10.1152/ajpcell.00179.2010.-Angiotensin II (AII) binds to G protein-coupled receptor AT(1) and stimulates extracellular signal-regulated kinase (ERK), leading to vascular smooth muscle cells (VSMC) proliferation. Proliferation of mammalian cells is tightly regulated by adhesion to the extracellular matrix, which occurs via integrins. To study cross-talk between G protein-coupled receptor-and integrin-induced signaling, we hypothesized that integrins are involved in AII-induced proliferation of VSMC. Using Oligo GEArray and quantitative RT-PCR, we established that messages for alpha(1)-, alpha(5)-, alpha(V)-, and beta(1)-integrins are predominant in VSMC. VSMC were cultured on plastic dishes or on plates coated with either extracellular matrix or poly-D-lysine (which promotes electrostatic cell attachment independent of integrins). AII significantly induced proliferation in VSMC grown on collagen I or fibronectin, and this effect was blocked by the ERK inhibitor PD-98059, suggesting that AII-induced proliferation requires ERK activity. VSMC grown on collagen I or on fibronectin demonstrated approximately three-and approximately sixfold increases in ERK phosphorylation after stimulation with 100 nM AII, respectively, whereas VSMC grown on poly-D-lysine demonstrated no significant ERK activation, supporting the importance of integrin-mediated adhesion. AII-induced ERK activation was reduced by > 65% by synthetic peptides containing an RGD (arginine-glycine-aspartic acid) sequence that inhibit alpha(5)beta(1)-integrin, and by similar to 60% by the KTS (lysine-threonine-serine)-containing peptides specific for integrin-alpha(1)beta(1). Furthermore, neutralizing antibody against beta(1)-integrin and silencing of alpha(1), alpha(5), and beta(1) expression by transfecting VSMC with short interfering RNAs resulted in decreased AII-induced ERK activation. This work demonstrates roles for specific integrins (most likely alpha(5)beta(1) and alpha(1)beta(1)) in AII-induced proliferation of VSMC. C1 Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Med Serv, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29425 USA. RP Garnovskaya, MN (reprint author), Med Univ S Carolina, Dept Med Nephrol, 96 Jonathan Lucas St,MSC 629, Charleston, SC 29425 USA. EM garnovsk@musc.edu FU Department of Veterans Affairs Basic Laboratory RD Service; American Heart Association [GIA 0655445U]; National Institutes of Health [DK52448, GM63909]; Medical University of South Carolina Division of Nephrology; Dialysis Clinics, Inc. FX This work was supported by grants from the Department of Veterans Affairs Basic Laboratory R&D Service (Merit Awards and a Research Enhancement Award Program Award to M. N. Garnovskaya and J. R. Raymond), American Heart Association (GIA 0655445U to M. N. Garnovskaya), the National Institutes of Health (DK52448 and GM63909 to J. R. Raymond), and a laboratory endowment jointly supported by the Medical University of South Carolina Division of Nephrology and Dialysis Clinics, Inc. (J. R. Raymond). NR 41 TC 8 Z9 8 U1 0 U2 5 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 MAR PY 2011 VL 300 IS 3 BP C647 EP C656 DI 10.1152/ajpcell.00179.2010 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 727MI UT WOS:000287803800027 PM 21148411 ER PT J AU Lu, L Li, TT Williams, G Petit, E Borowsky, M Walker, WA AF Lu, Lei Li, Tiantian Williams, Graham Petit, Elizabeth Borowsky, Mark Walker, W. Allan TI Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE microarray; immature enterocyte development; hydrocortisone; polarity-associated genes; tight junction-associated genes ID NEONATAL NECROTIZING ENTEROCOLITIS; SMALL-INTESTINE; IN-VITRO; CHOLERA-TOXIN; EPITHELIAL POLARITY; FETAL ENTEROCYTES; MODULATION; CELLS; GLUCOCORTICOIDS; RESPONSIVENESS AB Lu L, Li T, Williams G, Petit E, Borowsky M, Walker WA. Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes. Am J Physiol Gastrointest Liver Physiol 300: G425-G432, 2011. First published December 9, 2010; doi:10.1152/ajpgi.00011.2010.-It is known that functional maturation of the small intestine occurring during the weaning period is facilitated by glucocorticoids (such as hydrocortisone, HC), including an increased expression of digestive hydrolases. However, the molecular mechanisms are not well understood, particularly in the human gut. Here we report a microarray analysis of HC-induced changes in gene expression in H4 cells (a well-characterized human fetal small intestinal epithelial cell line). This study identified a large number of HC-regulated genes, some involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication. HC also regulates the expression of genes important for cell maturation such as development of cell polarity, tight junction formation, and interactions with extracellular matrices. Using human small intestinal xenografts, we also show that HC can regulate the expression of genes important for intestinal epithelial cell maturation. Our dataset may serve as a useful resource for understanding and dissecting the molecular mechanisms of intestinal epithelial cell maturation. C1 [Lu, Lei; Li, Tiantian; Petit, Elizabeth; Walker, W. Allan] Massachusetts Gen Hosp Children, Dev Gastroenterol Lab, Boston, MA USA. [Borowsky, Mark] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Borowsky, Mark] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Williams, Graham] Depauw Univ, Greencastle, IN 46135 USA. RP Lu, L (reprint author), Harvard Univ, Sch Med, Dev Gastroenterol Lab, Massachusetts Gen Hosp, 114 16th St 114-3503, Charlestown, MA 02129 USA. EM lul@helix.mgh.harvard.edu FU National Institutes of Health [R01-HD-12437,, R01-DK-70260, P01-DK-33506, P30-DK-40561] FX This work was supported by National Institutes of Health Grants R01-HD-12437, R01-DK-70260, P01-DK-33506, and P30-DK-40561 (W. A. Walker). NR 37 TC 7 Z9 7 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD MAR PY 2011 VL 300 IS 3 BP G425 EP G432 DI 10.1152/ajpgi.00011.2010 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 728CA UT WOS:000287850400007 PM 21148402 ER PT J AU David, V Martin, A Hedge, AM Drezner, MK Rowe, PSN AF David, Valentin Martin, Aline Hedge, Anne-Marie Drezner, Marc K. Rowe, Peter S. N. TI ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE matrix extracellular phosphoglycoprotein; dentin matrix protein-1; mineralization; osteomalacia; SIBLING proteins; fibroblast growth factor 23; X-linked hypophosphatemic rickets; 1,25 dihydroxy vitamin D3 ID MATRIX EXTRACELLULAR PHOSPHOGLYCOPROTEIN; LINKED GLYCOPROTEINS SIBLINGS; HUMAN OSTEOBLAST CELLS; BRUSH-BORDER; PHOSPHORYLATED OSTEOPONTIN; PHOSPHONOCARBOXYLIC ACIDS; HYPOPHOSPHATEMIC RICKETS; PHOSPHONOFORMIC ACID; BONE SIALOPROTEIN; KNOCKOUT MICE AB David V, Martin A, Hedge A-M, Drezner MK, Rowe PS. ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol 300: F783-F791, 2011. First published December 22, 2010; doi:10.1152/ajprenal.00304.2010.-Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg.day(-1).kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation. C1 [Rowe, Peter S. N.] Univ Kansas, Dept Internal Med, Div Nephrol & Hypertens, Kidney Inst,Med Ctr, Kansas City, KS 66160 USA. [David, Valentin; Martin, Aline] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Drezner, Marc K.] Univ Wisconsin, Dept Med, Madison, WI USA. [Drezner, Marc K.] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, Madison, WI 53792 USA. RP Rowe, PSN (reprint author), Univ Kansas, Dept Internal Med, Div Nephrol & Hypertens, Kidney Inst,Med Ctr, MS 3018,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM prowe@kumc.edu FU National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [RO-1-AR51598-01, R01-AR-27032-26, 1K12-RR-017614, R01-SK-65830-1, M01-RR-03186-21] FX We thank the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) for grant support to P. S. N. Rowe (Grant RO-1-AR51598-01) and M. K. Drezner (Grants R01-AR-27032-26, 1K12-RR-017614, R01-SK-65830-1, and M01-RR-03186-21). NR 65 TC 30 Z9 30 U1 0 U2 6 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 MAR PY 2011 VL 300 IS 3 BP F783 EP F791 DI 10.1152/ajprenal.00304.2010 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 730ZS UT WOS:000288076700024 PM 21177780 ER PT J AU Japuntich, SJ Leventhal, AM Piper, ME Bolt, DM Roberts, LJ Fiore, MC Baker, TB AF Japuntich, Sandra J. Leventhal, Adam M. Piper, Megan E. Bolt, Daniel M. Roberts, Linda J. Fiore, Michael C. Baker, Timothy B. TI Smoker Characteristics and Smoking-Cessation Milestones SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SOCIAL SUPPORT; QUITTING SMOKING; CLINICAL-TRIAL; TOBACCO USE; RELAPSE; STRESS; MODELS; INTERVENTION; PREDICTORS; INTENSITY AB Background: Contextual variables often predict long-term abstinence, but little is known about how these variables exert their effects. These variables could influence abstinence by affecting the ability to quit at all, or by altering risk of lapsing, or progressing from a lapse to relapse. Purpose: To examine the effect of common predictors of smoking-cessation failure on smoking-cessation processes. Methods: The current study (N = 1504, 58% female, 84% Caucasian; recruited from January 2005 to June 2007; data analyzed in 2009) uses the approach advocated by Shiffman et al. (2006), which measures cessation outcomes on three different cessation milestones (achieving initial abstinence, lapse risk, and the lapse-relapse transition) to examine relationships of smoker characteristics (dependence, contextual and demographic factors) with smoking-cessation process. Results: High nicotine dependence strongly predicted all milestones: not achieving initial abstinence, and a higher risk of both lapse and transitioning from lapse to complete relapse. Numerous contextual and demographic variables were associated with higher initial cessation rates and/or decreased lapse risk at 6 months post-quit (e. g., ethnicity, gender, marital status, education, smoking in the workplace, number of smokers in the social network, and number of supportive others). However, aside from nicotine dependence, only gender significantly predicted the risk of transition from lapse to relapse. Conclusions: These findings demonstrate that (1) higher nicotine dependence predicted worse outcomes across every cessation milestone; (2) demographic and contextual variables are generally associated with initial abstinence rates and lapse risk and not the lapse-relapse transition. These results identify groups who are at risk for failure at specific stages of the smoking-cessation process, and this may have implications for treatment. (Am J Prev Med 2011;40(3):286-294) (C) 2011 American Journal of Preventive Medicine C1 [Japuntich, Sandra J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Japuntich, Sandra J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Leventhal, Adam M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Japuntich, Sandra J.; Piper, Megan E.; Fiore, Michael C.; Baker, Timothy B.] Univ Wisconsin, Dept Med, Ctr Tobacco Res & Intervent, Sch Med & Publ Hlth, Madison, WI USA. [Bolt, Daniel M.] Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. [Roberts, Linda J.] Univ Wisconsin, Dept Human Dev & Family Studies, Madison, WI 53706 USA. RP Japuntich, SJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM sjapuntich@partners.org FU NIH/NIDA [P50 DA019706]; National Center for Research Resources, NIH [M01 RR03186]; Institutional Clinical and Translational Science Award (UW-Madison) [1KL2RR025012-01]; NIH [1K05CA139871, K08DA025041]; Pfizer; Glaxo Wellcome; Sanofi; Nabi; GlaxoSmithKline; Nabi Biopharmaceuticals FX This research was conducted at the University of Wisconsin-Madison and was supported by Grant P50 DA019706 from NIH/NIDA; by Grant M01 RR03186 from the General Clinical Research Centers Program of the National Center for Research Resources, NIH; by an Institutional Clinical and Translational Science Award (UW-Madison; KL2 Grant 1KL2RR025012-01); and by Grants 1K05CA139871 and K08DA025041 from the NIH. Medication was provided to participants at no cost under a research agreement with GlaxoSmithKline (GSK); no part of this manuscript was written or edited by anyone employed by GSK. The authors are solely responsible for the analyses, content, and writing of this article. The authors have full control of all primary data, and they agree to allow the journal to review the data if requested.; TBB has served as an investigator on research projects sponsored by pharmaceutical companies including Pfizer, Glaxo Wellcome, Sanofi, and Nabi. Over the past 3 years, MCF has served as an investigator in research studies at the University of Wisconsin that were funded by Pfizer, GlaxoSmithKline and Nabi Biopharmaceuticals. NR 63 TC 50 Z9 50 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 MAR PY 2011 VL 40 IS 3 BP 286 EP 294 DI 10.1016/j.amepre.2010.11.016 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 722PB UT WOS:000287445700006 PM 21335259 ER PT J AU Levinson, DF Duan, JB Oh, S Wang, K Sanders, AR Shi, JX Zhang, N Mowry, BJ Olincy, A Amin, F Cloninger, CR Silverman, JM Buccola, NG Byerley, WF Black, DW Kendler, KS Freedman, R Dudbridge, F Pe'er, I Hakonarson, H Bergen, SE Fanous, AH Holmans, PA Gejman, PV AF Levinson, Douglas F. Duan, Jubao Oh, Sang Wang, Kai Sanders, Alan R. Shi, Jianxin Zhang, Nancy Mowry, Bryan J. Olincy, Ann Amin, Farooq Cloninger, C. Robert Silverman, Jeremy M. Buccola, Nancy G. Byerley, William F. Black, Donald W. Kendler, Kenneth S. Freedman, Robert Dudbridge, Frank Pe'er, Itsik Hakonarson, Hakon Bergen, Sarah E. Fanous, Ayman H. Holmans, Peter A. Gejman, Pablo V. TI Copy Number Variants in Schizophrenia: Confirmation of Five Previous Findings and New Evidence for 3q29 Microdeletions and VIPR2 Duplications SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 60th Annual Meeting of the American-Society-of-Human-Genetics CY NOV 02-06, 2010 CL Washington, DC SP Amer Soc Human Genet ID 22Q11.2 DELETION SYNDROME; COMMON VARIANTS; GENOME; RISK; GENE; ASSOCIATION; POPULATION; DISORDER; DISEASE; 16P11.2 AB Objective: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. Method: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (< 1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. Results: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (> 100 kb and > 1 Mb) but not duplications. Conclusions: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. (Am J Psychiatry 2011; 168:302-316) C1 [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. NorthShore Univ, HealthSyst Res Inst, Evanston, IL USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia, PA 19104 USA. NCI, Bethesda, MD 20892 USA. Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Univ Colorado Denver, Dept Psychiat, Aurora, CO USA. Atlanta VA Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA USA. Emory Univ, Atlanta, GA 30322 USA. Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Louisiana State Univ, Sch Nursing, Hlth Sci Ctr, New Orleans, LA USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. Univ Iowa, Mental Hlth Clin Res Ctr, Iowa City, IA USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23284 USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA 23284 USA. London Sch Hyg & Trop Med, Dept Stat Genet & Epidemiol, London, England. Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. MIT, Stanley Ctr Psychiat Res, Broad Inst, Cambridge, MA 02139 USA. Harvard Univ, Cambridge, MA 02138 USA. Washington VA Med Ctr, Dept Psychiat, Washington, DC USA. Georgetown Univ, Sch Med, Washington, DC USA. Cardiff Univ, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. RP Levinson, DF (reprint author), Stanford Univ, Dept Psychiat & Behav Sci, Suite A-3325,701 Welch Rd, Palo Alto, CA 94304 USA. EM dflev@stanford.edu RI Cloninger, Claude/F-5357-2012; Bergen, Sarah/I-8313-2012; Holmans, Peter/F-4518-2015 OI Cloninger, Claude/0000-0003-3096-4807; Bergen, Sarah/0000-0002-5888-0034; Buccola, Nancy/0000-0003-1378-4636; Holmans, Peter/0000-0003-0870-9412 FU Medical Research Council [G1000718]; NCRR NIH HHS [U54 RR-020278, U54 RR020278]; NIMH NIH HHS [R01 MH059565, R01 MH-59565, R01 MH-59566, R01 MH-59571, R01 MH-59586, R01 MH-59587, R01 MH-59588, R01 MH-60870, R01 MH-60879, R01 MH-61675, R01 MH-67257, R01 MH-81800, R01 MH059566, R01 MH059571, R01 MH059586, R01 MH059587, R01 MH059588, R01 MH060870, R01 MH060879, R01 MH061675, R01 MH067257, R01 MH081800, U01 MH-46276, U01 MH-46289, U01 MH-46318, U01 MH-79469, U01 MH-79470, U01 MH046276, U01 MH046276-08, U01 MH046289, U01 MH046289-08, U01 MH046318, U01 MH046318-08, U01 MH079469, U01 MH079470] NR 42 TC 226 Z9 229 U1 3 U2 30 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 MAR PY 2011 VL 168 IS 3 BP 302 EP 316 DI 10.1176/appi.ajp.2010.10060876 PG 15 WC Psychiatry SC Psychiatry GA 729AG UT WOS:000287916900014 PM 21285140 ER PT J AU Cromwell, MA Carville, A Mansfield, K Klumpp, S Westmoreland, SV Lackner, AA Johnson, RP AF Cromwell, Mandy A. Carville, Angela Mansfield, Keith Klumpp, Sherry Westmoreland, Susan V. Lackner, Andrew A. Johnson, R. Paul TI SIV-Specific CD8+T Cells are Enriched in Female Genital Mucosa of Rhesus Macaques and Express Receptors for Inflammatory Chemokines SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE CD8+T cell responses; chemokines; CXCL9; CXCR3; mucosal immunity; SIV ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; DENDRITIC CELLS; INFECTION; KINETICS; MACROPHAGES; MIGRATION; RESPONSES; CERVIX AB Problem Mucosal T lymphocyte responses in the female reproductive tract, the primary site of HIV transmission in women, may be critical for initial control of virus infection. In addition, characterization of genital immune responses to HIV will be important for the development of a vaccine capable of preventing infection by this route. Method of study We analyzed lymphocytes isolated from vagina and cervix of chronically SIV-infected macaques for the frequency of SIV Gag tetramer-binding cells and expression of chemokine receptors. Results We found that the frequency of SIV-specific CD8+ T cell responses was 3- to 30-fold higher in genital tissues than in peripheral blood. SIV-specific CD8+ T cells in genital tissues expressed high levels of CXCR3 and CCR5, chemokine receptors normally expressed on memory T cells that home to inflamed tissues. Cells expressing CXCR3 colocalized with its chemokine ligand CXCL9 [monokine induced by interferon gamma, MIG] in the vaginal lamina propria. Conclusion These results indicate that the frequency of SIV-specific CD8+ T cells in the female genital mucosa is enriched compared with peripheral blood and provide initial information regarding the signals that direct recruitment of T cells to the female reproductive tract. C1 [Cromwell, Mandy A.; Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Carville, Angela; Mansfield, Keith] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Primate Med, Southborough, MA 01772 USA. [Klumpp, Sherry; Westmoreland, Susan V.; Lackner, Andrew A.] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Comparat Pathol, Southborough, MA 01772 USA. [Johnson, R. Paul] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Boston, MA USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Johnson, RP (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough Campus,Pine Hill Dr,POB 9102, Southborough, MA 01772 USA. EM paul_johnson@hms.harvard.edu FU NIH [AI062412, AI071306, RR00168] FX The authors thank John Altman (Emory University) for providing the Mamu A*01 Gag tetramers and Andrew Luster (Massachusetts General Hospital) for helpful discussions. This work was supported through NIH grants AI062412, AI071306, and RR00168. NR 16 TC 2 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD MAR PY 2011 VL 65 IS 3 BP 242 EP 247 DI 10.1111/j.1600-0897.2010.00966.x PG 6 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 717IP UT WOS:000287037200010 PM 21223428 ER PT J AU Xiang, M Yin, LH Li, YH Xiao, GZ Vodovotz, Y Billiar, TR Wilson, MA Fan, J AF Xiang, Meng Yin, Lianhua Li, Yuehua Xiao, Guozhi Vodovotz, Yoram Billiar, Timothy R. Wilson, Mark A. Fan, Jie TI Hemorrhagic Shock Activates Lung Endothelial Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase Via Neutrophil NADPH Oxidase SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE High mobility group box 1 (HMGB1); inflammation; lung; oxidants; Toll-like receptor ID OXYGEN SPECIES PRODUCTION; GLYCATION END-PRODUCTS; TUMOR-NECROSIS-FACTOR; TLR2 UP-REGULATION; NAD(P)H OXIDASE; CONFORMATIONAL-CHANGES; ALVEOLAR MACROPHAGES; LIVER ISCHEMIA; ANGIOTENSIN-II; CUTTING EDGE AB The vascular endothelium plays an important role in the regulation of inflammatory responses after trauma and hemorrhage. Interactions of neutrophils with endothelial cells (ECs) contribute to the activation of specific EC responses involved in innate immunity. We have previously reported that oxidants derived from the neutrophil reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a critical regulator to EC activation. Our objective was to test the role of neutrophil NADPH oxidase-derived oxidants in mediating and enhancing hemorrhagic shock (HS)-induced activation of lung endothelial NADPH oxidase. Mice were subjected to HS and neutrophil depletion. The mice were also replenished with the neutrophil from NADPH oxidase-deficient mice. The resultant activation of lung NADPH oxidase was analyzed. The in vivo studies were also recapitulated with in vitro neutrophil-EC coculture system. HS induces NADPH oxidase activation in neutrophils and lung through high-mobility group box 1/Toll-like receptor 4-dependent signaling. In neutropenic mice, shock-induced NADPH oxidase activation in the lung was reduced significantly, but was restored upon repletion with neutrophils obtained from wild-type mice subjected to shock, but not with neutrophils from shock mice lacking the gp91(phox) subunit of NADPH oxidase. The findings were recapitulated in mouse lung vascular ECs cocultured with neutrophils. The data further demonstrate that neutrophil-derived oxidants are key factors mediating augmented High mobility group box 1 (HMGB1)-induced endothelial NADPH oxidase activation through a Rac1-dependent, but p38 mitogen-activated protein kinase-independent, pathway. Oxidant signaling by neutrophil NADPH oxidase is an important determinant of activation of endothelial NADPH oxidase after HS. C1 [Wilson, Mark A.; Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Xiang, Meng; Li, Yuehua; Vodovotz, Yoram; Billiar, Timothy R.; Wilson, Mark A.; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Xiang, Meng; Yin, Lianhua] Fudan Univ, Dept Pathophysiol, Shanghai 200433, Peoples R China. [Xiao, Guozhi] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. RP Fan, J (reprint author), VAPHS, Bldg 1,Room 2W109,Univ Dr, Pittsburgh, PA 15240 USA. EM fanj2@upmc.edu FU National Institutes of Health [R01-HL-079669]; National Institutes of Health Center [P50-GM-53789]; U.S. Department of Veterans Affairs; National Heart, Lung, and Blood Institute (NHLBI); National Institute of General Medical Sciences; Department of Veterans Affairs; National Institutes of Health (NIH)/NHLBI [R33-HL-089082]; NIH/National Institute of Allergy and Infectious Diseases [R01-AI080799]; NIH/National Institute of General Medical Sciences [P50-GM-53789]; NIH/National Institute on Disability and Rehabilitation Research [H133E070024]; NIH/National Institute of Diabetes and Digestive and Kidney Diseases [UO1 DK072146] FX This work was supported by the National Institutes of Health grant R01-HL-079669 (J.F. and M.A.W.), National Institutes of Health Center grant P50-GM-53789 (T.R.B., Y.V. and J.F.), and a U.S. Department of Veterans Affairs merit award (J.F.).; J.F. has received sponsored grants from the National Heart, Lung, and Blood Institute (NHLBI) (more than $100,000), National Institute of General Medical Sciences (more than $100,000), and Department of Veterans Affairs (more than $100,000); Y.V. owns stock in Immunetrics, Inc. (more than $100,000), and has served as a principal investigator (PI) for the National Institutes of Health (NIH)/NHLBI (PI of grant R33-HL-089082, more than $100,000), NIH/National Institute of Allergy and Infectious Diseases (co-PI of grant R01-AI080799, more than $100,000), NIH/National Institute of General Medical Sciences (Project V PI on grant P50-GM-53789, more than $100,000), NIH/National Institute on Disability and Rehabilitation Research (Project 1 PI on grant H133E070024, more than $100,000), and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (Supplement PI on grant UO1 DK072146, $50,001-100,000); none of the other authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 48 TC 11 Z9 12 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAR PY 2011 VL 44 IS 3 BP 333 EP 340 DI 10.1165/rcmb.2009-0408OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 753KN UT WOS:000289772400012 PM 20418360 ER PT J AU Palanisamy, A Baxter, MG Keel, PK Xie, ZC Crosby, G Culley, DJ AF Palanisamy, Arvind Baxter, Mark G. Keel, Pamela K. Xie, Zhongcong Crosby, Gregory Culley, Deborah J. TI Rats Exposed to Isoflurane In Utero during Early Gestation Are Behaviorally Abnormal as Adults SO ANESTHESIOLOGY LA English DT Article ID PRENATAL ETHANOL EXPOSURE; GABA-A RECEPTOR; GUINEA-PIG; LEARNING-DISABILITIES; COGNITIVE DYSFUNCTION; FETAL EXPOSURE; BIRTH COHORT; BRAIN; ANESTHESIA; HIPPOCAMPAL AB Background: Preclinical evidence suggests that commonly used anesthetic agents induce long-lasting neurobehavioral changes when administered early in life, but there has been virtually no attention to the neurodevelopmental consequences for the fetus of maternal anesthesia. This study tested the hypothesis that fetal rats exposed to isoflurane during maternal anesthesia on gestational day 14, which corresponds to the second trimester in humans, would be behaviorally abnormal as adults. Methods: Timed, pregnant rats were randomly assigned on gestational day 14 to receive 1.4% isoflurane in 100% oxygen (n = 3) or 100% oxygen (n = 2) for 4 h. Beginning at 8 weeks of age, male offspring (N = 12-14 in control and anesthesia groups, respectively) were evaluated for spontaneous locomotor activity, hippocampal-dependent learning and memory (i.e., spontaneous alternations, novel object recognition, and radial arm maze), and anxiety (elevated plus maze). Results: Isoflurane anesthesia was physiologically well tolerated by the dams. Adult rats exposed prenatally to isoflurane were not different than controls on spontaneous locomotor activity, spontaneous alternations, or object recognition memory, but made more open arm entries on the elevated plus maze and took longer and made more errors of omission on the radial arm maze. Conclusions: Rats exposed to isoflurane in utero at a time that corresponds to the second trimester in humans have impaired spatial memory acquisition and reduced anxiety, compared with controls. This suggests the fetal brain may be adversely affected by maternal anesthesia, and raises the possibility that vulnerability to deleterious neurodevelopmental effects of isoflurane begins much earlier in life than previously recognized. C1 [Palanisamy, Arvind; Crosby, Gregory; Culley, Deborah J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesia, Cambridge, MA 02138 USA. [Xie, Zhongcong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia, Boston, MA USA. [Keel, Pamela K.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Baxter, Mark G.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. RP Culley, DJ (reprint author), Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. EM dculley@zeus.bwh.harvard.edu FU National Institutes of Health (Bethesda, Maryland) [R01 AG20253, R01 GM088817, K08NS048140, R21AG029856, R01 GM088801, KO8 GM077057]; Department of Anesthesiology, Perioperative, and Pain Medicine of the Brigham & Women's Hospital FX This study was supported by National Institutes of Health (Bethesda, Maryland) Grants R01 AG20253 and R01 GM088817 (Gregory Crosby); K08NS048140, R21AG029856 and R01 GM088801 (Zhongcong Xie); KO8 GM077057 (Deborah J. Culley) and by an intramural fellowship awarded by the Department of Anesthesiology, Perioperative, and Pain Medicine of the Brigham & Women's Hospital (Arvind Palanisamy). Presented in part as a poster presentation at the Association of University Anesthesiologists 57th Annual Meeting, Denver, Colorado, April 7-9, 2010 and as an oral presentation at the Society for Obstetric Anesthesia and Perinatology 42nd Annual Meeting, San Antonio, Texas, May 12-16, 2010. NR 51 TC 43 Z9 48 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2011 VL 114 IS 3 BP 521 EP 528 DI 10.1097/ALN.0b013e318209aa71 PG 8 WC Anesthesiology SC Anesthesiology GA 725QH UT WOS:000287660300011 PM 21307768 ER PT J AU Wang, E Feng, Y Zhang, M Zou, L Li, Y Buys, ES Huang, PG Brouckaert, P Chao, W AF Wang, E. Feng, Yan Zhang, Ming Zou, Lin Li, Yan Buys, Emmanuel S. Huang, Peigen Brouckaert, Peter Chao, Wei TI Toll-like Receptor 4 Signaling Confers Cardiac Protection against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms SO ANESTHESIOLOGY LA English DT Article ID MYOCARDIAL-ISCHEMIA; ISCHEMIA/REPERFUSION INJURY; DELAYED PROTECTION; REPERFUSION INJURY; INNATE IMMUNITY; KNOCKOUT MICE; TNF-ALPHA; IN-VIVO; MYD88; ENDOTOXIN AB Background: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-beta-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Methods: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGC alpha 1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. Results: Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 +/- 3.4% vs. 19.8 +/- 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protectiveeffect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGC alpha(-/-)(1) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. Conclusions: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection. C1 [Wang, E.; Feng, Yan; Zhang, Ming; Zou, Lin; Li, Yan; Chao, Wei] Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med,Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Wang, E.] Cent S Univ, Xiangya Hosp, Dept Anesthesiol, Changsha, Peoples R China. [Huang, Peigen] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brouckaert, Peter] Univ Ghent, Dept Mol Biomed Res, Flanders Inst Biotechnol, B-9000 Ghent, Belgium. [Brouckaert, Peter] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. RP Chao, W (reprint author), Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med,Anesthesia Ctr Crit Care Res, GRJ 4-444,55 Fruit St, Boston, MA 02114 USA. EM wchao@partners.org RI Feng, Yan/H-5808-2012 FU National Institutes of Health (Bethesda, Maryland) [GM-080906]; American Heart Association (Dallas, Texas) [0755890T] FX This work was supported by the National Institutes of Health grant GM-080906 (Bethesda, Maryland) and American Heart Association grant 0755890T (Dallas, Texas). NR 51 TC 22 Z9 27 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2011 VL 114 IS 3 BP 603 EP 613 DI 10.1097/ALN.0b013e31820a4d5b PG 11 WC Anesthesiology SC Anesthesiology GA 725QH UT WOS:000287660300021 PM 21270629 ER PT J AU Anderson, CD Biffi, A Rahman, R Ross, OA Jagiella, JM Kissela, B Cole, JW Cortellini, L Rost, NS Cheng, YC Greenberg, SM de Bakker, PIW Brown, RD Brott, TG Mitchell, BD Broderick, JP Worrall, BB Furie, KL Kittner, SJ Woo, D Slowik, A Meschia, JF Saxena, R Rosand, J AF Anderson, Christopher D. Biffi, Alessandro Rahman, Rosanna Ross, Owen A. Jagiella, Jeremiasz M. Kissela, Brett Cole, John W. Cortellini, Lynelle Rost, Natalia S. Cheng, Yu-Ching Greenberg, Steven M. de Bakker, Paul I. W. Brown, Robert D., Jr. Brott, Thomas G. Mitchell, Braxton D. Broderick, Joseph P. Worrall, Bradford B. Furie, Karen L. Kittner, Steven J. Woo, Daniel Slowik, Agnieszka Meschia, James F. Saxena, Richa Rosand, Jonathan CA Int Stroke Genetics Consortium TI Common Mitochondrial Sequence Variants in Ischemic Stroke SO ANNALS OF NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; CEREBRAL AMYLOID ANGIOPATHY; GENOME-WIDE ASSOCIATION; DISEASE; POWER; POLYMORPHISMS; EPIDEMIOLOGY; DYSFUNCTION; RISK AB Objective: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV). Methods: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke. Results: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037). Interpretation: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease. ANN NEUROL 2011;69:471-480 C1 [Anderson, Christopher D.; Biffi, Alessandro; Rahman, Rosanna; Cortellini, Lynelle; Rost, Natalia S.; Furie, Karen L.; Saxena, Richa; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Rahman, Rosanna; Cortellini, Lynelle; Rost, Natalia S.; Greenberg, Steven M.; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Rahman, Rosanna; Cortellini, Lynelle; Rost, Natalia S.; de Bakker, Paul I. W.; Saxena, Richa; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Ross, Owen A.; Brott, Thomas G.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Jagiella, Jeremiasz M.; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Kissela, Brett; Broderick, Joseph P.; Woo, Daniel] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Cole, John W.; Cheng, Yu-Ching; Mitchell, Braxton D.; Kittner, Steven J.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA. RP Rosand, J (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. EM jrosand@partners.org RI Ross, Owen/D-7573-2013; de Bakker, Paul/B-8730-2009; OI de Bakker, Paul/0000-0001-7735-7858; Anderson, Christopher/0000-0002-0053-2002; Mitchell, Braxton/0000-0003-4920-4744; Kissela, Brett/0000-0002-9773-4013 FU GENEVA Consortium; CIDR Genotyping and Data Coordinating Center at the University of Washington, Seattle, WA; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke FX We acknowledge the many study coordinators and technologists at all sites who assisted in the collection and analysis of samples for the current study. We also acknowledge the GENEVA Consortium, including the CIDR Genotyping and Data Coordinating Center at the University of Washington, Seattle, WA, for their support of the University of Maryland GEOS Study.; This research was supported by a grant from the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010N (C. D. A., A. B., J.R., K. L. F.)); Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (J.R., K. L. F.); Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine (O.A.R.); Marriott Mitochondrial Fund (O.A.R.); Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine (O.A.R.); National Institute for Neurologic Disorders and Stroke (R01NS059727 (J.R.), R01NS42733 (J.F.M), P50NS051343-04 (K. L. F., J.R.), K23NS064052 (N.S.R.), K24NS056207 (S. M. G.), R01NS042147 (S. M. G.), R01NS039987 (J.F.M.), R01NS36695 (D. W., J.P.B., B. K.), R01NS30678 (D. W., J.P.B., B. K.)); Greater Cincinnati Foundation Grant (D. W., J.P.B., B. K.); Myron and Jane Hanley Award in Stroke Research (D. W.); Fulbright Foundation (R. R.); American Association of University Women (R. R.); and the State Committee for Scientific Research (Poland) (2 PO5 CO1226 (A. S., J.M.J.)). NR 33 TC 16 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2011 VL 69 IS 3 BP 471 EP 480 DI 10.1002/ana.22108 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 744FW UT WOS:000289081300010 PM 20839239 ER PT J AU Shi, M Bradner, J Hancock, AM Chung, KA Quinn, JF Peskind, ER Galasko, D Jankovic, J Zabetian, CP Kim, HM Leverenz, JB Montine, TJ Ginghina, C Kang, UJ Cain, KC Wang, Y Aasly, J Goldstein, D Zhang, J AF Shi, Min Bradner, Joshua Hancock, Aneeka M. Chung, Kathryn A. Quinn, Joseph F. Peskind, Elaine R. Galasko, Douglas Jankovic, Joseph Zabetian, Cyrus P. Kim, Hojoong M. Leverenz, James B. Montine, Thomas J. Ginghina, Carmen Kang, Un Jung Cain, Kevin C. Wang, Yu Aasly, Jan Goldstein, David Zhang, Jing TI Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression SO ANNALS OF NEUROLOGY LA English DT Article ID MULTIPLE SYSTEM ATROPHY; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; TAU-PROTEIN; FRACTALKINE-RECEPTOR; LEWY BODIES; CSF; DEMENTIA; INFLAMMATION; MICROGLIA AB Objective: There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or alpha-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity. Methods: Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (A beta(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and alpha-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally. Results: The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/A beta(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples. Interpretation: We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression. ANN NEUROL 2011;69:570-580 C1 [Shi, Min; Bradner, Joshua; Hancock, Aneeka M.; Montine, Thomas J.; Ginghina, Carmen; Wang, Yu; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Peskind, Elaine R.; Leverenz, James B.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Zabetian, Cyrus P.; Kim, Hojoong M.; Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98104 USA. [Cain, Kevin C.] Univ Washington, Sch Med, Dept Biostat, Seattle, WA 98104 USA. [Chung, Kathryn A.; Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Peskind, Elaine R.; Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Zabetian, Cyrus P.; Kim, Hojoong M.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. [Galasko, Douglas] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA. [Kang, Un Jung] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Wang, Yu] Huazhong Univ Sci & Technol, Dept Neurosurg, Tongji Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [Aasly, Jan] St Olavs Hosp, Dept Neurol, Trondheim, Norway. [Goldstein, David] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, HMC Box 359635,325 9th Ave, Seattle, WA 98104 USA. EM zhangj@uw.edu RI Shi, Min/G-6165-2012; OI Shi, Min/0000-0002-6901-2558; Zabetian, Cyrus/0000-0002-7739-4306 FU NIH [NIEHS] [ES004696]; NIH [NINDS] [NS057567, NS060252, NS062684]; NIH [NIA] [AG025327, AG033398, AG005136, AG008017]; NIH [NCRR] [UL1RR025014]; Dana Foundation; Parkinson's Disease Foundation; Michael J. Fox Foundation; Friends of Alzheimer's Research; Alzheimer's Association of Western and Central Washington; Department of Veterans Affairs; NIH; Oregon Health and Science Univeristy; American Parkinson Disease Association; Alzheimer's center, NIH; Center of Excellence of the National Parkinson Foundation; Michael J Fox Foundation FX This research was supported by the NIH [ES004696 (J.Z.) from NIEHS, NS057567 (J.Z.), NS060252 (J.Z.), NS062684 (T.J.M., C.P.Z., J.B.L. and J.Z.) from NINDS, AG025327 (J.Z.), AG033398 (J.Z.), AG005136 (E. R. P and T.J.M.), AG008017 (K. A. C. and J.F.Q.) from NIA and UL1RR025014 (K. C. C) from NCRR]; Dana Foundation (J.F.Q.); Parkinson's Disease Foundation (C.P.Z.); Michael J. Fox Foundation (C.P.Z. and J.Z.); Friends of Alzheimer's Research (E. R. P.); Alzheimer's Association of Western and Central Washington (E. R. P.); Department of Veterans Affairs (C.P.Z. and E. R. P.).; K. C. C. and J.Z. received grant(s) from the NIH. A. M. H., C. G., J. B. and M. S. were supported by the NIH grants. K. A. C. received grant(s) from the Oregon Health and Science Univeristy; C.P.Z. received grants from The American Parkinson Disease Association, Department of Veterans Affairs, Michael J. Fox Foundation, NIH, and The Parkinson's Disease Foundation. J. F. Q. received an Alzheimer's center grant from the NIH. J. J. has grant(s) pending from the Center of Excellence of the National Parkinson Foundation. T. J. M. received grant funding and has grant(s) pending from the NIH. U. J. K. has been a consultant for CVS/caremark and has grants pending from the Michael J Fox Foundation and the NIH. All other authors had nothing to report. NR 54 TC 168 Z9 175 U1 4 U2 22 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2011 VL 69 IS 3 BP 570 EP 580 DI 10.1002/ana.22311 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 744FW UT WOS:000289081300020 PM 21400565 ER PT J AU Okereke, OI Copeland, M Hyman, BT Wanggaard, T Albert, MS Blacker, D AF Okereke, Olivia I. Copeland, Maura Hyman, Bradley T. Wanggaard, Taylor Albert, Marilyn S. Blacker, Deborah TI The Structured Interview & Scoring Tool-Massachusetts Alzheimer's Disease Research Center (SIST-M) Development, Reliability, and Cross-Sectional Validation of a Brief Structured Clinical Dementia Rating Interview SO ARCHIVES OF NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; MINI-MENTAL-STATE; INFORMANT INTERVIEW; WEIGHTED KAPPA; QUESTIONNAIRE; MULTICENTER; PREDICTION; AGREEMENT; VALIDITY; DECLINE AB Background: The Clinical Dementia Rating (CDR) and CDR Sum-of-Boxes can be used to grade mild but clinically important cognitive symptoms of Alzheimer disease. However, sensitive clinical interview formats are lengthy. Objectives: To develop a brief instrument for obtaining CDR scores and to assess its reliability and cross-sectional validity. Methods: Using legacy data from expanded interviews conducted among 347 community-dwelling older adults in a longitudinal study, we identified 60 questions (from a possible 131) about cognitive functioning in daily life using clinical judgment, inter-item correlations, and principal components analysis. Items were selected in 1 cohort (n=147), and a computer algorithm for generating CDR scores was developed in this same cohort and rerun in a replication cohort (n =200) to evaluate how well the 60 items retained information from the original 131 items. Short interviews based on the 60 items were then administered to 50 consecutively recruited older individuals, with no symptoms or mild cognitive symptoms, at an Alzheimer's Disease Research Center. Clinical Dementia Rating scores based on short interviews were compared with those from independent long interviews. Results: In the replication cohort, agreement between short and long CDR interviews ranged from kappa=0.65 to 0.79, with kappa=0.76 for Memory, kappa=0.77 for global CDR, and intraclass correlation coefficient for CDRSum-of-Boxes=0.89. In the cross-sectional validation, short interview scores were slightly lower than those from long interviews, but good agreement was observed for global CDR and Memory (kappa >= 0.70) as well as for CDR Sum-of-Boxes (intraclass correlation coefficient = 0.73). Conclusion: The Structured Interview & Scoring Tool Massachusetts Alzheimer's Disease Research Center is a brief, reliable, and sensitive instrument for obtaining CDR scores in persons with symptoms along the spectrum of mild cognitive change. C1 [Okereke, Olivia I.; Copeland, Maura; Wanggaard, Taylor; Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hyman, Bradley T.; Blacker, Deborah] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Albert, Marilyn S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Okereke, OI (reprint author), Massachusetts Gen Hosp, Gerontol Res Unit, 149 13th St,Ste 2691, Charlestown, MA 02129 USA. EM ookereke@partners.org RI Okereke, Olivia/R-9934-2016 FU Harvard NeuroDiscovery Center; National Institutes of Health [P01-AG004953, P50-AG005134] FX This study was supported by the Harvard NeuroDiscovery Center and grants P01-AG004953 and P50-AG005134 (the Massachusetts Alzheimer's Disease Research Center) from the National Institutes of Health. NR 35 TC 3 Z9 3 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAR PY 2011 VL 68 IS 3 BP 343 EP 350 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 735JE UT WOS:000288409400011 PM 21403019 ER PT J AU Wylie-Sears, J Aikawa, E Levine, RA Yang, JH Bischoff, J AF Wylie-Sears, Jill Aikawa, Elena Levine, Robert A. Yang, Jeong-Hee Bischoff, Joyce TI Mitral Valve Endothelial Cells With Osteogenic Differentiation Potential SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE endothelium; heart valves; vascular biology; EMT; endothelial cells; mitral valve; osteogenic differentiation ID MESENCHYMAL STEM-CELLS; MUSCLE-LIKE CELLS; PROGENITOR CELLS; HEART-VALVE; INTERSTITIAL-CELLS; IN-VITRO; AORTIC VALVES; CALCIFICATION; VIVO; ADAPTATION AB Objective-Cardiac valvular endothelium is unique in its ability to undergo endothelial-to-mesenchymal transformation, a differentiation process that is essential for valve development and has been proposed as mechanism for replenishing the interstitial cells of mature valves. We hypothesized that the valvular endothelium contains endothelial cells that are direct precursors to osteoblastic valvular interstitial cells (VICs). Methods and Results-Clonal cell populations from ovine mitral valve leaflets were isolated by single cell plating. Mitral valvular endothelial and mesenchymal clones were tested for osteogenic, adipogenic, and chondrogenic differentiation, determined by the expression of lineage-specific markers. Mitral valvular endothelial clones showed a propensity for osteogenic, as well as chondrogenic differentiation that was comparable to a mitral valvular VIC clone and to bone marrow-derived mesenchymal stem cells. Osteogenic differentiation was not detected in nonvalvular endothelial cells. Regions of osteocalcin expression, a marker of osteoblastic differentiation, were detected along the endothelium of mitral valves that had been subjected in vivo to mechanical stretch. Conclusion-Mitral valve leaflets contain endothelial cells with multilineage mesenchymal differentiation potential, including osteogenic differentiation. This unique feature suggests that postnatal mitral valvular endothelium harbors a reserve of progenitor cells that can contribute to osteogenic and chondrogenic VICs. (Arterioscler Thromb Vasc Biol. 2011;31:598-607.) C1 [Wylie-Sears, Jill; Yang, Jeong-Hee; Bischoff, Joyce] Harvard Univ, Sch Med, Vasc Biol Program, Childrens Hosp Boston, Boston, MA 02115 USA. [Wylie-Sears, Jill; Yang, Jeong-Hee; Bischoff, Joyce] Harvard Univ, Sch Med, Dept Surg, Childrens Hosp Boston, Boston, MA 02115 USA. [Aikawa, Elena] Brigham & Womens Hosp, Boston, MA 02115 USA. [Levine, Robert A.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Bischoff, J (reprint author), Harvard Univ, Sch Med, Vasc Biol Program, Childrens Hosp Boston, Boston, MA 02115 USA. EM joyce.bischoff@childrens.harvard.edu OI Bischoff, Joyce/0000-0002-6367-1974 FU NIH [HL060490]; Leducq Fondation Mitral Network [07CVD04] FX This work was supported initially by NIH grant HL060490 and then by Leducq Fondation Mitral Network grant 07CVD04. NR 39 TC 53 Z9 54 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2011 VL 31 IS 3 BP 598 EP 607 DI 10.1161/ATVBAHA.110.216184 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 722CZ UT WOS:000287409900020 PM 21164078 ER PT J AU Makimura, H Stanley, TL Sun, NL Connelly, JM Hemphill, LC Hrovat, MI Systrom, DM Grinspoon, SK AF Makimura, Hideo Stanley, Takara L. Sun, Noelle Connelly, Jean M. Hemphill, Linda C. Hrovat, Mirko I. Systrom, David M. Grinspoon, Steven K. TI Increased skeletal muscle phosphocreatine recovery after sub-maximal exercise is associated with increased carotid intima-media thickness SO ATHEROSCLEROSIS LA English DT Article DE MRS; Spectroscopy; Mitochondria; Cardiovascular risk ID MAGNETIC-RESONANCE-SPECTROSCOPY; MITOCHONDRIAL-FUNCTION; ADULTS AB Background: The association between skeletal muscle mitochondrial function and CVD risk in healthy subjects is unknown. Methods: Forty subjects were evaluated for CVD risk with lipid profile, oral glucose tolerance test and measurement of carotid intima-media thickness (cIMT). Skeletal muscle mitochondrial function was determined by phosphocreatine recovery after sub-maximal exercise with (31)Phosphorous-MRS and represented as tau PCr. Results: tau PCr was positively associated with age (r = +0.41; P = 0.009) and cIMT (r = +0.50; P = 0.001) on univariate analyses. In multivariate regression analysis controlling for age, the association between tau PCr and cIMT remained significant (beta = 0.003; P = 0.03). This association remained significant after controlling for traditional risk factors for CVD including age, gender, tobacco use, BMI, blood pressure, cholesterol and fasting glucose in a combined model (beta = 0.003; P = 0.04; R(2) = 0.53; P = 0.008 for overall model). Conclusions: These data suggest a novel association between skeletal muscle tau PCr and increased cIMT, independent of age or traditional CVD risk factors. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Makimura, Hideo; Stanley, Takara L.; Sun, Noelle; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Makimura, Hideo; Stanley, Takara L.; Sun, Noelle; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Makimura, Hideo; Stanley, Takara L.; Sun, Noelle; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stanley, Takara L.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Connelly, Jean M.; Hemphill, Linda C.] Massachusetts Gen Hosp, Boston Heart Fdn, Boston, MA 02114 USA. [Hrovat, Mirko I.; Systrom, David M.] Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. [Hrovat, Mirko I.; Systrom, David M.] Mirtech Inc, Brockton, MA 02301 USA. RP Makimura, H (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 211, Boston, MA 02114 USA. EM hmakimura@partners.org OI Systrom, David/0000-0002-9610-6330 FU National Center for Research Resources [1UL1RR025758-01]; Center for Functional Neuroimaging Technologies [P41RR14075]; National Institutes of Health [1R01HL085268-01A1, K24DK064545-06] FX Studies were conducted at the Clinical Research Center of the Massachusetts Institute of Technology and the Massachusetts General Hospital funded by grant number 1UL1RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. 31P-MRS imaging studies were conducted at the Athinoula A. Martinos Center for Biomedical Imaging which receives funding from the Center for Functional Neuroimaging Technologies P41RR14075. This work was supported in part by the National Institutes of Health grant 1R01HL085268-01A1 (to SG) and K24DK064545-06 (to SG). Sponsors did not play any role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication. NR 14 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2011 VL 215 IS 1 BP 214 EP 217 DI 10.1016/j.atherosclerosis.2010.11.037 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 730CN UT WOS:000288008700033 PM 21185022 ER PT J AU Waltz, P Carchman, EH Young, AC Rao, J Rosengart, MR Kaczorowski, D Zuckerbraun, BS AF Waltz, Paul Carchman, Evie H. Young, Atalie C. Rao, Jayashree Rosengart, Matthew R. Kaczorowski, David Zuckerbraun, Brian S. TI Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway SO AUTOPHAGY LA English DT Article DE sepsis; tumor necrosis factoralpha; RAW 264.7; peritoneal macrophages ID CARBON-MONOXIDE; MYCOBACTERIUM-TUBERCULOSIS; INNATE IMMUNITY; GENE-TRANSFER; CELLS; LIVER; EXPRESSION; PROTECTION; IL-1-BETA; PROTEINS AB Toll-like receptor (TLR) signaling is an important part of the innate immune response. One of the downstream responses to TLR4 signaling upon lipopolysaccharide (LPS) stimulation is the induction of autophagy, which is a key response to multiple stressors. An additional adaptive signaling molecule that is involved in the response to stress is heme oxygenase-1 (HO-1). HO-1 signaling is essential to limit inflammation and restore homeostasis. We found that LPS induced autophagic signaling in macrophages via a TLR4, HO-1 dependent pathway in macrophages. These data add to the developing contribution of autophagic signaling as part of the inflammatory response. C1 [Zuckerbraun, Brian S.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Waltz, Paul; Carchman, Evie H.; Young, Atalie C.; Rao, Jayashree; Rosengart, Matthew R.; Kaczorowski, David; Zuckerbraun, Brian S.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. RP Zuckerbraun, BS (reprint author), Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. EM zuckerbraunbs@upmc.edu FU NIGMS NIH HHS [R01 GM082830] NR 41 TC 37 Z9 37 U1 1 U2 12 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD MAR PY 2011 VL 7 IS 3 BP 315 EP 320 DI 10.4161/auto.7.3.14044 PG 6 WC Cell Biology SC Cell Biology GA 728BU UT WOS:000287849800009 PM 21307647 ER PT J AU Groblewski, PA Franken, FH Cunningham, CL AF Groblewski, Peter A. Franken, Frederick H. Cunningham, Christopher L. TI Inhibition of extracellular signal-regulated kinase (ERK) activity with SL327 does not prevent acquisition, expression, and extinction of ethanol-seeking behavior in mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Extinction; ERK; SL327; Conditioned place preference; Ethanol; DBA/2J ID CONDITIONED PLACE PREFERENCE; FEAR-POTENTIATED STARTLE; ACTIVATED PROTEIN-KINASE; D-CYCLOSERINE; NUCLEUS-ACCUMBENS; INDUCED SENSITIZATION; AMYGDALA DOPAMINE; PATHWAY; RECEPTORS; AVERSION AB Although extracellular signal-regulated kinase (ERK) activity is essential for the acquisition of a variety of associative learning tasks, its involvement in the acquisition and extinction of ethanol (EtOH)-induced conditioned place preference (CPP) remains unknown. Therefore, in these experiments we examined the effects of the ERK-kinase (MEK)-inhibitor SL327 on acquisition and expression of EtOH-CPP as well as the dose- and time-dependent effects of SL327 on CPP extinction. The parametric findings of Experiment 1 showed that three 30-min (but not 15- or 5-min) non-reinforced trials were required to completely extinguish EtOH-CPP in male, DBA/2J mice. In Experiments 2 and 3, SL327 (30 and 50 mg/kg), administered 30 or 90 min prior to extinction trials, was unable to impair EtOH-CPP extinction. Experiment 4 showed that SL327 (50 mg/kg) had no effect on acquisition of EtOH-CPP or the development of EtOH-induced sensitization during conditioning. When administered prior to testing in Experiments 5 and 6, SL327 did not alter expression of EtOH-CPP but did reduce test activity. Importantly, SL327 significantly reduced pERK protein levels when assessed in the dorsal striatum and motor cortex (Experiment 7). Together, these data suggest that EtOH-related learning and EtOH reward in mice, as assessed with CPP, are not impaired by the systemically administered MEK-inhibitor SL327. Published by Elsevier B.V. C1 [Groblewski, Peter A.; Franken, Frederick H.; Cunningham, Christopher L.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Groblewski, Peter A.; Cunningham, Christopher L.] Portland Alcohol Res Ctr, Portland, OR 97239 USA. [Franken, Frederick H.] Portland VA Med Ctr, Portland, OR USA. RP Groblewski, PA (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, L470,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM groblews@ohsu.edu FU National Institutes of Health [AA018052, AA007702, DA07262]; American Psychological Association; N.L. Tartar Research Fund FX This research was supported by grants from the National Institutes of Health (AA018052, AA007702, DA07262), the American Psychological Association, and the N.L. Tartar Research Fund. We would like to thank Courtney Zerizef for her contributions to Experiment 6. NR 46 TC 11 Z9 12 U1 2 U2 4 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 MAR 1 PY 2011 VL 217 IS 2 BP 399 EP 407 DI 10.1016/j.bbr.2010.11.018 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 712WZ UT WOS:000286698300018 PM 21074569 ER PT J AU Buchanan, RW Keefe, RSE Lieberman, JA Barch, DM Csernansky, JG Goff, DC Gold, JM Green, MF Jarskog, LF Javitt, DC Kimhy, D Kraus, MS McEvoy, JP Mesholam-Gately, RI Seidman, LJ Ball, MP McMahon, RP Kern, RS Robinson, J Marder, SR AF Buchanan, Robert W. Keefe, Richard S. E. Lieberman, Jeffrey A. Barch, Deanna M. Csernansky, John G. Goff, Donald C. Gold, James M. Green, Michael F. Jarskog, L. Fredrik Javitt, Daniel C. Kimhy, David Kraus, Michael S. McEvoy, Joseph P. Mesholam-Gately, Raquelle I. Seidman, Larry J. Ball, M. Patricia McMahon, Robert P. Kern, Robert S. Robinson, James Marder, Stephen R. TI A Randomized Clinical Trial of MK-0777 for the Treatment of Cognitive Impairments in People with Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Clinical trial; cognition; functional capacity; gamma-aminobutyric acid; schizophrenia; symptoms ID WORKING-MEMORY; PREFRONTAL CORTEX; GENE-EXPRESSION; RATING-SCALE; PYRAMIDAL NEURONS; AXON TERMINALS; MESSENGER-RNA; DEFICITS; MATRICS; BATTERY AB Background: In a previous pilot study, MK-0777-a gamma-aminobutyric acid (GABA)(A) alpha(2)/alpha(3) partial agonist-was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. Methods: Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. Results: There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. Conclusions: The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA(A) receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA(A) alpha 2 site might be needed for cognitive enhancement in schizophrenia. C1 [Buchanan, Robert W.; Gold, James M.; Ball, M. Patricia; McMahon, Robert P.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21228 USA. [Keefe, Richard S. E.; Kraus, Michael S.; McEvoy, Joseph P.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Lieberman, Jeffrey A.; Jarskog, L. Fredrik; Kimhy, David] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, New York, NY 10027 USA. [Lieberman, Jeffrey A.; Jarskog, L. Fredrik; Kimhy, David] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. [Javitt, Daniel C.; Robinson, James] NYU, Sch Med, Dept Psychiat, Nathan S Kline Inst Psychiat Res, New York, NY USA. [Barch, Deanna M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Csernansky, John G.] NW Feinberg Sch Med, Dept Psychiat, Chicago, IL USA. [Mesholam-Gately, Raquelle I.; Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Goff, Donald C.; Seidman, Larry J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Green, Michael F.; Kern, Robert S.; Marder, Stephen R.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Green, Michael F.; Kern, Robert S.; Marder, Stephen R.] VA VISN 22 Mental Illness Res Educ & Clin Ctr, Los Angeles, CA USA. RP Buchanan, RW (reprint author), Univ Maryland, Sch Med, Grounds Spring Grove Hosp, Dept Psychiat, Maple & Locust St,POB 21247, Baltimore, MD 21228 USA. EM rwbuchanan@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009; OI Kimhy, David/0000-0001-7735-9378 FU National Institute of Mental Health [HHSN278200441003C]; McDonnell Center for Higher Brain Function; National Alliance for Research on Schizophrenia and Depression; Allon; Novartis; Janssen Pharmaceutica; Eli Lilly; Sanofi Aventis; Pfizer; Janssen; GlaxoSmithKline; Department of Veterans Affairs; Singapore National Medical Research Council; AstraZeneca; MATRICS Assessment; Otsuka; VivoMetrics; Merck; Sepracor; Targacept; Wyeth; Schering Plough; Bristol Meyers Squibb; Roche; Lundbeck; Acadia; Jazz Pharmaceuticals FX This study was funded by National Institute of Mental Health Contract HHSN278200441003C to the University of California, Los Angeles (SRM, Principal Investigator). Double-blind medications were provided by Merck and Company. We wish to thank the following for their assistance in the conduct of the study: New York State Psychiatric Institute and College of Physicians and Surgeons, Columbia University: Marlene Carlson; Duke University Medical Center: Trina Walker and Leslie Yusko; Massachusetts General Hospital, Harvard Medical School: Shannon Sorenson and Joanne Wojcik; Maryland Psychiatric Research Center: Sharon August and Ilene Verovsky; Washington University in St. Louis School of Medicine: Meghan Flatley and Emily Thomason and UCLA Semel Institute for Neuroscience and Human Behavior: Ayala Ofek and Ewa Witt.; Ms. Ball reported consultant services with ePharmaLearning to provide training fora Pfizer trial. Dr. Barch disclosed the receipt of research funding from the National Institute of Mental Health, the McDonnell Center for Higher Brain Function, National Alliance for Research on Schizophrenia and Depression, Allon, and Novartis. Dr. Buchanan has served as a Data and Safety Monitoring Board member for Cephalon, Otsuka, and Pfizer; a consultant to Abbott, GlaxoSmithKline, Sanofi-Aventis, Scherring-Plough; and an Advisory Board member for Abbott, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He has received grant support from Janssen Pharmaceutica. Dr. Csernansky reported receipt of honoraria for service on Data Monitoring Committees for clinical trials sponsored by Eli Lilly and Sanofi Aventis. Dr. Goff has served as consultant and/or adviser to: Xytis, Forest Laboratories, Pfizer, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Solvay, Hoffman-La Roche, and Dianippon Sumitomo; served on a Data and Safety Monitoring Board for Otsuka and Wyeth; and received research funding from Pfizer, Janssen, Novartis, and GlaxoSmithKline. Dr. Gold disclosed royalties from the brief assessment of cognition in schizophrenia (BACS) and has served as a consultant for Pfizer, Solvay, GlaxoSmithKline, AstraZeneca, and Merck. Dr. Green has been a consultant to Abbot Laboratories, Astellas, Cypress Bioscience, Dainippon Sumitomo Pharma, GlaxoSmithKline, Lundbeck, Otsuka, Sanofi Aventis, Takeda, and Wyeth and a speaker for Janssen Cilag. Dr. Jarskog has received grant support from Novartis and GlaxoSmithKline. Dr. Javitt serves as Chair, scientific advisory board, and major shareholder of Glytech and Amino Acids Solutions. Over the past 2 years, Dr. Javitt has served as a consultant for pharmaceutical companies, including Sanofi Aventis, Solvay, Organon, Lundbeck, AstraZeneca, NPS Pharmaceuticals, Takeda, and Sepracor. He currently serves on a new treatment development advisory board for Pfizer, serves on the Scientific Advisory Board for Promentis Pharmaceuticals, and has received research support from the pharmaceutical industry, including, in the past year, Pfizer, Roche, and Jazz Pharmaceuticals. Dr. Keefe reports having received investigator-initiated research funding support from the National Institute of Mental Health, Department of Veterans Affairs, Allon, GlaxoSmithKline, Novartis, and the Singapore National Medical Research Council and an unrestricted educational grant from AstraZeneca. He disclosed receiving honoraria and served as a consultant or advisory board member for Abbott, Acadia, AstraZeneca, BiolioneRx, BrainCells, Bristol-Myers Squibb, CHDI, Cypress Bioscience, Dainippon Sumitomo Pharma, Eli Lilly, En Vivo, Johnson & Johnson, Lundbeck, Memory Pharmaceuticals, Merck, Neurosearch, NeuroCog Trials, Novartis, Orexigen, Orion, Otsuka, Pfizer, Prophase, Roche, SanofiAventis, Shire, Solvay, Takeda, Wyeth, and Xenoport. Dr. Keefe reports being a shareholder in NeuroCog Trials as well as receiving royalties from the BACS testing battery and the MATRICS Consensus Cognitive Battery (BA CS Symbol Coding). Dr. Kern receives financial support from MATRICS Assessment, a nonprofit organization that facilitates the distribution of the MATRICS Consensus Cognitive Battery. He also has received consultation fees from Otsuka. Dr. Kimhy has received an instrument grant from VivoMetrics. Dr.; Lieberman received grant/research funding from Allon, GlaxoSmithKline, Merck, Novartis, Pfizer Sepracor, and Targacept and also served on advisory boards for Bioline, Eli Lilly, GlaxoSmithKline, Intracellular Therapies, Pierre Fabre and Psychogenics; and he holds a patent for Repligen. Dr. Marder reports having received consulting fees from the following companies: Wyeth, Otsuka, Pfizer, Schering Plough, Bristol Meyers Squibb, Roche, Lundbeck, Sanofi Aventis, and Acadia. He received research support from Novartis and GlaxoSmithKline. Dr. McEvoy has received grants from GlaxoSmithKline, Pfizer, and Novartis as well as honoraria from Eli Lilly. Dr. Larry J. Seidman reports no financial disclosures or conflicts of interest for the past 2 years. He has been a speaker for Shire Pharmaceuticals and received an unrestricted education grant from Janssen Pharmaceuticals in the past 5 years. All other authors report no biomedical financial interests or potential conflicts of interest. NR 47 TC 72 Z9 74 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2011 VL 69 IS 5 BP 442 EP 449 DI 10.1016/j.biopsych.2010.09.052 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 727SO UT WOS:000287822000008 PM 21145041 ER PT J AU Pulsipher, MA Young, NS Tolar, J Risitano, AM Deeg, HJ Anderlini, P Calado, R Kojima, S Eapen, M Harris, R Scheinberg, P Savage, S Maciejewski, JP Tiu, RV DiFronzo, N Horowitz, MM Antin, JH AF Pulsipher, Michael A. Young, Neal S. Tolar, Jakub Risitano, Antonio M. Deeg, H. Joachim Anderlini, Paolo Calado, Rodrigo Kojima, Seiji Eapen, Mary Harris, Richard Scheinberg, Phillip Savage, Sharon Maciejewski, Jaroslaw P. Tiu, Ramon V. DiFronzo, Nancy Horowitz, Mary M. Antin, Joseph H. TI Optimization of Therapy for Severe Aplastic Anemia Based on Clinical, Biologic, and Treatment Response Parameters: Conclusions of an International Working Group on Severe Aplastic Anemia Convened by the Blood and Marrow Transplant Clinical Trials Network, March 2010 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Severe aplastic anemia; Blood and marrow transplantation; Immunosuppressive therapy; Telomeres ID STEM-CELL TRANSPLANTATION; ALTERNATIVE DONOR TRANSPLANTS; HIGH-DOSE CYCLOPHOSPHAMIDE; ANTI-THYMOCYTE GLOBULIN; TERM-FOLLOW-UP; ANTITHYMOCYTE GLOBULIN; IMMUNOSUPPRESSIVE THERAPY; CONDITIONING REGIMEN; BONE-MARROW; ANTILYMPHOCYTE GLOBULIN AB Although recent advances in therapy offer the promise for improving survival in patients with severe aplastic anemia (SAA), the small size of the patient population, lack of a mechanism in North America for longitudinal follow-up of patients, and inadequate cooperation among hematologists, scientists, and transplant physicians remain obstacles to conducting large studies that would advance the field. To address this issue, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a group of international experts in March 2010 to define the most important questions in the basic science, immunosuppressive therapy (IST), and bone marrow transplantation (BMT) of SAA and propose initiatives to facilitate clinical and biologic research. Key conclusions of the working group were: ( 1) new patients should obtain accurate, expert diagnosis and early identification of biologic risk; (2) a population-based SAA outcomes registry should be established in North America to collect data on patients longitudinally from diagnosis through and after treatment; (3) a repository of biologic samples linked to the clinical data in the outcomes registry should be developed; (4) innovative approaches to unrelated donor BMT that decrease graft-versus-host disease are needed; and (5) alternative donor transplantation approaches for patients lacking HLA-matched unrelated donors must be improved. A partnership of BMT, IST, and basic science researchers will develop initiatives and partner with advocacy and funding organizations to address these challenges. Collaboration with similar study groups in Europe and Asia will be pursued. Biol Blood Marrow Transplant 17: 291-299 (2011) (C) 2011 American Society fin. Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Primary Childrens Med Ctr, Salt Lake City, UT 84113 USA. [Young, Neal S.; Calado, Rodrigo; Scheinberg, Phillip] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Tolar, Jakub] Univ Minnesota, Minneapolis, MN USA. [Risitano, Antonio M.] Univ Naples Federico 2, Naples, Italy. [Deeg, H. Joachim] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kojima, Seiji] Childrens Med Ctr, Nagoya, Aichi, Japan. [Eapen, Mary; Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Harris, Richard] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Savage, Sharon] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Maciejewski, Jaroslaw P.; Tiu, Ramon V.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Pulsipher, MA (reprint author), Univ Utah, Sch Med, Primary Childrens Med Ctr, 100 N Mario Capecchi Dr, Salt Lake City, UT 84113 USA. EM michael.pulsipher@hsc.utah.edu RI Calado, Rodrigo/G-2619-2011; Kojima, Seiji/I-1601-2012 FU Blood and Marrow Transplant Clinical Trials Network; National Heart, Lung, and Blood Institute; National Cancer Institute; Genzyme FX Financial disclosure: This International Working Group was supported by the Blood and Marrow Transplant Clinical Trials Network, the National Heart, Lung, and Blood Institute, the National Cancer Institute, and a grant from Genzyme. The authors gratefully acknowledge the participating centers and co-investigators of the BMT CTN 0301 study. NR 49 TC 23 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2011 VL 17 IS 3 BP 291 EP 299 DI 10.1016/j.bbmt.2010.10.028 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 725GM UT WOS:000287633200002 PM 21034841 ER PT J AU Zilberberg, J Friedman, TM Dranoff, G Korngold, R AF Zilberberg, Jenny Friedman, Thea M. Dranoff, Glenn Korngold, Robert TI Treatment with GM-CSF Secreting Myeloid Leukemia Cell Vaccine Prior to Autologous-BMT Improves the Survival of Leukemia-Challenged Mice SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE AML; Autologous BMT; Immunotherapy ID COLONY-STIMULATING FACTOR; BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; MINOR HISTOCOMPATIBILITY ANTIGENS; POTENT ANTITUMOR IMMUNITY; BEARING DENDRITIC CELLS; T-CELLS; LANGERHANS CELLS; IMMUNOTHERAPY; RESPONSES AB Vaccination with irradiated autologous tumor cells, engineered to secrete granulocyte macrophage-colony stimulating factor (GM-CSF) (GM tumor), can generate potent antitumor effects when combined with autologous bone marrow transplantation (BMT). That notwithstanding, the post-BMT milieu, characterized by marked cytopenia, can pose a challenge to the implementation of vaccine immunotherapies. To bypass this problem, partial post-BMT immune reconstitution has been allowed to develop prior to vaccination. However, delaying vaccination can also potentially allow the expansion of residual tumor cells. Other approaches have used reinfusion of "primed" autologous lymphocytes and multiple administrations of GM tumor cells, which required the processing of large amounts of tumor. Utilizing the MMB3.19 murine myeloid leukemia model, we tested whether a single dose of GM tumor cells, 7 days prior to syngeneic BMT, could be a curative treatment in MMB3.19-challenged recipient mice. This vaccination protocol significantly improved survival of mice by eliciting long-lasting host immune responses that survived lethal irradiation, and were even protective against post-BMT tumor rechallenge. Furthermore, we demonstrated that mature donor lymphocytes can also play a limited role in mounting the antitumor response, but our pre-BMT vaccination strategy obviated the need for either established de novo immune reconstitution or the use of multiple post-BMT immunizations. Biol Blood Marrow Transplant 17: 330-340 (2011) (C) 2011 American Society for Blood and Marrow Transplantation C1 [Zilberberg, Jenny; Friedman, Thea M.; Korngold, Robert] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ 07601 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zilberberg, J (reprint author), Hackensack Univ, Med Ctr, John Theurer Canc Ctr, 30 Prospect Ave, Hackensack, NJ 07601 USA. EM jzilberberg@humed.com FU NIH [U19-AI029530] FX We thank Eugenia Dziopa and Kristin Vazzana for help with the BMT experiments, and Themaba Nyirenda, PhD, for consultation on statistical analysis. This work was supported by Project 3 of NIH Grant U19-AI029530 (R.K). NR 38 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2011 VL 17 IS 3 BP 330 EP 340 DI 10.1016/j.bbmt.2010.09.020 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 725GM UT WOS:000287633200006 PM 20946965 ER PT J AU Issa, NC Marty, FM Gagne, LS Koo, S Verrill, KA Alyea, EP Cutler, CS Koreth, J Armand, P Ho, VT Antin, JH Soiffer, RJ Baden, LR AF Issa, Nicolas C. Marty, Francisco M. Gagne, Lisa S. Koo, Sophia Verrill, Kelly A. Alyea, Edwin P. Cutler, Corey S. Koreth, John Armand, Philippe Ho, Vincent T. Antin, Joseph H. Soiffer, Robert J. Baden, Lindsey R. TI Seroprotective Titers against 2009 H1N1 Influenza A Virus after Vaccination in Allogeneic Hematopoietic Stem Cell Transplantation Recipients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Immune response; Swine Influenza; rituximab; bone marrow transplantation ID MARROW-TRANSPLANTATION; INFECTIONS; RESPONSES; IMMUNIZATION; EXPERIENCE AB Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer >= 1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy. Biol Blood Marrow Transplant 17: 434-438 (2011) (C) 2011 American Society fir Blood and Marrow Transplantation C1 [Issa, Nicolas C.; Marty, Francisco M.; Gagne, Lisa S.; Koo, Sophia; Verrill, Kelly A.; Cutler, Corey S.; Baden, Lindsey R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Issa, Nicolas C.; Marty, Francisco M.; Koo, Sophia; Alyea, Edwin P.; Cutler, Corey S.; Koreth, John; Armand, Philippe; Ho, Vincent T.; Antin, Joseph H.; Soiffer, Robert J.; Baden, Lindsey R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Issa, NC (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Infect Dis, 75 Francis St,PBB A-4, Boston, MA 02115 USA. EM nissa@partners.org OI Koo, Sophia/0000-0002-4973-7439 FU National Cancer Institute [CA142106]; Jock and Bunny Adams Education and Research Fund FX We thank David W. Kubiak, PharmD, BCPS, Anne McDonnell, PharmD, Emily Mui, PharmD, and Juliette Kim, PharmD for their help in retrieving pharmacy data on vaccine administration oseltamivir, intravenous immunoglobulin, rituximab, and alemtuzumab use. This study was supported in part by National Cancer Institute Grant CA142106 and the Jock and Bunny Adams Education and Research Fund. NR 21 TC 34 Z9 34 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2011 VL 17 IS 3 BP 434 EP 438 DI 10.1016/j.bbmt.2010.10.002 PG 5 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 725GM UT WOS:000287633200018 PM 20950701 ER PT J AU Kuranov, RV Qiu, JZ McElroy, AB Estrada, A Salvaggio, A Kiel, J Dunn, AK Duong, TQ Milner, TE AF Kuranov, Roman V. Qiu, Jinze McElroy, Austin B. Estrada, Arnold Salvaggio, Anthony Kiel, Jeffrey Dunn, Andrew K. Duong, Timothy Q. Milner, Thomas E. TI Depth-resolved blood oxygen saturation measurement by dual-wavelength photothermal (DWP) optical coherence tomography SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID SIGNALS; SCATTERING; SPECTROSCOPY; ABSORPTION; RESOLUTION; VELOCITY; OXIMETRY; TISSUE; CORTEX; MEDIA AB Non-invasive depth-resolved measurement of hemoglobin oxygen saturation (SaO(2)) levels in discrete blood vessels may have implications for diagnosis and treatment of various pathologies. We introduce a novel Dual-Wavelength Photothermal (DWP) Optical Coherence Tomography (OCT) for non-invasive depth-resolved measurement of SaO(2) levels in a blood vessel phantom. DWP OCT SaO(2) is linearly correlated with blood-gas SaO(2) measurements. We demonstrate 6.3% precision in SaO(2) levels measured a phantom blood vessel using DWP-OCT with 800 and 765 nm excitation wavelengths. Sources of uncertainty in SaO(2) levels measured with DWP-OCT are identified and characterized. (C) 2011 Optical Society of America C1 [Kuranov, Roman V.; Kiel, Jeffrey; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Kuranov, Roman V.; Qiu, Jinze; McElroy, Austin B.; Estrada, Arnold; Salvaggio, Anthony; Dunn, Andrew K.; Milner, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Kuranov, RV (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. EM kuranov@uthscsa.edu RI Qiu, Jinze /I-2272-2013; Dunn, Andrew/I-9527-2014 OI Qiu, Jinze /0000-0001-8466-1460; FU NIH [UL1RR025767, KL2RR025766, R01 EY018855, R01 EY014211]; San Antonio Area Foundation [130977]; Department of Veterans Affairs FX This research was partially supported by NIH KL2 training grants (parent grants UL1RR025767 and KL2RR025766), San Antonio Area Foundation grant 130977 to RVK, Department of Veterans Affairs (VA MERIT Award) to T. Q. Duong and NIH (R01 EY018855 and R01 EY014211) to T. Q. Duong. NR 41 TC 20 Z9 20 U1 1 U2 9 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD MAR 1 PY 2011 VL 2 IS 3 BP 491 EP 504 DI 10.1364/BOE.2.000491 PG 14 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886SW UT WOS:000299875200009 PM 21412455 ER PT J AU Dehaes, M Grant, PE Sliva, DD Roche-Labarbe, N Pienaar, R Boas, DA Franceschini, MA Selb, J AF Dehaes, Mathieu Grant, P. Ellen Sliva, Danielle D. Roche-Labarbe, Nadege Pienaar, Rudolph Boas, David A. Franceschini, Maria Angela Selb, Juliette TI Assessment of the frequency-domain multi-distance method to evaluate the brain optical properties: Monte Carlo simulations from neonate to adult SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; TIME-RESOLVED REFLECTANCE; HIGHLY SCATTERING MEDIA; CEREBRAL BLOOD-VOLUME; PHOTON MIGRATION; INFANT BRAIN; HUMAN HEAD; NONINVASIVE DETERMINATION; HEMODYNAMIC-RESPONSE; NEWBORN-INFANTS AB The near infrared spectroscopy (NIRS) frequency-domain multi-distance (FD-MD) method allows for the estimation of optical properties in biological tissue using the phase and intensity of radiofrequency modulated light at different source-detector separations. In this study, we evaluated the accuracy of this method to retrieve the absorption coefficient of the brain at different ages. Synthetic measurements were generated with Monte Carlo simulations in magnetic resonance imaging (MRI)-based heterogeneous head models for four ages: newborn, 6 and 12 month old infants, and adult. For each age, we determined the optimal set of source-detector separations and estimated the corresponding errors. Errors arise from different origins: methodological (FD-MD) and anatomical (curvature, head size and contamination by extra-cerebral tissues). We found that the brain optical absorption could be retrieved with an error between 8-24% in neonates and infants, while the error increased to 19-44% in adults over all source-detector distances. The dominant contribution to the error was found to be the head curvature in neonates and infants, and the extra-cerebral tissues in adults. (C) 2011 Optical Society of America C1 [Dehaes, Mathieu; Grant, P. Ellen; Sliva, Danielle D.; Pienaar, Rudolph] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Dehaes, Mathieu; Grant, P. Ellen; Sliva, Danielle D.; Pienaar, Rudolph] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Grant, P. Ellen; Roche-Labarbe, Nadege; Boas, David A.; Franceschini, Maria Angela; Selb, Juliette] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Grant, P. Ellen; Roche-Labarbe, Nadege; Boas, David A.; Franceschini, Maria Angela; Selb, Juliette] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Dehaes, M (reprint author), Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM mathieu.dehaes@childrens.harvard.edu RI Roche-Labarbe, Nadege/N-9101-2015 OI Roche-Labarbe, Nadege/0000-0002-5010-0400 FU NIH/NICHD [R01-HD042908, R21-HD058725]; NIH/NCRR [P41-RR14075]; Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT-B3, Canada) FX The authors thank Myong-Sun Choe (CHB) and Lilla Zollei (MGH). This work was supported by the NIH/NICHD grants # R01-HD042908 and R21-HD058725, the NIH/NCRR grant # P41-RR14075 and the Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT-B3, Canada). NR 45 TC 33 Z9 34 U1 0 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD MAR 1 PY 2011 VL 2 IS 3 BP 552 EP 567 DI 10.1364/BOE.2.000552 PG 16 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886SW UT WOS:000299875200015 PM 21412461 ER PT J AU Dehaes, M Gagnon, L Lesage, F Pelegrini-Issac, M Vignaud, A Valabregue, R Grebe, R Wallois, F Benali, H AF Dehaes, Mathieu Gagnon, Louis Lesage, Frederic Pelegrini-Issac, Melanie Vignaud, Alexandre Valabregue, Romain Grebe, Reinhard Wallois, Fabrice Benali, Habib TI Quantitative investigation of the effect of the extra-cerebral vasculature in diffuse optical imaging: a simulation study SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; PRIMARY VISUAL-CORTEX; ADULT HUMAN HEAD; BRAIN ACTIVATION; TISSUE OXYGENATION; INDOCYANINE GREEN; PHOTON MIGRATION; FOCAL CHANGES; BLOOD-FLOW; MODEL AB Diffuse optical imaging (DOI) is a non invasive technique allowing the recovery of hemodynamic changes in the brain. Due to the diffusive nature of photon propagation in turbid media and the fact that cerebral tissues are located around 1.5 cm under the adult human scalp, DOI measurements are subject to partial volume errors. DOI measurements are also sensitive to large pial vessels because oxygenated and deoxygenated hemoglobin are the dominant chromophores in the near infrared window. In this study, the effect of the extra-cerebral vasculature in proximity of the sagittal sinus was investigated for its impact on DOI measurements simulated over the human adult visual cortex. Numerical Monte Carlo simulations were performed on two specific models of the human head derived from magnetic resonance imaging (MRI) scans. The first model included the extra-cerebral vasculature in which constant hemoglobin concentrations were assumed while the second did not. The screening effect of the vasculature was quantified by comparing recovered hemoglobin changes from each model for different optical arrays and regions of activation. A correction factor accounting for the difference between the recovered and the simulated hemoglobin changes was computed in each case. The results show that changes in hemoglobin concentration are better estimated when the extra-cerebral vasculature is modeled and the correction factors obtained in this case were at least 1.4-fold lower. The effect of the vasculature was also examined in a high-density diffuse optical tomography configuration. In this case, the difference between changes in hemoglobin concentration recovered with each model was reduced down to 10%. (C) 2011 Optical Society of America C1 [Dehaes, Mathieu; Pelegrini-Issac, Melanie; Benali, Habib] Univ Paris 06, INSERM, UMR S 678, LIF & LINeM, Paris, France. [Dehaes, Mathieu; Grebe, Reinhard; Wallois, Fabrice] Univ Picardie Jules Verne, GRAMFC, EA 4293, Amiens, France. [Gagnon, Louis] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gagnon, Louis] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Lesage, Frederic] Ecole Polytech, Dept Genie Elect, Montreal, PQ H3C 3A7, Canada. [Vignaud, Alexandre] Siemens Healthcare, St Denis, France. [Valabregue, Romain] Univ Paris 06, INSERM, UMR S 975, CRICM CENIR, Paris, France. RP Dehaes, M (reprint author), Childrens Hosp Boston, Dept Med, Div Newborn Med, 300 Longwood Ave, Boston, MA 02115 USA. EM mathieu.dehaes@childrens.harvard.edu FU Regional Council of Picardie (France); European Regional Development Fund (ERDF); Fonds Quebecois de la Recherche sur la Nature et les Technologies [FQRNT-B3]; MIT; National Sciences and Engineering Research Council (NSERC) of Canada FX The authors thank David A. Boas, Ph.D. for helpful discussions on the methodology proposed in this work. They acknowledge funds from the Regional Council of Picardie (France), the European Regional Development Fund (ERDF), the Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT-B3), the IDEA-squared program at MIT and the National Sciences and Engineering Research Council (NSERC) of Canada. NR 54 TC 15 Z9 15 U1 0 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD MAR 1 PY 2011 VL 2 IS 3 BP 680 EP 695 DI 10.1364/BOE.2.000680 PG 16 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886SW UT WOS:000299875200026 PM 21412472 ER PT J AU Marques, L LeBlanc, N Weingarden, H Greenberg, JL Traeger, LN Keshaviah, A Wilhelm, S AF Marques, Luana LeBlanc, Nicole Weingarden, Hilary Greenberg, Jennifer L. Traeger, Lara N. Keshaviah, Aparna Wilhelm, Sabine TI Body dysmorphic symptoms: Phenomenology and ethnicity SO BODY IMAGE LA English DT Article DE BDD; Ethnic differences; Body parts; Compensatory behaviors ID OBSESSIVE-COMPULSIVE SCALE; POPULATION-BASED SURVEY; COLLEGE-STUDENTS; ASIAN-AMERICAN; FOLLOW-UP; DISORDER; PREVALENCE; RELIABILITY; SAMPLE; IMAGE AB Differences in the presentation of clinical features of body dysmorphic disorder (BDD) across ethnic groups have received little investigation. The current study assessed BDD symptoms in an ethnically diverse sample of adults (n=401) using an online survey. Participants completed self-report measures assessing BDD symptoms, body parts of concern and BDD behaviors. Compared to Caucasian participants, no significant differences were found in body parts or behaviors reported by Latino or African American participants. Significant group differences did emerge between Asian and Caucasian participants. Specifically, Asians reported more concern with straight hair and dark skin and fewer body shape concerns than Caucasians. Asians also endorsed lower rates of grooming, touching body parts, and camouflaging and higher rates of exercise compared to Caucasians. Although most clinical features of BDD appear similar across ethnic groups, results showed some differences in body parts and behaviors between Caucasians and Asian Americans with BDD symptoms. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Marques, Luana] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Ctr Anxiety & Traumat Stress Disorder,Sch Med, Boston, MA 02114 USA. [Marques, Luana; LeBlanc, Nicole; Weingarden, Hilary; Greenberg, Jennifer L.; Traeger, Lara N.; Keshaviah, Aparna; Wilhelm, Sabine] Harvard Univ, Sch Med, Boston, MA 02114 USA. [LeBlanc, Nicole; Weingarden, Hilary] Tufts Univ, Medford, MA 02155 USA. RP Marques, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Ctr Anxiety & Traumat Stress Disorder,Sch Med, 1 Bowdoin Sq, Boston, MA 02114 USA. EM lmarques@partners.org NR 34 TC 10 Z9 10 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1740-1445 J9 BODY IMAGE JI Body Image PD MAR PY 2011 VL 8 IS 2 BP 163 EP 167 DI 10.1016/j.bodyim.2010.12.006 PG 5 WC Psychology, Clinical; Psychiatry; Psychology, Multidisciplinary SC Psychology; Psychiatry GA 758AK UT WOS:000290131600009 PM 21354876 ER PT J AU Saless, N Litscher, SJ Vanderby, R Demant, P Blank, RD AF Saless, Neema Litscher, Suzanne J. Vanderby, Ray Demant, Peter Blank, Robert D. TI Linkage mapping of principal components for femoral biomechanical performance in a reciprocal HCB-8 x HCB-23 intercross SO BONE LA English DT Article DE Principal components; Biomechanics; Linkage; Recombinant congenic mice; Osteoporosis ID QUANTITATIVE TRAIT LOCI; RECOMBINANT CONGENIC STRAINS; INBRED MOUSE STRAINS; BONE-MINERAL DENSITY; MICE; PRECISION; C57BL/6J; STRENGTH; GEOMETRY; CROSSES AB Studies of bone genetics have addressed an array of related phenotypes, including various measures of biomechanical performance, bone size, bone, shape, and bone mineral density. These phenotypes are not independent, resulting in redundancy of the information they provide. Principal component (PC) analysis transforms multiple phenotype data to a new set of orthogonal "synthetic" phenotypes. We performed PC analysis on 17 femoral biomechanical, anatomic, and body size phenotypes in a reciprocal intercross of HcB-8 and HcB-23, accounting for 80% of the variance in 4 PCs. Three of the 4 PCs were mapped in the cross. The linkage analysis revealed a quantitative trait locus (QTL) with LOD = 4.7 for PC2 at 16 cM on chromosome 19 that was not detected using the directly measured phenotypes. The chromosome 19 QTL falls within a similar to 10 megabase interval, with Osf1 as a positional candidate gene. PC QTLs were also found on chromosomes 1, 2, 4, 6, and 10 that coincided with those identified for directly measured or calculated material property phenotypes. The novel chromosome 19 QTL illustrates the power advantage that attends use of PC phenotypes for linkage mapping. Constraint of the chromosome 19 candidate interval illustrates an important advantage of experimental crosses between recombinant congenic mouse strains. Published by Elsevier Inc. C1 [Saless, Neema; Blank, Robert D.] Univ Wisconsin, Cellular & Mol Biol Program, Madison, WI USA. [Litscher, Suzanne J.] Univ Wisconsin, Dept Med, Madison, WI USA. [Vanderby, Ray] Univ Wisconsin, Dept Orthoped Surg, Madison, WI USA. [Demant, Peter] Roswell Pk Canc Inst, Dept Genet, Buffalo, NY 14263 USA. [Blank, Robert D.] Univ Wisconsin, Dept Med, Madison, WI USA. [Blank, Robert D.] William S Middleton Mem Vet Adm Med Ctr, GRECC Serv, Madison, WI USA. RP Blank, RD (reprint author), H4-556 CSC 5148,600 Highland Ave, Madison, WI 53792 USA. EM rdb@medicine.wisc.edu FU Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs (RDB); NIH [AR-54753] FX This material is based upon work supported by the Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs (RDB) and performed in the Geriatrics Research, Education, and Clinical Center at the William S. Middleton Memorial Veterans Hospital. This report is Madison GRECC manuscript 2010-09. This work is supported by NIH grant AR-54753 (R.D.B.). NR 42 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR 1 PY 2011 VL 48 IS 3 BP 647 EP 653 DI 10.1016/j.bone.2010.10.165 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 740EG UT WOS:000288773800029 PM 20969983 ER PT J AU Bastepe, M Altug-Teber, O Agarwal, C Oberfield, SE Bonin, M Juppner, H AF Bastepe, Murat Altug-Teber, Oezge Agarwal, Chhavi Oberfield, Sharon E. Bonin, Michael Juppner, Harald TI Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib) SO BONE LA English DT Article DE Pseudohypoparathyroidism; Parathyroid hormone; Stimulatory G protein; GNAS; Imprinting ID ALBRIGHTS HEREDITARY OSTEODYSTROPHY; GNAS LOCUS; AUTOSOMAL-DOMINANT; EPIGENETIC DEFECTS; DISOMY; METHYLATION; FEATURES; DELETION; ELEMENT; 20Q AB Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end-organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100 K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype. (C) 2010 Elsevier Inc. All rights reserved. C1 [Bastepe, Murat; Juppner, Harald] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Bastepe, Murat; Juppner, Harald] Harvard Univ, Sch Med, Boston, MA USA. [Altug-Teber, Oezge; Bonin, Michael] Univ Clin Tubingen, Dept Med Genet, Tubingen, Germany. [Agarwal, Chhavi; Oberfield, Sharon E.] Columbia Univ, Med Ctr, Dept Pediat Endocrinol Diabet & Metab, New York, NY USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. EM jueppner@helix.mgh.harvard.edu FU National Institutes of Diabetes and Digestive and Kidney Disease [R01 DK073911, R37 DK46718] FX The authors would like to thank Michael P. Goldman, BS, for his help in reviewing the patient's clinical and laboratory findings. This work was funded by research grants from National Institutes of Diabetes and Digestive and Kidney Disease R01 DK073911 to MB and R37 DK46718 to HJ. NR 25 TC 33 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR 1 PY 2011 VL 48 IS 3 BP 659 EP 662 DI 10.1016/j.bone.2010.10.168 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 740EG UT WOS:000288773800031 PM 20965295 ER PT J AU Wasif, N Etzioni, D Maggard, MA Tomlinson, JS Ko, CY AF Wasif, Nabil Etzioni, David Maggard, Melinda A. Tomlinson, James S. Ko, Clifford Y. TI Trends, Patterns, and Outcomes in the Management of Malignant Colonic Polyps in the General Population of the United States SO CANCER LA English DT Article DE malignant colon polyps; lymph nodes; survival; colon cancer; surgical resection ID COLORECTAL-CANCER; QUALITY MEASURES; RISK-FACTORS; SURVEILLANCE; POLYPECTOMY; COLECTOMY; SOCIETY AB BACKGROUND: Colonoscopic screening has increased detection of malignant colonic polyps (MPs). The goal of this study was to analyze trends and patterns in the surgical treatment of MPs and to assess outcomes as measured by lymph node retrieval and patient survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried to identify 19,743 patients with MPs from 1988 to 2003. RESULTS: The majority of MPs were present in the sigmoid and descending colon (54%), and 38% were tubular, 40% were tubulovillous, and 22% were villous. During the study period, the incidence of MPs increased from 29% to 42% and surgical resection (SR) was increasingly used for treatment, from 54% to 70%. Predictors of SR were aged <70 years (odds ratio [OR], 1.3; 95% confidence interval [95% CI], 1.2-1.4), high-grade tumors (OR, 1.5; 95% Cl, 1.2-1.9), diagnosis in 1999 through 2003 (OR, 1.7; 95% Cl, 1.5-1.9), villous subtype (OR, 2.3; 95% Cl, 2.0-2.6), and right colon location (OR, 8.1; 95% Cl, 7.0-9.4). In patients undergoing SR, the mean and median number of lymph nodes was only 4 and 1, respectively. A significant percentage of patients (49%) had no lymph nodes retrieved and a worse overall survival at 5 years compared with patients who had at least 1 lymph node examined (64% vs 74%; P<001). CONCLUSIONS: MPs appear to be increasing in incidence, and there is a trend toward increased use of SR for treatment. However, patients undergoing SR for MPs undergo suboptimal assessment of lymph nodes, with a detrimental impact on survival. Adequate lymphadenectomy and lymph node evaluation are crucial to improve outcomes in patients with these potentially curable lesions. Cancer 2011;117:931-7. (C) 2010 American Cancer Society C1 [Wasif, Nabil] St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Wasif, Nabil; Etzioni, David] Mayo Clin Scottsdale, Dept Surg, Scottsdale, AZ USA. [Maggard, Melinda A.; Tomlinson, James S.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Tomlinson, James S.; Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Wasif, N (reprint author), Mayo Clin, Dept Surg, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM wasif.nabil@mayo.edu NR 19 TC 12 Z9 12 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 MAR 1 PY 2011 VL 117 IS 5 BP 931 EP 937 DI 10.1002/cncr.25657 PG 7 WC Oncology SC Oncology GA 725LM UT WOS:000287646200010 PM 20960490 ER PT J AU Cramer, DW Bast, RC Berg, CD Diamandis, EP Godwin, AK Hartge, P Lokshin, AE Lu, KH McIntosh, MW Mor, G Patriotis, C Pinsky, PF Thornquist, MD Scholler, N Skates, SJ Sluss, PM Srivastava, S Ward, DC Zhang, Z Zhu, CS Urban, N AF Cramer, Daniel W. Bast, Robert C., Jr. Berg, Christine D. Diamandis, Eleftherios P. Godwin, Andrew K. Hartge, Patricia Lokshin, Anna E. Lu, Karen H. McIntosh, Martin W. Mor, Gil Patriotis, Christos Pinsky, Paul F. Thornquist, Mark D. Scholler, Nathalie Skates, Steven J. Sluss, Patrick M. Srivastava, Sudhir Ward, David C. Zhang, Zhen Zhu, Claire S. Urban, Nicole TI Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens SO CANCER PREVENTION RESEARCH LA English DT Article ID BIOTINYLATED RECOMBINANT ANTIBODIES; DIAGNOSTIC MARKERS; SERUM; MANAGEMENT AB Establishing a cancer screening biomarker's intended performance requires "phase III" specimens obtained in asymptomatic individuals before clinical diagnosis rather than "phase II" specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. Cancer Prev Res; 4(3); 365-74. (C)2011 AACR. C1 [Cramer, Daniel W.] Brigham & Womens Hosp, Div Epidemiol, Boston, MA 02115 USA. [Bast, Robert C., Jr.; Lu, Karen H.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Berg, Christine D.; Pinsky, Paul F.; Zhu, Claire S.] NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Diamandis, Eleftherios P.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lokshin, Anna E.] Univ Pittsburgh, Pittsburgh, PA USA. [McIntosh, Martin W.; Thornquist, Mark D.; Urban, Nicole] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Mor, Gil] Yale Univ, New Haven, CT USA. [Patriotis, Christos; Srivastava, Sudhir] NCI, Canc Biomarker Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Scholler, Nathalie] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Skates, Steven J.; Sluss, Patrick M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ward, David C.] Univ Honolulu, Canc Res Ctr, Honolulu, HI USA. [Zhang, Zhen] Johns Hopkins Univ, Baltimore, MD USA. RP Cramer, DW (reprint author), Brigham & Womens Hosp, Div Epidemiol, 221 Longwood Ave,RFB 365, Boston, MA 02115 USA. EM dcramer@partners.org RI Bast, Robert/E-6585-2011; Berg , Christine/K-1047-2014; Scholler, Nathalie/O-9003-2014; OI Bast, Robert/0000-0003-4621-8462; Diamandis, Eleftherios/0000-0002-1589-820X FU Ovarian Cancer SPOREs at FHCRC [P50 CA083636]; MDACC [P50 CA83639]; FCCC/UPenn [P50 CA083638]; NCI [N01-CN-43309]; EDRN CVC [5U01 CA113916]; Ovarian Cancer SPORE at BWH [P50 CA105009]; EDRN [5U01 CA86381]; Golfers Against Cancer; Wiley Mossy Foundation FX This work was supported in part by the Ovarian Cancer SPOREs at FHCRC (P50 CA083636), to N. Urban, MDACC (P50 CA83639) to R. C. Bast and FCCC/UPenn (P50 CA083638), an NCI contract (N01-CN-43309), an EDRN CVC (5U01 CA113916) to A. K. Godwin; an Ovarian Cancer SPORE at BWH (P50 CA105009) and an EDRN (5U01 CA86381) to D. W. Cramer; and grants from Golfers Against Cancer and the Wiley Mossy Foundation to R. C. Bast. NR 26 TC 118 Z9 126 U1 1 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2011 VL 4 IS 3 BP 365 EP 374 DI 10.1158/1940-6207.CAPR-10-0195 PG 10 WC Oncology SC Oncology GA 729PV UT WOS:000287963800013 PM 21372036 ER PT J AU Zhu, CS Pinsky, PF Cramer, DW Ransohoff, DF Hartge, P Pfeiffer, RM Urban, N Mor, G Bast, RC Moore, LE Lokshin, AE McIntosh, MW Skates, SJ Vitonis, A Zhang, Z Ward, DC Symanowski, JT Lomakin, A Fung, ET Sluss, PM Scholler, N Lu, KH Marrangoni, AM Patriotis, C Srivastava, S Buys, SS Berg, CD AF Zhu, Claire S. Pinsky, Paul F. Cramer, Daniel W. Ransohoff, David F. Hartge, Patricia Pfeiffer, Ruth M. Urban, Nicole Mor, Gil Bast, Robert C., Jr. Moore, Lee E. Lokshin, Anna E. McIntosh, Martin W. Skates, Steven J. Vitonis, Allison Zhang, Zhen Ward, David C. Symanowski, James T. Lomakin, Aleksey Fung, Eric T. Sluss, Patrick M. Scholler, Nathalie Lu, Karen H. Marrangoni, Adele M. Patriotis, Christos Srivastava, Sudhir Buys, Saundra S. Berg, Christine D. CA PLCO Project Team TI A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID SCREENING TRIAL; PROTEOMIC PATTERNS; TUMOR-MARKERS; PROSTATE; SERUM; LUNG; POPULATION; PREDICTION; DESIGN AB A panel of biomarkers may improve predictive performance over individual markers. Although many biomarker panels have been described for ovarian cancer, few studies used prediagnostic samples to assess the potential of the panels for early detection. We conducted a multisite systematic evaluation of biomarker panels using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial. Using a nested case-control design, levels of 28 biomarkers were measured laboratory-blinded in 118 serum samples obtained before cancer diagnosis and 951 serum samples from matched controls. Five predictive models, each containing 6 to 8 biomarkers, were evaluated according to a predetermined analysis plan. Three sequential analyses were conducted: blinded validation of previously established models (step 1); simultaneous split-sample discovery and validation of models (step 2); and exploratory discovery of new models (step 3). Sensitivity, specificity, sensitivity at 98% specificity, and AUC were computed for the models and CA125 alone among 67 cases diagnosed within one year of blood draw and 476 matched controls. In step 1, one model showed comparable performance to CA125, with sensitivity, specificity, and AUC at 69.2%, 96.6%, and 0.892, respectively. Remaining models had poorer performance than CA125 alone. In step 2, we observed a similar pattern. In step 3, a model derived from all 28 markers failed to show improvement over CA125. Thus, biomarker panels discovered in diagnostic samples may not validate in prediagnostic samples; utilizing prediagnostic samples for discovery may be helpful in developing validated early detection panels. Cancer Prev Res; 4(3); 375-83. (C)2011 AACR. C1 [Berg, Christine D.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Cramer, Daniel W.; Vitonis, Allison] Brigham & Womens Hosp, Ob Gyn Epidemiol Ctr, Boston, MA 02115 USA. [Ransohoff, David F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hartge, Patricia; Pfeiffer, Ruth M.; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Urban, Nicole; McIntosh, Martin W.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Mor, Gil] Yale Univ, Sch Med, Dept Obstet & Gynecol & Reprod Sci, Reprod Immunol Unit, New Haven, CT USA. [Bast, Robert C., Jr.; Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX USA. [Lokshin, Anna E.; Marrangoni, Adele M.] Univ Pittsburgh, Inst Med, Hillman Canc Ctr, Pittsburgh, PA USA. [Skates, Steven J.; Sluss, Patrick M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhang, Zhen] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD USA. [Ward, David C.] Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Symanowski, James T.] Nevada Canc Inst, Las Vegas, NV USA. [Lomakin, Aleksey] MIT, Boston, MA USA. [Fung, Eric T.] Vermillion Inc, Fremont, CA USA. [Scholler, Nathalie] Univ Penn, Sch Med, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT USA. RP Berg, CD (reprint author), NCI, Canc Prevent Div, NIH, 6130 Execut Blvd,Rm 3112, Bethesda, MD 20892 USA. EM bergc@mail.nih.gov RI Bast, Robert/E-6585-2011; Pfeiffer, Ruth /F-4748-2011; Berg , Christine/K-1047-2014; Scholler, Nathalie/O-9003-2014 OI Bast, Robert/0000-0003-4621-8462; FU National Cancer Institute; National Cancer Institute [P50 CA083636, P50 CA083639, 5U01 CA86381, R01 CA127913, U01 CA084986]; Golfers Against Cancer; Wiley Mossy Foundation FX This work was supported in part by contracts from the National Cancer Institute to 10 PLCO screening centers, a coordinating center and a central analytic laboratory; grants from the National Cancer Institute (P50 CA083636 to NU, P50 CA083639 to R. C. Bast, 5U01 CA86381 to DWC, R01 CA127913 and U01 CA084986 to G. Mor); and grants from Golfers Against Cancer and the Wiley Mossy Foundation to R. C. Bast. NR 29 TC 92 Z9 93 U1 2 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2011 VL 4 IS 3 BP 375 EP 383 DI 10.1158/1940-6207.CAPR-10-0193 PG 9 WC Oncology SC Oncology GA 729PV UT WOS:000287963800014 PM 21372037 ER PT J AU Demers, M Ho-Tin-Noe, B Schatzberg, D Yang, JJ Wagner, DD AF Demers, Melanie Ho-Tin-Noe, Benoit Schatzberg, Daphne Yang, Janie J. Wagner, Denisa D. TI Increased Efficacy of Breast Cancer Chemotherapy in Thrombocytopenic Mice SO CANCER RESEARCH LA English DT Article ID INTERSTITIAL FLUID PRESSURE; ANTI-ANGIOGENIC THERAPY; ANTIANGIOGENIC THERAPY; MONOCLONAL-ANTIBODY; MAMMARY-TUMOR; INFLAMMATION; HEMORRHAGE; RESISTANCE; PLATELETS; PROTEINS AB Platelets contribute to homeostasis of the tumor vasculature by helping prevent hemorrhage. Thus, we hypothesized that inducing thrombocytopenia would increase tumor vascular leakiness and facilitate the effective delivery of chemotherapeutic agents to tumors. In a mammary carcinoma murine model, platelet depletion induced bleeding specifically at the tumor site, favoring the accumulation of fluorescently labeled microspheres only in the tumor. Moreover, induction of thrombocytopenia in tumor-bearing mice before injection of paclitaxel increased its intratumoral accumulation and reduced growth of both slow- and fast-growing tumors, compared with mice with normal platelet counts that were treated only with paclitaxel. Histologic analysis confirmed the expectation of an increase in tumor apoptosis and a reduction in tumor proliferation in thrombocytopenic mice receiving chemotherapy. No increased toxicity was seen in other organs or blood cells. Taken together, our results indicate that low platelet count selectively induces leakiness of tumor vessels and favors the delivery of chemotherapy to tumor sites, enhancing its tumoricidal effects. Cancer Res; 71(5); 1540-9. (C)2011 AACR. C1 [Demers, Melanie; Ho-Tin-Noe, Benoit; Schatzberg, Daphne; Yang, Janie J.; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Demers, Melanie; Ho-Tin-Noe, Benoit; Schatzberg, Daphne; Yang, Janie J.; Wagner, Denisa D.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Demers, Melanie; Ho-Tin-Noe, Benoit; 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, 3 Blackfan Circle, Boston, MA 02115 USA. EM wagner@idi.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [P01 HL066105, R01 41002]; Terry Fox Foundation through the Canadian Cancer Society [TF-018748] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grants P01 HL066105 and R01 41002 (to D.D. Wagner). M. Demers was supported by a fellowship from the Terry Fox Foundation through the Canadian Cancer Society (TF-018748). NR 32 TC 24 Z9 24 U1 1 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 MAR 1 PY 2011 VL 71 IS 5 BP 1540 EP 1549 DI 10.1158/0008-5472.CAN-10-2038 PG 10 WC Oncology SC Oncology GA 728AH UT WOS:000287845300006 PM 21212409 ER PT J AU Tanwar, PS Zhang, LH Roberts, DJ Teixeira, JM AF Tanwar, Pradeep S. Zhang, LiHua Roberts, Drucilla J. Teixeira, Jose M. TI Stromal Deletion of the APC Tumor Suppressor in Mice Triggers Development of Endometrial Cancer SO CANCER RESEARCH LA English DT Article ID BETA-CATENIN; INTESTINAL TUMORIGENESIS; BREAST CARCINOMAS; UTERINE STROMA; GROWTH-FACTOR; ER-BETA; ESTROGEN; CELLS; MICROENVIRONMENT; DIFFERENTIATION AB The contribution of the stromal microenvironment to the progression of endometrial cancer has not been well explored. We have conditionally expressed a mutant allele of adenomatous polyposis coli (APC(cKO)) in murine uterine stroma cells to study its effect on uterine development and function. In addition to metrorrhagia, the mice develop complex atypical endometrial gland hyperplasia that progresses to endometrial carcinoma in situ and endometrial adenocarcinoma as evidenced by myometrial invasion. Stromal cells subjacent to the carcinoma cells express alpha-smooth muscle actin (alpha SMA) with fewer cells expressing platelet-derived growth factor alpha compared with normal stromal cells, suggesting that the mutant stromal cells have acquired a more myofibroblastic phenotype, which have been described as cancer-associated fibroblasts and have been shown to induce carcinogenesis in other organ systems. Analyses of human endometrial cancer specimens showed substantial alpha SMA expression in the stroma compared with normal endometrial stroma cells. We also show that APC(cKO) mutant uteri and human endometrial cancer have decreased stromal levels of transforming growth factor beta and bone morphogenetic protein activities and that the mutant uteri failed to respond to exogenous estradiol stimulation. The mutant stroma cells also had higher levels of vascular endothelial growth factor and stromal derived factor signaling components and diminished expression of estrogen receptor a and progesterone receptor, which is common in advanced stages of human endometrial cancer and is an indicator of poor prognosis. Our results indicate that de novo mutation or loss of heterozygosity in stromal APC is sufficient to induce endometrial hyperplasia and endometrial carcinogenesis by mechanisms that are consistent with unopposed estrogen signaling in the endometrial epithelium. Cancer Res; 71(5); 1584-96. (C)2011 AACR. C1 [Tanwar, Pradeep S.; Zhang, LiHua; Teixeira, Jose M.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Teixeira, Jose M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Teixeira, JM (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol Thier 931, 55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU NICHD [HD057201]; Vincent Memorial Research Fund FX These studies were supported in part by a grant from NICHD, HD057201, and by the Vincent Memorial Research Fund to J.M. Texeira. NR 56 TC 29 Z9 30 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 MAR 1 PY 2011 VL 71 IS 5 BP 1584 EP 1596 DI 10.1158/0008-5472.CAN-10-3166 PG 13 WC Oncology SC Oncology GA 728AH UT WOS:000287845300010 PM 21363919 ER PT J AU Mahida, S Lubitz, SA Rienstra, M Milan, DJ Ellinor, PT AF Mahida, Saagar Lubitz, Steven A. Rienstra, Michiel Milan, David J. Ellinor, Patrick T. TI Monogenic atrial fibrillation as pathophysiological paradigms SO CARDIOVASCULAR RESEARCH LA English DT Review DE Atrial fibrillation; Mutation; Family; Genetics ID LONG-QT SYNDROME; OF-FUNCTION MUTATION; DOMINANT DILATED CARDIOMYOPATHY; SYSTEM GENE POLYMORPHISMS; GAP-JUNCTION DISTRIBUTION; CONGESTIVE-HEART-FAILURE; OUTWARD K+ CURRENT; I-KS CHANNELS; SODIUM-CHANNEL; NATRIURETIC-PEPTIDE AB Atrial fibrillation (AF) is the most common cardiac rhythm abnormality and represents a major burden, both to patients and to health-care systems. In recent years, increasing evidence from population-based studies has demonstrated that AF is a heritable condition. Although familial forms of AF have been recognized for many years, they represent a rare subtype of the arrhythmia. However, despite their limited prevalence, the identification of mutations in monogenic AF kindreds has provided valuable insights into the molecular pathways underlying the arrhythmia and a framework for investigating AF encountered in the general population. In contrast to these rare families, the typical forms of AF occurring in the community are likely to be multigenic and have significant environmental influences. Recently, genome-wide association studies have uncovered common sequence variants that confer increased susceptibility to the arrhythmia. In the future, the elucidation of the genetic substrate underlying both familial and more typical forms of AF will hopefully lead to the development of novel diagnostic tools as well as more targeted rhythm control strategies. In this article, we will focus on monogenic forms of AF and also provide an overview of case-control association studies for AF. C1 [Mahida, Saagar; Lubitz, Steven A.; Rienstra, Michiel; Milan, David J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Milan, David J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. EM pellinor@partners.org OI Rienstra, Michiel/0000-0002-2581-070X FU Netherlands Organization of Scientific Research (Rubicon) [825.09.020]; National Institutes of Health [T32 HL007575, R21HL096009, R21DA026982, R01HL104156, R21DA027021, R01HL092577, K24HL105780).] FX This work was supported by a grant from the Netherlands Organization of Scientific Research to M. R. (Rubicon Grant 825.09.020), grants from the National Institutes of Health to S.A.L. (T32 HL007575), D.J.M. (R21HL096009 and R21DA026982), and P. T. E. (R01HL104156, R21DA027021, R01HL092577, and K24HL105780). NR 134 TC 47 Z9 47 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR PY 2011 VL 89 IS 4 BP 692 EP 700 DI 10.1093/cvr/cvq381 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 723DV UT WOS:000287487400002 PM 21123219 ER PT J AU Sinner, MF Ellinor, PT Meitinger, T Benjamin, EJ Kaab, S AF Sinner, Moritz F. Ellinor, Patrick T. Meitinger, Thomas Benjamin, Emelia J. Kaeaeb, Stefan TI Genome-wide association studies of atrial fibrillation: past, present, and future SO CARDIOVASCULAR RESEARCH LA English DT Review DE Atrial fibrillation; Genetics; Genome-wide association study; Single nucleotide polymorphism; Arrhythmia ID TRANSCRIPTION FACTOR ATBF1; CA2+-ACTIVATED K+ CHANNEL; QT INTERVAL DURATION; LEFT-RIGHT ASYMMETRY; SMALL-CONDUCTANCE; CHROMOSOME 4Q25; COMMON VARIANTS; RISK-FACTORS; PR INTERVAL; HEART-RATE AB Genome-wide association studies (GWAS) for atrial fibrillation (AF) have identified three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 that are associated with the arrhythmia. Susceptibility loci also have been identified by GWAS for PR interval duration, a quantitative phenotype related to AF. In this review article, we have sought to summarize the latest findings for population-based genetic studies of AF, to highlight ongoing functional studies, and to explore the future directions of genetic research on AF. C1 [Sinner, Moritz F.; Kaeaeb, Stefan] Univ Hosp Munich, Dept Med 1, D-81377 Munich, Germany. [Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Sinner, Moritz F.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Sinner, Moritz F.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Prevent Med Sect, Boston, MA 02118 USA. RP Kaab, S (reprint author), Univ Hosp Munich, Dept Med 1, Campus Grosshadern,Marchioninistr 15, D-81377 Munich, Germany. EM skaab@med.lmu.de RI Meitinger, Thomas/O-1318-2015; OI Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [1R01HL092577, 1RC1HL101056, 1R01HL102214, 1R01HL104156, 5R21DA027021, 1K24HL105780]; Bundesministerium fur Bildung und Forschung BMBF (German Competence Network on AF AFNET [01 GI 0204/N]; German National Genome Research Network NGFN [01GS0499, 01GS0838]; Leducq Foundation [07-CVD 03]; LMU Excellence Initiative [557/569]; German Heart Foundation FX This work was supported by the National Institutes of Health (1R01HL092577 to E.J.B. and P.T.E.; 1RC1HL101056, 1R01HL102214 to E.J.B; 1R01HL104156, 5R21DA027021, 1K24HL105780 to P.T.E.); Bundesministerium fur Bildung und Forschung BMBF (German Competence Network on AF AFNET 01 GI 0204/N, German National Genome Research Network NGFN 01GS0499, 01GS0838 to S. K.; Leducq Foundation (07-CVD 03 to E.J.B., P. T. E. and S. K.); LMU Excellence Initiative to S. K.; LMU Research grant (FoFoLe 557/569 to M.F.S.). M.F.S. is supported by the German Heart Foundation. NR 77 TC 43 Z9 44 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR PY 2011 VL 89 IS 4 BP 701 EP 709 DI 10.1093/cvr/cvr001 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 723DV UT WOS:000287487400003 PM 21245058 ER PT J AU Schon, A Madani, N Smith, AB Lalonde, JM Freire, E AF Schoen, Arne Madani, Navid Smith, Amos B. Lalonde, Judith M. Freire, Ernesto TI Some Binding-Related Drug Properties are Dependent on Thermodynamic Signature SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE binding affinity; enthalpy; entropy; isothermal titration calorimetry; thermodynamic optimization ID PROTEIN-PROTEIN INTERACTIONS; SMALL-MOLECULE INHIBITORS; HIV-1 GP120; RECEPTOR; CD4; ANTIBODY; NEUTRALIZATION; RETROVIRUS; REDUCTASE; LIGANDS AB The binding affinity is determined by the Gibbs energy of binding (Delta G) which is the sum of enthalpic (Delta H) and entropic (-T Delta S) contributions. Because the enthalpy and entropy contribute in an additive way to the binding energy, the same binding affinity can be achieved by many different combinations of enthalpic and entropic contributions; however, do compounds with similar binding affinities but different thermodynamic signatures (i.e., different Delta H, -T Delta S combinations) exhibit the same functional effects? Are there characteristics of compounds that can be modulated by modifying their thermodynamic signatures? In this paper, we consider the minimization of unwanted conformational effects arising during the development of CD4/gp120 inhibitors, a new class of HIV-1 cell entry inhibitors. Competitive inhibitors of protein/protein interactions run the risk of triggering the very same signals that they are supposed to inhibit. Here, we show that for CD4/gp120 inhibitors, the magnitude of those unwanted effects is related to the proportion in which the enthalpy and entropy changes contribute to the binding affinity. The thermodynamic optimization plot (TOP) previously proposed to optimize binding affinity can also be used to obtain appropriate enthalpy/entropy combinations for drug candidates. C1 [Schoen, Arne; Freire, Ernesto] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Madani, Navid] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Madani, Navid] Harvard Univ, Div Aids, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Smith, Amos B.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Lalonde, Judith M.] Bryn Mawr Coll, Dept Chem, Bryn Mawr, PA 19010 USA. RP Freire, E (reprint author), Johns Hopkins Univ, Dept Biol, 3400 N Charles, Baltimore, MD 21218 USA. EM ef@jhu.edu FU National Institutes of Health [GM56550, GM57144]; National Science Foundation [MCB0641252] FX This work was supported by grants from the National Institutes of Health (GM56550 and GM57144) and the National Science Foundation (MCB0641252). NR 27 TC 18 Z9 18 U1 0 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD MAR PY 2011 VL 77 IS 3 BP 161 EP 165 DI 10.1111/j.1747-0285.2010.01075.x PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 718SJ UT WOS:000287146200001 PM 21288305 ER PT J AU Suh, WM Seto, AH Margey, RJP Cruz-Gonzalez, I Jang, IK AF Suh, William M. Seto, Arnold H. Margey, Ronan J. P. Cruz-Gonzalez, Ignacio Jang, Ik-Kyung TI Intravascular Detection of the Vulnerable Plaque SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerosis; acute coronary syndrome; cardiac imaging techniques ID OPTICAL COHERENCE TOMOGRAPHY; CORONARY-ARTERY-DISEASE; RADIOFREQUENCY DATA-ANALYSIS; NEAR-INFRARED SPECTROSCOPY; IN-VIVO CHARACTERIZATION; ATHEROSCLEROTIC PLAQUES; VIRTUAL HISTOLOGY; TISSUE CHARACTERIZATION; MAGNETIC-RESONANCE; RAMAN-SPECTROSCOPY C1 [Suh, William M.; Seto, Arnold H.; Margey, Ronan J. P.; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Cruz-Gonzalez, Ignacio] Univ Hosp Salamanca, Div Cardiol, Salamanca, Spain. RP Jang, IK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRB800, Boston, MA 02114 USA. EM ijang@partners.org RI 2011, Secribsal/D-9425-2012 FU LightLab/St Jude; Medtronic; Abbott Vascular FX Dr Jang has received research grants from LightLab/St Jude, Medtronic, and Abbott Vascular. NR 62 TC 51 Z9 55 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2011 VL 4 IS 2 BP 169 EP 178 DI 10.1161/CIRCIMAGING.110.958777 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 734WC UT WOS:000288370500016 PM 21406663 ER PT J AU Cheng, EM Cunningham, WE Towfighi, A Sanossian, N Bryg, RJ Anderson, TL Guterman, JJ Gross-Schulman, SG Beanes, S Jones, AS Liu, HH Ettner, SL Saver, JL Vickrey, BG AF Cheng, Eric M. Cunningham, William E. Towfighi, Amytis Sanossian, Nerses Bryg, Robert J. Anderson, Thomas L. Guterman, Jeffrey J. Gross-Schulman, Sandra G. Beanes, Sylvia Jones, Andrea S. Liu, Honghu Ettner, Susan L. Saver, Jeffrey L. Vickrey, Barbara G. TI Randomized, Controlled Trial of an Intervention to Enable Stroke Survivors Throughout the Los Angeles County Safety Net to "Stay With the Guidelines" SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE stroke; secondary prevention; risk factors; self-management; care coordination ID TRANSIENT ISCHEMIC ATTACK; IMPROVING PRIMARY-CARE; RISK-FACTORS; BLOOD-PRESSURE; GROUP VISITS; SECONDARY PREVENTION; SELF-MANAGEMENT; CHRONIC ILLNESS; CHRONIC DISEASE; WARNING SIGNS AB Background-Stroke is the leading cause of adult disability. Inpatient programs optimize secondary stroke prevention care at the time of hospital discharge, but such care may not be continued after hospital discharge. Methods-To improve the delivery of secondary stroke preventive services after hospital discharge, we have designed a chronic care model-based program called SUSTAIN (Systemic Use of STroke Averting INterventions). This care intervention includes group clinics, self-management support, report cards, decision support through care guides and protocols, and coordination of ongoing care. The first specific aim is to test, in a randomized, controlled trial, whether SUSTAIN improves blood pressure control among an analytic sample of 268 patients with a recent stroke or transient ischemic attack discharged from 4 Los Angeles County public hospitals. Secondary outcomes consist of control of other stroke risk factors, lifestyle habits, medication adherence, patient perceptions of care quality, functional status, and quality of life. A second specific aim is to conduct a cost analysis of SUSTAIN from the perspective of the Los Angeles County Department of Health Services by using direct costs of the intervention, cost equivalents of associated utilization of county system resources, and cost equivalents of the observed and predicted averted vascular events. Conclusions-If SUSTAIN is effective, we will have the expertise and findings to advocate for its continued support at Los Angeles County hospitals and to disseminate the SUSTAIN program to other settings serving indigent, minority populations. C1 [Cheng, Eric M.] Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, VA Greater Angeles UCLA, Los Angeles, CA 90073 USA. [Cheng, Eric M.; Vickrey, Barbara G.] VA Greater Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA USA. [Cunningham, William E.; Guterman, Jeffrey J.; Liu, Honghu; Ettner, Susan L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90073 USA. [Towfighi, Amytis] Rancho Los Amigos Natl Rehabil Ctr, Dept Neurol, Los Angeles, CA USA. [Towfighi, Amytis; Sanossian, Nerses] Univ So Calif, Dept Neurol, Los Angeles, CA USA. [Bryg, Robert J.] Olive View UCLA Med Ctr, Dept Med, Sylmar, CA 91342 USA. [Anderson, Thomas L.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Neurol, Torrance, CA 90509 USA. [Guterman, Jeffrey J.; Gross-Schulman, Sandra G.] Olive View UCLA Med Ctr, Los Angeles Cty Dept Hlth Serv, Sylmar, CA 91342 USA. [Beanes, Sylvia] Amer Heart Assoc, Los Angeles, CA USA. [Jones, Andrea S.] Charles R Drew Univ Med & Sci, Los Angeles, CA 90059 USA. RP Cheng, EM (reprint author), Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, VA Greater Angeles UCLA, 11301 Wilshire Blvd,ML 127, Los Angeles, CA 90073 USA. EM eric.cheng@va.gov OI Saver, Jeffrey/0000-0001-9141-2251 FU American Heart Association; National Institutes of Health/National Institute of Neurological Disorders and Stroke [K23NS058571]; UCLA/DREW [P20MD000148/P20MD000182]; UCLA Center for Health Improvement of Minority Elderly/Resource Centers for Minority Aging Research (National Institute on Aging) [P30AG021684] FX This work was supported by an award from the American Heart Association Pharmaceutical Roundtable and David and Stevie Spina. There are no sponsor-imposed restrictions on publication of this article and any subsequent articles about this study. Dr Eric Cheng is supported by a Career Development Award from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (K23NS058571). Drs Cheng and Cunningham also received partial support from the UCLA/DREW project EXPORT (NCMHD grants No. P20MD000148/P20MD000182). Dr Cunningham also receives partial support from the UCLA Center for Health Improvement of Minority Elderly/Resource Centers for Minority Aging Research (National Institute on Aging grant No. P30AG021684). NR 50 TC 13 Z9 13 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAR PY 2011 VL 4 IS 2 BP 229 EP 234 DI 10.1161/CIRCOUTCOMES.110.951012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 734WN UT WOS:000288372200016 PM 21406671 ER PT J AU Dhingra, R Gaziano, JM Djousse, L AF Dhingra, Ravi Gaziano, J. Michael Djousse, Luc TI Chronic Kidney Disease and the Risk of Heart Failure in Men SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; congestive; epidemiology; renal disease ID LEFT-VENTRICULAR HYPERTROPHY; STAGE RENAL-DISEASE; CARDIOVASCULAR-DISEASE; PHYSICIANS HEALTH; MORTALITY RISK; SERUM PHOSPHORUS; BLOOD-PRESSURE; LIFETIME RISK; CYSTATIN-C; VITAMINS E AB Background-The relations between chronic kidney disease (CKD) and incident heart failure remain unclear. Methods and Results-We related CKD to incident nonfatal heart failure and cardiovascular (CVD) death (as separate and combined end points) in 10 181 male participants (mean age, 67 years). Kidney function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation in clinically relevant categories of <60 and >= 60 mL . min(-1) . 1.73 m(-2) (referent) and <45, 45 to 60, 60 to 90, and >= 90 mL . min(-1) . 1.73 m(-2) (referent). During follow-up (mean, 10.1 years; range, 0.03 to 12.2), 439 developed heart failure and 832 had CVD death/heart failure. In multivariable models, men with eGFR <60 mL . min(-1) . 1.73 m(-2) had a 2-fold risk of heart failure (95% confidence interval, 1.62 to 2.56, P < 0.0001) compared with referent category. The hazard ratio (with corresponding 95% confidence interval) for development of heart failure according to eGFR categories of 60 to 90, 45 to 60, and <45 mL . min(-1) . 1.73 m(-2) compared with referent category were 1.24 (0.98 to 1.56), 2.58 (1.91 to 3.49), and 1.52 (0.92 to 2.76), respectively. In the analyses restricted to subgroup of nondiabetic individuals and normotensive individuals at baseline (n = 7545), men with eGFR <60 mL . min(-1) . 1.73 m(-2) had a 2.2-fold risk of heart failure (95% confidence interval, 1.66 to 2.95), compared with men with eGFR >= 60 mL . min(-1) . 1.73 m(-2). Additionally, risk of heart failure or CVD death was >2.5-fold higher among individuals with eGFR 45 to 60 and <45 mL . min(-1) . 1.73 m(-2), compared with referent category. Conclusions-Moderate level of CKD, even in absence of diabetes and hypertension at baseline, is associated with a higher risk of development of heart failure and CVD death/heart failure in men. (Circ Heart Fail. 2011;4:138-144.) C1 [Dhingra, Ravi] Dartmouth Hitchcock Med Ctr, Cardiol Sect, Lebanon, NH 03756 USA. [Dhingra, Ravi; Gaziano, J. Michael; Djousse, Luc] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Gaziano, J. Michael; Djousse, Luc] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Gaziano, J. Michael; Djousse, Luc] VA Boston Healthcare Syst, Ctr Geriatr Res Educ & Clin, Boston, MA USA. RP Dhingra, R (reprint author), Dartmouth Hitchcock Med Ctr, Cardiol Sect, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM ravi.dhingra@hitchcock.org RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Institutes of Health, Bethesda, MD [CA-34944, CA-40360, CA-097193, HL-26490, HL-34595]; National Institutes of Health; Veterans Administration, Veroscience; Amgen; Biomedical Research Institute, Brigham and Women's Hospital FX The Physicians' Health Study is supported by grants CA-34944, CA-40360, CA-097193, HL-26490, and HL-34595 from the National Institutes of Health, Bethesda, MD.; Dr Gaziano reported receiving investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, Veroscience, and Amgen; serving as a consultant or receiving honoraria from Bayer AG and serving as an expert witness for Merck. Dr Djousse reported that he is currently the recipient of investigator-initiated grants from the National Institutes of Health and that over the past 5 years he has received an investigator-initiated grant from the Biomedical Research Institute, Brigham and Women's Hospital. NR 42 TC 18 Z9 21 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAR PY 2011 VL 4 IS 2 BP 138 EP 144 DI 10.1161/CIRCHEARTFAILURE.109.899070 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 735UM UT WOS:000288445300007 PM 21216838 ER PT J AU Gao, ZJ Xu, XY McClane, B Zeng, Q Litkouhi, B Welch, WR Berkowitz, RS Mok, SC Garner, EIO AF Gao, Zhijian Xu, Xiaoyin McClane, Bruce Zeng, Qing Litkouhi, Babak Welch, William R. Berkowitz, Ross S. Mok, Samuel C. Garner, Elizabeth I. O. TI C Terminus of Clostridium perfringens Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin SO CLINICAL CANCER RESEARCH LA English DT Article ID TIGHT JUNCTION PROTEINS; EPITHELIAL-CELLS; GENE-EXPRESSION; CLAUDIN-4; CARCINOMA; FRAGMENT; STRANDS; PACLITAXEL; RECEPTORS; DIVISION AB Purpose: We have previously shown that CLDN4 (encoding claudin-4), a cell tight junction (TJ) protein, is highly expressed in human epithelial ovarian carcinomas (EOC) but undetectable in normal ovaries. CLDN4 has been identified as a specific receptor for C terminus of Clostridium perfringens enterotoxin (C-CPE), a nontoxic molecule that may disrupt TJ barrier function and enhance cellular absorption. The purpose of this study was to determine the potential clinical applications of C-CPE and its effects on CLDN4 expression in EOC. Experimental Design: Using a 3-dimensional culture model and monolayer culture of EOC cells, we examined the effects of C-CPE on CLDN4 expression by quantitative real-time PCR, immunofluorescence, and Western blot. The synergistic effect of C-CPE to clinically relevant chemotherapies (Taxol and Carboplatin) was observed in EOC culture and xenograft mice. Furthermore, we determined through oligonucleotide microarray analysis that the transcript profile alterations dysregulated as a consequence of C-CPE treatment. Results: C-CPE treatment decreased protein expression and relocated CLDN4 from cell-cell contact regions to the cytoplasm. Particularly, C-CPE sensitized EOC cells to chemotherapeutic administration at low dosages and significantly inhibited tumor growth in a nontoxic manner. Furthermore, we provided genome-wide molecular evidence that C-CPE treatment is involved in the stimulation of the ubiquitin-proteasome pathway and the inhibition of cell metabolism in EOC cells. Conclusions: The addition of C-CPE can enhance the effectiveness of Taxol or Carboplatin and significantly inhibited EOC cell growth in a CLDN4-dependent manner, suggesting that C-CPE may have promising therapeutic potential for EOC. Clin Cancer Res; 17(5); 1065-74. (C)2010 AACR. C1 [Gao, Zhijian; Litkouhi, Babak; Berkowitz, Ross S.; Garner, Elizabeth I. O.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol,Div Gynecol Onc, Boston, MA 02115 USA. [Xu, Xiaoyin; Zeng, Qing] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [McClane, Bruce] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. [Welch, William R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Berkowitz, Ross S.; Garner, Elizabeth I. O.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Mok, Samuel C.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. RP Gao, ZJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol,Div Gynecol Onc, Boston, MA 02115 USA. EM zhijian_gao@yahoo.com FU Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE, National Institute of Health [P50CA105009]; Robert Wood Johnson; The University of Texas MD Anderson Ovarian Cancer SPORE, National Institutes of Health [P50CA083639, RO1CA133057]; University of Pittsburgh School of Medicine, National Institutes of Health [R37 AI19844] FX This study was supported in part by Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE Grant P50CA105009 from the National Institute of Health, Harold Amos Minority Faculty Development Award from Robert Wood Johnson, The University of Texas MD Anderson Ovarian Cancer SPORE grants P50CA083639 and RO1CA133057 from the National Institutes of Health, and University of Pittsburgh School of Medicine Grant R37 AI19844 from the National Institutes of Health. NR 39 TC 21 Z9 22 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2011 VL 17 IS 5 BP 1065 EP 1074 DI 10.1158/1078-0432.CCR-10-1644 PG 10 WC Oncology SC Oncology GA 728ZT UT WOS:000287914400013 PM 21123456 ER PT J AU Janne, PA Boss, DS Camidge, DR Britten, CD Engelman, JA Garon, EB Guo, F Wong, S Liang, J Letrent, S Millham, R Taylor, I Eckhardt, SG Schellens, JHM AF Jaenne, Pasi A. Boss, David S. Camidge, D. Ross Britten, Carolyn D. Engelman, Jeffrey A. Garon, Edward B. Guo, Feng Wong, Steven Liang, Jane Letrent, Stephen Millham, Robert Taylor, Ian Eckhardt, S. Gail Schellens, Jan H. M. TI Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MUTATIONS; GEFITINIB; ERBB2; EGFR; HKI-272; CI-1033 AB Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies. Experimental Design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients. Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804. Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. Clin Cancer Res; 17(5); 1131-9. (C)2011 AACR. C1 [Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Boss, David S.; Schellens, Jan H. M.] Netherlands Canc Inst, Div Clin Pharmacol, Amsterdam, Netherlands. [Camidge, D. Ross; Eckhardt, S. Gail] Univ Colorado, Aurora, CO USA. [Britten, Carolyn D.; Garon, Edward B.; Wong, Steven] Univ Calif Los Angeles, UCLA Med Ctr, Los Angeles, CA USA. [Guo, Feng] Pfizer China Res & Dev Ctr, Shanghai, Peoples R China. [Liang, Jane; Millham, Robert; Taylor, Ian] Pfizer Oncol, New London, CT USA. [Letrent, Stephen] Pfizer Oncol, Clin Dev & Med Affairs, San Diego, CA USA. [Schellens, Jan H. M.] Univ Utrecht, Fac Pharmaceut Sci, Div Drug Toxicol, Utrecht, Netherlands. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D820,44 Binney St, Boston, MA 02115 USA. EM pjanne@partners.org FU Pfizer Inc.; National Institutes of Health [R01CA135257]; National Cancer Institute Lung [SPORE P50CA090578]; Pfizer FX This study was funded by Pfizer Inc. and supported in part by grants from the National Institutes of Health R01CA135257 (P.A. Janne and J.A. Engelman) and the National Cancer Institute Lung SPORE P50CA090578 (P.A. Janne and J.A. Engelman).; P.A. Janne: commercial research grant, Pfizer; ownership interest, Gatekeeper Pharmaceuticals; consultant/advisor, Boeringher Ingelheim, AVEO Pharmaceuticals, Pfizer, Roche, Astra Zeneca, and OSI Pharmaceuticals; royalties from DFCI owned patent on EGFR mutations licensed to Genzyme. C.D. Britten and J.H.M. Schellens: commercial research grant, Pfizer. J.A. Engelmann: ownership interest, Gatekeeper Pharmaceuticals; consultant/advisor, Roche, AVEO Pharmaceuticals, and OSI Pharmaceuticals. F. Guo, J. Liang, S. Letrent, R. Milham, and I. Taylor: employment and ownership interest, Pfizer. S.G. Eckhardt: commercial research grant and consultant/advisor, Pfizer. NR 22 TC 85 Z9 88 U1 1 U2 7 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 MAR 1 PY 2011 VL 17 IS 5 BP 1131 EP 1139 DI 10.1158/1078-0432.CCR-10-1220 PG 9 WC Oncology SC Oncology GA 728ZT UT WOS:000287914400020 PM 21220471 ER PT J AU Abu Dayyeh, BK Lautz, DB Thompson, CC AF Abu Dayyeh, Barham K. Lautz, David B. Thompson, Christopher C. TI Gastrojejunal Stoma Diameter Predicts Weight Regain After Roux-en-Y Gastric Bypass SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Weight Loss; Obesity; Surgery; ROC; PPV ID VERTICAL BANDED GASTROPLASTY; BARIATRIC SURGERY; DILATED GASTROJEJUNOSTOMY; ENERGY-EXPENDITURE; FOOD-INTAKE; FOLLOW-UP; REDUCTION; GHRELIN; SCLEROTHERAPY; METAANALYSIS AB BACKGROUND & AIMS: Weight regain after Roux-en-Y gastric bypass (RYGB) is associated with reductions in health status and quality of life. We evaluated whether gastrojejunal stoma diameter is a risk factor for weight regain after RYGB. METHODS: We examined data collected over 4 years from consecutive patients referred to a tertiary care bariatric center for upper endoscopy after RYGB. We used linear regression analysis to determine the association between the gastrojejunal stoma diameter and weight regain. We applied a logistic regression model using clinical and endoscopic parameters to develop a prediction rule for weight gain after RYGB. RESULTS: Among 165 patients included in our study, 59% had significant weight regain (>= 20% of maximum weight lost after the RYGB) and 41% did not. The mean percentage of maximal weight lost after RYGB that was regained in the entire cohort was 30% +/- 22%. Gastrojejunal stoma diameter was associated significantly with weight regain after RYGB surgery in univariate analysis (beta = .31, P < .0001). This association remained significant after adjusting for several known or purported risk factors for weight regain (beta = .19, P = .003). We developed a simple prediction rule for weight regain after RYGB using a 7-point scoring system that includes the gastrojejunal stoma diameter, race, and percentage of maximal body weight lost after RYGB; a cut-off score of 4 or more points had an area under receiver operating characteristic curve of 0.76 and a positive predictive value of 75%. CONCLUSIONS: Increased gastrojejunal stoma diameter is a risk factor for weight regain after RYGB and can be incorporated in a novel prediction rule. C1 [Thompson, Christopher C.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Abu Dayyeh, Barham K.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Abu Dayyeh, Barham K.; Thompson, Christopher C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lautz, David B.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Thompson, CC (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St,Thorn 14, Boston, MA 02115 USA. EM christopher_thompson@hms.harvard.edu FU NIDDK NIH HHS [T32 DK007191, P30 DK034854, T32 DK007191-36, T32 DK007533, T32DK007191] NR 40 TC 25 Z9 25 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD MAR PY 2011 VL 9 IS 3 BP 228 EP 233 DI 10.1016/j.cgh.2010.11.004 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 737FY UT WOS:000288555700015 PM 21092760 ER PT J AU Musher, DM Sampath, R Rodriguez-Barradas, MC AF Musher, Daniel M. Sampath, Rahul Rodriguez-Barradas, Maria C. TI The Potential Role for Protein-Conjugate Pneumococcal Vaccine in Adults: What Is the Supporting Evidence? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID HIV-INFECTED ADULTS; RENAL-TRANSPLANT RECIPIENTS; COST-EFFECTIVENESS ANALYSIS; PLACEBO-CONTROLLED TRIAL; POLYSACCHARIDE VACCINE; STREPTOCOCCUS-PNEUMONIAE; DOUBLE-BLIND; OLDER-ADULTS; CAPSULAR POLYSACCHARIDES; HEMOPHILUS-INFLUENZAE AB Vaccination with protein-conjugate pneumococcal vaccine (PCV) provides children with extraordinary protection against pneumococcal disease, although the protective effect may be blunted by the emergence of replacement strains. Studies in adults have compared PCV with pneumococcal polysaccharide vaccine (PPV) using surrogate markers of protection, namely, serum anticapsular IgG antibody and opsonic activity. Results suggest that PCV is at least as effective as PPV for the strains covered, but a definitive and consistent advantage has not been demonstrated. Unfortunately, persons who are most in need of vaccine do not respond as well as otherwise healthy adults to either vaccine. Newer formulations of PCV will protect against the most prevalent of the current replacement strains, but replacement strains will create a moving target for PCVs. Unless an ongoing trial comparing 13-valent PCV with placebo (not to PPV) demonstrates a clearly better effect than that seen in the past with PPV, cost-effectiveness considerations are likely to prevent widespread use of PCV in adults. C1 Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Med Care Line Infect Dis Sect, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol Virol, Houston, TX 77030 USA. Baylor Coll Med, Dept Microbiol, Houston, TX 77030 USA. RP Musher, DM (reprint author), Michael E DeBakey VAMC, Infect Dis Sect, Houston, TX 77030 USA. EM dmusher@bcm.edu NR 65 TC 44 Z9 44 U1 0 U2 2 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 MAR 1 PY 2011 VL 52 IS 5 BP 633 EP 640 DI 10.1093/cid/ciq207 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 716RR UT WOS:000286991700017 PM 21292668 ER PT J AU Gupta, K Hooton, TM Naber, KG Wullt, B Colgan, R Miller, LG Moran, GJ Nicolle, LE Raz, R Schaeffer, AJ Soper, DE AF Gupta, Kalpana Hooton, Thomas M. Naber, Kurt G. Wullt, Bjorn Colgan, Richard Miller, Loren G. Moran, Gregory J. Nicolle, Lindsay E. Raz, Raul Schaeffer, Anthony J. Soper, David E. TI International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID URINARY-TRACT-INFECTION; TRIMETHOPRIM-SULFAMETHOXAZOLE RESISTANCE; EXTENDED-RELEASE CIPROFLOXACIN; RANDOMIZED CONTROLLED-TRIAL; SINGLE-DOSE FOSFOMYCIN; ESCHERICHIA-COLI; DOUBLE-BLIND; ANTIBIOTIC-RESISTANCE; 400 MG; ANTIMICROBIAL SUSCEPTIBILITY AB A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations. C1 [Gupta, Kalpana] Vet Affairs Boston Hlth Care Syst, Dept Med, Boston, MA USA. [Gupta, Kalpana] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hooton, Thomas M.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Colgan, Richard] Univ Maryland, Dept Family & Community Med, Baltimore, MD 21201 USA. [Miller, Loren G.] Harbor UCLA Med Ctr, Div Infect Dis, Torrance, CA 90509 USA. [Moran, Gregory J.] Olive View UCLA Med Ctr, Dept Emergency Med, Slymar, CA USA. [Moran, Gregory J.] Olive View UCLA Med Ctr, Div Infect Dis, Slymar, CA USA. [Schaeffer, Anthony J.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Soper, David E.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Soper, David E.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Nicolle, Lindsay E.] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Nicolle, Lindsay E.] Univ Manitoba, Dept Med Mirobiol, Winnipeg, MB, Canada. [Naber, Kurt G.] Tech Univ Munich, Munich, Germany. [Wullt, Bjorn] Univ Lund Hosp, S-22185 Lund, Sweden. [Raz, Raul] HaEmek Med Ctr, Infect Dis Unit, Afula, Israel. [Raz, Raul] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. RP Gupta, K (reprint author), VA Boston HCS, 1400 VFW Pkwy,111 Med, W Roxbury, MA 02132 USA. EM kalpana.gupta@va.gov FU The Infectious Diseases Society of America; UpToDate; American Urological Association; Bionorica; Daiichi; Sankyo; Janssen Cilag; Johnson Johnson; OM Pharma; Pierre Fabre; Sanofi Aventis; Zambon; Mer-Lion Pharmaceuticals; Rosen Pharma; Cubist; Pfizer Pharmaceuticals FX Financial support. The Infectious Diseases Society of America.; K.G. (Chair) has served as a consultant to Pfizer and Pinnacle Pharmaceutical. A.J.S. has served as a consultant to Novabay Pharmaceuticals, Pfizer, Propagate Pharmaceuticals, Hagen/Sinclair Research Recruiting, Swiss Precision Diagnostics Development Company, and FlashPointMedica; has received honoraria from BMJ Group (British Medical Journal) and Advanstar Communications; received a royalty payment from UpToDate; and received remuneration from the American Urological Association. G.J.M. has served as a consultant to Cerexa, Cubist, Eisai, Forest, Merck, Ortho-McNeil, Pfizer, and Schering-Plough and has received honoraria from Cubist and Merck. K.G.N. has received remuneration as consultant or speaker from Bionorica, Daiichi Sankyo, Janssen Cilag, Johnson & Johnson, OM Pharma, Pierre Fabre, Sanofi Aventis, and Zambon and has received research grants from Mer-Lion Pharmaceuticals, Rosen Pharma, and OM Pharma. L.E.N. has served as a consultant to Pfizer, Leo pharmaceuticals, Cerexa, and Johnson & Johnson and served on the advisory board for Leo Pharmaceuticals and Cerexa. L.G.M. has served as a consultant to Forest and Theravance Laboratories and received research grants from Cubist and Pfizer Pharmaceuticals. T.M.H. has served as a consultant to Pfizer, Alita Pharmaceuticals, and Pinnacle Pharmaceuticals All other authors: no conflicts. NR 62 TC 476 Z9 494 U1 10 U2 39 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 MAR 1 PY 2011 VL 52 IS 5 BP E103 EP E120 DI 10.1093/cid/ciq257 PG 18 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 716RR UT WOS:000286991700001 PM 21292654 ER PT J AU Dolan, MM Heyworth, BE Bedi, A Duke, G Kelly, BT AF Dolan, Mark M. Heyworth, Benton E. Bedi, Asheesh Duke, Gavin Kelly, Bryan T. TI CT Reveals a High Incidence of Osseous Abnormalities in Hips with Labral Tears SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID FEMORO-ACETABULAR IMPINGEMENT; FEMOROACETABULAR IMPINGEMENT; RADIOGRAPHIC EVALUATION; OSTEOARTHRITIS; ANTEVERSION; RETROVERSION; NECK; YOUNG; ARTHROSCOPY; EPIPHYSIS AB Acetabular labral tears are being diagnosed with increasing frequency and there is a growing consensus that these tears rarely occur in the absence of osseous abnormalities. We therefore determined the presence of structural abnormalities in patients with acetabular labral tears using a standardized CT protocol. We evaluated 135 consecutive patients with labral tears diagnosed by MRI with CT scans of the symptomatic hip. The CT scans were evaluated in a standardized fashion to determine acetabular and femoral pathomorphologic features. Acetabular evaluation included version measurements and anterior and lateral center-edge angles. Femoral parameters evaluated included version, alpha angle, and neck-shaft angle. One hundred twenty-two (90%) of the 135 hips had structural abnormalities. One hundred two (76%) had an alpha angle greater than 50A degrees, 18 (13%) had femoral version less than 5A degrees, 22 (16%) had femoral version greater than 25A(0), and five (4%) had coxa valga. Fifty-eight (43%) patients had acetabular retroversion and five (4%) had a lateral center-edge angle less than 20A(0). Of the 58 patients with acetabular retroversion, 23 had isolated cranial retroversion, 12 had isolated central retroversion, and 23 had combined cranial and central retroversion. Sixty-seven of the 121 hips (55%) with bony abnormalities had a combination of abnormalities. Ninety percent of patients with labral tears had structural abnormalities seen on CT scans. These structural abnormalities frequently occur in combination, and understanding these underlying morphologic features of the hip can help guide treatment. Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Dolan, Mark M.] NW Orthopaed Inst, Chicago, IL 60611 USA. [Dolan, Mark M.] Northwestern Univ, Feinberg Sch Med, Dept Orthopaed Surg, Chicago, IL 60611 USA. [Heyworth, Benton E.] Massachusetts Gen Hosp, Dept Sports Med, Boston, MA 02114 USA. [Bedi, Asheesh] Univ Michigan, Dept Orthopaed Surg, Ann Arbor, MI 48109 USA. [Duke, Gavin] New York Presbyterian Hosp, New York, NY USA. [Kelly, Bryan T.] Hosp Special Surg, Ctr Hip Pain & Preservat, New York, NY 10021 USA. RP Dolan, MM (reprint author), NW Orthopaed Inst, 680 N Lake Shore Dr,Suite 924, Chicago, IL 60611 USA. EM markmdolan@gmail.com NR 34 TC 41 Z9 42 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAR PY 2011 VL 469 IS 3 BP 831 EP 838 DI 10.1007/s11999-010-1539-6 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 716BJ UT WOS:000286939600030 PM 20886325 ER PT J AU Hatsukami, DK Jorenby, DE Gonzales, D Rigotti, NA Glover, ED Oncken, CA Tashkin, DP Reus, VI Akhavain, RC Fahim, REF Kessler, PD Niknian, M Kalnik, MW Rennard, SI AF Hatsukami, D. K. Jorenby, D. E. Gonzales, D. Rigotti, N. A. Glover, E. D. Oncken, C. A. Tashkin, D. P. Reus, V. I. Akhavain, R. C. Fahim, R. E. F. Kessler, P. D. Niknian, M. Kalnik, M. W. Rennard, S. I. TI Immunogenicity and Smoking-Cessation Outcomes for a Novel Nicotine Immunotherapeutic SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CONJUGATE VACCINE; IMMUNIZATION; RATS; RECOMMENDATIONS; BRAIN AB NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N = 301 smokers) tested the results of 200- and 400-mu g doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-mu g dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified. C1 [Hatsukami, D. K.] Univ Minnesota, Dept Psychiat, Tobacco Use Programs, Minneapolis, MN 55455 USA. [Jorenby, D. E.] Univ Wisconsin, Dept Med, Madison, WI USA. [Gonzales, D.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Rigotti, N. A.] Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Glover, E. D.] Univ Maryland, Dept Behav & Community Hlth, Sch Publ Hlth, College Pk, MD 20742 USA. [Oncken, C. A.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Tashkin, D. P.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Reus, V. I.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Akhavain, R. C.; Fahim, R. E. F.; Kessler, P. D.; Niknian, M.; Kalnik, M. W.] Nabi Biopharmaceut, Rockville, MD USA. [Rennard, S. I.] Univ Nebraska Med Ctr, Dept Med, Omaha, NE USA. RP Hatsukami, DK (reprint author), Univ Minnesota, Dept Psychiat, Tobacco Use Programs, Minneapolis, MN 55455 USA. EM hatsu001@umn.edu RI reus, victor/I-7923-2015; OI reus, victor/0000-0002-8193-5697; Gonzales, David/0000-0002-4323-198X FU NIDA NIH HHS [R01 DA017894, R01 DA017894-01A1, 1R01DA017894-01A1] NR 19 TC 86 Z9 86 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2011 VL 89 IS 3 BP 392 EP 399 DI 10.1038/clpt.2010.317 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 722NS UT WOS:000287439600019 PM 21270788 ER PT J AU von Kanel, R Carney, RM Zhao, SJ Whooley, MA AF von Kaenel, Roland Carney, Robert M. Zhao, Shoujun Whooley, Mary A. TI Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: findings from the Heart and Soul Study SO CLINICAL RESEARCH IN CARDIOLOGY LA English DT Article DE Autonomic nervous system; Biomarkers; Cardiac autonomic function; Cardiovascular disease; Heart rate variability; Inflammation ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION; ARTERY-DISEASE; CARDIOVASCULAR-DISEASES; AUTONOMIC FUNCTION; PROGNOSTIC VALUE; ANGINA-PECTORIS; UNSTABLE ANGINA; INTERLEUKIN-6; MARKERS AB Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD). We studied the relationship between HRV and CRP, IL-6, and fibrinogen in 862 outpatients with CHD. All participants provided fasting blood samples and underwent 24-h ambulatory monitoring to assess time-domain measures of HRV (MeanNN, SDNN, SDANN, and RMSSD). Regression analyses were adjusted for age, sex, ethnicity, body mass index, smoking, diabetes, beta blocker use, and cardiopulmonary history. MeanNN, SDNN, and SDANN were significantly and inversely associated with CRP and IL-6 levels in age-adjusted models and after adjustment for all covariates (p a parts per thousand currency sign 0.02). MeanNN, SDNN, and SDANN were also inversely associated with fibrinogen levels in age-adjusted models (p < 0.03), but not significantly so in multivariable-adjusted models. Reduced vagal modulation of heart rate (RMSSD) was not significantly associated with any inflammatory measures. Reduced cardiac autonomic control is associated with increased systemic inflammation in patients with stable CHD. This relationship was largely independent of important covariates. C1 [von Kaenel, Roland] Univ Bern, Dept Gen Internal Med, Div Psychosomat Med, Inselspital,Bern Univ Hosp, CH-3010 Bern, Switzerland. [Carney, Robert M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Zhao, Shoujun] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Whooley, Mary A.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP von Kanel, R (reprint author), Univ Bern, Dept Gen Internal Med, Div Psychosomat Med, Inselspital,Bern Univ Hosp, CH-3010 Bern, Switzerland. EM roland.vonkaenel@insel.ch FU Department of Veterans Affairs, Washington, DC; Robert Wood Johnson Foundation, Princeton, New Jersey; American Federation for Aging Research, New York, NY; Ischemia Research and Education Foundation, San Bruno, CA FX The Heart and Soul Study was supported by grants from the Department of Veterans Affairs (Epidemiology Merit Review Program), Washington, DC; The Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), Princeton, New Jersey; the American Federation for Aging Research Paul Beeson Faculty Scholars in Aging Research Program), New York, NY; and the Ischemia Research and Education Foundation, San Bruno, CA. NR 45 TC 23 Z9 23 U1 2 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-0684 EI 1861-0692 J9 CLIN RES CARDIOL JI Clin. Res. Cardiol. PD MAR PY 2011 VL 100 IS 3 BP 241 EP 247 DI 10.1007/s00392-010-0236-5 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 723KQ UT WOS:000287505800008 PM 20857123 ER PT J AU Trinh, NHT Shyu, I McGrath, PJ Clain, A Baer, L Fava, M Yeung, A AF Trinh, Nhi-Ha T. Shyu, Irene McGrath, Patrick J. Clain, Alisabet Baer, Lee Fava, Maurizio Yeung, Albert TI Examining the role of race and ethnicity in relapse rates of major depressive disorder SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID MINORITY PATIENTS; PRIMARY-CARE; ANXIETY DISORDERS; AFRICAN-AMERICAN; ASIAN-AMERICANS; UNITED-STATES; BELIEFS; STIGMA; DRUG AB Objective: We test the hypothesis that racial or ethnic differences exist in relapse rates to fluoxetine discontinuation in major depressive disorder (MDD). Method: Data are from a prospective study examining the relapse rates secondary to fluoxetine discontinuation in MDD. Subjects in the discontinuation phase consisted of 255 adults aged 18 to 65: 214 subjects who self-identified as white, 22 as African American, 13 as Latino American, and 6 as Asian American. Results: In both the fluoxetine and placebo groups, no statistically significant differences emerged when comparing time to relapse for minority groups as compared to the white population. Adjusting for statistically significant predictors of relapse (symptom severity, neurovegetative symptom pattern, sex) and for educational level did not change the outcome of the survival analyses. Conclusions: Although the size of minority groups in this sample was modest, in a randomized, controlled trial setting, minority and white patients may have similar rates of relapse in MDD. This finding reinforces the importance of maintenance treatment in relapse for both minority as well as white patients with MDD. Given the self-selecting nature of clinical trials, future studies are needed to further examine the potential influence of underlying cultural factors on clinical outcomes in minority populations. (C) 2011 Elsevier Inc. All rights reserved. C1 [Trinh, Nhi-Ha T.; Shyu, Irene; Clain, Alisabet; Baer, Lee; Fava, Maurizio; Yeung, Albert] Massachusetts Gen Hosp, Depress & Clin Res Program, Boston, MA 02114 USA. [McGrath, Patrick J.] New York State Psychiat Inst & Hosp, Dept Psychiat, Depress Evaluat Serv, New York, NY 10032 USA. RP Trinh, NHT (reprint author), Massachusetts Gen Hosp, Depress & Clin Res Program, Boston, MA 02114 USA. EM ntrinh@partners.org FU NIMH NIH HHS [R10 MH056057, R10 MH056057-05] NR 27 TC 2 Z9 2 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAR-APR PY 2011 VL 52 IS 2 BP 151 EP 155 DI 10.1016/j.comppsych.2010.05.004 PG 5 WC Psychiatry SC Psychiatry GA 725MB UT WOS:000287647700006 PM 21295221 ER PT J AU Potts, BC Albitar, MX Anderson, KC Baritaki, S Berkers, C Bonavida, B Chandra, J Chauhan, D Cusack, JC Fenical, W Ghobrial, IM Groll, M Jensen, PR Lam, KS Lloyd, GK McBride, W McConkey, DJ Miller, CP Neuteboom, STC Oki, Y Ovaa, H Pajonk, F Richardson, PG Roccaro, AM Sloss, CM Spear, MA Valashi, E Younes, A Palladino, MA AF Potts, B. C. Albitar, M. X. Anderson, K. C. Baritaki, S. Berkers, C. Bonavida, B. Chandra, J. Chauhan, D. Cusack, J. C., Jr. Fenical, W. Ghobrial, I. M. Groll, M. Jensen, P. R. Lam, K. S. Lloyd, G. K. McBride, W. McConkey, D. J. Miller, C. P. Neuteboom, S. T. C. Oki, Y. Ovaa, H. Pajonk, F. Richardson, P. G. Roccaro, A. M. Sloss, C. M. Spear, M. A. Valashi, E. Younes, A. Palladino, M. A. TI Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials SO CURRENT CANCER DRUG TARGETS LA English DT Review DE Proteasome inhibitor; marizomib; bortezomib; NF-kappa B; multiple myeloma; pharmacodynamics; combination therapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; PANCREATIC-CANCER CELLS; ADVANCED SOLID TUMORS; ACTINOMYCETE SALINISPORA-TROPICA; SALINOSPORAMIDE-A NPI-0052; MULTIPLE-MYELOMA CELLS; GROWTH-FACTOR RECEPTOR; NON-HODGKINS-LYMPHOMA; ACID-BASED PROTEASOME AB The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade (R)) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique beta-lactone-gamma-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid (R)), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside. C1 [Potts, B. C.; Lam, K. S.; Lloyd, G. K.; Neuteboom, S. T. C.; Spear, M. A.; Palladino, M. A.] Nereus Pharmaceut Inc, San Diego, CA 92121 USA. [Albitar, M. X.] Quest Diagnost Inc, Dept Hematopathol, San Juan Capistrano, CA 92675 USA. [Anderson, K. C.; Chauhan, D.; Ghobrial, I. M.; Richardson, P. G.; Roccaro, A. M.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Anderson, K. C.; Chauhan, D.; Ghobrial, I. M.; Richardson, P. G.; Roccaro, A. M.] Harvard Univ, Sch Med, Jerome Lipper Myeloma Ctr, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Baritaki, S.; Bonavida, B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Berkers, C.; Ovaa, H.] Netherlands Canc Inst, Div Cell Biol, Amsterdam, Netherlands. [Chandra, J.; Miller, C. P.] Univ Texas Houston, Childrens Canc Hosp MD Anderson, Dept Pediat Res, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Cusack, J. C., Jr.; Sloss, C. M.] Harvard Univ, Massachusetts Gen Hosp, Div Surg Oncol, Sch Med, Boston, MA 02114 USA. [Fenical, W.; Jensen, P. R.] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, San Diego, CA 92093 USA. [Groll, M.] Tech Univ Munich, Ctr Integrated Prot Sci, Dept Chem, Lehrstuhl Biochem, D-85747 Garching, Germany. [McBride, W.; Pajonk, F.; Valashi, E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA. [McConkey, D. J.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Oki, Y.; Younes, A.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. RP Potts, BC (reprint author), Nereus Pharmaceut Inc, 10480 Wateridge Circle, San Diego, CA 92121 USA. EM bpotts@nereuspharm.com; mpalladino@nereuspharm.com RI Pajonk, Frank/E-4247-2010; Groll, Michael/F-5572-2015; Berkers, Celia/I-3848-2016 FU NIH [SPORE-P50100707, PO1-CA078378, NIH RO1CA050947, NIH R01CA98871, F31 CA123645, NIH R01CA115811, NCI R37CA044848] FX We gratefully acknowledge the contributions of the many individuals whose research findings are captured in this review and whose efforts have contributed to the extensive body of knowledge on marizomib. We thank SR Potts for contributing Fig. (1). This work was supported by NIH grants SPORE-P50100707, PO1-CA078378, and NIH RO1CA050947 to DC and KCA; NIH R01CA98871 to JCC; F31 CA123645 to CPM; NIH R01CA115811 to JC; and NCI R37CA044848 to WF. NR 208 TC 94 Z9 94 U1 8 U2 21 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 EI 1873-5576 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD MAR PY 2011 VL 11 IS 3 BP 254 EP 284 PG 31 WC Oncology SC Oncology GA 743BF UT WOS:000288989700003 PM 21247382 ER PT J AU Singh, JA Reddy, SG Kundukulam, J AF Singh, Jasvinder A. Reddy, Supriya G. Kundukulam, Joseph TI Risk factors for gout and prevention: a systematic review of the literature SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE alcohol; chronic diseases; diet; gout; gouty arthritis; medications; risk factors; systematic review ID URIC-ACID LEVEL; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; INCIDENT GOUT; FOLLOW-UP; TAIWAN ABORIGINES; PROSPECTIVE COHORT; HIGH PREVALENCE; RENAL-FAILURE; DIURETIC USE AB Purpose of review Our objective was to perform a systematic review of risk factors and prevention of gout. We searched Medline for fully published reports in English using keywords including but not limited to 'gout', 'epidemiology', 'primary prevention', 'secondary prevention', 'risk factors'. Data from relevant articles meeting inclusion criteria were extracted using standardized forms. Recent findings Of the 751 titles and abstracts, 53 studies met the criteria and were included in the review. Several risk factors were studied. Alcohol consumption increased the risk of incident gout, especially beer and hard liquor. Several dietary factors increased the risk of incident gout, including meat intake, seafood intake, sugar sweetened soft drinks, and consumption of foods high in fructose. Diary intake, folate intake, and coffee consumption were each associated with a lower risk of incident gout and in some cases a lower rate of gout flares. Thiazide and loop diuretics were associated with higher risk of incident gout and higher rate of gout flares. Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity, and early menopause were each associated with a higher risk of incident gout and/or gout flares. Summary Several dietary risk factors for incident gout and gout flares are modifiable. Prevention and optimal management of comorbidities are likely to decreased risk of gout. Research in preventive strategies for the treatment of gout is needed. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA. [Singh, Jasvinder A.; Reddy, Supriya G.; Kundukulam, Joseph] Univ Alabama, Dept Med, Sch Publ Hlth, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama, Div Epidemiol, Sch Publ Hlth, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Sch Med, Dept Orthoped Surg, Rochester, MN USA. [Reddy, Supriya G.] Univ Alabama, Dept Hlth Sci, Tuscaloosa, AL USA. RP Singh, JA (reprint author), Univ Alabama, Dept Med, Sch Publ Hlth, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com OI singh, jasvinder/0000-0003-3485-0006 FU Allergan; Takeda; Savient; Wyeth; Amgen; URL pharmaceuticals; Novartis; Birmingham VA Medical Center, Alabama, USA FX We thank Louise Falzon, of the Cochrane Library, for performing and updating the search for this systematic review and April DeMedicis, of the Birmingham VA Medical Center, for reviewing titles and abstracts prior to conducting the full text review as well as assisting with the data abstraction process. This material is the result of work supported with the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA.; There are no financial conflicts related to this work. J.A.S. has received speaker honoraria from Abbott; research and travel grants from Allergan, Takeda, Savient, Wyeth and Amgen; and consultant fees from Savient, URL pharmaceuticals and Novartis. NR 73 TC 43 Z9 60 U1 4 U2 56 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD MAR PY 2011 VL 23 IS 2 BP 192 EP 202 DI 10.1097/BOR.0b013e3283438e13 PG 11 WC Rheumatology SC Rheumatology GA 715JB UT WOS:000286879200013 PM 21285714 ER PT J AU LoCascio, SA Spinelli, J Kurtz, J AF LoCascio, Samuel A. Spinelli, Joia Kurtz, Josef TI Hematopoietic Stem Cell Transplantation for the Treatment of Autoimmunity in Type 1 Diabetes SO CURRENT STEM CELL RESEARCH & THERAPY LA English DT Review DE Diabetes; tolerance; chimerism; allogeneic; hematopoietic ID BONE-MARROW-TRANSPLANTATION; REGULATORY T-CELLS; IMMUNOLOGICAL SELF-TOLERANCE; NOD MICE; COSTIMULATORY BLOCKADE; HYGIENE HYPOTHESIS; MIXED CHIMERISM; APOPTOSIS RESISTANCE; SUSCEPTIBILITY GENES; ANTI-CD154 ANTIBODY AB Type 1 diabetes (T1D) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic beta cells. While there is no current cure, recent work in the field of allogeneic hematopoietic stem cell transplantation (HSCT) and the induction of mixed chimerism, a state in which multilineage hematopoietic populations of both recipient and donor co-exist, has demonstrated that it is possible to provide protection from disease onset, as well as reverse the autoimmune state in spontaneously diabetic mice. Furthermore, the establishment of mixed chimerism induces donor-specific tolerance, providing the potential to normalize glucose regulation via pancreatic islet transplantation without the requirement of life-long immunosuppression. Current studies are aimed at understanding the mechanisms involved in both the reversal of autoimmunity and the induction of tolerance, with the aim of moving this promising approach to curing T1D into the clinic. C1 [LoCascio, Samuel A.; Spinelli, Joia; Kurtz, Josef] Univ Cambridge Emmanuel Coll, Boston, MA 02115 USA. [LoCascio, Samuel A.; Kurtz, Josef] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. RP Kurtz, J (reprint author), Univ Cambridge Emmanuel Coll, 400 Fenway, Boston, MA 02115 USA. EM kurtzj@emmanuel.edu NR 76 TC 9 Z9 9 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-888X J9 CURR STEM CELL RES T JI Curr. Stem Cell Res. Ther. PD MAR PY 2011 VL 6 IS 1 BP 29 EP 37 PG 9 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 910LN UT WOS:000301638700005 PM 20955158 ER PT J AU Shivakumar, G Brandon, AR Snell, PG Santiago-Munoz, P Johnson, NL Trivedi, MH Freeman, MP AF Shivakumar, Geetha Brandon, Anna R. Snell, Peter G. Santiago-Munoz, Patricia Johnson, Neysa L. Trivedi, Madhukar H. Freeman, Marlene P. TI ANTENATAL DEPRESSION: A RATIONALE FOR STUDYING EXERCISE SO DEPRESSION AND ANXIETY LA English DT Review DE exercise; physical activity; pregnancy; postpartum; mood; depression; gestational diabetes; preeclampsia ID GESTATIONAL DIABETES-MELLITUS; TIME PHYSICAL-ACTIVITY; ADULT-NEUROGENESIS; PREGNANT-WOMEN; ANTIDEPRESSANT TREATMENT; POSTPARTUM DEPRESSION; PERINATAL DEPRESSION; AMERICAN-COLLEGE; AEROBIC EXERCISE; CONTROLLED-TRIAL AB Background: Major depressive disorder (MDD) in pregnancy or antenatal depression poses unique treatment challenges and has serious consequences for mothers, unborn babies, and families when untreated. This review presents current knowledge on exercise during pregnancy, antidepressant effects of exercise, and the rationale for the specific study of exercise for antenatal depression. Method: A systematic literature review was performed using English language articles published in Medline, PsycINFO, CINAHL, and the Cochrane Library from 1985 to January 2010. Results: There is a broad literature supporting the antidepressant effects of exercise, but a paucity of studies specifically for antenatal depression. A small number of observational studies have reported that regular physical activities improve self-esteem and reduce symptoms of anxiety and depression during pregnancy. To date, there have not been randomized controlled studies of exercise for the treatment of MDD in pregnant women. Conclusions: Systematic studies are needed to assess exercise as a treatment alternative for MDD during pregnancy. In consideration of the benefits of exercise for the mother and baby, and the burden of depression, studies are needed to determine the role of exercise for pregnant women with depression. Depression and Anxiety 28:234-242, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Shivakumar, Geetha] Dallas VA Med Ctr, Mental Hlth Trauma Serv, Dallas, TX 75216 USA. [Shivakumar, Geetha; Brandon, Anna R.; Johnson, Neysa L.; Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Snell, Peter G.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX 75390 USA. [Santiago-Munoz, Patricia; Johnson, Neysa L.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Freeman, Marlene P.] Massachusetts Gen Hosp, Ctr Womens Mental Hlth, Perinatal & Reprod Psychiat Program, Boston, MA 02114 USA. RP Shivakumar, G (reprint author), Dallas VA Med Ctr, Mental Hlth Trauma Serv, 4500 S Lancaster Rd,Mail Code 116A, Dallas, TX 75216 USA. EM Geetha.Shivakumar@va.gov FU NIH [1 UL1 RR024982-01]; NIMH [1K23MH085007-02, 5R01MH067692-04]; Glaxo Smith Kline; Eli Lilly; Forest FX The authors disclose the following financial relationships within the past 3 years: Contract grant sponsor: NIH; Contract grant number: 1 UL1 RR024982-01; Contract grant sponsor: NIMH; Contract grant numbers: 1K23MH085007-02; 5R01MH067692-04.; Dr. Geetha Shivakumar acknowledges 12 months support from NIH (1 UL1 RR024982-01). Dr. Anna Brandon reports current support from the NIMH (1K23MH085007-02) and the NIH (1 UL1 RR024982-01). Drs. Peter Snell, Patricia Santiago-Munoz, and Neysa Johnson have no disclosures to report. Dr. Marlene Freeman acknowledges support in last 12 months from Glaxo Smith Kline, Eli Lilly, Forest; Honorarium for CME content: Pam Lab. Dr. Madhukar Trivedi acknowledges NIMH 5R01MH067692-04 for his work on this manuscript. NR 72 TC 18 Z9 19 U1 2 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2011 VL 28 IS 3 BP 234 EP 242 DI 10.1002/da.20777 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 734JZ UT WOS:000288331700008 PM 21394856 ER PT J AU Killgore, WDS Britton, JC Price, LM Gold, AL Deckersbach, T Rauch, SL AF Killgore, William D. S. Britton, Jennifer C. Price, Lauren M. Gold, Andrea L. Deckersbach, Thilo Rauch, Scott L. TI NEURAL CORRELATES OF ANXIETY SENSITIVITY DURING MASKED PRESENTATION OF AFFECTIVE FACES SO DEPRESSION AND ANXIETY LA English DT Article DE FMRI; neuroimaging; anxiety sensitivity; ASI; insula; specific phobia; healthy controls ID PANIC DISORDER; BRAIN ACTIVATION; PHYSIOLOGICAL CONDITION; HIERARCHICAL STRUCTURE; INSULAR CORTEX; CO2 CHALLENGE; AMYGDALA; PHOBIA; INTEROCEPTION; INDEX AB Background: Anxiety Sensitivity (AS), the tendency to fear the thoughts, symptoms, and social consequences associated with the experience of anxiety, is associated with increased risk for developing anxiety disorders. Some evidence suggests that higher scores on the Anxiety Sensitivity Index (ASI), a measure of the AS construct, are associated with activation of the anterior insular cortex during overt emotion perception. Although the ASI provides subscale scores measuring Physical, Mental Incapacitation, and Social Concerns of AS, no study has examined the relationship between these factors and regional brain activation during affect processing. We hypothesized that insular responses to fear-related stimuli would be primarily related to the Physical Concerns subscale of the ASI, particularly for a sample of subjects with specific phobias. Methods: Adult healthy controls (HC; n = 22) and individuals with specific phobia, small animal subtype (SAP; n = 17), completed the ASI and underwent functional magnetic resonance imaging while engaged in a backward-masked affect perception task that presents emotional facial stimuli below the threshold of conscious perception. Results: Groups did not differ in ASI, state or trait anxiety scores, or insula activation. Total ASI scores were positively correlated with activation in the right middle/anterior insula for the combined sample and for the HC and SAP groups separately. Multiple regression analysis revealed that the relationship between AS and insular activation was primarily accounted for by Physical Concerns only. Conclusions: Findings support the hypothesized role of the right anterior insula in the visceral/interoceptive aspects of AS, even in response to masked affective stimuli. Depression and Anxiety 28:243-249, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Killgore, William D. S.] Harvard Univ, McLean Hosp, Sch Med, Affect Neurosci Lab,Neuroimaging Ctr, Belmont, MA 02478 USA. [Britton, Jennifer C.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Deckersbach, Thilo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. [Deckersbach, Thilo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Belmont, MA 02478 USA. [Gold, Andrea L.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Killgore, WDS (reprint author), Harvard Univ, McLean Hosp, Sch Med, Affect Neurosci Lab,Neuroimaging Ctr, 115 Mill St, Belmont, MA 02478 USA. EM killgore@mclean.harvard.edu RI Britton, Jennifer/J-4501-2013; OI Gold, Andrea/0000-0003-4447-776X; Killgore, William/0000-0002-5328-0208 FU NIMH [R01 MH070730-04]; National Institute of Health FX The authors disclose the following financial relationships within the past 3 years: Contract grant sponsor: NIMH; Contract grant number: R01 MH070730-04; Contract grant sponsor: National Institute of Health. NR 41 TC 15 Z9 15 U1 6 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2011 VL 28 IS 3 BP 243 EP 249 DI 10.1002/da.20788 PG 7 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 734JZ UT WOS:000288331700009 PM 21308886 ER PT J AU Nostro, MC Sarangi, F Ogawa, S Holtzinger, A Corneo, B Li, XL Micallef, SJ Park, IH Basford, C Wheeler, MB Daley, GQ Elefanty, AG Stanley, EG Keller, G AF Nostro, M. Cristina Sarangi, Farida Ogawa, Shinichiro Holtzinger, Audrey Corneo, Barbara Li, Xueling Micallef, Suzanne J. Park, In-Hyun Basford, Christina Wheeler, Michael B. Daley, George Q. Elefanty, Andrew G. Stanley, Edouard G. Keller, Gordon TI Stage-specific signaling through TGF beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells SO DEVELOPMENT LA English DT Article DE Endoderm differentiation; Human embryonic stem cells; Human induced pluripotent stem cells; beta-Cell; Pancreas ID NODAL-RELATED SIGNALS; ISLET-LIKE CLUSTERS; DIRECTED DIFFERENTIATION; DEFINITIVE ENDODERM; PRIMITIVE STREAK; IN-VIVO; MOUSE; INSULIN; GASTRULATION; GENERATION AB The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGF beta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+cells. C1 [Nostro, M. Cristina; Sarangi, Farida; Ogawa, Shinichiro; Holtzinger, Audrey; Keller, Gordon] Univ Hlth Network, McEwen Ctr Regenerat Med, Toronto, ON M5G 1L7, Canada. [Corneo, Barbara] New York Neural Stem Cell Inst, Rensselaer, NY 12144 USA. [Li, Xueling; Micallef, Suzanne J.; Elefanty, Andrew G.; Stanley, Edouard G.] Monash Univ, Monash Immunol & Stem Cell Labs, Clayton, Vic 3800, Australia. [Park, In-Hyun] Yale Univ, Sch Med, Dept Genet, Yale Stem Cell Ctr, New Haven, CT 06520 USA. [Basford, Christina; Wheeler, Michael B.] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada. [Daley, George Q.] Childrens Hosp, Cell Transplantat Program, Div Pediat Hematol Oncol, Manton Ctr Orphan Dis Res,Howard Hughes Med Inst, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Keller, G (reprint author), Univ Hlth Network, McEwen Ctr Regenerat Med, Toronto, ON M5G 1L7, Canada. EM gkeller@uhnresearch.ca RI Stanley, Ed/A-2985-2013; Elefanty, Andrew/A-6066-2008; OI Stanley, Ed/0000-0002-6389-3665; Wheeler, Michael/0000-0002-7480-7267 FU NIH/NIDDK [U01-DK072513]; JDRF; ASCC; NHMRC (Australia) FX We would like to thank members of the Keller laboratory, Dr Nadeem Moghal and Dr Benjamin Neel for comments on the manuscript. This work was supported by a grant from NIH/NIDDK (U01-DK072513) to G.K. M.C.N. was supported by a JDRF postdoctoral fellowship. A.G.E., E.G.S., X.L. and S.J.M. are supported by grants from the JDRF, the ASCC and the NHMRC (Australia). A.G.E. and E.G.S. are Senior Research Fellows of the NHMRC. Deposited in PMC for release after 12 months. NR 63 TC 170 Z9 172 U1 2 U2 28 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 1 PY 2011 VL 138 IS 5 BP 861 EP 871 DI 10.1242/dev.055236 PG 11 WC Developmental Biology SC Developmental Biology GA 724KX UT WOS:000287576100007 PM 21270052 ER PT J AU Bacci, S Rizza, S Prudente, S Spoto, B Powers, C Facciorusso, A Pacilli, A Lauro, D Testa, A Zhang, YY Di Stolfo, G Mallamaci, F Tripepi, G Xu, R Mangiacotti, D Aucella, F Lauro, R Gervino, EV Hauser, TH Copetti, M De Cosmo, S Pellegrini, F Zoccali, C Federici, M Doria, A Trischitta, V AF Bacci, Simonetta Rizza, Stefano Prudente, Sabrina Spoto, Belinda Powers, Christine Facciorusso, Antonio Pacilli, Antonio Lauro, Davide Testa, Alessandra Zhang, Yuan-Yuan Di Stolfo, Giuseppe Mallamaci, Francesca Tripepi, Giovanni Xu, Rui Mangiacotti, Davide Aucella, Filippo Lauro, Renato Gervino, Ernest V. Hauser, Thomas H. Copetti, Massimiliano De Cosmo, Salvatore Pellegrini, Fabio Zoccali, Carmine Federici, Massimo Doria, Alessandro Trischitta, Vincenzo TI The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals Evidence for Interaction With Obesity in Diabetic Patients SO DIABETES LA English DT Article ID CORONARY-ARTERY-DISEASE; BODY-MASS INDEX; INSULIN-RESISTANCE; K121Q POLYMORPHISM; MYOCARDIAL-INFARCTION; METABOLIC SYNDROME; REVERSE EPIDEMIOLOGY; HEART-DISEASE; ASSOCIATION; GENE AB OBJECTIVE-Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS-A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata. Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS-Incidence of cardiovascular events per 100 person-years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS-The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding. Diabetes 60:1000-1007, 2011 C1 [Mangiacotti, Davide; Trischitta, Vincenzo] IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. [Bacci, Simonetta; Pacilli, Antonio; De Cosmo, Salvatore] IRCCS Casa Sollievo Sofferenza, Unit Endocrinol, San Giovanni Rotondo, Italy. [Rizza, Stefano; Lauro, Davide; Lauro, Renato; Federici, Massimo] Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy. [Prudente, Sabrina] IRCCS Casa Sollievo Sofferenza, Mendel Lab, San Giovanni Rotondo, Italy. [Spoto, Belinda; Testa, Alessandra; Mallamaci, Francesca; Tripepi, Giovanni; Zoccali, Carmine] CNR IBIM, Res Unit Clin Epidemiol & Physiopathol Renal Dis, Reggio Di Calabria, Italy. [Powers, Christine; Zhang, Yuan-Yuan; Xu, Rui; Doria, Alessandro] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Facciorusso, Antonio; Di Stolfo, Giuseppe] IRCCS Casa Sollievo Sofferenza, Unit Cardiol, San Giovanni Rotondo, Italy. [Zhang, Yuan-Yuan; Xu, Rui; Gervino, Ernest V.; Hauser, Thomas H.; Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Aucella, Filippo] IRCCS Casa Sollievo Sofferenza, Unit Nepluol & Dialysis, San Giovanni Rotondo, Italy. [Gervino, Ernest V.; Hauser, Thomas H.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Copetti, Massimiliano; Pellegrini, Fabio] IRCCS Casa Sollievo Sofferenza, Unit Biostat, San Giovanni Rotondo, Italy. [Pellegrini, Fabio] Consorzio Mario Negri Sud, Dept Clin Pharmacol & Epidemiol, Chieti, Italy. [Trischitta, Vincenzo] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. RP Trischitta, V (reprint author), IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. EM v.trischitta@operapadrepio.it RI Federici, Massimo/G-9940-2012; Prudente, Sabrina/H-2886-2016; De Cosmo, Salvatore/J-7420-2016; Trischitta, Vincenzo/K-1487-2016; Copetti, Massimiliano/K-3186-2016; OI Federici, Massimo/0000-0003-4989-5194; Prudente, Sabrina/0000-0001-9220-8981; Zoccali, Carmine/0000-0002-6616-1996; De Cosmo, Salvatore/0000-0001-8787-8286; Trischitta, Vincenzo/0000-0003-1174-127X; Copetti, Massimiliano/0000-0002-7960-5947; TESTA, ALESSANDRA/0000-0002-0529-6571; Lauro, Davide/0000-0002-8597-4415 FU Italian Ministry of Health; Fondazione Roma; National Institutes of Health [HL73168, DK36836] FX This study was partly supported by the Italian Ministry of Health ("Ricerca Corrente 2009 and 2010") (to S.P. and V.T.), by Fondazione Roma ("Sostegno alla ricerca scientifica biomedica 2008") (to V.T.), and by the National Institutes of Health Grants HL73168 (to A.D.) and DK36836 to the Genetics Core of the Diabetes & Endocrinology Research Center at the Joslin Diabetes Center. NR 54 TC 19 Z9 20 U1 2 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2011 VL 60 IS 3 BP 1000 EP 1007 DI 10.2337/db10-1300 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 730UM UT WOS:000288060300035 PM 21282363 ER PT J AU Goebel-Fabbri, AE Anderson, BJ Fikkan, J Franko, DL Pearson, K Weinger, K AF Goebel-Fabbri, Ann E. Anderson, Barbara J. Fikkan, Janna Franko, Debra L. Pearson, Kimberly Weinger, Katie TI Improvement and Emergence of Insulin Restriction in Women With Type 1 Diabetes SO DIABETES CARE LA English DT Article ID CLINICAL EATING-DISORDERS; MICROVASCULAR COMPLICATIONS; MELLITUS; BEHAVIOR; INVENTORY; OMISSION; FEMALES; ADULTS; GIRLS; IDDM AB OBJECTIVE To determine the distinguishing characteristics of women who report stopping insulin restriction at 11 years of follow-up from those continuing to endorse insulin restriction as well as those characteristics differing in patients who continue to Use insulin appropriately from new insulin restrictors. RESEARCH DESIGN AND METHODS This is an 11-year follow-up study of 207 women with type 1 diabetes. Insulin restriction, diabetes self-care behaviors, diabetes-specific distress, and psychiatric and eating disorder symptoms were assessed using self-report surveys. RESULTS Of the original sample, 57% participated in the follow-up study. Mean age was 44 +/- 12 years, diabetes duration was 28 +/- 11 years, and A1C was 7.9 +/- 1.3%. At follow-up, 20 of 60 baseline insulin restrictors had stopped restriction. Women who stopped reported improved diabetes self-care and distress, fewer problems with diabetes self-management, and lower levels of psychologic distress and eating disorder symptoms. Logistic regression indicated that lower levels of fear of weight gain with improved blood glucose and fewer problems with diabetes self-management predicted stopping restriction. At follow-up, 34 women (23%) reported new restriction, and a larger proportion of new insulin restrictors, relative to nonrestrictors, endorsed fear of weight gain with improved blood glucose. CONCLUSIONS Findings indicate that fear of weight gain associated with improved blood glucose and problems with diabetes self-care are core issues related to both the emergence and resolution of insulin restriction. Greater attention to these concerns may help treatment teams to better meet the unique treatment needs of women struggling with insulin restriction. Diabetes Care 34:545-550, 2011 C1 [Goebel-Fabbri, Ann E.; Weinger, Katie] Joslin Diabet Ctr, Boston, MA 02215 USA. [Goebel-Fabbri, Ann E.; Pearson, Kimberly; Weinger, Katie] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Anderson, Barbara J.] Texas Childrens Hosp, Dept Pediat, Houston, TX 77030 USA. [Fikkan, Janna] Duke Univ, Med Ctr, Durham, NC USA. [Franko, Debra L.] Northeastern Univ, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. [Pearson, Kimberly] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Weinger, K (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM katie.weinger@joslin.harvard.edu FU Center of Excellence in Women's Health; Harvard Medical School; National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-060115, P30-DK-36836]; National Institutes of Health; Herbert Graetz Fund FX This project was funded by a grant from the Center of Excellence in Women's Health, Harvard Medical School and the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-060115 and P30-DK-36836). The original work was supported by grants from the National Institutes of Health-supported Diabetes and Endocrinology Research Center at Joslin Diabetes Center and the Herbert Graetz Fund. NR 19 TC 8 Z9 8 U1 4 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 545 EP 550 DI 10.2337/dc10-1547 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400003 PM 21266653 ER PT J AU Markowitz, SM Park, ER Delahanty, LM O'Brien, KE Grant, RW AF Markowitz, Sarah M. Park, Elyse R. Delahanty, Linda M. O'Brien, Kelsey E. Grant, Richard W. TI Perceived Impact of Diabetes Genetic Risk Testing Among Patients at High Phenotypic Risk for Type 2 Diabetes SO DIABETES CARE LA English DT Article ID INTERVENTIONS; METAANALYSIS; PERCEPTIONS; PREDICTION; VARIANTS; MELLITUS; OUTCOMES AB OBJECTIVE-Rapid advances in diabetes genetic epidemiology may lead to a new era of "personalized medicine" based on individual genetic risk assessment. There is minimal experience to guide how best to clinically implement such testing so that results (e.g., "higher" or "lower" relative genetic risk) improve rather than reduce patient motivation for behavior change. RESEARCH DESIGN AND METHODS-Between November 2009 and May 2010, we conducted in-depth interviews with 22 overweight participants at high phenotypic risk for type 2 diabetes to explore perceptions of diabetes genetic risk testing compared with currently available prediction using nongenetic risk factors (e.g., family history, abnormal fasting glucose, obesity). We used hypothetical scenarios to specifically investigate the impact of both "higher" and "lower" relative genetic risk results on participants' views about diabetes prevention. RESULTS-Many participants conferred a unique value on personal genetic risk information relative to nongenetic risk based on the perceived scientific certainty and durability of genetic results. In contrast, other participants considered their genetic risk within the overall context of their other measured risk factors. Reactions to diabetes genetic test results differed by current motivation levels. Whereas most subjects reported that "higher" risk results would motivate behavior change, subjects with lower current motivation often reported that "lower" genetic risk results would further reduce their motivation to engage in diabetes prevention behaviors. CONCLUSIONS-To be effective, future clinical implementation of type 2 diabetes genetic risk testing should be individualized based on each patient's risk perception and current level of motivation to prevent diabetes. C1 [Park, Elyse R.; Delahanty, Linda M.; O'Brien, Kelsey E.; Grant, Richard W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Markowitz, Sarah M.] Wells Coll, Aurora, NY USA. [Park, Elyse R.] Mongan Inst Hlth Policy, Boston, MA USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [O'Brien, Kelsey E.; Grant, Richard W.] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Grant, RW (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM rgrant@partners.org OI Grant, Richard/0000-0002-6164-8025 FU NIDDK NIH HHS [R21 DK084527-01, R21 DK084527] NR 24 TC 22 Z9 23 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 568 EP 573 DI 10.2337/dc10-1960 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400007 PM 21285385 ER PT J AU Fiallo-Scharer, R Cheng, J Beck, RW Buckingham, BA Chase, HP Kollman, C Laffel, L Lawrence, JM Mauras, N Tamborlane, WV Wilson, DM Wolpert, H Bode, B Ruedy, KJ Weinzimer, S Xing, DY AF Fiallo-Scharer, Rosanna Cheng, Jing Beck, Roy W. Buckingham, Bruce A. Chase, H. Peter Kollman, Craig Laffel, Lori Lawrence, Jean M. Mauras, Nelly Tamborlane, William V. Wilson, Darrell M. Wolpert, Howard Bode, Bruce Ruedy, Katrina J. Weinzimer, Stuart Xing, Dongyuan CA JDRF Continuous Glucose Monitoring TI Factors Predictive of Severe Hypoglycemia in Type 1 Diabetes Analysis from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized control trial dataset SO DIABETES CARE LA English DT Article ID BLOOD-GLUCOSE; CHILDREN; VALIDATION; ACCURACY; THERAPY; RISK AB OBJECTIVE-Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH. RESEARCH DESIGN AND METHODS-In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon. RESULTS-The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were <= 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (< 5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM. CONCLUSIONS-SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low. C1 [Cheng, Jing; Beck, Roy W.; Kollman, Craig; Ruedy, Katrina J.; Xing, Dongyuan] Jaeb Ctr Hlth Res, Tampa, FL USA. [Fiallo-Scharer, Rosanna; Chase, H. Peter] Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Buckingham, Bruce A.; Wilson, Darrell M.] Stanford Univ, Stanford, CA 94305 USA. [Laffel, Lori; Wolpert, Howard] Joslin Diabet Ctr, Boston, MA 02215 USA. [Lawrence, Jean M.] Kaiser Permanente, San Diego, CA USA. [Mauras, Nelly] Nemours Childrens Clin, Jacksonville, FL USA. [Tamborlane, William V.; Weinzimer, Stuart] Yale Univ, New Haven, CT USA. [Bode, Bruce] Atlanta Diabet Associates, Atlanta, GA USA. RP Beck, RW (reprint author), Jaeb Ctr Hlth Res, Tampa, FL USA. EM jdrfapp@jaeb.org FU JDRF [22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, 01-2006-8031]; Medtronic MiniMed, Inc.; DexCom, Inc.; Abbott Diabetes Care, Inc. FX The study funding was provided by JDRF (grant numbers 22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, and 01-2006-8031).; B.B. reports having received consulting fees, honoraria, travel reimbursement, and research funds from Medtronic MiniMed, Inc. and grant support from DexCom, Inc. B.A.B. reports having received grant support and serving on the Medical Advisory Board for Medtronic MiniMed, Inc., grant support and a speaker honorarium from Abbott Diabetes Care, Inc., and grant support from DexCom, Inc. C.K. reports having received consulting fees from Medtronic MiniMed, Inc. L.L. reports having received consulting fees and a speaker honorarium from Abbott Diabetes Care, Inc., and consulting fees and research funding from Medtronic MiniMed, Inc. W.V.T. reports having received consulting fees from Medtronic MiniMed, Inc. S.W. reports having received research support, a speaker honorarium and travel reimbursement from Medtronic MiniMed, Inc., and a speaker honorarium from Animas Corp/LifeScan, Inc. No other potential conflicts of interest relevant to this article were reported. NR 20 TC 22 Z9 22 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 586 EP 590 DI 10.2337/dc10-1111 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400010 ER PT J AU Cheng, PY Neugaard, B Foulis, P Conlin, PR AF Cheng, Peiyao Neugaard, Britta Foulis, Philip Conlin, Paul R. TI Hemoglobin A(1c) as a Predictor of Incident Diabetes SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR-DISEASE; US POPULATION; RISK; A1C; PREVALENCE; HBA(1C); ADULTS; ASSOCIATION; DIAGNOSIS; VETERANS AB OBJECTIVE-Several studies have suggested that HbA(1c) levels may predict incident diabetes. With new recommendations for use of HbA(1c) in diagnosing diabetes, many patients with HbA(1c) results below the diagnostic threshold will be identified. Clinicians will need to categorize risk for a subsequent diabetic diagnosis in such patients. The objective of this study was to determine the ability of HbA(1c) to predict the incidence of a diabetic diagnosis. RESEARCH DESIGN AND METHODS-We performed a historical cohort study using electronic medical record data from two Department of Veterans Affairs Medical Centers. Patients (n = 12,589) were identified with a baseline HbA(1c) < 6.5% between January 2000 and December 2001 and without a diagnosis of diabetes. Patients (12,375) had at least one subsequent follow-up visit. These patients were tracked for 8 years for a subsequent diagnosis of diabetes. RESULTS-During an average follow-up of 4.4 years, 3,329 (26.9%) developed diabetes. HbA(1c) >= 5.0% carried a significant risk for developing diabetes during follow-up. When compared with the reference group (HbA(1c) < 4.5%), HbA(1c) increments of 0.5% between 5.0 and 6.4% had adjusted odds ratios of 1.70(5.0-5.4%), 4.87 (5.5-5.9%), and 16.06(6.0-6.4%) (P < 0.0001). Estimates of hazard ratios similarly showed significant increases for HbA(1c) >= 5.0% A risk model for incident diabetes within 5 years was developed and validated using HbA(1c), age, BMI, and systolic blood pressure. CONCLUSIONS-The incidence of diabetes progressively and significantly increased among patients with an HbA(1c) >= 5.0%, with substantially expanded risk for those with HbA(1c) 6.0-6.4%. C1 [Conlin, Paul R.] VA Boston Healthcare Syst, Boston, MA USA. [Cheng, Peiyao; Neugaard, Britta; Foulis, Philip] Dept Vet Affairs Med Ctr, Tampa, FL USA. [Neugaard, Britta] Univ S Florida, Coll Publ Hlth, Dept Epidemiol & Biostat, Tampa, FL USA. [Neugaard, Britta; Foulis, Philip] Univ S Florida, Coll Med, Dept Pathol & Cell Biol, Tampa, FL USA. [Conlin, Paul R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Conlin, PR (reprint author), VA Boston Healthcare Syst, Boston, MA USA. EM paul.conlin@va.gov FU VA Health Services Research and Development Service [TEL-02-100, IIR-04-045]; National Institutes of Health [K24-DK063214]; Tosoh Bioscience FX Funding for this work was provided by the VA Health Services Research and Development Service. (Grants TEL-02-100 and IIR-04-045), the National Institutes of Health (Grant K24-DK063214), and Tosoh Bioscience. NR 23 TC 19 Z9 19 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 610 EP 615 DI 10.2337/dc10-0625 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400017 PM 21289229 ER PT J AU Lautz, D Halperin, F Goebel-Fabbri, A Goldfine, AB AF Lautz, David Halperin, Florencia Goebel-Fabbri, Ann Goldfine, Allison B. TI The Great Debate: Medicine or Surgery What is best for the patient with type 2 diabetes? SO DIABETES CARE LA English DT Review ID GASTRIC-BYPASS-SURGERY; BARIATRIC SURGICAL-PROCEDURES; DUODENAL-JEJUNAL EXCLUSION; LIFE-STYLE INTERVENTION; BODY-MASS INDEX; WEIGHT-LOSS; HYPERINSULINEMIC HYPOGLYCEMIA; CARDIOVASCULAR OUTCOMES; LONGITUDINAL ASSESSMENT; GLYCEMIC CONTROL C1 [Lautz, David; Halperin, Florencia; Goldfine, Allison B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lautz, David] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Halperin, Florencia; Goebel-Fabbri, Ann; Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Halperin, Florencia; Goldfine, Allison B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Goebel-Fabbri, Ann] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Goldfine, AB (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM allison.goldfine@joslin.harvard.edu FU National Institutes of Health [1RC1-DK-086918, KL2-RR-025757]; DERC [P30-DK-36836]; Covidien; Nestle; LifeScan, a Division of Johnson Johnson; Mercodia; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by National Institutes of Health Grants 1RC1-DK-086918 and KL2-RR-025757 (to F.H.), and DERC P30-DK-36836.; Additional funds and supplies to support the trial are provided by Covidien; Nestle; LifeScan, a Division of Johnson & Johnson; and Mercodia. D.L. has worked occasionally as a consultant for Covidien, largely reviewing their instrumentation; this has always been less than $2000/year and has always been vetted by the Brigham and Women's Hospital Corporate Sponsored Research office. Neither D.L. nor A.B.G. has personal financial interest in Covidien. No other potential conflicts of interest relevant to this article were reported. The authors note they are conducting an investigator-initiated clinical trial sponsored by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (clinical trials identifier NCT01073020). NR 61 TC 16 Z9 16 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 763 EP 770 DI 10.2337/dc10-1859 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400048 PM 21357363 ER PT J AU Boyko, EJ Meigs, JB AF Boyko, Edward J. Meigs, James B. TI Does Diabetes Always Confer Coronary Heart Disease Risk Equivalent to a Prior Myocardial Infarction? Implications for prevention SO DIABETES CARE LA English DT Editorial Material ID BLOOD-GLUCOSE CONTROL; SCIENTIFIC STATEMENT; TYPE-2; COMPLICATIONS; ASPIRIN; INTERVENTION; METAANALYSIS; ASSOCIATION; INFORMATION; METFORMIN C1 [Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Boyko, Edward J.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Meigs, James B.] Harvard Univ, Sch Med, Div Gen Med, Boston, MA USA. RP Boyko, EJ (reprint author), VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. EM eboyko@uw.edu FU NIDDK NIH HHS [P30 DK017047, P30-DK17047, K24-DK080140, K24 DK080140] NR 17 TC 8 Z9 8 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2011 VL 34 IS 3 BP 782 EP 784 DI 10.2337/dc10-1958 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 731YA UT WOS:000288145400051 PM 21357366 ER PT J AU Bains, SS Egede, LE AF Bains, Sujeev S. Egede, Leonard E. TI Associations Between Health Literacy, Diabetes Knowledge, Self-Care Behaviors, and Glycemic Control in a Low Income Population with Type 2 Diabetes SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID MEDICATION ADHERENCE; MORTALITY; OUTCOMES; EDUCATION; DISEASE; RISK; COMPLICATIONS; METAANALYSIS; MELLITUS; PEOPLE AB Objective: This study assessed associations among health literacy, diabetes knowledge, self-care, and glycemic control in a low income, predominately minority population with type 2 diabetes. Methods: One hundred twenty-five adults with diabetes were recruited from a primary care clinic. Subjects completed validated surveys to measure health literacy, diabetes knowledge, and self-care (medication adherence, diet, exercise, blood sugar testing, and foot care). Hemoglobin A1c values were extracted from the medical record. Spearman's correlation and multiple linear regression were used to assess the relationship among health literacy, diabetes knowledge, self-care, and glycemic control controlling for covariates. Results: Cronbach's alpha was 0.95 for the Revised Rapid Estimate of Adult Literacy in Medicine. The majority of the sample was < 65 years old (50.7%), female (72.5%), and African American (71.4%), had less than a high school education (68.2%) and a household income <$15,000 (64.2%), and reported their health status as worse than last year (73.9%). In adjusted models that examined the associations among health literacy, diabetes knowledge, medication adherence, and self-care, health literacy was only significantly associated with diabetes knowledge (beta = 0.55; 95% confidence interval [CI] 0.29, 0.82). In the final adjusted model for independent factors associated with glycemic control, both diabetes knowledge (beta = 0.12; 95% CI 0.01, 0.23) and perceived health status (beta = 1.14; 95% CI 0.13, 2.16) were significantly associated with glycemic control, whereas health literacy was not associated with glycemic control (beta = -0.03; 95% CI -0.19, 0.13). Conclusions: Diabetes knowledge and perceived health status are the most important factors associated with glycemic control in this population. Health literacy appears to exert its influence through diabetes knowledge and is not directly related to self-care or medication adherence. C1 [Bains, Sujeev S.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Bains, Sujeev S.; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280H, Charleston, SC 29425 USA. EM egedel@musc.edu FU NIDDK NIH HHS [R01 DK081121, T35 DK007431] NR 50 TC 56 Z9 59 U1 2 U2 23 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD MAR PY 2011 VL 13 IS 3 BP 335 EP 341 DI 10.1089/dia.2010.0160 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727KO UT WOS:000287798200007 PM 21299402 ER PT J AU Xing, DY Kollman, C Beck, RW Tamborlane, WV Laffel, L Buckingham, BA Wilson, DM Weinzimer, S Fiallo-Scharer, R Ruedy, KJ AF Xing, Dongyuan Kollman, Craig Beck, Roy W. Tamborlane, William V. Laffel, Lori Buckingham, Bruce A. Wilson, Darrell M. Weinzimer, Stuart Fiallo-Scharer, Rosanna Ruedy, Katrina J. CA Juvenile Diabet Res Fdn Continuous TI Optimal Sampling Intervals to Assess Long-Term Glycemic Control Using Continuous Glucose Monitoring SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID TRIAL; ACCURACY; CHILDREN; SYSTEM AB Aims and Hypothesis: The optimal duration and frequency of short-term continuous glucose monitoring (CGM) to reflect long-term glycemia have not been determined. The Juvenile Diabetes Research Foundation CGM randomized trials provided a large dataset of longitudinal CGM data for this type of analysis. Methods: The analysis included 185 subjects who had 334 3-month intervals of CGM data meeting specific criteria. For various glucose indices, correlations (r(2)) were computed for the entire 3-month interval versus selected sampling periods ranging from 3 to 15 days. Other computed agreement measures included median relative absolute difference, values within +/- 10% and +/- 20% of full value, and median absolute difference. Results: As would be expected, the more days of glucose data that were sampled, the higher the correlation with the full 3 months of data. For 3 days of sampling, the r(2) value ranged from 0.32 to 0.47, evaluating mean glucose, percentage of values 71-180 mg/dL, percentage of values > 180mg/dL, percentage of values <= 70mg/dL, and coefficient of variation; in contrast, for 15 days of sampling, the r(2) values ranged from 0.66 to 0.75. The results were similar when the analysis intervals were stratified by age group (8-14, 15-24, and >= 25 years), by baseline hemoglobin A1c level (< 7.0% and >= 7.0%), and by CGM device type. Conclusions and Interpretation: Our data suggest that a 12-15-day period of monitoring every 3 months may be needed to optimally assess overall glucose control. Shorter periods of sampling can be useful, but the correlation with 3-month measures of glycemic control is lower. C1 [Xing, Dongyuan; Kollman, Craig; Beck, Roy W.; Ruedy, Katrina J.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Tamborlane, William V.; Weinzimer, Stuart] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Laffel, Lori] Joslin Diabet Ctr, Boston, MA 02215 USA. [Buckingham, Bruce A.; Wilson, Darrell M.] Stanford Univ, Stanford, CA 94305 USA. [Fiallo-Scharer, Rosanna] Barbara Davis Ctr, Aurora, CO USA. RP Xing, DY (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM jdrfapp@jaeb.org FU Juvenile Diabetes Research Foundation, Inc. [22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, 01-2006-8031]; Medical Advisory Board for Medtronic MiniMed, Inc.; Abbott Diabetes Care, Inc.; DexCom, Inc.; Medtronic MiniMed, Inc. FX The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group would like to recognize the efforts of the subjects and their families and thank them for their participation. Study funding was provided by the Juvenile Diabetes Research Foundation, Inc. with grant numbers 22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, and 01-2006-8031.; Continuous glucose monitors and sensors were purchased at a bulk discount price from DexCom, Inc. (San Diego, CA), Medtronic MiniMed, Inc. (Northridge, CA), and Abbott Diabetes Care, Inc. (Alameda, CA). Home glucose meters and test strips were provided to the study by LifeScan, Inc. and Abbott Diabetes Care, Inc. The companies had no involvement in the design, conduct, or analysis of the trial or the manuscript preparation. Below is a listing of relationships of the investigators with companies that make products relevant to the article between July 1, 2006 and present; research funds where listed below were provided to the legal entity that employs the individual and not directly to the individual: B.A.B. reports having received grant support and serving on the Medical Advisory Board for Medtronic MiniMed, Inc., grant support and a speaker honorarium from Abbott Diabetes Care, Inc., and grant support from DexCom, Inc.; C.K. reports having received consulting fees from Medtronic MiniMed, Inc.; L.L. reports having received consulting fees and a speaker honorarium from Abbott Diabetes Care, Inc. and consulting fees and research funding from Medtronic MiniMed, Inc.; W.V.T. reports having received consulting fees from Medtronic MiniMed, Inc.; and S.W. reports having received research support, a speaker honorarium, and travel reimbursement from Medtronic MiniMed, Inc. and a speaker honorarium from Animas Corp./Lifescan, Inc. NR 14 TC 12 Z9 12 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD MAR PY 2011 VL 13 IS 3 BP 351 EP 358 DI 10.1089/dia.2010.0156 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727KO UT WOS:000287798200009 PM 21299401 ER PT J AU Aguayo-Mazzucato, C Koh, A El Khattabi, I Li, WC Toschi, E Jermendy, A Juhl, K Mao, K Weir, GC Sharma, A Bonner-Weir, S AF Aguayo-Mazzucato, C. Koh, A. El Khattabi, I. Li, W. -C. Toschi, E. Jermendy, A. Juhl, K. Mao, K. Weir, G. C. Sharma, A. Bonner-Weir, S. TI Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells SO DIABETOLOGIA LA English DT Article DE Beta cell development; Insulin secretion; MAFA; Maturation ID EMBRYONIC STEM-CELLS; ENDOCRINE PANCREAS; IN-VIVO; GENE; TRANSCRIPTION; ISLETS; PDX-1; MATURATION; HORMONE; DIFFERENTIATION AB Neonatal beta cells lack glucose-stimulated insulin secretion and are thus functionally immature. We hypothesised that this lack of glucose responsiveness results from a generalised low expression of genes characteristic of mature functional beta cells. Important glucose-responsive transcription factors, Mafa and Pdx1, regulate genes involved in insulin synthesis and secretion, and have been implicated in late beta cell development. The aim of this study was to assess whether Mafa and/or Pdx1 regulates the postnatal functional maturation of beta cells. By quantitative PCR we evaluated expression of these and other beta cell genes over the first month compared with adult. After infection with adenovirus expressing MAFA, Pdx1 or green fluorescent protein (Gfp), P2 rat islets were evaluated by RT-PCR and insulin secretion with static incubation and reverse haemolytic plaque assay (RHPA). At P2 most beta cell genes were expressed at about 10% of adult, but by P7 Pdx1 and Neurod1 no longer differ from adult; by contrast, Mafa expression remained significantly lower than adult through P21. Overexpression of Pdx1 increased Mafa, Neurod1, glucokinase (Gck) mRNA and insulin content but failed to enhance glucose responsiveness. Similar overexpression of MAFA resulted in increased Neurod1, Nkx6-1, Gck and Glp1r mRNAs and no change in insulin content but, importantly, acquisition of glucose-responsive insulin secretion. Both the percentage of secreting beta cells and the amount of insulin secreted per beta cell increased, approaching that of adult beta cells. In the process of functional maturation acquiring glucose-responsive insulin secretion, neonatal beta cells undergo a coordinated gene expression programme in which Mafa plays a crucial role. C1 [Aguayo-Mazzucato, C.; Koh, A.; El Khattabi, I.; Li, W. -C.; Toschi, E.; Jermendy, A.; Juhl, K.; Mao, K.; Weir, G. C.; Sharma, A.; Bonner-Weir, S.] Harvard Univ, Sch Med, Sect Islet Cell & Regenerat Biol, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Sharma, A (reprint author), Harvard Univ, Sch Med, Sect Islet Cell & Regenerat Biol, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM arun.sharma@joslin.harvard.edu; susan.bonner-weir@joslin.harvard.edu FU NIH [R01 DK 66056, R01 DK 60127]; Joslin Diabetes and Endocrinology Research Center (DERC) [P30 DK36836]; Juvenile Diabetes Research Foundation; Diabetes Research and Wellness Foundation; Graetz Fund; Joslin [T32 DK007260]; JDRF; Singapore National Medical Research Council; Lundbeckfonden fellowship FX The authors thank J. Lock, T. Salameh and C. Cahill, all of the Joslin Diabetes Center, for their expert technical assistance. This study was supported by NIH R01 DK 66056 (S. Bonner-Weir), R01 DK 60127 (A. Sharma), P30 DK36836 Joslin Diabetes and Endocrinology Research Center (DERC) Advanced Microscopy Core grants as well as the Juvenile Diabetes Research Foundation, Diabetes Research and Wellness Foundation, the Graetz Fund and an important group of private donors. I. El Khattabi was supported by Joslin T32 DK007260, W. C. Li by a JDRF Post doctoral fellowship, A. Koh by a Singapore National Medical Research Council Research fellowship grant, and K. Juhl by a Lundbeckfonden fellowship. NR 40 TC 52 Z9 53 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2011 VL 54 IS 3 BP 583 EP 593 DI 10.1007/s00125-010-2026-z PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716PX UT WOS:000286987000016 PM 21190012 ER PT J AU Jermendy, A Toschi, E Aye, T Koh, A Aguayo-Mazzucato, C Sharma, A Weir, GC Sgroi, D Bonner-Weir, S AF Jermendy, A. Toschi, E. Aye, T. Koh, A. Aguayo-Mazzucato, C. Sharma, A. Weir, G. C. Sgroi, D. Bonner-Weir, S. TI Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells SO DIABETOLOGIA LA English DT Article DE Glucose responsiveness; Immature function; Mitochondrial shuttles; Neonatal islet ID STIMULATED INSULIN-SECRETION; LASER-CAPTURE MICRODISSECTION; GENE-EXPRESSION; PANCREATIC-ISLETS; MITOCHONDRIAL METABOLISM; PYRUVATE-CARBOXYLASE; NEWBORN RATS; GLUCOSE; FETAL; SHUTTLE AB Fetal and neonatal beta cells have poor glucose-induced insulin secretion and only gain robust glucose responsiveness several weeks after birth. We hypothesise that this unresponsiveness is due to a generalised immaturity of the metabolic pathways normally found in beta cells rather than to a specific defect. Using laser-capture microdissection we excised beta cell-enriched cores of pancreatic islets from day 1 (P1) neonatal and young adult Sprague-Dawley rats in order to compare their gene-expression profiles using Affymetrix U34A microarrays (neonatal, n = 4; adult, n = 3). Using dChip software for analysis, 217 probe sets for genes/38 expressed sequence tags (ESTs) were significantly higher and 345 probe sets for genes/33 ESTs significantly lower in beta cell-enriched cores of neonatal islets compared with those of adult islets. Among the genes lower in the neonatal beta cells were key metabolic genes including mitochondrial shuttles (malate dehydrogenase, glycerol-3-phosphate dehydrogenase and glutamate oxalacetate transaminase), pyruvate carboxylase and carnitine palmitoyl transferase 2. Differential expression of these enzyme genes was confirmed by quantitative PCR on RNA from isolated neonatal (P2 until P28) and adult islets and with immunostaining of pancreas. Even by 28 days of age some of these genes were still expressed at lower levels than in adults. The lack of glucose responsiveness in neonatal islets is likely to be due to a generalised immaturity of the metabolic specialisation of pancreatic beta cells. C1 [Jermendy, A.; Toschi, E.; Aye, T.; Koh, A.; Aguayo-Mazzucato, C.; Sharma, A.; Weir, G. C.; Bonner-Weir, S.] Harvard Univ, Sch Med, Sect Islet Cell & Regenerat Biol, Res Div,Joslin Diabet Ctr,Dept Med, Boston, MA 02215 USA. [Jermendy, A.] Semmelweis Univ, Dept Pediat 1, H-1085 Budapest, Hungary. [Sgroi, D.] Harvard Univ, Sch Med, Mol Pathol Unit, Massachusetts Gen Hosp,Dept Pathol, Boston, MA 02215 USA. RP Bonner-Weir, S (reprint author), Harvard Univ, Sch Med, Sect Islet Cell & Regenerat Biol, Res Div,Joslin Diabet Ctr,Dept Med, 1 Joslin Pl, Boston, MA 02215 USA. EM Susan.Bonner-Weir@joslin.harvard.edu FU National Institutes of Health [R01 DK 66056]; Beta-cell Biology Consortium [DK 61251]; Advanced Microscopy, Genomics and Bioinformatics cores of Joslin Diabetes and Endocrinology Research Center [P30 DK 36836]; Juvenile Diabetes Research Foundation [JDRF 1-2004-120]; Diabetes Research and Wellness Foundation; Graetz Fund; Hungarian-American Enterprise Scholarship Fund; Singapore National Medical Research Council; Lawson-Wilkins Fellowship; Endocrine Fellow Foundation; [TAMOP-4.2.2-08/01/KMR-2008-2004] FX The authors thank J. Lock (Joslin Diabetes Center) for her expert technical assistance, J. Schroeder and I-H. Wu (Joslin Diabetes Center) for help with bioinformatics. This study was supported by National Institutes of Health Grants R01 DK 66056 (S. Bonner-Weir), DK 61251 beta-cell Biology Consortium (D. Sgroi), the Advanced Microscopy, Genomics and Bioinformatics cores of Joslin Diabetes and Endocrinology Research Center (P30 DK 36836) as well as the Juvenile Diabetes Research Foundation (JDRF 1-2004-120 to S. Bonner-Weir), Diabetes Research and Wellness Foundation, the Graetz Fund, and an important group of private donors. A. Jermendy was supported partially by the Hungarian-American Enterprise Scholarship Fund and TAMOP-4.2.2-08/01/KMR-2008-2004 research grant, A. Koh by a Singapore National Medical Research Council Research fellowship grant, and T. Aye by a Lawson-Wilkins Fellowship and an Endocrine Fellow Foundation award. The data discussed in this publication have been deposited in NCBI Gene Expression Omnibus [46] and are accessible through GEO Series accession number GSE24790 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE24790). NR 46 TC 42 Z9 42 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2011 VL 54 IS 3 BP 594 EP 604 DI 10.1007/s00125-010-2036-x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716PX UT WOS:000286987000017 PM 21240476 ER PT J AU Borsook, D Becerra, L Hargreaves, R AF Borsook, David Becerra, Lino Hargreaves, Richard TI Biomarkers for Chronic Pain and Analgesia. Part 1: The Need, Reality, Challenges, and Solutions SO DISCOVERY MEDICINE LA English DT Article AB Chronic pain remains a significant clinical problem that has few effective therapies. Currently the success rate for treating chronic pain with analgesics is around 30%. Both treatment and research into chronic pain are greatly compromised by the fact that there is no objective diagnostic test that can complement the subjective assessment of chronic pain conditions. Chronic pain is now considered to be a disease of the central nervous system. Since behavior (including pain or analgesia) results from activity in brain circuits through the participation of many brain regions, we suggest that specific measures for the disease state and for drug effects can be defined using functional brain imaging. Tremendous advances have been made in functional imaging in the field of pain and analgesics and the development of CNS imaging biomarkers for pain may be close at hand. The successful identification of functional brain "signatures" for both drug action (analgesia) and disease state (neuropathic pain) when qualified could provide objective biomarkers to guide for drug development and clinical practice. In this two-part review, we discuss the potential of biomarkers for chronic pain including functional neuroimaging together with the challenges and limitations that are likely to be faced during the implementation of this strategy. The fit-for-purpose, scientific validation, and clinical qualification of novel CNS biomarkers for chronic pain could dramatically change the current outlook for treatment of chronic pain and research into its etiology. [Discovery Medicine 11(58):197-207, March 2011] C1 [Borsook, David; Becerra, Lino] Harvard Univ, Sch Med, McLean Hosp, PAIN Grp,Massachusetts Gen Hosp, Belmont, MA 02478 USA. [Borsook, David; Becerra, Lino] Harvard Univ, Sch Med, Childrens Hosp, Belmont, MA 02478 USA. [Hargreaves, Richard] Merck & Co Inc, Merck Res Labs, West Point, PA 19486 USA. RP Borsook, D (reprint author), Harvard Univ, Sch Med, McLean Hosp, PAIN Grp,Massachusetts Gen Hosp, Belmont, MA 02478 USA. EM dborsook@partners.org FU NINDS [K24 (NS064050)]; Herlands Fund FX Supported by NINDS K24 (NS064050) to D.B. and the L. Herlands Fund to the P.A.I.N. group (D.B., L.B.). We thank Gautam Pendse, M.A., M.S., for his contribution to Figure 3. NR 63 TC 44 Z9 44 U1 0 U2 2 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD MAR PY 2011 VL 11 IS 58 BP 197 EP 207 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V27UY UT WOS:000208639300003 PM 21447279 ER PT J AU Borsook, D Becerra, L Hargreaves, R AF Borsook, David Becerra, Lino Hargreaves, Richard TI Biomarkers for Chronic Pain and Analgesia. Part 2: How, Where, and What to Look for Using Functional Imaging SO DISCOVERY MEDICINE LA English DT Article AB Rapid advances in brain imaging chronic pain patients have yielded exciting data sets that could provide the basis for the development of chronic pain biomarkers that could increase the probability of success in analgesic drug development, aid clinicians in understanding, tracking, and treating disease, and link patients to the most effective therapies for their pain conditions. This review explores the potential of brain imaging techniques to detect functional, morphometric, and chemical changes that could serve as biomarkers for disease state and therapeutic efficacy. An important area for future research is to image clinical ongoing pain to further our knowledge of brain function in different pain states and the effects of treatment. [Discovery Medicine 11(58):209-219, March 2011] C1 [Borsook, David; Becerra, Lino] Harvard Univ, Sch Med, McLean Hosp, PAIN Grp,Massachusetts Gen Hosp, Belmont, MA 02478 USA. [Borsook, David; Becerra, Lino] Harvard Univ, Sch Med, Childrens Hosp, Belmont, MA 02478 USA. [Hargreaves, Richard] Merck & Co Inc, Merck Res Labs, West Point, PA 19486 USA. RP Borsook, D (reprint author), Harvard Univ, Sch Med, McLean Hosp, PAIN Grp,Massachusetts Gen Hosp, Belmont, MA 02478 USA. EM dborsook@partners.org FU NINDS [K24 (NS064050)]; Herlands Fund FX Supported by NINDS K24 (NS064050) to D.B. and the L. Herlands Fund to the P.A.I.N. group (D.B., L.B.). NR 116 TC 32 Z9 32 U1 0 U2 2 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD MAR PY 2011 VL 11 IS 58 BP 209 EP 219 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V27UY UT WOS:000208639300004 PM 21447280 ER PT J AU Hildebrandt, T Lai, JK Langenbucher, JW Schneider, M Yehuda, R Pfaff, DW AF Hildebrandt, Tom Lai, Justine K. Langenbucher, James W. Schneider, Melanie Yehuda, Rachel Pfaff, Donald W. TI The diagnostic dilemma of pathological appearance and performance enhancing drug use SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Anabolic-androgenic steroids; Appearance and performance enhancing drugs; Substance use disorder; Diagnosis; Body image disturbance; Compulsive exercise ID ANDROGENIC STEROID USE; SUBSTANCE USE DISORDERS; MALE NORMAL VOLUNTEERS; ITEM RESPONSE THEORY; OF-THE-LITERATURE; ANABOLIC-STEROIDS; EXERCISE-DEPENDENCE; DSM-V; MUSCLE DYSMORPHIA; BODY-IMAGE AB Appearance and performance enhancing drug (APED) use includes the use of a range of pharmacologically distinct substances and concurrent investment in outward appearance or achievement, dietary control, and frequent exercise. A number of existing reviews and conceptual papers have defined pathological forms of APED use within the APED class of anabolic-androgenic steroids (AASs) and using the framework of AAS dependence. We review published data on APED use including human studies of AAS users and identified three defining phenomenological features associated with increased health risk and pathology. These features included (1) polypharmacy or the concurrent use of several pharmacologically distinct substances used to change outward appearance or increase likelihood of personal achievement: (2) significant body image disturbance: (3) rigid practices and preoccupations with diet and exercise. Investigations into the latent structure of APED use suggest these features cluster together in a homogenous group of APED users who have the highest health risk and most psychopathology. These features are discussed in the context of AAS dependence and problems with defining classic tolerance-withdrawal symptoms among APED users. Suggestions for a resolution and outline for future research needed to determine the best system for identifying and diagnosing pathological APED use are discussed. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Hildebrandt, Tom; Lai, Justine K.] Mt Sinai Sch Med, Eating & Weight Disorders Program, New York, NY 10029 USA. [Langenbucher, James W.; Schneider, Melanie] Rutgers State Univ, Piscataway, NJ 08854 USA. [Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Pfaff, Donald W.] Rockefeller Univ, New York, NY 10128 USA. RP Hildebrandt, T (reprint author), Mt Sinai Sch Med, Eating & Weight Disorders Program, 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM tom.hildebrandt@mssm.edu OI Hildebrandt, Thomas/0000-0001-7054-9590 FU National Institute on Drug Abuse [K23 024034] FX Dr. Hildebrandt's time was supported by National Institute on Drug Abuse grant K23 024034. NR 146 TC 12 Z9 12 U1 16 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2011 VL 114 IS 1 BP 1 EP 11 DI 10.1016/j.drugalcdep.2010.09.018 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 734CZ UT WOS:000288312100001 PM 21115306 ER PT J AU Puzanov, I Flaherty, KT Sosman, JA Grippo, JF Su, F Nolop, K Lee, RJ Bollag, G AF Puzanov, I. Flaherty, K. T. Sosman, J. A. Grippo, J. F. Su, F. Nolop, K. Lee, R. J. Bollag, G. TI VEMURAFENIB B-raf Kinase Inhibitor Oncolytic SO DRUGS OF THE FUTURE LA English DT Article DE PLX-4032; R-7204; RG-7204; RO-5185426 ID THYROID-CARCINOMA CELLS; METASTATIC MELANOMA; DRUG-RESISTANCE; BRAF; PLX4032; PATHWAY; MUTATIONS; GROWTH; PROLIFERATION; ACTIVATION AB Vemurafenib (RG-7204, PLX-4032) is a potent inhibitor of the V600E mutation-positive B-raf kinase. Mutations in this protein have been implicated in approximately 50% of melanomas, 30-70% of thyroid tumors, 30% of serous low-grade ovarian tumors and 10% of colorectal cancers. Vemurafenib has shown promising preclinical and clinical efficacy against mutant BRAF cell lines and tumors. Vemurafenib exhibits selectivity over a broad range of kinases, which has translated into cellular selectivity for cancer cell lines expressing BRAF(V600E), BRAF(V600D) and BRAF(V600R), with no activity against cells lacking oncogenic B-raf. Pharmacokinetic analyses have shown that exposure increases with dose from 160 mg to 1,120 mg twice daily, and a dose of 960 mg twice daily was selected for phase II and III evaluation. Phase I and II clinical data have demonstrated promising activity, with the recently reported BRIM-2 study in patients with metastatic melanoma having met its primary endpoint, demonstrating a best overall response rate of > 50% in the context of manageable side effects. C1 [Puzanov, I.; Sosman, J. A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Puzanov, I.; Sosman, J. A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Flaherty, K. T.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Grippo, J. F.; Su, F.; Lee, R. J.] Hoffmann La Roche, Nutley, NJ USA. [Nolop, K.; Bollag, G.] Plexxikon Inc, Berkeley, CA USA. RP Puzanov, I (reprint author), Vanderbilt Ingram Canc Ctr, Nashville, TN USA. EM igor.puzanov@vanderbilt.edu NR 39 TC 6 Z9 6 U1 2 U2 12 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD MAR PY 2011 VL 36 IS 3 BP 191 EP 199 DI 10.1358/dof.2011.36.3.1590788 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 781TP UT WOS:000291959700003 ER PT J AU van Ryn, M Burgess, DJ Dovidio, JF Phelan, SM Saha, S Malat, J Griffin, JM Fu, SS Perry, S AF van Ryn, Michelle Burgess, Diana J. Dovidio, John F. Phelan, Sean M. Saha, Somnath Malat, Jennifer Griffin, Joan M. Fu, Steven S. Perry, Sylvia TI THE IMPACT OF RACISM ON CLINICIAN COGNITION, BEHAVIOR, AND CLINICAL DECISION MAKING SO DU BOIS REVIEW-SOCIAL SCIENCE RESEARCH ON RACE LA English DT Article DE Racial Inequity; Health Care Disparities; Racial Bias; Providers; Racism; Stereotypes; Discrimination; Interracial Interaction ID HEALTH-CARE DISPARITIES; IMPLICIT ASSOCIATION TEST; STEREOTYPE THREAT; CULTURAL COMPETENCE; PHYSICIANS PERCEPTIONS; AFRICAN-AMERICANS; AVERSIVE RACISM; PUBLIC-HEALTH; ATTITUDES; RACE AB Over the past two decades, thousands of studies have demonstrated that Blacks receive lower quality medical care than Whites, independent of disease status, setting, insurance, and other clinically relevant factors. Despite this, there has been little progress towards eradicating these inequities. Almost a decade ago we proposed a conceptual model identifying mechanisms through which clinicians' behavior, cognition, and decision making might be influenced by implicit racial biases and explicit racial stereotypes, and thereby contribute to racial inequities in care. Empirical evidence has supported many of these hypothesized mechanisms, demonstrating that White medical care clinicians: (1) hold negative implicit racial biases and explicit racial stereotypes, (2) have implicit racial biases that persist independently of and in contrast to their explicit (conscious) racial attitudes, and (3) can be influenced by racial bias in their clinical decision making and behavior during encounters with Black patients. This paper applies evidence from several disciplines to further specify our original model and elaborate on the ways racism can interact with cognitive biases to affect clinicians' behavior and decisions and in turn, patient behavior and decisions. We then highlight avenues for intervention and make specific recommendations to medical care and grant-making organizations. C1 [van Ryn, Michelle; Phelan, Sean M.] Univ Minnesota, Sch Med, Dept Family Med & Community Hlth, Minneapolis, MN 55414 USA. [Burgess, Diana J.; Griffin, Joan M.; Fu, Steven S.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55414 USA. [Dovidio, John F.; Perry, Sylvia] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Gen Internal Med Sect, Portland, OR 97201 USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Div Gen Internal Med & Geriatr, Portland, OR 97201 USA. [Malat, Jennifer] Univ Cincinnati, Dept Sociol, Cincinnati, OH 45221 USA. [Burgess, Diana J.; Griffin, Joan M.; Fu, Steven S.] Univ Minnesota, Minneapolis VA Med Ctr, Ctr Chron Dis Outcomes Res, Minneapolis, MN 55414 USA. RP van Ryn, M (reprint author), Univ Minnesota, Sch Med, Dept Family Med & Community Hlth, Room 221,925 Delaware St SE, Minneapolis, MN 55414 USA. EM vanry001@umn.edu RI Burgess, Diana/A-1946-2016 FU NHLBI NIH HHS [R01 HL085631] NR 89 TC 41 Z9 42 U1 12 U2 43 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1742-058X J9 DU BOIS REV JI Du Bois Rev. PD SPR PY 2011 VL 8 IS 1 SI SI BP 199 EP 218 DI 10.1017/S1742058X11000191 PG 20 WC Ethnic Studies; Sociology SC Ethnic Studies; Sociology GA 051ZD UT WOS:000312166600015 PM 24761152 ER PT J AU Kind, A Anderson, P Hind, J Robbins, J Smith, M AF Kind, Amy Anderson, Paul Hind, Jacqueline Robbins, JoAnne Smith, Maureen TI Omission of Dysphagia Therapies in Hospital Discharge Communications SO DYSPHAGIA LA English DT Article DE Care management; Communication; Continuity of care; Hospital discharge; Deglutition; Deglutition disorders ID MEDICAL REHABILITATION REPORT; RANDOMIZED CONTROLLED-TRIAL; UNIFORM DATA SYSTEM; GENERAL-PRACTITIONERS; ACUTE STROKE; ALZHEIMERS-DISEASE; PATIENT SAFETY; CLINICAL-TRIAL; HIP FRACTURE; FOLLOW-UP AB Despite the wide implementation of dysphagia therapies, it is unclear whether these therapies are successfully communicated beyond the inpatient setting. The aim of this study was to examine the rate of dysphagia recommendation omissions in hospital discharge summaries for high-risk subacute care (i.e., skilled nursing facility, rehabilitation, long-term care) populations. We performed a retrospective cohort study that included all stroke and hip fracture patients billed for inpatient dysphagia evaluations by speech-language pathologists (SLPs) and discharged to subacute care from 2003 through 2005 from a single large academic medical center (N = 187). Dysphagia recommendations from final SLP hospital notes and from hospital (physician) discharge summaries were abstracted, coded, and compared for each patient. Recommendation categories included dietary (food and liquid), postural/compensatory techniques (e.g., chin tuck), rehabilitation (e.g., exercise), meal pacing (e.g., small bites), medication delivery (e.g., crush pills), and provider/supervision (e.g., 1-to-1 assist). Forty-five percent of discharge summaries omitted all SLP dysphagia recommendations. Forty-seven percent (88/186) of patients with SLP dietary recommendations, 82% (93/114) with postural, 100% (16/16) with rehabilitation, 90% (69/77) with meal pacing, 95% (21/22) with medication, and 79% (96/122) with provider/supervision recommendations had these recommendations completely omitted from their discharge summaries. Discharge summaries omitted all categories of SLP recommendations at notably high rates. Improved post-hospital communication strategies are needed for discharges to subacute care. C1 [Kind, Amy] Univ Wisconsin, Geriatr Sect, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Kind, Amy; Anderson, Paul; Hind, Jacqueline; Robbins, JoAnne] William S Middleton Mem Vet Adm Med Ctr, United States Dept Vet Affairs, Geriatr Res Educ & Clin Ctr GRECC, Madison, WI 53705 USA. [Kind, Amy] Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Hind, Jacqueline; Robbins, JoAnne] Univ Wisconsin, Gastroenterol & Hepatol Sect, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Smith, Maureen] Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI 53726 USA. [Smith, Maureen] Univ Wisconsin, Dept Family Med, Sch Med & Publ Hlth, Madison, WI 53726 USA. RP Kind, A (reprint author), Univ Wisconsin, Geriatr Sect, Dept Med, Sch Med & Publ Hlth, 2500 Overlook Terrace, Madison, WI 53705 USA. EM ajk@medicine.wisc.edu FU University of Wisconsin (UW) Hartford Center of Excellence in Geriatrics; UW Health Innovation Program; UW Shapiro Summer Medical Student Research Fellowship; K-L2 through the NIH [1KL2RR025012-01]; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR); National Center for Research Resources, National Institutes of Health [IUL1RR025011] FX Special thanks to UW Health Innovation Program staff Geoff Wodtke and Wen-Jan Tuan for data management and cleaning, Inna Larsen for administrative support, Colleen Brown and Kristin Slovenkay for manuscript formatting, and Peggy Munson for IRB assistance, and to Bruce Grau and Tim Kamps for assistance with data collection. Funding for this project was provided by the University of Wisconsin (UW) Hartford Center of Excellence in Geriatrics, the UW Health Innovation Program, and the UW Shapiro Summer Medical Student Research Fellowship. Dr. Kind is supported by a K-L2 through the NIH grant 1KL2RR025012-01 [Institutional Clinical and Translational Science Award (UW-Madison) (KL2)]. This project was also supported by the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR), grant IUL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources, National Institutes of Health. The UW Health Innovation Program provided assistance with IRB application, Medicare outcomes variable creation and linkage, data management and cleaning, and manuscript formatting. No other funding source had a role in the design or conduct data collection, management, analysis, or interpretation; or preparation, review, or approval of the manuscript. NR 73 TC 14 Z9 14 U1 5 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD MAR PY 2011 VL 26 IS 1 BP 49 EP 61 DI 10.1007/s00455-009-9266-4 PG 13 WC Otorhinolaryngology SC Otorhinolaryngology GA 732VQ UT WOS:000288218200008 PM 20098999 ER PT J AU Tritos, NA AF Tritos, Nicholas A. TI Serum Dehydroepiandrosterone Sulfate in the Diagnosis of Adrenal Insufficiency: Ready for Prime Time? SO ENDOCRINE PRACTICE LA English DT Editorial Material ID SEPTIC SHOCK; ACTH STIMULATION; CORTISOL-LEVELS; AXIS; HYDROCORTISONE; CORTICOTROPIN; DYSFUNCTION C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. EM ntritos@partners.org NR 22 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD MAR-APR PY 2011 VL 17 IS 2 BP 167 EP 169 DI 10.4158/EP10385.ED PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V28XV UT WOS:000208714400010 PM 21247840 ER PT J AU Park, JH Daheron, L Kantarci, S Lee, BS Teixeira, JM AF Park, Joo Hyun Daheron, Laurence Kantarci, Sibel Lee, Byung Seok Teixeira, Jose M. TI Human Endometrial Cells Express Elevated Levels of Pluripotent Factors and Are More Amenable to Reprogramming into Induced Pluripotent Stem Cells SO ENDOCRINOLOGY LA English DT Article ID SMALL-MOLECULE COMPOUNDS; HUMAN AMNIOTIC-FLUID; HUMAN SOMATIC-CELLS; DEFINED FACTORS; GENERATION; INDUCTION; FIBROBLASTS; EFFICIENCY; OCT4 AB The human endometrium is a tissue with remarkable plasticity and regenerative capacity. Additionally, endometrial cells can be retrieved using minimally invasive procedures, which makes them an ideal source for reprogramming into a pluripotent state. Endometrial cells were obtained from donors in their fifth decade and reprogrammed into induced pluripotent stem (iPS) cells using retroviral transduction with SOX2, OCT4, KLF4, and MYC. The human endometrial cells displayed accelerated expression of endogenous NANOG and OCT4 during reprogramming compared with neonatal skin fibroblasts. As a result, iPS cell colonies that could be subcultured and propagated were established as early as 12 d after transduction rather than the usually reported 3-4 wk for other cell types. After 3 wk of reprogramming, the human endometrial cells also yielded significantly higher numbers of iPS colonies in comparison with the neonatal skin fibroblasts. Although the efficiency of iPS colony formation varied depending on the donor, the basal level of endogenous expression of the defined factors was positively correlated with reprogramming efficiency. The reprogramming resulted in an average colony-forming efficiency of 0.49 +/- 0.10%, with a range from 0.31-0.66%, compared with the neonatal skin fibroblasts, resulting in an average efficiency of 0.03 +/- 0.00% per transduction, with a range from 0.02-0.03%. Our studies show that the human endometrium expresses elevated levels of pluripotent factors, which with additional defined factors, results in significantly more efficient and accelerated generation of induced pluripotent stem cells compared with conventional somatic cells. (Endocrinology 152: 1080-1089, 2011) C1 [Park, Joo Hyun; Teixeira, Jose M.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Dept Obstet & Gynecol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Daheron, Laurence; Teixeira, Jose M.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Kantarci, Sibel] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. [Lee, Byung Seok] Yonsei Univ, Coll Med, Dept Obstet & Gynecol, Severance Hosp, Seoul 120752, South Korea. RP Teixeira, JM (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol Their 931, 55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU National Institute of Child Health and Human Development [HD052701]; Vincent Memorial research funds FX These studies were supported in part by a grant from the National Institute of Child Health and Human Development (HD052701) and by Vincent Memorial research funds to J.M.T. NR 40 TC 19 Z9 22 U1 3 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2011 VL 152 IS 3 BP 1080 EP 1089 DI 10.1210/en.2010-1072 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 723QC UT WOS:000287520900033 PM 21209016 ER PT J AU Hershman, JM Okunyan, A Rivina, Y Cannon, S Hogen, V AF Hershman, Jerome M. Okunyan, Armen Rivina, Yelena Cannon, Sophie Hogen, Victor TI Prevention of DNA Double-Strand Breaks Induced by Radioiodide-I-131 in FRTL-5 Thyroid Cells SO ENDOCRINOLOGY LA English DT Article ID REPAIR; RADIATION; CANCER; REARRANGEMENT; CHROMOSOMES; SYMPORTER; IODIDE AB Radioiodine-131 released from nuclear reactor accidents has dramatically increased the incidence of papillary thyroid cancer in exposed individuals. The deposition of ionizing radiation in cells results in double-strand DNA breaks (DSB) at fragile sites, and this early event can generate oncogenic rearrangements that eventually cause cancer. The aims of this study were to develop a method to show DNA DSBs induced by I-131 in thyroid cells; to test monovalent anions that are transported by the sodium/iodide symporter to determine whether they prevent I-131-induced DSB; and to test other radioprotective agents for their effect on irradiated thyroid cells. Rat FRTL-5 thyroid cells were incubated with I-131. DSBs were measured by nuclear immunofluorescence using antibodies to p53-binding protein 1 or gamma H2AX. Incubation with 1-10 mu Ci I-131 per milliliter for 90 min resulted in a dose-related increase of DSBs; the number of DSBs increased from a baseline of 4-15% before radiation to 65-90% after radiation. GH3 or CHO cells that do not transport iodide did not develop DSBs when incubated with I-131. Incubation with 20-100 mu M iodide or thiocyanate markedly attenuated DSBs. Perchlorate was about 6 times more potent than iodide or thiocyanate. The effects of the anions were much greater when each was added 30-120 min before the I-131. Two natural organic compounds recently shown to provide radiation protection partially prevented DSBs caused by I-131 and had an additive effect with perchlorate. In conclusion, we developed a thyroid cell model to quantify the mitogenic effect of I-131. I-131 causes DNA DSBs in FRTL-5 cells and had no effect on cells that do not transport iodide. Perchlorate, iodide, and thiocyanate protect against DSBs induced by I-131. (Endocrinology 152: 1130-1135, 2011) C1 [Hershman, Jerome M.] W Los Angeles Vet Affairs Med Ctr, Endocrinol & Diabet Div, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90073 USA. RP Hershman, JM (reprint author), W Los Angeles Vet Affairs Med Ctr, Endocrinol & Diabet Div, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jhershmn@ucla.edu FU University of California, Los Angeles, Center of Biological Radioprotectors; National Institutes of Health FX This work was supported by a research grant from the University of California, Los Angeles, Center of Biological Radioprotectors and the National Institutes of Health. NR 20 TC 7 Z9 7 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2011 VL 152 IS 3 BP 1130 EP 1135 DI 10.1210/en.2010-1163 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 723QC UT WOS:000287520900038 PM 21190956 ER PT J AU Liu, YY Nakatani, T Kogai, T Mody, K Brent, GA AF Liu, Yan-Yun Nakatani, Teruyo Kogai, Takahiko Mody, Kaizeen Brent, Gregory A. TI Thyroid Hormone and COUP-TF1 Regulate Kallikrein-Binding Protein (KBP) Gene Expression SO ENDOCRINOLOGY LA English DT Article ID PROMOTER-TRANSCRIPTION FACTORS; HUMAN TISSUE KALLIKREIN; RECEPTOR DNA-BINDING; COREPRESSOR N-COR; NEGATIVE REGULATION; RETINOIC ACID; HISTONE DEACETYLASE; ESTROGEN-RECEPTOR; RESPONSE ELEMENTS; GROWTH-HORMONE AB Kallikrein-binding protein (KBP) is a component of the kallikrein-kinin system that mediates vasodilation and inhibits tumor growth by antagonizing vascular endothelial growth factor-mediated angiogenesis. We demonstrate that KBP gene expression is repressed by T(3) and modulated by the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1). In hypothyroid mice, KBP mRNA expression in the testis was increased 2.1-fold compared with euthyroid mice. We have identified two negative thyroid hormone response elements (nTREs) in the mouse KBP gene, nTRE1 located in the 5' flanking region (-53 to -29) and nTRE2, located in the first intron (104-132). We used functional assays, cofactor knockdown, and chromatin immunoprecipitation assays to characterize nTRE1 and nTRE2 in hepatic (HepG2) and testes (GC-1spg) cell lines. Reporter expression directed by both elements was enhanced with addition of thyroid hormone receptor and repressed with the addition of T(3). COUP-TF1 enhanced basal expression of both elements but blunted unliganded thyroid hormone receptor enhancement and T(3) repression of nTRE1 but not nTRE2. Both nTREs bound nuclear corepressor and binding increased in response to T(3). Nuclear corepressor knockdown resulted in loss of T(3) repression of both nTRE1 and nTRE2. COUP-TF1, which usually represses T(3) induction of positive thyroid hormone response elements, reverses T(3) repression mediated by nTRE1 in the mouse KBP gene. Endogenous KBP expression is repressed by T(3) and two functional nTREs, both of which are required, have been characterized in the KBP gene. COUP-TF1 may be an important factor to modulate expression of genes that are repressed by T(3). (Endocrinology 152: 1143-1153, 2011) C1 [Brent, Gregory A.] Vet Affairs Greater Los Angeles Hlth Care Syst, Mol Endocrinol Lab, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Physiol, David Geffen Sch Med, Los Angeles, CA 90073 USA. RP Brent, GA (reprint author), Vet Affairs Greater Los Angeles Hlth Care Syst, Mol Endocrinol Lab, Bldg 114,Room 230,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM gbrent@ucla.edu FU Department of Veterans Affairs; National Institutes of Health [RO1 DK67233] FX This work was supported by Merit Review funds from the Department of Veterans Affairs and Grant RO1 DK67233 from the National Institutes of Health. NR 63 TC 4 Z9 4 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2011 VL 152 IS 3 BP 1143 EP 1153 DI 10.1210/en.2010-0580 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 723QC UT WOS:000287520900040 PM 21266512 ER PT J AU Garavalia, L Ho, PM Garavalia, B Foody, JM Kruse, H Spertus, JA Decker, C AF Garavalia, Linda Ho, P. Michael Garavalia, Brian Foody, JoAnne M. Kruse, Heather Spertus, John A. Decker, Carole TI Clinician-patient discord: Exploring differences in perspectives for discontinuing clopidogrel SO EUROPEAN JOURNAL OF CARDIOVASCULAR NURSING LA English DT Article DE Myocardial infarction; Medication discontinuance; Patient-provider communication; Qualitative research ID ACUTE CORONARY SYNDROMES; HEALTH BELIEF MODEL; PREMATURE DISCONTINUATION; MEDICATION; PHYSICIANS; ADHERENCE; OUTCOMES; THERAPY; COMMUNICATION; METAANALYSIS AB Background: Premature stopping of anti-platelet therapy has potentially fatal consequences for myocardial infarction (MI) patients who have received a drug-eluting stent (DES). Exploring multiple perspectives to identify contributing factors to the problem is essential. Aim: We gained patient and clinician perspectives as to why MI patients prematurely stop anti-platelet therapy (clopidogrel) after DES implantation. Methods: This qualitative, descriptive study of DES-treated MI patients (n=22) and of clinicians (physicians and nurse practitioners; n=17) from multiple U.S. cities used content analysis of interview data. Findings across patients and clinicians were then compared to examine congruent and contrasting reasons for premature clopidogrel discontinuance. Findings: Patients frequently identified communication and education (e.g. unaware they should be taking clopidogrel, unaware of intended duration of therapy) as the primary reasons for having stopped. Patients rarely cited cost, while clinicians most commonly cited cost as a reason for premature stopping. Conclusions: The discrepancy in perceptions of patients and clinicians as to the primary reason for early discontinuance suggests an important opportunity for improving persistence. Rather than focusing on the high costs of medications, something outside of their control, physicians should consider communicating more effectively the importance and intended duration of clopidogrel to their patients. (C) 2010 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. C1 [Garavalia, Brian; Spertus, John A.; Decker, Carole] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Garavalia, Linda] Univ Missouri Kansas City, Sch Pharm, Kansas City, MO USA. [Ho, P. Michael] Univ Colorado Denver, Denver VA Med Ctr, Denver, CO USA. [Ho, P. Michael] Hlth Sci Ctr, San Antonio, TX USA. [Foody, JoAnne M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Kruse, Heather] Univ Missouri Kansas City, Dept Psychol, Kansas City, MO USA. [Spertus, John A.] Univ Missouri Kansas City, Sch Med, Kansas City, MO USA. [Decker, Carole] Univ Missouri Kansas City, Sch Nursing, Kansas City, MO USA. RP Decker, C (reprint author), St Lukes Hosp, Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM cldecker@saint-lukes.org FU Sanofi-Aventis; NIH SCCOR [P50 HL077113] FX Funding was received from Sanofi-Aventis and NIH SCCOR (P50 HL077113) grants. The sponsors were not involved in the conduct of the study, analysis of the data, or preparation of the manuscript. NR 29 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1474-5151 J9 EUR J CARDIOVASC NUR JI Eur. J. Cardiovasc. Nurs. PD MAR PY 2011 VL 10 IS 1 BP 50 EP 55 DI 10.1016/j.ejcnurse.2010.04.002 PG 6 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA 734TL UT WOS:000288361600008 PM 20483665 ER PT J AU Carroll, DL AF Carroll, D. L. TI Needs of older patients and their spouses after a cardiovascular procedure SO EUROPEAN JOURNAL OF CARDIOVASCULAR NURSING LA English DT Meeting Abstract C1 [Carroll, D. L.] Massachusetts Gen Hospitla, Boston, MA USA. 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 1474-5151 J9 EUR J CARDIOVASC NUR JI Eur. J. Cardiovasc. Nurs. PD MAR PY 2011 VL 10 SU 1 BP S44 EP S44 DI 10.1016/S1474-5151(11)60153-9 PG 1 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA 048GO UT WOS:000311899300140 ER PT J AU Matura, LA McDonough, AJ Carroll, DL AF Matura, L. A. McDonough, A. J. Carroll, D. L. TI Symptom burden and symptom clusters in pulmonary arterial hypertension: a pilot study SO EUROPEAN JOURNAL OF CARDIOVASCULAR NURSING LA English DT Meeting Abstract C1 [Matura, L. A.] Northeastern Univ, Boston, MA 02115 USA. [McDonough, A. J.] Univ Massachusetts Lowell, Lowell, MA USA. [Carroll, D. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1474-5151 J9 EUR J CARDIOVASC NUR JI Eur. J. Cardiovasc. Nurs. PD MAR PY 2011 VL 10 SU 1 BP S38 EP S38 DI 10.1016/S1474-5151(11)60136-9 PG 1 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA 048GO UT WOS:000311899300123 ER PT J AU Hsia, TY Ringewald, JM Stroud, RE Forbus, GA Bradley, SM Chung, WK Spinale, FG AF Hsia, Tain-Yen Ringewald, Jeremy M. Stroud, Robert E. Forbus, Geoffrey A. Bradley, Scott M. Chung, Wendy K. Spinale, Francis G. TI Determinants of extracellular matrix remodelling are differentially expressed in paediatric and adult dilated cardiomyopathy SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Cardiomyopathy; Extracellular matrix; Matrix metalloproteinase; Paediatrics ID LEFT-VENTRICULAR FUNCTION; CONGESTIVE-HEART-FAILURE; TISSUE INHIBITORS; METALLOPROTEINASE INHIBITION; CARDIOPULMONARY BYPASS; RELEASE; FIBROBLASTS; MYOCARDITIS; INDUCTION; SYSTEM AB Aims The left ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in paediatric and adult patients. However, the aetiology of paediatric DCM is usually idiopathic, and often leads an aggressive clinical course. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tested the hypothesis that different MMP/TIMP profiles occur in paediatric and adult DCM patients. Methods and results Left ventricular samples from paediatric (age 9 +/- 5 years; n = 10) and adult (age 62 +/- 3 years; n = 20) DCM (at time of transplant) were subjected to an MMP/TIMP multiplex array and immunoassay in order to measure the MMP subclasses; collagenases (MMP-8, -13), gelatinases (MMP-2, -9), stromelysin/matrilysin (MMP-3, -7), membrane type (MT1-MMP), as well as for the four known TIMPs. MMP-8 and -9 levels increased by over 150% (P < 0.05), whereas MMP-3 and -7 levels decreased by over 30% (P < 0.05) in paediatric DCM when compared with adult DCM. TIMP-1 and -2 levels increased two-fold (P < 0.05), but TIMP-3 fell by 41% (P < 0.05) in paediatric DCM. Myocardial levels of specific interleukins (IL-1beta, IL-2, IL-8) were increased by approximately 50% in paediatric DCM. Conclusions These unique findings demonstrated that a specific MMP/TIMP profile occurs in paediatric DCM when compared with adult DCM, and that local cytokine induction may contribute to this process. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of DCM in children. C1 [Hsia, Tain-Yen; Ringewald, Jeremy M.; Stroud, Robert E.; Forbus, Geoffrey A.; Bradley, Scott M.; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29403 USA. [Hsia, Tain-Yen; Ringewald, Jeremy M.; Stroud, Robert E.; Forbus, Geoffrey A.; Bradley, Scott M.; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Chung, Wendy K.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. RP Spinale, FG (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, 114 Doughty St, Charleston, SC 29403 USA. EM wilburnm@musc.edu FU NIH [HL059165-09, HL057952-08]; Veterans' Affairs Health Administration; Children's Cardiomyopathy Foundation, USA FX This work was supported by NIH grants HL059165-09, HL057952-08, a Merit Award from the Veterans' Affairs Health Administration and the Children's Cardiomyopathy Foundation, USA. NR 33 TC 6 Z9 7 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD MAR PY 2011 VL 13 IS 3 BP 271 EP 277 DI 10.1093/eurjhf/hfq184 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 723HG UT WOS:000287496800007 PM 21147820 ER PT J AU Yakimchuk, K Roura-Mir, C Magalhaes, KG de Jong, A Kasmar, AG Granter, SR Budd, R Steere, A Pena-Cruz, V Kirschning, C Cheng, TY Moody, DB AF Yakimchuk, Konstantin Roura-Mir, Carme Magalhaes, Kelly G. de Jong, Annemieke Kasmar, Anne G. Granter, Scott R. Budd, Ralph Steere, Allen Pena-Cruz, Victor Kirschning, Carsten Cheng, Tan-Yun Moody, D. Branch TI Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-beta SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD1; DC; IL-1; Lyme disease; T cells ID HUMAN DENDRITIC CELLS; KILLER T-CELLS; EARLY LYME-DISEASE; CLASS-II TRANSPORT; NF-KAPPA-B; MYCOBACTERIUM-TUBERCULOSIS; ANTIGEN PRESENTATION; HUMAN MONOCYTES; CUTTING EDGE; INFLAMMASOME ACTIVATION AB The appearance of group 1 CD1 proteins (CD1a, CD1b and CD1c) on maturing myeloid DC is a key event that converts myeloid DC to effective lipid APC. Here, we show that Borrelia burgdorferi, the causative agent of Lyme disease, triggers appearance of group 1 CD1 proteins at high density on the surface of human myeloid DC during infection. Within human skin, CD1b and CD1c expression was low or absent prior to infection, but increased significantly after experimental infections and in erythema migrans lesions from Lyme disease patients. The induction of CD1 was initiated by borrelial lipids acting through TLR-2 within minutes, but required 3 days for maximum effect. The delay in CD1 protein appearance involved a multi-step process whereby TLR-2 stimulated cells release soluble factors, which are sufficient to transfer the CD1-inducing effect in trans to other cells. Analysis of these soluble factors identified IL-1 beta as a previously unknown pathway leading to group 1 CD1 protein function. This study establishes that upregulation of group 1 CD1 proteins is an early event in B. burgdorferi infection and suggests a stepwise mechanism whereby bacterial cell walls, TLR activation and cytokine release cause DC precursors to express group 1 CD1 proteins. C1 [Yakimchuk, Konstantin; Roura-Mir, Carme; Magalhaes, Kelly G.; de Jong, Annemieke; Kasmar, Anne G.; Cheng, Tan-Yun; Moody, D. Branch] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Granter, Scott R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Granter, Scott R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Budd, Ralph] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Steere, Allen] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Pena-Cruz, Victor] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kirschning, Carsten] Univ Duisburg Essen, Inst Med Microbiol, Essen, Germany. RP Moody, DB (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Smith Bldg,Room 514,1 Jimmy Fund Way, Boston, MA 02115 USA. EM bmoody@rics.bwh.harvard.edu RI Roura-Mir, Carme/D-4538-2013 OI Roura-Mir, Carme/0000-0003-0514-337X FU NIH [AI R01049313, AR R01048632, AR R0120358]; Pew Foundation; Burroughs Wellcome Fund for Translational Research; Cancer Research Institute and Centers for Disease Control and Prevention [CCU110 291]; The English; Bonter; Mitchell Foundation; Eshe Fund; Lyme/Arthritis Research Fund at Massachusetts General Hospital FX This work was supported by grants from the NIH (AI R01049313, AR R01048632, AR R0120358), the Pew Foundation Scholars in the Biomedical Sciences Program, The Burroughs Wellcome Fund for Translational Research, the Cancer Research Institute and Centers for Disease Control and Prevention, (CCU110 291), The English, Bonter, Mitchell Foundation, the Eshe Fund, and the Lyme/Arthritis Research Fund at Massachusetts General Hospital. The authors thank Justin D. Radolf for providing B. burgdorferi strains and advice, Sam Behar and Steve Porcelli for providing antibodies to CD1, Nitin Damle and Vijay Sikand for performing the skin biopsies, and Jenny Shin for cutting sections of the EM biopsy samples. NR 63 TC 19 Z9 19 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2011 VL 41 IS 3 BP 694 EP 705 DI 10.1002/eji.201040808 PG 12 WC Immunology SC Immunology GA 731HU UT WOS:000288097700015 PM 21246541 ER PT J AU Sandoval, KE Farr, SA Banks, WA Niehoff, ML Morley, JE Crider, AM Witt, KA AF Sandoval, Karin E. Farr, Susan A. Banks, William A. Niehoff, Michael L. Morley, John E. Crider, Albert M. Witt, Ken A. TI Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Somatostatin subtype-4 receptor agonist; NNC 26-9100; Alzheimer's disease; Learning; Memory ID AMYLOID-BETA PEPTIDE; BLOOD-BRAIN-BARRIER; FOOTSHOCK AVOIDANCE ACQUISITION; LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; SENILE-DEMENTIA; A-BETA; PROTEIN; NEPRILYSIN; RETENTION AB Selective somatostatin receptor subtype agonists have been proposed as a means to mitigate learning and memory loss associated with Alzheimer's disease. The first aim of this study evaluated blood-to-brain transport and regional brain distribution of NNC 26-9100, a selective somatostatin subtype-4 (sst4) receptor agonist. The entry rate of I-131-NNC 26-9100 was K-i = 0.25 mu l/g min, with an similar to 93% association with the parenchymal component. The second goal of this study was to evaluate the effect of chronic NNC 26-9100 administration (i.p.) on learning and memory, brain A beta(x-42) levels, and protein expression of sst4 receptor and amyloid precursor protein (APP) in the senescence-accelerated mouse p8 (SAMP8) model of Alzheimer's disease. Mice chronically treated with NNC 26-9100 showed improved learning (day 21) and memory (day 28) using the T-maze paradigm (20 and 200 mu g). Ex vivo tissue analyses showed a decline in A beta(x-42) levels at the 20 mu g dose, while no alterations were observed in sst4 receptor or APP protein expression compared to vehicle controls. These findings indicate NNC 26-9100 is taken up into key brain regions associated with learning and memory. Furthermore, chronic administration of NNC 26-9100 improved learning and memory and decreased A beta(x-42) brain levels. These results suggest sst4 receptor agonists may provide a viable therapy in the treatment of Alzheimer's disease and other forms of cognitive impairment. (C) 2010 Elsevier B.V. All rights reserved. C1 [Witt, Ken A.] So Illinois Univ, Sch Pharm, Dept Pharmaceut Sci, Edwardsville, IL 62026 USA. [Farr, Susan A.; Niehoff, Michael L.; Morley, John E.] Vet Affairs Med Ctr St Louis, Ctr Geriatr Res Educ & Clin, St Louis, MO USA. [Farr, Susan A.; Niehoff, Michael L.; Morley, John E.] St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr, St Louis, MO 63103 USA. [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. [Banks, William A.] Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA USA. RP Witt, KA (reprint author), So Illinois Univ, Sch Pharm, Dept Pharmaceut Sci, Campus Box 2000, Edwardsville, IL 62026 USA. EM kwitt@siue.edu RI morley, john/F-9177-2011 OI morley, john/0000-0001-6444-2965 FU Alzheimer's Drug Discovery Foundation [261105.01]; VA; National Institutes of Health National Institute on Aging [R21AG029318] FX This work was supported by the Alzheimer's Drug Discovery Foundation (Grant: 261105.01), VA merit review, and the National Institutes of Health National Institute on Aging (Grant: R21AG029318). NR 42 TC 11 Z9 13 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAR 1 PY 2011 VL 654 IS 1 BP 53 EP 59 DI 10.1016/j.ejphar.2010.12.013 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 720OY UT WOS:000287291200008 PM 21185826 ER PT J AU Bubber, P Hartounian, V Gibson, GE Blass, JP AF Bubber, P. Hartounian, V. Gibson, G. E. Blass, J. P. TI Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Mitochondria; Tricarboxylic acid cycle; Energy metabolism; Postmortem interval; Schizophrenia ID ALPHA-KETOGLUTARATE DEHYDROGENASE; MITOCHONDRIAL DYSFUNCTION; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; GLUCOSE-TOLERANCE; PREFRONTAL CORTEX; ENZYMES; METABOLISM; COMPLEX; GLYCOLYSIS AB Images of brain metabolism and measurements of activities of components of the electron transport chain support earlier studies that suggest that brain glucose oxidation is inherently abnormal in a significant proportion of persons with schizophrenia. Therefore, we measured the activities of enzymes of the tricarboxylic (TCA) cycle in dorsolateral-prefrontal-cortex from schizophrenia patients (N=13) and non-psychiatric disease controls (N=13): the pyruvate dehydrogenase complex (PDHC), citrate synthase (CS), aconitase, isocitrate dehydrogenase (ICDH), the alpha-ketoglutarate dehydrogenase complex (KGDHC), succinate thiokinase (STH), succinate dehydrogenase (SDH), fumarase and malate dehydrogenase (MDH). Activities of aconitase (18.4%, p<0.05), KGDHC (26%) and STH (28.2%, p<0.05), enzymes in the first half of the TCA cycle, were lower, but SDH (18.3%, p<0.05) and MDH (34%, p<0.005), enzymes in the second half, were higher than controls. PDHC, CS, ICDH and fumarase activities were unchanged. There were no significant correlations between enzymes of TCA cycle and cognitive function, age or choline acetyl transferase activity, except for aconitase activity which decreased slightly with age (r = 0.55, p = 003). The increased activities of dehydrogenases in the second half of the TCA cycle may reflect a compensatory response to reduced activities of enzymes in the first half. Such alterations in the components of TCA cycle are adequate to alter the rate of brain metabolism. These results are consistent with the imaging studies of hypometabolism in schizophrenia. They suggest that deficiencies in mitochondrial enzymes can be associated with mental disease that takes the form of schizophrenia. (C) 2010 Elsevier B.V. and ECNP. All rights reserved. C1 [Gibson, G. E.] Cornell Univ, Weill Cornell Med Sch, Burke Med Res Inst, Weill Med Coll, White Plains, NY 10605 USA. [Hartounian, V.] Mt Sinai Sch Med, New York, NY USA. [Hartounian, V.] Bronx Vet Affairs Med Ctr, MIRECC, Bronx, NY 10468 USA. RP Gibson, GE (reprint author), Cornell Univ, Weill Cornell Med Sch, Burke Med Res Inst, Weill Med Coll, 785 Mamaroneck Ave, White Plains, NY 10605 USA. EM ggibson@med.cornell.edu FU Burke Medical Research Institute; NIH [AG14600, AG11921, AG14930]; [MH064673]; [MH066392] FX This work was supported by grants MH064673 and MH066392, AG14600, AG11921, AG14930, AG11921 and Burke Medical Research Institute. The funding sources were not involved in study design, collection analysis or interpretation of the data, the writing of the report nor submission to Schizophrenia Research.; This work was supported by NIH grants AG14600, AG11921 and AG14930. NR 49 TC 28 Z9 29 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2011 VL 21 IS 3 BP 254 EP 260 DI 10.1016/j.euroneuro.2010.10.007 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 728UU UT WOS:000287900800005 PM 21123035 ER PT J AU Vickers, A Savage, C Bianco, F Mulhall, J Sandhu, J Guillonneau, B Cronin, A Scardino, P AF Vickers, Andrew Savage, Caroline Bianco, Fernando Mulhall, John Sandhu, Jaspreet Guillonneau, Bertrand Cronin, Angel Scardino, Peter TI Cancer Control and Functional Outcomes After Radical Prostatectomy as Markers of Surgical Quality: Analysis of Heterogeneity Between Surgeons at a Single Cancer Center SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Radical prostatectomy; Surgeon heterogeneity; Erectile funcion; Urinary function ID VOLUME; CURVE AB Background: Previous studies have shown that complications and biochemical recurrence rates after radical prostatectomy (RP) vary between different surgeons to a greater extent than might be expected by chance. Data on urinary and erectile outcomes, however, are lacking. Objective: In this study, we examined whether between-surgeon variation, known as heterogeneity, exists for urinary and erectile outcomes after RP. Design, setting, and participants: Our study consisted of 1910 RP patients who were treated by 1 of 11 surgeons between January 1999 and July 2007. Intervention: All patients underwent RP at Memorial Sloan-Kettering Cancer Center. Measurements: Patients were evaluated for functional outcome 1 yr after surgery. Multivariable random effects models were used to evaluate the heterogeneity in erectile or urinary outcome between surgeons, after adjustment for case mix (age, prostate-specific antigen, pathologic stage and grade, comorbidities) and year of surgery. Results and limitations: We found significant heterogeneity in functional outcomes after RP (p < 0.001 for both urinary and erectile function). Four surgeons had adjusted rates of full continence <75%, whereas three had rates >85%. For erectile function, two surgeons in our series had adjusted rates <20%; another two had rates >45%. We found some evidence suggesting that surgeons' erectile and urinary outcomes were correlated. Contrary to the hypothesis that surgeons "trade off" functional outcomes and cancer control, better rates of functional preservation were associated with lower biochemical recurrence rates. Conclusions: A patient's likelihood of recovering erectile and urinary function may differ depending on which of two surgeons performs his RP. Functional preservation does not appear to come at the expense of cancer control; rather, both are related to surgical quality. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Vickers, Andrew] Mem Sloan Kettering Canc Ctr, Hlth Outcomes Res Grp, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Vickers, Andrew; Savage, Caroline; Mulhall, John; Sandhu, Jaspreet; Guillonneau, Bertrand; Scardino, Peter] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Bianco, Fernando] Columbia Univ, Div Urol, Mt Sinai Med Ctr, New York, NY USA. [Mulhall, John; Sandhu, Jaspreet; Guillonneau, Bertrand; Scardino, Peter] Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. [Cronin, Angel] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Vickers, A (reprint author), Mem Sloan Kettering Canc Ctr, Hlth Outcomes Res Grp, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. EM vickersa@mskcc.org OI Vickers, Andrew/0000-0003-1525-6503 FU Prostate Cancer Foundation; Sidney Kimmel Center for Prostate and Urologic Cancers; National Cancer Institute [P50-CA92629] FX Supported in part by funds from David H. Koch provided through the Prostate Cancer Foundation, the Sidney Kimmel Center for Prostate and Urologic Cancers, and a P50-CA92629 SPORE grant from the National Cancer Institute to Peter Scardino. NR 11 TC 52 Z9 55 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAR PY 2011 VL 59 IS 3 BP 317 EP 322 DI 10.1016/j.eururo.2010.10.045 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 712IA UT WOS:000286658600007 PM 21095055 ER PT J AU Ament, JD Stryjewski, TP Pujari, S Siddique, S Papaliodis, GN Chodosh, J Dohlman, CH AF Ament, J. D. Stryjewski, T. P. Pujari, S. Siddique, S. Papaliodis, G. N. Chodosh, J. Dohlman, C. H. TI Cost effectiveness of the type II Boston keratoprosthesis SO EYE LA English DT Article DE decision analysis; cost utility; cost effectiveness; keratoprosthesis; autoimmune diseases ID OSTEO-ODONTO-KERATOPROSTHESIS; STEVENS-JOHNSON-SYNDROME; OCULAR SURFACE DISEASE; TOTAL HIP-ARTHROPLASTY; PENETRATING KERATOPLASTY; EFFECTIVENESS THRESHOLD; CATARACT-SURGERY; UTILITY ANALYSIS; CHEMOPROPHYLAXIS; DECISIONS AB Purpose Despite demonstrated cost effectiveness, not all corneal disorders are amenable to type I Boston keratoprosthesis (KPro) implantation. This includes patients with autoimmune diseases, such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Type II KPro is implanted through the eyelids in severe dry eye and cicatricial diseases, and its cost effectiveness was sought. Patients and methods In a retrospective chart review, 29 patients who underwent type II KPro surgery at the Massachusetts Eye and Ear Infirmary between the years 2000 and 2009 were identified. A total of 11 patients had 5-year follow-up data. Average cost effectiveness was determined by cost-utility analysis, comparing type II KPro surgery with no further intervention. Results Using the current parameters, the cost utility of KPro from third-party insurer (Medicare) perspective was 63 196 $/quality-adjusted life year. Conclusion Efforts to refer those less likely to benefit from traditional corneal transplantation or type I KPro, for type II KPro surgery, may decrease both patient and societal costs. Eye (2011) 25, 342-349; doi:10.1038/eye.2010.197; published online 24 December 2010 C1 [Ament, J. D.; Stryjewski, T. P.; Pujari, S.; Siddique, S.; Papaliodis, G. N.; Chodosh, J.; Dohlman, C. H.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Ament, JD (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM jaredament@post.harvard.edu FU Dr Dohlman's research and development fund FX Dr Dohlman receives no personal profits from the sale of the Boston Keratoprosthesis. Proceeds go to the Massachusetts Eye and Ear Infirmary, and are used to support research and development. The authors are/were employees of the Massachusetts Eye and Ear Infirmary, and receive no financial benefit from the publication of this data. Dr Ament is a Clinical Research Fellow who is paid directly from Dr Dohlman's research and development fund. NR 37 TC 7 Z9 7 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X EI 1476-5454 J9 EYE JI Eye PD MAR PY 2011 VL 25 IS 3 BP 342 EP 349 DI 10.1038/eye.2010.197 PG 8 WC Ophthalmology SC Ophthalmology GA 733DG UT WOS:000288240500010 PM 21183944 ER PT J AU Jia, WW Wang, SW Horner, JW Wang, N Wang, HY Gunther, EJ DePinho, RA Zhu, JY AF Jia, Wenwen Wang, Shuwen Horner, James W. Wang, Ning Wang, Huayan Gunther, Edward J. DePinho, Ronald A. Zhu, Jiyue TI A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis SO FASEB JOURNAL LA English DT Article DE transgenic mouse; hTERT gene; mammary tumor; bioluminescent imaging ID MOUSE TELOMERASE; STEM-CELLS; CATALYTIC SUBUNIT; IMMORTAL CELLS; HTERT GENE; C-MYC; CANCER; EXPRESSION; MICE; ACTIVATION AB Telomerase is tightly regulated in humans relative to mice, owing to the differential regulation of TERT genes. To explore hTERT regulation in vivo, we engineered mice with a 160-kb transgenic bacterial artificial chromosome (BAC) spanning the hTERT locus with a Renilla luciferase (Rluc) cassette downstream of its promoter. Analysis of multiple founder lines revealed that the Rluc expression profile from the transgenic hTERT reporter locus reproduced that of the native hTERT gene in all tissues and organs examined, demonstrating that genetic sequence determined the species-specific developmental regulation of the hTERT gene and that mouse epigenetic and transcription machineries faithfully regulated hTERT transcription. Thus, these mice allowed detailed analyses of developmental hTERT regulation. Both the transgenic hTERT reporter and the endogenous mTERT locus were expressed in early embryonic stages, and their mRNA levels progressively decreased throughout embryonic and postnatal development. Whereas hTERT transcription was much lower than mTERT expression in most organs, it increased significantly during postnatal development of thymus, testis, and ovary. In testis, the Rluc mRNA was enriched in elongating spermatids of seminiferous tubules. In addition, the transcription of transgenic hTERT reporter, but surprisingly not the endogenous mTERT gene, was activated during Wnt1-induced mammary tumorigenesis, allowing the monitoring of tumor development via noninvasive bioluminescent imaging. Collectively, our results demonstrate that the hTERT transgenic reporter system recapitulates the developmental regulation of the hTERT gene in a chromosomal position-independent manner and serves as a legitimate model to explore telomerase regulation in the development of normal and neoplastic tissues in vivo.-Jia, W., Wang, S., Horner, J. W., Wang, N., Wang, H., Gunther, E. J., DePinho, R. A., Zhu, J. A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis. FASEB J. 25, 979-989 (2011). www.fasebj.org C1 [Jia, Wenwen; Wang, Huayan] NW Agr & Forestry A&F Univ, Coll Vet Med, Shaanxi Ctr Stem Cell Engn & Technol, Yangling, Shaanxi, Peoples R China. [Jia, Wenwen; Wang, Shuwen; Wang, Ning; Zhu, Jiyue] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Gunther, Edward J.] Penn State Univ, Coll Med, Jake Gittlen Canc Res Fdn, Hershey, PA 17033 USA. [Horner, James W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. RP Zhu, JY (reprint author), Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, 500 Univ Dr,C4605, Hershey, PA 17033 USA. EM jozl@psu.edu FU U.S. National Institutes of Health [R21CA106470, R01GM071725]; Chinese National Programs for Fundamental Research and Development [2009CB941002]; Chinese Ministry of Education FX The authors thank Longgui Chen for technical assistance, Aimin Liu for RNA in situ hybridization, and Kang Li for the preparation of tissue cryosections. The authors also thank the Macromolecular and Molecular Genetics Core Facilities at Penn State College of Medicine for the excellent services. The work was supported in part by U.S. National Institutes of Health grants R21CA106470 and R01GM071725 (J.Z.), a 973 grant (2009CB941002) from the Chinese National Programs for Fundamental Research and Development (H.W.), and a Ph.D. student scholarship from the Chinese Ministry of Education (W.J.). None of the authors have professional or financial affiliations that can be perceived to bias the presentation of this work. NR 50 TC 11 Z9 11 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2011 VL 25 IS 3 BP 979 EP 989 DI 10.1096/fj.10-173989 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 727MZ UT WOS:000287806200018 PM 21135040 ER PT J AU Bhattacharya, A Lustgarten, M Shi, Y Liu, YH Jang, YC Pulliam, D Jernigan, AL Van Remmen, H AF Bhattacharya, Arunabh Lustgarten, Michael Shi, Yun Liu, Yuhong Jang, Youngmok C. Pulliam, Daniel Jernigan, Amanda L. Van Remmen, Holly TI Increased mitochondrial matrix-directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Oxidative stress; Superoxide; Fatty acid hydroperoxides; Hydrogen peroxide; Mitochondria; Free radicals ID ELECTRON-TRANSPORT CHAIN; RAT-HEART MITOCHONDRIA; NADH-UBIQUINONE OXIDOREDUCTASE; OXYGEN SPECIES PRODUCTION; REACTIVE OXYGEN; COMPLEX-I; ARACHIDONIC-ACID; OXIDATIVE STRESS; BRAIN MITOCHONDRIA; RESPIRATORY CHAIN AB Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOHs) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of this study was to determine whether FA-OOHs can alter skeletal muscle mitochondrial function. We found that FA-OOHs (at low-micromolar concentrations) induce mitochondrial dysfunction assessed by a decrease in the rate of ATP production, oxygen consumption, and activity of respiratory chain complexes land Ill. Using methods to distinguish superoxide release toward the matrix and toward the intermembrane space, we demonstrate that FA-OOHs significantly elevate oxidative stress in the mitochondrial matrix (and not the intermembrane space), with complex I as the major site of superoxide production (most probably from a site upstream of the ubiquinone binding site but downstream from the flavin binding site the-iron sulfur clusters). Our results are the first to indicate that FA-OOHs are, important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOHs, e.g., denervation-induced muscle atrophy. (C) 2010 Published by Elsevier Inc. C1 [Bhattacharya, Arunabh; Lustgarten, Michael; Shi, Yun; Liu, Yuhong; Jang, Youngmok C.; Pulliam, Daniel; Jernigan, Amanda L.; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Bhattacharya, Arunabh; Liu, Yuhong; Pulliam, Daniel; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Shi, Yun; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Van Remmen, Holly] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Van Remmen, H (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. EM vanremmen@uthscsa.edu FU National Institute of Aging [AG20591]; Muscular Dystrophy Association [MDA 10047] FX This work was supported by the National Institute of Aging (Grant AG20591 to H.V.R.) and the Muscular Dystrophy Association (Grant MDA 10047 to H.V.R.). We greatly appreciate the editorial support provided by Ms. Corinne Price. NR 67 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR 1 PY 2011 VL 50 IS 5 BP 592 EP 601 DI 10.1016/j.freeradbiomed.2010.12.014 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 719BQ UT WOS:000287174700005 PM 21172427 ER PT J AU Chan, AT Ogino, S Giovannucci, EL Fuchs, CS AF Chan, Andrew T. Ogino, Shuji Giovannucci, Edward L. Fuchs, Charles S. TI Inflammatory Markers Are Associated With Risk of Colorectal Cancer and Chemopreventive Response to Anti-Inflammatory Drugs SO GASTROENTEROLOGY LA English DT Article DE Colon Cancer; Prevention; Inflammation; Chemoprevention ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; CORONARY-HEART-DISEASE; NATIONAL DEATH INDEX; FACTOR-ALPHA; ASPIRIN USE; DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE AB BACKGROUND & AIMS: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) lower the risk of colorectal cancer (CRC). We investigated whether plasma inflammatory markers were associated with risk of CRC and if use of anti-inflammatory drugs was differentially associated with risk of CRC according to levels of inflammatory markers. METHODS: We measured levels of high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and the soluble tumor necrosis factor receptor 2 (sTNFR-2) in blood samples from 32,826 women, collected from 1989 to 1990. Through 2004, we documented 280 cases of incident CRC; each case was matched for age to 2 randomly selected participants without cancer (controls). Information on anti-inflammatory drug (aspirin and NSAIDs) use was collected biennially. RESULTS: Compared with women in the lowest quartile of plasma levels of sTNFR-2, women in the highest quartile had an increased risk of CRC (multivariate relative risk [RR], 1.67; 95% confidence interval [CI], 1.05-2.68; P for trend = .03). Among women with high baseline levels of sTNFR-2, those who initiated aspirin/NSAID use after blood collection had significant reductions in subsequent risk of CRC (multivariate RR, 0.39; 95% CI, 0.18-0.86). In contrast, among women with low baseline levels of sTNFR-2, initiation of aspirin/NSAID use was not associated with significant risk reduction (multivariate RR, 0.86; 95% CI, 0.41-1.79). Plasma levels of CRP and IL-6 were not significantly associated with CRC risk. CONCLUSIONS: Plasma levels of sTNFR-2, but not CRP or IL-6, are associated with an increased risk of CRC. Anti-inflammatory drugs appear to reduce risk of CRC among women with high, but not low, baseline levels of sTNFR-2. Certain subsets of the population, defined by inflammatory markers, may obtain different benefits from anti-inflammatory drugs. C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chan, Andrew T.; Ogino, Shuji; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, GRJ 722, Boston, MA 02114 USA. EM achan@partners.org FU National Institutes of Health [P01CA87969, P01CA55075, P50CA127003]; [R01 137178]; [U01 CA049449] FX Supported by grants R01 137178, U01 CA049449. P01CA87969, P01CA55075, and P50CA127003 from the National Institutes of Health. Dr Chan is a Damon Runyon Cancer Research Foundation Clinical Investigator. NR 59 TC 23 Z9 23 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2011 VL 140 IS 3 BP 799 EP U183 DI 10.1053/j.gastro.2010.11.041 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730EC UT WOS:000288014700021 ER PT J AU Lok, AS Everhart, JE Wright, EC Di Bisceglie, AM Kim, HY Sterling, RK Everson, GT Lindsay, KL Lee, WM Bonkovsky, HL Dienstag, JL Ghany, MG Morishima, C Morgan, TR AF Lok, Anna S. Everhart, James E. Wright, Elizabeth C. Di Bisceglie, Adrian M. Kim, Hae-Young Sterling, Richard K. Everson, Gregory T. Lindsay, Karen L. Lee, William M. Bonkovsky, Herbert L. Dienstag, Jules L. Ghany, Marc G. Morishima, Chihiro Morgan, Timothy R. CA Halt-C Trial Grp TI Maintenance Peginterferon Therapy and Other Factors Associated With Hepatocellular Carcinoma in Patients With Advanced Hepatitis C SO GASTROENTEROLOGY LA English DT Article DE Interferon Therapy; Hepatitis C Clinical Trial; Interferon Nonresponders; Liver Cancer ID SUSTAINED VIROLOGICAL RESPONSE; LOW-DOSE PEGINTERFERON; INTERFERON-ALPHA; PROLONGED THERAPY; RISK-FACTORS; CIRRHOSIS; TRIAL; METAANALYSIS; PROGRESSION; SURVIVAL AB BACKGROUND & AIMS: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period. METHODS: The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores >= 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years. RESULTS: Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a >= 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03). CONCLUSIONS: Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls. C1 [Lok, Anna S.] Univ Michigan Hlth Syst, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA. [Kim, Hae-Young] New England Res Inst, Watertown, MA 02172 USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Hepatol Sect, Med Ctr, Richmond, VA USA. [Everson, Gregory T.] Univ Colorado, Denver Sch Med, Div Gastroenterol & Hepatol, Sect Hepatol, Aurora, CO USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Morishima, Chihiro] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. RP Lok, AS (reprint author), Univ Michigan Hlth Syst, Div Gastroenterol, 3912 Taubman Ctr,SPC 5362, Ann Arbor, MI 48109 USA. EM aslok@umich.edu OI Yang, Shuman/0000-0002-9638-0890 FU University of Massachusetts Medical Center, Worcester, Massachusetts [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, Connecticut [M01RR-06192]; Saint Louis University School of Medicine, St Louis, Missouri [N01-DK-9-2324]; Massachusetts General Hospital, Boston, Massachusetts (Harvard Clinical and Translational Science Center) [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver School of Medicine, Aurora, Colorado [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California-Irvine, Irvine, California [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, Texas (North and Central Texas Clinical and Translational Science Initiative) [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, California [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, Michigan (Michigan Center for Clinical and Health Research) [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, Virginia [N01-DK-9-2322, M01RR-00065]; University of Washington, Seattle, Washington [N01-DK-9-2318]; New England Research Institutes, Watertown, Massachusetts [N01-DK-9-2328]; Hoffmann-La Roche, Inc; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Research Resources, National Institutes of Health; National Institutes of Health FX In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct, and/or care of patients enrolled in this study at each of the participating institutions: University of Massachusetts Medical Center, Worcester, Massachusetts (contract N01-DK-9-2326): Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, and Donna Giansiracusa, RN; University of Connecticut Health Center, Farmington, Connecticut (grant M01RR-06192): Gloria Borders, RN, and Michelle Kelley, RN, ANP; Saint Louis University School of Medicine, St Louis, Missouri (contract N01-DK-9-2324): Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, and Debra King, RN; Massachusetts General Hospital, Boston, Massachusetts (contract N01-DK-9-2319, grant M01RR-01066; grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center): Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, and David P. Lundmark; University of Colorado Denver School of Medicine, Aurora, Colorado (contract N01-DK-9-2327, grant M01RR-00051, grant 1 UL1 RR 025780-01): Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, and Carol McKinley, RN; University of California-Irvine, Irvine, California (contract N01-DK-9-2320, grant M01RR-00827): John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, and Choon Park, RN; University of Texas Southwestern Medical Center, Dallas, Texas (contract N01-DK-9-2321, grant M01RR-00633, grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative): Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, and Nancy Liston, MPH; University of Southern California, Los Angeles, California (contract N01-DK-9-2325, grant M01RR-00043): Sugantha Govindarajan, MD, Carol B. Jones, RN, and Susan L. Milstein, RN; University of Michigan Medical Center, Ann Arbor, Michigan (contract N01-DK-9-2323, grant M01RR-00042, grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research): Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, and R. Tess Bonham, BS; Virginia Commonwealth University Health System, Richmond, Virginia (contract N01-DK-9-2322, grant M01RR-00065): Mitchell L. Shiffman, MD, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, and Paula Smith, RN; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland: T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, and Vanessa Haynes-Williams, RN; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, Maryland: Leonard B. Seeff, MD, Patricia R. Robuck, PhD, and Jay H. Hoofnagle, MD; University of Washington, Seattle, Washington (contract N01-DK-9-2318): David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, and Natalia Antonov, MEd; New England Research Institutes, Watertown, Massachusetts (contract N01-DK-9-2328): Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, and Margaret C. Bell, MS, MPH; Inova Fairfax Hospital, Falls Church, Virginia: Zachary D. Goodman, MD, PhD, Fanny Monge, and Michelle Parks; Data and Safety Monitoring Board Members: Gary L. Davis, MD (Chair), Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, and Robert P. Perrillo, MD.; The authors disclose the following: Dr Lok is a consultant and receives research support from Hoffmann-La Roche, Inc; Dr Di Bisceglie is a consultant and receives research support from Hoffmann-La Roche, Inc; Dr Sterling is a consultant and receives research support from Hoffmann-La Roche, Inc; Dr Everson is a consultant and receives research support from Hoffmann-La Roche, Inc; Dr Lindsay was a consultant and received research support from Hoffmann-La Roche, Inc, during this study and is now an employee of Tibotec, Inc (a subsidiary of Johnson and Johnson; Titusville, NJ); Dr Lee receives research support from Hoffmann-La Roche, Inc; Dr Bonkovsky receives research support from Hoffmann-La Roche, Inc; and Dr Morgan receives research support from Hoffmann-La Roche, Inc. The remaining authors disclose no conflicts.; Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed in the acknowledgments). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, and General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the acknowledgments). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc, through a Cooperative Research and Development Agreement with the National Institutes of Health. NR 29 TC 107 Z9 114 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2011 VL 140 IS 3 BP 840 EP U230 DI 10.1053/j.gastro.2010.11.050 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730EC UT WOS:000288014700025 PM 21129375 ER PT J AU Parekkadan, B Upadhyay, R Dunham, J Iwamoto, Y Mizoguchi, E Mizoguchi, A Weissleder, R Yarmush, ML AF Parekkadan, Biju Upadhyay, Rabi Dunham, Joshua Iwamoto, Yoshiko Mizoguchi, Emiko Mizoguchi, Atsushi Weissleder, Ralph Yarmush, Martin L. TI Bone Marrow Stromal Cell Transplants Prevent Experimental Enterocolitis and Require Host CD11b(+) Splenocytes SO GASTROENTEROLOGY LA English DT Article DE Crohn's Disease; Mesenchymal Stem Cells; Monocyte; Imaging ID MESENCHYMAL STEM-CELLS; INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; IMMUNE-RESPONSE; IN-VIVO; THERAPY; INFUSION; MICE; DIFFERENTIATION AB BACKGROUND & AIMS: Bone marrow stromal cells (MSCs) are being evaluated as a cellular therapeutic for immune-mediated diseases. We investigated the effects of MSCs in mice with chemically induced colitis and determined the effects of CD11b(+) cells based on the hypothesis that MSCs increase numbers of regulatory T cells. METHODS: Colitis was induced in mice using trinitrobenzene sulfonic acid; symptoms were monitored as a function of MSC delivery. An immunomodulatory response was determined by measuring numbers of regulatory T cells in mesenteric lymph nodes. In vitro cocultures were used to assess the interaction of MSCs with regulatory T cells and CD11b(+) cells; findings were supported using near-infrared tracking of MSCs in vivo. We chemically and surgically depleted splenic CD11b(+) cells before colitis was induced with trinitrobenzene sulfonic acid to monitor the effects of MSCs. We adoptively transferred CD11b(+) cells that were cocultured with MSCs into mice with colitis. RESULTS: Intravenous grafts of MSCs prevented colitis and increased survival times of mice. Numbers of Foxp3(+) regulatory T cells increased in mesenteric lymph nodes in mice given MSCs. MSCs increased the numbers of Foxp3(+) splenocytes in a CD11b(+) cell-dependent manner. Transplanted MSCs colocalized near splenic CD11b(+) cells in vivo. Loss of CD11b(+) cells eliminated the therapeutic effect of MSCs. MSCs increased the anticolitis effects of CD11b(+) cells in mice. CONCLUSIONS: MSC transplants, delivered by specific parameters, reduce colitis in mice. Interactions between MSC and CD11b(+) regulatory T cells might be used to develop potency assays for MSCs, to identify nonresponders to MSC therapy, and to create new cell grafts that are composed of CD11b(+) cells preconditioned by MSCs. C1 [Parekkadan, Biju; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Parekkadan, Biju; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA USA. [Upadhyay, Rabi; Dunham, Joshua; Iwamoto, Yoshiko; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Mizoguchi, Atsushi] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Dept Med, Boston, MA 02114 USA. RP Parekkadan, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, 51 Blossom St, Boston, MA 02114 USA. EM biju_parekkadan@hms.harvard.edu FU National Institutes of Health [5R01DK059766-06, R01 DK80070, U24CA092782]; Broad Foundation [BMRP498382]; Shriners Hospitals for Children FX This work was partially supported by grants from the National Institutes of Health (5R01DK059766-06, R01 DK80070, and U24CA092782), the Broad Medical Research Program of the Broad Foundation (BMRP498382), and the Shriners Hospitals for Children. NR 34 TC 22 Z9 24 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2011 VL 140 IS 3 BP 966 EP U385 DI 10.1053/j.gastro.2010.10.013 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730EC UT WOS:000288014700037 PM 20955701 ER PT J AU Lugea, A Tischler, D Nguyen, J Gong, J Gukovsky, I French, SW Gorelick, FS Pandol, SJ AF Lugea, Aurelia Tischler, David Nguyen, Janie Gong, Jun Gukovsky, Ilya French, Samuel W. Gorelick, Fred S. Pandol, Stephen J. TI BASIC-LIVER, PANCREAS, AND BILIARY TRACT SO GASTROENTEROLOGY LA English DT Article DE Alcohol Disease; Transcription Factors; ER Protein Folding; Organelle ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; ER STRESS; TRANSLATIONAL CONTROL; IN-VITRO; ETHANOL; XBP1; CELL AB BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress responses (collectively known the unfolded protein response [UPR]) have important roles in several human disorders, but their contribution to alcoholic pancreatitis is not known. We investigated the role of X-box binding protein 1 (XBP1), a UPR regulator, in prevention of alcohol-induced ER stress in the exocrine pancreas. METHODS: Wild-type and Xbp1(+/-) mice were fed control or ethanol diets for 4 weeks. Pancreatic tissue samples were then examined by light and electron microscopy to determine pancreatic alterations; UPR regulators were analyzed biochemically. RESULTS: In wild-type mice, ethanol activated a UPR, increasing pancreatic levels of XBP1 and XBP1 targets such as protein disulfide isomerase (PDI). In these mice, pancreatic damage was minor. In ethanol-fed Xbp1(+/-) mice, XBP1 and PDI levels were significantly lower than in ethanol-fed-wild-type mice. The combination of XBP1 deficiency and ethanol feeding reduced expression of regulators of ER function and the up-regulation of proapoptotic signals. Moreover, ethanol feeding induced oxidation of PDI, which might compromise PDI-mediated disulfide bond formation during ER protein folding. In ethanol-fed Xbp1(+/-) mice, ER stress was associated with disorganized and dilated ER, loss of zymogen granules, accumulation of autophagic vacuoles, and increased acinar cell death. CONCLUSIONS: Long-term ethanol feeding causes oxidative ER stress, which activates a UPR and increases XBP1 levels and activity. A defective UPR due to XBP1 deficiency results in ER dysfunction and acinar cell pathology. C1 [Lugea, Aurelia; Tischler, David; Nguyen, Janie; Gong, Jun; Gukovsky, Ilya; Pandol, Stephen J.] Univ Calif Los Angeles, Vet Adm Greater Los Angeles Healthcare Syst, So Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA 90073 USA. [French, Samuel W.] Harbor UCLA Med Ctr, Dept Pathol, Torrance, CA 90509 USA. [Gorelick, Fred S.] Yale Univ, VA Med Ctr, West Haven, CT USA. RP Lugea, A (reprint author), Univ Calif Los Angeles, Vet Adm Greater Los Angeles Healthcare Syst, So Calif Res Ctr ALPD & Cirrhosis, 11301 Wilshire Blvd,Bldg 258,R339, Los Angeles, CA 90073 USA. EM alugea@ucla.edu FU National Institute on Alcohol Abuse and Alcoholism [R21 AA016010]; National Center for Complementary and Alternative Medicine [1P01AT003960] FX Supported by the National Institute on Alcohol Abuse and Alcoholism (grant R21 AA016010) and the National Center for Complementary and Alternative Medicine (grant 1P01AT003960). NR 53 TC 48 Z9 49 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2011 VL 140 IS 3 BP 987 EP U415 DI 10.1053/j.gastro.2010.11.038 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730EC UT WOS:000288014700039 PM 21111739 ER PT J AU Zatzick, D Rivara, F Jurkovich, G Russo, J Trusz, SG Wang, J Wagner, A Stephens, K Dunn, C Uehara, E Petrie, M Engel, C Davydow, D Katon, W AF Zatzick, Douglas Rivara, Frederick Jurkovich, Gregory Russo, Joan Trusz, Sarah Geiss Wang, Jin Wagner, Amy Stephens, Kari Dunn, Chris Uehara, Edwina Petrie, Megan Engel, Charles Davydow, Dimitri Katon, Wayne TI Enhancing the population impact of collaborative care interventions: mixed method development and implementation of stepped care targeting posttraumatic stress disorder and related comorbidities after acute trauma SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE PTSD; Stepped collaborative care; Acute care; Population impact; Traumatic injury ID RANDOMIZED CONTROLLED-TRIAL; POST-CABG DEPRESSION; FUNCTIONAL OUTCOMES; ANXIETY DISORDERS; PREVENTIVE INTERVENTIONS; BEHAVIORAL ACTIVATION; CLINICAL-RESEARCH; PHYSICAL INJURY; ALCOHOL-ABUSE; FOLLOW-UP AB Objective: The objective of the study was to develop and implement a stepped collaborative care intervention targeting posttraumatic stress disorder (PTSD) and related comorbidities to enhance the population impact of early trauma-focused interventions. Method: We describe the design and implementation of the Trauma Survivors Outcomes and Support study. An interdisciplinary treatment development team was composed of trauma surgical, clinical psychiatric and mental health services "change agents" who spanned the boundaries between frontline trauma center clinical care and acute care policy. Mixed method clinical epidemiologic and clinical ethnographic studies informed the development of PTSD screening and intervention procedures. Results: Two hundred seven acutely injured trauma survivors with high early PTSD symptom levels were randomized into the study. The stepped collaborative care model integrated care management (i.e., posttraumatic concern elicitation and amelioration, motivational interviewing and behavioral activation) with cognitive behavioral therapy and pharmacotherapy targeting PTSD. The model was feasibly implemented by frontline acute care masters in social work and nurse practioner providers. Conclusions: Stepped care protocols targeting PTSD may enhance the population impact of early interventions developed for survivors of individual and mass trauma by extending the reach of collaborative care interventions to acute care medical settings and other nonspecialty posttraumatic contexts. (C) 2011 Elsevier Inc. All rights reserved. C1 [Zatzick, Douglas; Dunn, Chris] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Harborview Injury Prevent & Res Ctr, Seattle, WA 98104 USA. [Rivara, Frederick] Univ Washington, Sch Med, Dept Pediat, Harborview Injury Prevent & Res Ctr, Seattle, WA 98104 USA. [Jurkovich, Gregory] Univ Washington, Sch Med, Dept Surg, Harborview Injury Prevent & Res Ctr, Seattle, WA 98104 USA. [Russo, Joan; Davydow, Dimitri; Katon, Wayne] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Trusz, Sarah Geiss; Stephens, Kari; Petrie, Megan] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Wang, Jin] Univ Washington, Harborview Med Ctr, Sch Med, Seattle, WA 98104 USA. [Wagner, Amy] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97207 USA. [Uehara, Edwina] Univ Washington, Sch Med, Sch Social Work, Seattle, WA 98104 USA. [Engel, Charles] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. RP Zatzick, D (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Harborview Injury Prevent & Res Ctr, Seattle, WA 98104 USA. EM dzatzick@u.washington.edu FU National Institute of Mental Health [MH073613, MH086814] FX This work was funded by grants MH073613 and MH086814 from the National Institute of Mental Health. The authors thank Jeffrey Love, B.A., for his assistance with the preparation of the manuscript. The views expressed in this article are those of the authors and do not reflect official policy or position of the Department of the Army, The Department of Defense, or any other U.S. Government agency or department. NR 138 TC 31 Z9 31 U1 12 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAR-APR PY 2011 VL 33 IS 2 BP 123 EP 134 DI 10.1016/j.genhosppsych.2011.01.001 PG 12 WC Psychiatry SC Psychiatry GA 745RP UT WOS:000289183700006 PM 21596205 ER PT J AU Ogino, S Chan, AT Fuchs, CS Giovannucci, E AF Ogino, Shuji Chan, Andrew T. Fuchs, Charles S. Giovannucci, Edward TI Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field SO GUT LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; BODY-MASS INDEX; LIFE-STYLE FACTORS; III COLON-CANCER; TUMOR MICROSATELLITE INSTABILITY; K-RAS MUTATIONS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MGMT PROMOTER METHYLATION; ONE-CARBON METABOLISM; SINGLE NUCLEOTIDE POLYMORPHISM AB Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function on a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signalling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic and pathologic process, somatic molecular changes and tumour biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumour molecular changes and the exposures of interest on tumour behaviour (prognosis or clinical outcome) can lead to a better understanding of tumour molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent 'molecular pathologic epidemiology', which is a multidisciplinary field of investigations of the interrelationship between exogenous and endogenous (eg, genetic) factors, tumoural molecular signatures and tumour progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathological investigation is a promising area (GWAS-MPE approach). Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathological epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimise personalised prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward. C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward] Canc Epidemiol Program, Boston, MA USA. [Ogino, Shuji; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Gastrointestinal Malignancies Program, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Fuchs, Charles S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Pathol, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. National Institute of Health [P01 CA87969, P01 CA55075, P50 CA127003, R01 CA137178, K07 CA122826, R01 CA151993] FX This work was supported by U.S. National Institute of Health (P01 CA87969, to S. E. Hankinson; P01 CA55075, to W. C. Willett; P50 CA127003, to CSF; R01 CA137178, to ATC; K07 CA122826, to SO; and R01 CA151993, to SO). NR 308 TC 199 Z9 202 U1 8 U2 39 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD MAR PY 2011 VL 60 IS 3 BP 397 EP 411 DI 10.1136/gut.2010.217182 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 716LJ UT WOS:000286969800019 PM 21036793 ER PT J AU Sinner, MF Lubitz, SA Pfeufer, A Makino, S Beckmann, BM Lunetta, KL Steinbeck, G Perz, S Rahman, R Sonni, A Greenberg, SM Furie, KL Wichmann, HE Meitinger, T Peters, A Benjamin, EJ Rosand, J Ellinor, PT Kaab, S AF Sinner, Moritz F. Lubitz, Steven A. Pfeufer, Arne Makino, Seiko Beckmann, Britt-Maria Lunetta, Kathryn L. Steinbeck, Gerhard Perz, Siegfried Rahman, Rosanna Sonni, Akshata Greenberg, Steven M. Furie, Karen L. Wichmann, H. -Erich Meitinger, Thomas Peters, Annette Benjamin, Emelia J. Rosand, Jonathan Ellinor, Patrick T. Kaeaeb, Stefan TI Lack of replication in polymorphisms reported to be associated with atrial fibrillation SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Arrhythmia; Genetics; Single nucleotide polymorphism; Replication; Meta-analysis ID GENOME-WIDE ASSOCIATION; GENETIC SUSCEPTIBILITY; FAMILIAL AGGREGATION; CHROMOSOME 4Q25; COMMON VARIANTS; CHANNEL GENES; HEART-DISEASE; RISK-FACTORS; LONE; POPULATION AB BACKGROUND Atrial fibrillation (AF) is the most common sustained arrhythmia and has a substantial heritable component. Numerous associations between single nucleotide polymorphisms (SNPs) and AF have been described, but few have been replicated. OBJECTIVE We sought to systematically replicate SNPs that are reported to be associated with AF in two large study samples of European descent. METHODS We searched PubMed for studies reporting associations between SNPs and AF published before July 1, 2007. SNPs were genotyped in two independent case-control samples from Germany and the United States. Associations between SNPs and AF were assessed using logistic regression models adjusting for age, sex, and hypertension. A meta-analysis of the results from the two studies was performed. RESULTS We identified 21 SNPs and the angiotensin-converting enzyme insertion/deletion polymorphism that were reported to be associated with AF in the literature. Nine of these genetic variants were not represented on common genome-wide SNP arrays. We successfully genotyped 21 of these 22 variants in 2,145 cases with AF from the German Competence Network for Atrial Fibrillation and 4,073 controls from the KORA S4 study and 16 variants in 790 cases and 1,330 controls from the Massachusetts General Hospital. None of the SNPs replicated in independent populations with AF. CONCLUSION Our results suggest that previously reported associations to AF were likely false positives and highlight the need for systematic replication of genetic associations in large, independent cohorts to accurately detect variants associated with disease. C1 [Sinner, Moritz F.; Beckmann, Britt-Maria; Steinbeck, Gerhard; Kaeaeb, Stefan] LMU Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81366 Munich, Germany. [Sinner, Moritz F.; Lubitz, Steven A.; Makino, Seiko; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Sinner, Moritz F.; Lunetta, Kathryn L.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Sinner, Moritz F.; Lunetta, Kathryn L.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Lubitz, Steven A.; Meitinger, Thomas] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, Munich, Germany. [Pfeufer, Arne] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Rahman, Rosanna; Sonni, Akshata; Greenberg, Steven M.; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. [Rahman, Rosanna; Sonni, Akshata; Greenberg, Steven M.; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Wichmann, H. -Erich] LMU Munchen, IBE, Chair Epidemiol, D-81366 Munich, Germany. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Whitaker Cardiovasc Inst,Cardiol Div, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Whitaker Cardiovasc Inst,Prevent Med Div, Boston, MA 02118 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. RP Kaab, S (reprint author), LMU Munchen, Klinikum Grosshadern, Dept Med 1, D-81366 Munich, Germany. EM Stefan.Kaab@med.uni-muenchen.de RI Kaab, Stefan/H-3915-2012; Pfeufer, Arne/B-6634-2013; Peters, Annette/A-6117-2011; Meitinger, Thomas/O-1318-2015; OI Lunetta, Kathryn/0000-0002-9268-810X; Benjamin, Emelia/0000-0003-4076-2336 FU LMU [577/569]; German National Genome Research Network NGFN [01 GS 0499, 01 GS 0838]; German Federal Ministry of research [01 EZ 0874]; German Competence Network on AF (AFNET) [01 GI 0204/N]; Leducq Foundation [07-CVD 03]; LMU Excellence Initiative; BMBF German Federal Ministry of research [01EZ0874]; Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; National Institutes of Health [R01NS059727, 5P50NS051343, T32HL007575, R01HL092577]; BMBF; State of Bavaria FX MF Sinner, SA Lubitz, PT Ellinor, and S Kaab contributed equally to this study. This study was funded by an LMU Research Grant FoFoLe 577/569 to Dr. Sinner; the German National Genome Research Network NGFN 01 GS 0499, 01 GS 0838, German Federal Ministry of research 01 EZ 0874, German Competence Network on AF (AFNET) 01 GI 0204/N, Leducq Foundation 07-CVD 03, and LMU Excellence Initiative to Dr. Kaab; the German National Genome Research Network NGFN 01GR0803 and the BMBF German Federal Ministry of research 01EZ0874 to Dr. Pfeufer; the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke to Dr. Ellinor; and the National Institutes of Health to Dr. Rosand (R01NS059727), Dr. Furie (5P50NS051343), Dr. Lubitz (T32HL007575), and Drs. Ellinor and Benjamin (R01HL092577). The KORA platform is funded by the BMBF and by the State of Bavaria. NR 48 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2011 VL 8 IS 3 BP 403 EP 409 DI 10.1016/j.hrthm.2010.11.003 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 726PA UT WOS:000287736200018 PM 21056700 ER PT J AU Martins, PN Chang, S Mahadevapa, B Martins, AB Sheiner, P AF Martins, Paulo N. Chang, Sue Mahadevapa, Basant Martins, Ann-Britt Sheiner, Patricia TI Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury SO HPB LA English DT Article DE liver; transplantation; ischaemia reperfusion injury; outcomes; aging ID SINGLE-CENTER EXPERIENCE; HEAT-SHOCK RESPONSE; EXTENDED CRITERIA; COLD ISCHEMIA; RISK-FACTORS; ORGAN-TRANSPLANTATION; PRIMARY NONFUNCTION; IMMUNE-RESPONSE; AGE; SURVIVAL AB Background: There is a general concern that aged organs are more susceptible to ischaemia. In the light of recent proposals to change the liver allocation system by expanding regional sharing, it is feared that increased cold ischaemia time of grafts from older donors may reduce graft survival. The aim of this study was to correlate donor age and the patterns of ischaemia reperfusion injury and synthetic function early after liver transplantation. Methods: We performed a retrospective study of first transplants using a single-centre electronic database. Patterns of liver injury (based on transaminases and post-reperfusion biopsy), synthetic function (international normalized ratio [INR]), and graft and patient survival in recipients receiving liver grafts from donors aged >= 65 years (group 1, n = 50) were compared with equivalent patterns in a matched cohort of recipients transplanted with grafts from donors aged < 65 years (group 2, n = 50). Results: There was no significant difference in transaminase levels from day 0 to day 6 after transplantation. When groups 1 and 2 were subdivided into two subgroups based on the duration of graft cold ischaemia time (< 8 h and >= 8 h), there was no statistical difference in transaminase levels during the first 7 days. There were two cases (4%) of primary non-function in group 1 and one (2%) in group 2. Initial poor function did not differ significantly between the groups (26% vs. 24%; P = 0.81). In addition, there was no difference in histological changes in post-reperfusion biopsies (21% vs. 34%; P = 0.078) and rate of acute rejection episodes in the first year (30% vs. 32%; P = 0.99). There was no significant difference between groups 1 and 2 in 1-year patient and graft survivals (78% vs. 90% [P = 0.17]; 88% vs. 94% [P = 0.48], respectively). Conclusions: Judiciously selected livers from aged donors are not associated with major increased susceptibility to ischaemia reperfusion injury. C1 [Martins, Paulo N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplant Ctr, Boston, MA 02114 USA. [Chang, Sue; Mahadevapa, Basant; Martins, Ann-Britt; Sheiner, Patricia] New York Med Coll, Dept Surg, Div Hepatobiliary Surg & Transplantat, New York, NY USA. RP Martins, PN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplant Ctr, 55 Fruit St, Boston, MA 02114 USA. EM pnmartins@partners.org NR 56 TC 9 Z9 11 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1365-182X J9 HPB JI HPB PD MAR PY 2011 VL 13 IS 3 BP 212 EP 220 DI 10.1111/j.1477-2574.2010.00275.x PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 719VY UT WOS:000287240800012 PM 21309940 ER PT J AU Kuijk, EW Lopes, SMCDS Geijsen, N Macklon, N Roelen, BAJ AF Kuijk, Ewart W. Lopes, Susana M. Chuva de Sousa Geijsen, Niels Macklon, Nick Roelen, Bernard A. J. TI The different shades of mammalian pluripotent stem cells SO HUMAN REPRODUCTION UPDATE LA English DT Review DE pluripotency; embryonic stem cells; epigenetics; germ cells; iPS cells ID PRIMORDIAL GERM-CELLS; LEUKEMIA INHIBITORY FACTOR; PREIMPLANTATION MOUSE EMBRYOS; CHROMATIN REMODELING COMPLEX; MARMOSET CALLITHRIX-JACCHUS; EARLY LINEAGE SEGREGATION; LONG-TERM PROLIFERATION; PATERNAL X-CHROMOSOME; SELF-RENEWAL; IN-VITRO AB BACKGROUND: Pluripotent stem cells have been derived from a variety of sources such as from the inner cell mass of preimplantation embryos, from primordial germ cells, from teratocarcinomas and from male germ cells. The recent development of induced pluripotent stem cells demonstrates that somatic cells can be reprogrammed to a pluripotent state in vitro. METHODS: This review summarizes our current understanding of the origins of mouse and human pluripotent cells. We pay specific attention to transcriptional and epigenetic regulation in pluripotent cells and germ cells. Furthermore, we discuss developmental aspects in the germline that seem to be of importance for the transition of germ cells towards pluripotency. This review is based on literature from the Pubmed database, using Boolean search statements with relevant keywords on the subject. RESULTS: There are distinct molecular mechanisms involved in the generation and maintenance of the various pluripotent cell types. Furthermore, there are important similarities and differences between the different categories of pluripotent cells in terms of phenotype and epigenetic modifications. Pluripotent cell lines from various origins differ in growth characteristics, developmental potential, transcriptional activity and epigenetic regulation. Upon derivation, pluripotent stem cells generally acquire new properties, but they often also retain a 'footprint' of their tissue of origin. CONCLUSIONS: In order to further our knowledge of the mechanisms underlying self-renewal and pluripotency, a thorough comparison between different pluripotent stem cell types is required. This will progress the use of stem cells in basic biology, drug discovery and future clinical applications. C1 [Roelen, Bernard A. J.] Univ Utrecht, Fac Vet Med, Dept Farm Anim Hlth, NL-3584 CM Utrecht, Netherlands. [Kuijk, Ewart W.; Macklon, Nick] Univ Med Ctr Utrecht, Dept Reprod Med & Gynaecol, Utrecht, Netherlands. [Kuijk, Ewart W.; Geijsen, Niels] Hubrecht Inst KNAW, Utrecht, Netherlands. [Lopes, Susana M. Chuva de Sousa] Leiden Univ, Med Ctr, Dept Anat & Embryol, Leiden, Netherlands. [Geijsen, Niels] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Geijsen, Niels] Harvard Univ, Harvard Stem Cell Inst, Boston, MA USA. [Macklon, Nick] Univ Southampton, Princess Anne Hosp, Div Dev Origins Adult Dis, Dept Obstet & Gynaecol, Southampton, Hants, England. RP Roelen, BAJ (reprint author), Univ Utrecht, Fac Vet Med, Dept Farm Anim Hlth, Yalelaan 104, NL-3584 CM Utrecht, Netherlands. EM b.a.j.roelen@uu.nl OI Kuijk, Ewart/0000-0002-1385-6516 FU Nederlands Organization for Scientific Research [VENI 916.76.015]; Dutch Science Organization NWO; National Institutes of Health FX SCDSL was funded by the Nederlands Organization for Scientific Research (VENI 916.76.015 grant), N.G. was funded by the Dutch Science Organization NWO and the National Institutes of Health. NR 216 TC 18 Z9 18 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD MAR-APR PY 2011 VL 17 IS 2 BP 254 EP 271 DI 10.1093/humupd/dmq035 PG 18 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 723FH UT WOS:000287491400010 PM 20705693 ER PT J AU Subramanian, S Yates, M Vandenbark, AA Offner, H AF Subramanian, Sandhya Yates, Melissa Vandenbark, Arthur A. Offner, Halina TI Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3+regulatory T cells implicates compensatory pathways including regulatory B cells SO IMMUNOLOGY LA English DT Article DE B cells; experimental autoimmune encephalomyelitis; Foxp3-DTR; Foxp3; oestrogen ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; PRODUCE CXCL13; CUTTING EDGE; MICE; INDUCTION; TOLERANCE; ARTHRITIS; RESPONSES; SEVERITY AB P>Oestrogen (17 beta-oestradiol, E(2)) is a highly effective treatment for experimental autoimmune encephalomyelitis (EAE) that may potentiate Foxp3+ regulatory T (Treg) cells, which in turn limit the expansion of encephalitogenic T-cell specificities. To determine if Treg cells constitute the major non-redundant protective pathway for E(2), we evaluated E(2) protection of EAE after targeted deletion of Foxp3 expression in Foxp3-DTR mice. Unexpectedly, E(2)-treated Foxp3-deficient mice were completely protected against clinical and histological myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide-induced EAE before succumbing to diphtheria toxin-induced mortality. This finding indicated the presence of alternative E(2)-dependent EAE-protective pathways that could compensate for the lack of Treg cells. Further investigation revealed that E(2) treatment inhibited proliferation and expression of CCL2 and CXCL2, but enhanced secretion of interleukin-10 (IL-10) and IL-13 by MOG-35-55-specific spleen cells. These changes occurred concomitantly with increased expression of several chemokines and receptors, including CXCL13 and CXCR5, and the negative co-activation molecules, PD-L1 and B7.2, by B cells and dendritic cells. Furthermore, E(2) treatment resulted in higher percentages of spleen and lymph node T cells expressing IL-17, interferon-gamma and tumour necrosis factor-alpha, but with lower expression of CCR6, suggesting sequestration of MOG-35-55 peptide-specific T cells in peripheral immune organs. Taken together, these data suggest that E(2)-induced mechanisms that provide protection against EAE in the absence of Foxp3+ Treg cells include induction of regulatory B cells and peripheral sequestration of encephalitogenic T cells. C1 [Subramanian, Sandhya; Yates, Melissa; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. [Yates, Melissa; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU National Institutes of Health [NS45445, NS49210]; National Multiple Sclerosis Society [RG3405-C-6, FG1832-A-1]; Biomedical Laboratory R&D Service, Department of Veterans' Affairs FX The authors wish to thank Dr Sushmita Sinha for helpful discussions and Ms Eva Niehaus for assistance with manuscript preparation. This work was supported by National Institutes of Health grants NS45445 and NS49210; National Multiple Sclerosis Society grant RG3405-C-6; and the Biomedical Laboratory R&D Service, Department of Veterans' Affairs. Dr Melissa Yates is a Postdoctoral Fellow of the National Multiple Sclerosis Society and this work was supported in part by the National Multiple Sclerosis Society Postdoctoral Fellowship FG1832-A-1. NR 37 TC 23 Z9 27 U1 1 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD MAR PY 2011 VL 132 IS 3 BP 340 EP 347 DI 10.1111/j.1365-2567.2010.03380.x PG 8 WC Immunology SC Immunology GA 714WI UT WOS:000286839300004 PM 21091909 ER PT J AU Marley, CS Lerner, LB Panagopoulos, G Kavaler, E AF Marley, Clara S. Lerner, Lori B. Panagopoulos, Georgia Kavaler, Elizabeth TI Personal, Professional and Financial Satisfaction among American Women Urologists SO INTERNATIONAL BRAZ J UROL LA English DT Article DE urology; urologists; women; clinical practice ID CAREER SATISFACTION; SURGICAL SUBSPECIALTY; GENDER-DIFFERENCES; SURGEONS; PHYSICIANS AB Purpose: Although nearly half of American medical school classes are comprised of women, less than 5% of female medical students enter the surgical subspecialties compared to nearly 20% of male students. Many women are concerned that a career in a surgical field will limit their personal choices. In an effort to evaluate if urology is conducive to a satisfying lifestyle, we surveyed all 365 board certified women urologists in the United States in 2007 to find out how satisfied they are with their choice of urology. Materials and Methods: A 114 item anonymous survey was mailed to all 365 American Board Certified female urologists in 2007. Results were analyzed. Results: Of the 244 women (69%) who responded, 86.8% (211) reported being satisfied with their decision to enter urology. Given the choice to repeat the decision, 81% (198) said that they would remain in medicine and 91.4% (222) would choose a surgical subspecialty again. The majority of respondents who stated they would choose a career outside of medicine also stated their family life had been significantly compromised by their career. Those who did not think their family life was compromised reported they would remain in medicine. There was a positive correlation between the level of satisfaction with the work itself and with income level (p = 0.006). Conclusions: Despite the small number of women who choose a career in urology, the number of satisfied women indicates urology is a career conducive to having a balanced and fulfilling life; professionally, personally and financially. C1 [Marley, Clara S.; Panagopoulos, Georgia; Kavaler, Elizabeth] Lenox Hill Hosp, Dept Urol, New York, NY 10075 USA. [Lerner, Lori B.] VA Boston Healthcare Syst, W Roxbury, MA USA. RP Marley, CS (reprint author), Lenox Hill Hosp, Dept Urol, 100 E 77th St, New York, NY 10075 USA. EM ciaramarley@hotmail.com NR 14 TC 3 Z9 3 U1 0 U2 2 PU BRAZILIAN SOC UROL PI RIO DE JANEIRO PA RUA BAMBINA, 153, RIO DE JANEIRO, 2251-050, BRAZIL SN 1677-5538 J9 INT BRAZ J UROL JI Int. Braz J Urol PD MAR-APR PY 2011 VL 37 IS 2 BP 187 EP 192 DI 10.1590/S1677-55382011000200005 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 773RF UT WOS:000291325900013 PM 21557835 ER PT J AU Bleier, BS Schlosser, RJ AF Bleier, Benjamin S. Schlosser, Rodney J. TI Endoscopic anatomy of the postganglionic pterygopalatine innervation of the posterolateral nasal mucosa SO INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY LA English DT Article; Proceedings Paper CT 56th Annual Fall Scientific Meeting of the American-Rhinologic-Society (ARS) CY SEP 25-28, 2010 CL Boston, MA SP Amer Rhinol Soc (ARS) DE vidian neurectomy; vasomotor rhinitis; neurogenic rhinitis; pterygopalatine fossa; parasympathetic innervation ID VIDIAN NEURECTOMY; GANGLION EFFERENTS; CHRONIC RHINITIS AB Background: Recent anatomic dissections have redefined the sinonasal parasympathetic pathway suggesting that individual rami project from the pterygopalatine ganglion (PPG) to innervate the nasal mucosa via multiple small nerve fascicles. The purpose of this study is correlate these anatomic descriptions with endoscopic findings and to define the pattern and location of the posterolateral neurovascular rami. Methods: Eight cadaver heads were utilized for a total of 16 individual sides. A lateral nasal submucosal flap was elevated while preserving all neurovascular bundles perforating the palatine bone. All nerves were traced proximally to confirm their origin. Results: Excluding the sphenopalatine foraminal contents, accessory posterolateral nerves were noted in 87.5%(14/16) of specimens, 50% (7/14) of which contained greater than one. All nerves could be traced directly to the PPG or greater palatine nerve. Of the 25 accessory nerves identified, the most common location was posterosuperior to the horizontal attachment of the inferior turbinate (40%, 10/25). Conclusion: This study supports prior work suggesting that neurons project from the PPG via multiple individual postganglionic rami to supply the nasal mucosa. This new anatomic insight may be exploited to selectively lesion these nerve fascicles in patients with vasomotor rhinitis to improve outcomes while avoiding the morbidities associated with vidian neurectomy. (C) 2011 ARS-AAOA, LLC. C1 [Bleier, Benjamin S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Schlosser, Rodney J.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Bleier, BS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM bleierb@gmail.com NR 14 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2042-6976 J9 INT FORUM ALLERGY RH JI Int. Forum Allergy Rhinol. PD MAR-APR PY 2011 VL 1 IS 2 BP 113 EP 117 DI 10.1002/alr.20011 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 007TW UT WOS:000308912300007 PM 22287329 ER PT J AU Shima, K Nosho, K Baba, Y Cantor, M Meyerhardt, JA Giovannucci, EL Fuchs, CS Ogino, S AF Shima, Kaori Nosho, Katsuhiko Baba, Yoshifumi Cantor, Mami Meyerhardt, Jeffrey A. Giovannucci, Edward L. Fuchs, Charles S. Ogino, Shuji TI Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: cohort study and literature review SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colon cancer; CDKN2A; epigenetics; hypermethylation; prognosis; clinical outcome; survival ID POPULATION-BASED SERIES; MICROSATELLITE INSTABILITY; COLON-CANCER; PHENOTYPE CIMP; CLINICOPATHOLOGICAL FEATURES; LINE-1 HYPOMETHYLATION; INVERSE CORRELATIONS; SHORTER SURVIVAL; DNA METHYLATION; POOR-PROGNOSIS AB A cyclin-dependent kinase inhibitor CDKN2A (p16/Ink4a) is a tumor suppressor and upregulated in cellular senescence. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype ((IMP) in colon cancer. However, prognostic significance of CDKN2A methylation or loss of CDKN2A (p16) expression independent of CIMP status remains uncertain. Using a database of 902 colorectal cancers in 2 independent cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we quantified CDKN2A promoter methylation and detected hypermethylation in 269 tumors (30%). By immunohistochemistry, we detected loss of CDKN2A (p16) expression in 25% (200/804) of tumors. We analyzed for LINE-1 hypomethylation and hypermethylation at 7 (IMP-specific CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of TP53 (p53), CTNNB1 (beta-catenin), CDKN1A (p21), CDKN1B (p27), CCND1 (cyclin D1), FASN (fatty acid synthase) and PTGS2 (cyclooxygenase-2). CDKN2A promoter methylation and loss of CDKN2A (p16) were associated with shorter overall survival in univariate Cox regression analysis [hazard ratio (HR): 1.36, 95% Cl: 1.10-1.66, p = 0.0036 for CDKN2A methylation; HR: 1.30, 95% Cl: 1.03-1.63, p = 0.026 for CDKN2A (p16) loss] but not in multivariate analysis that adjusted for clinical and tumor variables, including (IMP, MSI and LINE-1 methylation. Neither CDKN2A promoter methylation nor toss of CDKN2A (p16) was associated with colorectal cancer-specific mortality in uni- or multivariate analysis. Despite its well-established role in carcinogenesis, CDKN2A (p16) promoter methylation or loss of expression in colorectal cancer is not independently associated with patient prognosis. C1 [Ogino, Shuji] Harvard Univ, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Brigham & Womens Hosp,Med Sch,Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Brigham & Womens Hosp,Med Sch,Dept Med Oncol, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. National Institute of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; The Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX Grant sponsor: U.S. National Institute of Health; Grant numbers: P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826; Grant sponsors: The Bennett Family Fund, the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance, the Japan Society for Promotion of Science; This work was supported by U.S. National Institute of Health (NIH) grants (to S.H., W.W., C.S.F. and S.O.), and in part by grants from The Bennett Family Fund and from the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No conflicts of interest exist. NR 61 TC 43 Z9 46 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2011 VL 128 IS 5 BP 1080 EP 1094 DI 10.1002/ijc.25432 PG 15 WC Oncology SC Oncology GA 716HS UT WOS:000286960300008 PM 20473920 ER PT J AU Yang, HY Magpayo, N Held, KD AF Yang, Hongying Magpayo, Nicole Held, Kathryn D. TI Targeted and non-targeted effects from combinations of low doses of energetic protons and iron ions in human fibroblasts SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article DE targeted effects; non-targeted effects; energetic protons; iron ions ID MEDIATED INTERCELLULAR COMMUNICATION; INDUCED GENOMIC INSTABILITY; IRRADIATED GLIOMA-CELLS; C3H 10T(1)/(2) CELLS; BYSTANDER RESPONSES; IONIZING-RADIATION; NITRIC-OXIDE; ADAPTIVE RESPONSE; CELLULAR COMMUNICATION; UNIRRADIATED CELLS AB Purpose: In space, astronauts are exposed to mixed radiation fields consisting of energetic protons and high atomic number, high energy (HZE) particles at low dose rates. Therefore, it is critical to understand effects of combinations of low doses of different radiation types at the cellular level. Materials and methods: AG01522 normal human skin fibroblasts and a transwell insert co-culture system were used. Irradiations used were 1 GeV/amu (gigaelectron volt/atomic mass unit) protons and 1 GeV/amu iron (Fe) ions. DNA damage was measured as micronucleus (MN) formation and p53 binding protein 1 (53BP1) foci induction. Results: The same magnitude of DNA damage was induced in cells sequentially exposed to 1 cGy protons and 1 cGy Fe ions as in cells irradiated with either protons or Fe ions alone. The same magnitude of DNA damage was also observed in non-irradiated bystander cells sharing medium with cells irradiated with either 1 cGy protons or iron ions or protons plus iron ions. However, when the 'bystander' cells were exposed to 1 cGy protons up to 3 h before co-culture with Fe ion-irradiated cells, no DNA damage in the 'bystander' cells was observed. Conclusions: These data provide the first evidence of interactions between targeted and non-targeted DNA damage caused by dual exposure to low doses of energetic protons and iron ions. C1 [Yang, Hongying] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA 02129 USA. RP Yang, HY (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, R4406,Bldg 149,CNY, Charlestown, MA 02129 USA. EM hyang5@partners.org FU NSRL; Medical and Biology Departments of Brookhaven National Laboratory; NASA [NNX07AE40G] FX The authors acknowledge the excellent assistance from the support personnel at NSRL and in the Medical and Biology Departments of Brookhaven National Laboratory. In particular, the authors thank Drs Adam Rusek, I-Hung Chiang and Michael Sivertz for their invaluable physics and dosimetry support at NSRL. The authors thank Drs Kevin M. Prise, Howard L. Liber and Robert W. Redmond for many helpful discussions. This research was supported by NASA grant # NNX07AE40G. NR 49 TC 12 Z9 12 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD MAR PY 2011 VL 87 IS 3 BP 311 EP 319 DI 10.3109/09553002.2010.537431 PG 9 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 728GI UT WOS:000287862200008 PM 21158498 ER PT J AU Fan, BJ Wang, DY Pasquale, LR Haines, JL Wiggs, JL AF Fan, Bao Jian Wang, Dan Yi Pasquale, Louis R. Haines, Jonathan L. Wiggs, Janey L. TI Genetic Variants Associated with Optic Nerve Vertical Cup-to-Disc Ratio Are Risk Factors for Primary Open Angle Glaucoma in a US Caucasian Population SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID INTRAOCULAR-PRESSURE; OCULAR HYPERTENSION; HERITABILITY; HEAD; SIZE; EYE; ANOPHTHALMIA; PREVALENCE; EXPRESSION; PREVENTION AB PURPOSE. Genetically complex disorders, such as primary open angle glaucoma (POAG), may include highly heritable quantitative traits as part of the overall phenotype, and mapping genes influencing the related quantitative traits may effectively identify genetic risk factors predisposing to the complex disease. Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample. METHODS. Five SNPs previously associated with optic disc area, or VCDR, were genotyped in 539 POAG cases and 336 controls. Genotype data were analyzed for single SNP associations and SNP interactions with VCDR and POAG. RESULTS. SNPs associated with VCDR rs1063192 (CDKN2B) and rs10483727 (SIX1/SLX6) were also associated with POAG (P = 0.0006 and P = 0.0043 for rs1063192 and rs10483727, respectively). rs1063192, associated with smaller VCDR, had a protective effect (odds ratio [OR] = 0.73; 95% confidence interval [CH 0.58-0.90), whereas rs10483727, associated with larger VCDR, increased POAG risk (OR = 1.33; 95% CI, 1.08-1.65). POAG risk associated with increased VCDR was significantly influenced by the C allele of rs1900004 (ATOH7), associated with increased optic nerve area (P-interaction = 0.025; OR = 1.89; 95% CI, 1.22-2.94). CONCLUSIONS. Genetic variants influencing VCDR are associated with POAG in a US Caucasian population. Variants associated with optic nerve area are not independently associated with disease but can influence the effects of VCDR variants suggesting that increased optic disc area can significantly contribute to POAG risk when coupled with risk factors controlling VCDR. (Incest Ophthalmol Vis Sci.. 2011; 52:1788-1792) DOI:10.1167/iovs.10-6339 C1 [Fan, Bao Jian; Wang, Dan Yi; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Haines, Jonathan L.] Vanderbilt Univ Sch Med, Ctr Human Genet Res, Nashville, TN USA. RP Wiggs, JL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu RI Haines, Jonathan/C-3374-2012; OI Fan, Baojian/0000-0002-6851-2737 FU National Institutes of Health [EY015872, P30EY014104]; Massachusetts Lions Eye Research Fund; Research to Prevent Blindness FX Supported in part by National Institutes of Health Grants EY015872 and P30EY014104, the Massachusetts Lions Eye Research Fund, and Research to Prevent Blindness. NR 28 TC 61 Z9 63 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2011 VL 52 IS 3 BP 1788 EP 1792 DI 10.1167/iovs.10-6339 PG 5 WC Ophthalmology SC Ophthalmology GA 742SR UT WOS:000288965300071 PM 21398277 ER PT J AU Kim, EH Bird, JA Kulis, M Laubach, S Pons, L Shreffler, W Steele, P Kamilaris, J Vickery, B Burks, AW AF Kim, Edwin H. Bird, J. Andrew Kulis, Michael Laubach, Susan Pons, Laurent Shreffler, Wayne Steele, Pamela Kamilaris, Janet Vickery, Brian Burks, A. Wesley TI Sublingual immunotherapy for peanut allergy: Clinical and immunologic evidence of desensitization SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Peanut allergy; sublingual immunotherapy; desensitization; food allergy ID ANAPHYLACTIC REACTIONS; FOOD ALLERGY; DOUBLE-BLIND; KIWI FRUIT; EXTRACT; FATALITIES; MECHANISMS; CELLS AB Background: There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. Objective: We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. Methods: In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. Results: Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size (P = .020) and decreased basophil responsiveness after stimulation with 10(-2) mu g/mL (P = .009) and 10(-3) mu g/mL (P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months (P = .002) and then steadily decreased over the remaining 8 months (P = .003), whereas peanut-specific IgG4 levels increased during the 12 months (P = .014). Lastly, IL-5 levels decreased after 12 months (P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-gamma production. Conclusion: Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance. (J Allergy Clin Immunol 2011;127:640-6.) C1 [Kim, Edwin H.; Bird, J. Andrew; Kulis, Michael; Laubach, Susan; Pons, Laurent; Steele, Pamela; Kamilaris, Janet; Vickery, Brian; Burks, A. Wesley] Duke Univ, Med Ctr, Dept Pediat, Div Allergy & Immunol, Durham, NC 27710 USA. [Shreffler, Wayne] Massachusetts Gen Hosp, Food Allergy Ctr MGH, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Burks, AW (reprint author), Duke Univ, Med Ctr, Dept Pediat, Div Allergy & Immunol, Box 2644, Durham, NC 27710 USA. EM wesley.burks@duke.edu OI Bird, John/0000-0003-3772-6078 FU National Institutes of Health [NCCAM R01-AT004435-03, 5T32-AI007062-32]; American Academy of Allergy, Asthma & Immunology/Food Allergy Initiative; Wallace Research Foundation [WRF2010.01]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024128]; NIH Roadmap for Medical Research; NIAID; NIH/NIAID; Thrasher Research Fund; American Lung Association; Cephalon; Anaphylaxis Network (FAAN); Wallace Research Foundation FX Supported by the National Institutes of Health: NCCAM R01-AT004435-03, 5T32-AI007062-32; the American Academy of Allergy, Asthma & Immunology/Food Allergy Initiative Howard Gittis Memorial 3rd Year/4th Year Fellowship/Instructor Award (J. A. B.); and the Wallace Research Foundation (WRF2010.01). Additional support for the project was provided by grant UL1RR024128 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.; J. A. Bird has received research support from the American Academy of Allergy, Asthma & Immunology and the Food Allergy Initiative. M. Kulis has received research support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID). W. Shreffler has received research support from the NIAID. B. Vickery has received research support from the NIH/NIAID, Thrasher Research Fund, American Lung Association, and Cephalon. A. W. Burks has consulted for ActoGeniX NV, Intelliject, McNeil Nutritionals, Novartis, and Schering-Plough; is a minority stockholder in Allertein and MastCell, Inc; is on an advisory board for Dannon Co Probiotics; is on an expert panel for Nutricia; has received research support from the NIH, Food Allergy and Anaphylaxis Network (FAAN), and Wallace Research Foundation; and is on the medical board of directors of FAAN. The rest of the authors have declared that they have no conflict of interest. NR 27 TC 144 Z9 150 U1 2 U2 18 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2011 VL 127 IS 3 BP 640 EP U153 DI 10.1016/j.jaci.2010.12.1083 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 730FG UT WOS:000288018400013 PM 21281959 ER PT J AU Marshall-Berenz, EC Vujanovic, AA Zvolensky, MJ AF Marshall-Berenz, Erin C. Vujanovic, Anka A. Zvolensky, Michael J. TI Main and interactive effects of a nonclinical panic attack history and distress tolerance in relation to PTSD symptom severity SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE PTSD; Distress tolerance; Panic attacks; Anxiety ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE PROCESSING THERAPY; PSYCHOMETRIC PROPERTIES; ANXIETY DISORDERS; SCALE; TRAUMA; QUESTIONNAIRE; RELIABILITY; VALIDATION; EXPOSURE AB The current study investigated the main and interactive effects of a nonclinical panic attack history and distress tolerance in relation to PTSD symptoms. The sample consisted of 91 adults (62.6% women; M(age) = 23.45, SD = 9.56) who met DSM-IV criteria for trauma exposure, 53.8% of whom met criteria for a recent (past 2 years) history of nonclinical panic attacks. Results indicated that distress tolerance, as measured by the Distress Tolerance Scale (Simons & Gaher, 2005), was significantly related to all PTSD symptom clusters, and a nonclinical panic attack history was significantly related to PTSD re-experiencing and hyperarousal symptoms. The interaction of a nonclinical panic attack history and distress tolerance significantly predicted unique variance in only PTSD hyperarousal symptoms. Implications and future directions are discussed for the role of nonclinical panic attacks and distress tolerance in PTSD symptom expression. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Marshall-Berenz, Erin C.; Zvolensky, Michael J.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Vujanovic, Anka A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Zvolensky, MJ (reprint author), Univ Vermont, Dept Psychol, 2 Colchester Ave,John Dewey Hall, Burlington, VT 05405 USA. EM Michael.Zvolensky@uvm.edu FU NIDA NIH HHS [1 R01 DA027533-01, R01 DA027533]; NIMH NIH HHS [1 F31 MH080453-01A1, 1 R01 MH076629-01, F31 MH080453, R01 MH076629, R01 MH076629-01A2] NR 43 TC 12 Z9 12 U1 5 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD MAR PY 2011 VL 25 IS 2 BP 185 EP 191 DI 10.1016/j.janxdis.2010.09.001 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 716YJ UT WOS:000287009100005 PM 20888732 ER PT J AU Wu, XX Patki, A Lara-Castro, C Cui, XQ Zhang, K Walton, RG Osier, MV Gadbury, GL Allison, DB Martin, M Garvey, WT AF Wu, Xuxia Patki, Amit Lara-Castro, Cristina Cui, Xiangqin Zhang, Kui Walton, R. Grace Osier, Michael V. Gadbury, Gary L. Allison, David B. Martin, Mitchell Garvey, W. Timothy TI Genes and biochemical pathways in human skeletal muscle affecting resting energy expenditure and fuel partitioning SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE microarray; human; skeletal muscle; G protein-coupled receptor; ubiquitin; protein phosphatase 2A; mitochondrial function; respiratory quotient ID BODY-WEIGHT GAIN; BROWN ADIPOSE-TISSUE; BETA-ADRENERGIC-BLOCKADE; PROTEIN MESSENGER-RNA; METABOLIC-RATE; UNCOUPLING PROTEINS; RESPIRATORY QUOTIENT; UBIQUITIN-PROTEASOME; INSULIN-RESISTANCE; DIABETES-MELLITUS AB Wu X, Patki A, Lara-Castro C, Cui X, Zhang K, Walton RG, Osier MV, Gadbury GL, Allison DB, Martin M, Garvey WT. Genes and biochemical pathways in human skeletal muscle affecting resting energy expenditure and fuel partitioning. J Appl Physiol 110: 746-755, 2011. First published November 25, 2010; doi:10.1152/japplphysiol.00293.2010.-Genes influencing resting energy expenditure (REE) and respiratory quotient (RQ) represent candidate genes for obesity and the metabolic syndrome because of the involvement of these traits in energy balance and substrate oxidation. We aim to explore the molecular basis for individual variation in REE and fuel partitioning as reflected by RQ. We performed microarray studies in human vastus lateralis muscle biopsies from 40 healthy subjects with measured REE and RQ values. We identified 2,392 and 1,115 genes significantly correlated with REE and RQ, respectively. Genes correlated with REE and RQ encompass a broad array of functions, including carbohydrate and lipid metabolism, gene expression, mitochondrial processes, and membrane transport. Microarray pathway analysis revealed that REE was positively correlated with upregulation of G protein-coupled receptor signaling (meet criteria/total genes: 65 of 283) involved in autonomic nervous system functions, including those receptors mediating adrenergic, dopamine, gamma-aminobutyric acid (GABA), neuropeptide Y (NPY), and serotonin action (meet criteria/total genes: 46 of 176). Reduced REE was associated with an increase in genes participating in ubiquitin-proteasome-dependent proteolytic pathways (58 of 232). Serine-type peptidase activity (9 of 76) was positively correlated with RQ, while genes involved in the protein phosphatase type 2A complex (4 of 9), mitochondrial function and cellular respiration (38 of 315), and unfolded protein binding (19 of 97) were associated with reduced RQ values and a preference for lipid fuel metabolism. Individual variations in whole body REE and RQ are regulated by differential expressions of specific genes and pathways intrinsic to skeletal muscle. C1 [Wu, Xuxia; Lara-Castro, Cristina; Walton, R. Grace; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Patki, Amit; Cui, Xiangqin; Zhang, Kui; Allison, David B.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Osier, Michael V.] Rochester Inst Technol, Sch Biol & Med Sci, Rochester, NY 14623 USA. [Gadbury, Gary L.] Kansas State Univ, Dept Stat, Manhattan, KS 66506 USA. [Martin, Mitchell] Roche, Mol Med Labs, Nutley, NJ USA. RP Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, 1675 Univ Blvd, Birmingham, AL 35294 USA. EM garveyt@uab.edu OI Cui, Xiangqin/0000-0003-0621-9313; Allison, David/0000-0003-3566-9399 FU National Institutes of Health [DK-038764, DK-083562, HL-055782]; American Heart Association; Department of Veterans Affairs; University of Alabama at Birmingham (UAB) Center for Clinical and Translational Science [UL1-RR-025777]; UAB Nutrition and Obesity Research Center [P30-DK-56336]; UAB Diabetes Research and Training Center [P60-DK-079626] FX This work was supported by grants from the National Institutes of Health (DK-038764, DK-083562, and HL-055782 to W. T. Garvey), by an American Heart Association Beginning Grant-in-Aid (X. Wu), and by the Merit Review program of the Department of Veterans Affairs (W. T. Garvey). We gratefully acknowledge the support of the research core facilities of the University of Alabama at Birmingham (UAB) Center for Clinical and Translational Science (UL1-RR-025777), the UAB Nutrition and Obesity Research Center (P30-DK-56336), and the UAB Diabetes Research and Training Center (P60-DK-079626). NR 78 TC 7 Z9 7 U1 0 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD MAR PY 2011 VL 110 IS 3 BP 746 EP 755 DI 10.1152/japplphysiol.00293.2010 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 731RN UT WOS:000288127100023 PM 21109598 ER PT J AU Porterfield, JE Larson, ER Jenkins, JT Escobedo, D Valvano, JW Pearce, JA Feldman, MD AF Porterfield, John E. Larson, Erik R. Jenkins, James T. Escobedo, Daniel Valvano, Jonathan W. Pearce, John A. Feldman, Marc D. TI Left ventricular epicardial admittance measurement for detection of acute LV dilation SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE early detection of heart failure; bioimpedance; left ventricular preload; end-diastolic volume; conductance ID CHRONIC HEART-FAILURE; CARDIAC-RESYNCHRONIZATION; IMPLANTABLE DEFIBRILLATOR; CONDUCTANCE CATHETER; HEMODYNAMIC MONITOR; VOLUME; SYSTEM; ALPHA; RESISTIVITY; FEASIBILITY AB There are two implanted heart failure warning systems incorporated into biventricular pacemakers/automatic implantable cardiac defibrillators and tested in clinical trials: right heart pressures, and lung conductance measurements. However, both warning systems postdate measures of the earliest indicator of impending heart failure: left ventricular (LV) volume. There are currently no proposed implanted technologies that can perform LV blood volume measurements in humans. We propose to solve this problem by incorporating an admittance measurement system onto currently deployed biventricular and automatic implantable cardiac defibrillator leads. This study will demonstrate that an admittance measurement system can detect LV blood conductance from the epicardial position, despite the current generating and sensing electrodes being in constant motion with the heart, and with dynamic removal of the myocardial component of the returning voltage signal. Specifically, in 11 pigs, it will be demonstrated that 1) a physiological LV blood conductance signal can be derived; 2) LV dilation in response to dose-response intravenous neosynephrine can be detected by blood conductance in a similar fashion to the standard of endocardial crystals when admittance is used, but not when only traditional conductance is used; 3) the physiological impact of acute left anterior descending coronary artery occlusion and resultant LV dilation can be detected by blood conductance, before the anticipated secondary rise in right ventricular systolic pressure; and 4) a pleural effusion simulated by placing saline outside the pericardium does not serve as a source of artifact for blood conductance measurements. C1 [Jenkins, James T.; Escobedo, Daniel; Feldman, Marc D.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78248 USA. [Porterfield, John E.; Larson, Erik R.; Valvano, Jonathan W.; Pearce, John A.] Univ Texas Austin, Austin, TX 78712 USA. [Jenkins, James T.; Escobedo, Daniel; Feldman, Marc D.] S Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Feldman, MD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Rm 5-642,7703 Floyd Curl Dr, San Antonio, TX 78248 USA. EM feldmanm@uthscsa.edu FU National Institutes of Health [R21 HL 079926]; National Center for Research Resources [UL 1RR025767]; University of Texas Health Science Center in San Antonio (Biscoe Division of Cardiology and South Texas Technology Management); Medtronic Corporation (Minneapolis, MN) FX This study was supported in part by National Institutes of Health Grant R21 HL 079926, Grant UL 1RR025767 from the National Center for Research Resources, and grants from the University of Texas Health Science Center in San Antonio (Biscoe Division of Cardiology and South Texas Technology Management). Research was funded in part by a grant given by Medtronic Corporation (Minneapolis, MN). NR 33 TC 3 Z9 3 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD MAR PY 2011 VL 110 IS 3 BP 799 EP 806 DI 10.1152/japplphysiol.01047.2010 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 731RN UT WOS:000288127100029 PM 21148342 ER PT J AU Sabatini, ME Wolkovich, AM Macklin, EA Wright, DL Souter, I Toth, TL AF Sabatini, Mary E. Wolkovich, Ann M. Macklin, Eric A. Wright, Diane L. Souter, Irene Toth, Thomas L. TI Pronuclear embryo cryopreservation experience: outcomes for reducing the risk of ovarian hyperstimulation syndrome and for fertility preservation in cancer patients SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article DE Ovarian hyperstimulation syndrome; OHSS; IVF; Cancer; Fertility preservation ID IN-VITRO FERTILIZATION; ELECTIVE CRYOPRESERVATION; SUBSEQUENT TRANSFER; PREGNANCY RATE; FRESH EMBRYOS; PREVENTION; WOMEN; OHSS; EFFICIENCY; PROTOCOL AB Purpose To evaluate pregnancy rate (PR) and live birth rate (LBR) after freezing pronuclear (PN) embryos for two purposes: to reduce the risk of ovarian hyperstimulation syndrome (OHSS) and to bank embryos for cancer patients anticipating gametotoxic chemotherapy/radiotherapy. Methods Data from 3,621 consecutive IVF cycles were retrospectively analyzed. PN freezing was offered to patients at risk for OHSS and for those wishing to preserve fertility prior to cancer therapy. Primary outcomes evaluated were PR and LBR. Outcomes were compared to patients who underwent fresh embryo transfer (ET) in 2006. Results Sixty-six patients froze PN embryos. Thirty-eight were at risk for OHSS. The LBR was 34.3% after one transfer, and 51.4% after a mean of 1.4 transfers. Twenty-eight cancer patients froze embryos. The LBR was 16.7% after one transfer and 25.0% after a mean of 1.5 transfers. The LBR was 35.5% for patients who underwent fresh ET. Conclusion PN freezing with delayed ET is an effective tool for achieving pregnancy for patients at risk of OHSS and for cancer patients wishing to preserve fertility. C1 [Sabatini, Mary E.; Wolkovich, Ann M.; Wright, Diane L.; Souter, Irene; Toth, Thomas L.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. [Sabatini, Mary E.; Macklin, Eric A.; Souter, Irene; Toth, Thomas L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Sabatini, ME (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, 55 Fruit St, Boston, MA 02114 USA. EM msabatini@partners.org RI Macklin, Eric/E-2955-2013 OI Macklin, Eric/0000-0003-1618-3502 NR 36 TC 5 Z9 6 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD MAR PY 2011 VL 28 IS 3 BP 279 EP 284 DI 10.1007/s10815-010-9515-3 PG 6 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA 778BL UT WOS:000291674000015 PM 21107899 ER PT J AU Zhao, XF Burger, M Liu, Y Das, MK Combs, W Wenk, JF Guccione, JM Kassab, GS AF Zhao, Xuefeng Burger, Mike Liu, Yi Das, Mithilesh K. Combs, William Wenk, Jonathan F. Guccione, Julius M. Kassab, Ghassan S. TI Simulation of LV Pacemaker Lead in Marginal Vein: Potential Risk Factors for Acute Dislodgement SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE pacing lead; lead dislodgement; dynamic analysis ID CORONARY-SINUS; STABILITY; MODEL AB Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design. [DOI: 10.1115/1.4003323] C1 [Kassab, Ghassan S.] Indiana Univ Purdue Univ Indianapolis, Dept Surg, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ Indianapolis, Dept Biomed Engn, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Burger, Mike] Livermore Software Technol Corp, Livermore, CA 94550 USA. [Das, Mithilesh K.] Indiana Univ Sch Med, Roudebush VA Med Ctr, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. [Wenk, Jonathan F.; Guccione, Julius M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA. [Wenk, Jonathan F.; Guccione, Julius M.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Kassab, GS (reprint author), Indiana Univ Purdue Univ Indianapolis, Dept Surg, Indianapolis, IN 46202 USA. EM gkassab@iupui.edu RI Zhao, Xuefeng/A-3260-2013 OI Zhao, Xuefeng/0000-0003-3834-9091 NR 10 TC 2 Z9 2 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD MAR PY 2011 VL 133 IS 3 AR 031006 DI 10.1115/1.4003323 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 718BY UT WOS:000287096100006 ER PT J AU McCurdy, MR Sharafkhaneh, A Abdel-Monem, H Rojo, J Tittel, FK AF McCurdy, Matthew R. Sharafkhaneh, Amir Abdel-Monem, Hanan Rojo, Javier Tittel, Frank K. TI Exhaled nitric oxide parameters and functional capacity in chronic obstructive pulmonary disease SO JOURNAL OF BREATH RESEARCH LA English DT Article ID COPD; ASTHMA; EXCHANGE; BIOMARKERS; DIFFUSION; MARKERS; MODEL; AIR AB The extended exhaled nitric oxide (eNO) parameters, including peripheral or alveolar eNO, are investigational biomarkers in COPD. In this study, the hypothesis was tested that elevated peripheral eNO correlates with decreased functional capacity and lower global health status. Twenty-seven subjects with the Global Initiative for Chronic Obstructive Lung Disease stage 3 and 4 COPD were enrolled. Functional capacity and health status were tested using the 6 min walk test and St George's Respiratory Questionnaire (SGRQ) respectively. eNO parameters were estimated using multiple exhalation flow rates and were corrected for axial diffusion. The extended NO measurements were FE(NO)0.05 14.2 ppb (range 5.1-23.2), C(ANO) 4.6 ppb (2.2-6.9), D(awNO) 8.8 ml s(-1) (4.8-12.9), C(awNO) 83.2 ppb (29.9-128.7) and J'(awNO) 405 pl s(-1) (111-731). The distance traveled in the 6 min walk test was correlated with peripheral nitric oxide (r = -0.59, p = 0.03). SGRQ symptom score was correlated with maximum airway NO flux (r = -0.73, p = 0.01). SGRQ total score was correlated with maximum airway NO flux (r = -0.56, p = 0.05). In this study of subjects with severe COPD, peripheral nitric oxide correlated with functional capacity while large airway NO parameters correlated with symptom scores. C1 [McCurdy, Matthew R.; Tittel, Frank K.] Rice Univ, Rice Quantum Inst, Houston, TX 77251 USA. [McCurdy, Matthew R.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Div Radiat Oncol, Houston, TX 77030 USA. [Sharafkhaneh, Amir; Abdel-Monem, Hanan] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Div Pulm Crit Care & Sleep Med, Houston, TX 77030 USA. [Rojo, Javier] Rice Univ, Dept Stat, Houston, TX 77251 USA. RP Tittel, FK (reprint author), Rice Univ, Rice Quantum Inst, Houston, TX 77251 USA. EM fkt@rice.edu NR 34 TC 28 Z9 28 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1752-7155 J9 J BREATH RES JI J. Breath Res. PD MAR PY 2011 VL 5 IS 1 AR 016003 DI 10.1088/1752-7155/5/1/016003 PG 6 WC Biochemical Research Methods; Respiratory System SC Biochemistry & Molecular Biology; Respiratory System GA 732SM UT WOS:000288210000004 PM 21378438 ER PT J AU Rojas, CA Jaimes, CE El-Sherief, AH Medina, HM Chung, JH Ghoshhajra, B Abbara, S AF Rojas, Carlos A. Jaimes, Camilo E. El-Sherief, Ahmed H. Medina, Hector M. Chung, Jonathan H. Ghoshhajra, Brian Abbara, Suhny TI Cardiac CT of non-shunt pathology of the interatrial septum SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Interatrial septum; Interatrial septal aneurysm; Lipomatous hypertrophy of the interatrial septum AB The development and anatomy of the interatrial septum is complex. With the increasing use of cardiac CT and its precise delineation of the anatomy, it is important for the cardiac imager to become familiar with the normal anatomic structures that compose the interatrial septum and their variants. Furthermore, it is important to recognize pathologic processes occurring in this region other than atrial septal defects and potential imaging pitfalls. This pictorial essay provides a detailed review of these topics with emphasis in CT appearance and related technical aspects. (C) 2011 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Rojas, Carlos A.; El-Sherief, Ahmed H.; Medina, Hector M.; Chung, Jonathan H.; Ghoshhajra, Brian; Abbara, Suhny] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiac Imaging, Boston, MA 02114 USA. [Jaimes, Camilo E.] Univ Rosario, Sch Med & Hlth Sci, Bogota, Colombia. RP Rojas, CA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiac Imaging, 165 Cambridge St, Boston, MA 02114 USA. EM caranrojas@gmail.com RI Ghoshhajra, Brian/J-2114-2016 OI Ghoshhajra, Brian/0000-0002-3865-3432 NR 30 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD MAR-APR PY 2011 VL 5 IS 2 BP 93 EP 100 DI 10.1016/j.jcct.2010.10.011 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA V34CH UT WOS:000209064000004 PM 21130061 ER PT J AU Shih, YYI Wey, HY De La Garza, BH Duong, TQ AF Shih, Yen-Yu I. Wey, Hsiao-Ying De La Garza, Bryan H. Duong, Timothy Q. TI Striatal and cortical BOLD, blood flow, blood volume, oxygen consumption, and glucose consumption changes in noxious forepaw electrical stimulation SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE CBF; CBV; CMRglc; CMRO(2); high-field fMRI; striatum ID FUNCTIONAL MRI; BASAL GANGLIA; SOMATOSENSORY STIMULATION; NEURONAL-ACTIVITY; NEURAL ACTIVITY; RAT; FMRI; ORGANIZATION; ARTERIAL; DYNAMICS AB Recent reports showed noxious forepaw stimulation in rats evoked an unexpected sustained decrease in cerebral blood volume (CBV) in the bilateral striatum, whereas increases in spike activity and Fos-immunoreactive cells were observed. This study aimed to further evaluate the hemodynamic and metabolic needs in this model and the sources of negative functional magnetic resonance imaging (fMRI) signals by measuring blood oxygenation-level-dependent (BOLD), cerebral-blood-flow (CBF), CBV, and oxygen-consumption (i.e., cerebral metabolic rate of oxygen (CMRO(2))) changes using an 11.7-T MRI scanner, and glucose-consumption (i.e., cerebral metabolic rate of glucose (CMRglc)) changes using micro-positron emission tomography. In the contralateral somatosensory cortex, BOLD, CBF, CBV, CMRO(2) (n = 7, P < 0.05), and CMRglc (n = 5, P < 0.05) increased. In contrast, in the bilateral striatum, BOLD, CBF, and CBV decreased (P < 0.05), CMRO(2) decreased slightly, although not significantly from baseline, and CMRglc was not statistically significant from baseline (P > 0.05). These multimodal functional imaging findings corroborate the unexpected negative hemodynamic changes in the striatum during noxious forepaw stimulation, and support the hypothesis that striatal hemodynamic response is dominated by neurotransmitter-mediated vasoconstriction, overriding the stimulus-evoked fMRI signal increases commonly accompany elevated neuronal activity. Multimodal functional imaging approach offers a means to probe the unique attributes of the striatum, providing novel insights into the neurovascular coupling in the striatum. These findings may have strong implications in fMRI studies of pain. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 832-841; doi:10.1038/jcbfm.2010.173; published online 13 October 2010 C1 [Shih, Yen-Yu I.; Wey, Hsiao-Ying; De La Garza, Bryan H.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Wey, Hsiao-Ying; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Duong, Timothy Q.] SW Natl Primate Res Ctr, San Antonio, TX USA. RP Shih, YYI (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM shihy@uthscsa.edu; duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Wey, Hsiao-Ying/G-3031-2012; OI Shih, Yen-Yu Ian/0000-0001-6529-911X FU NIH [R01-NS45879]; American Heart Association [10POST4290091]; San Antonio Area Foundation; Defense Advanced Research Projects Agency [HR0011-07-C-0027]; NIH/NCRR [S10 RR023038] FX This work is supported by NIH R01-NS45879 to TQD, American Heart Association (10POST4290091), and San Antonio Area Foundation to YYIS.; The authors acknowledge Dr Fuqiang Zhao and Dr Ai-Ling Lin for valuable discussion and Mr David A Lewis and Dr Kihak Lee for their assistance with the PET scans. The authors acknowledge the resource supports of the Defense Advanced Research Projects Agency (Comprehensive Facility for Animal Imaging Research (CFAIR), HR0011-07-C-0027) and NIH/NCRR (S10 RR023038). NR 42 TC 26 Z9 26 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2011 VL 31 IS 3 BP 832 EP 841 DI 10.1038/jcbfm.2010.173 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 727ZS UT WOS:000287842700006 PM 20940730 ER PT J AU Pallais, JC Kemp, EH Bergwitz, C Kantham, L Slovik, DM Weetman, AP Brown, EM AF Pallais, J. Carl Kemp, E. Helen Bergwitz, Clemens Kantham, Lakshmi Slovik, David M. Weetman, Anthony P. Brown, Edward M. TI Autoimmune Hypocalciuric Hypercalcemia Unresponsive to Glucocorticoid Therapy in a Patient with Blocking Autoantibodies against the Calcium-Sensing Receptor SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PARATHYROID-HORMONE LEVELS; ACQUIRED HYPOPARATHYROIDISM; ANTIBODIES; HYPERPARATHYROIDISM; CORTICOSTEROIDS; TARGET; CELLS AB Context: Autoantibodies directed against the calcium-sensing receptor (CaSR) have been reported in several individuals with various autoimmune disorders and PTH-mediated hypercalcemia. Previously, glucocorticoid treatment has been shown to decrease the CaSR autoantibody titers and normalize the hypercalcemia in a patient with autoimmune hypocalciuric hypercalcemia (AHH). Objective: The objective of the study was to evaluate a patient with AHH for the presence of blocking autoantibodies against the CaSR and to monitor her biochemical and serological responses to a trial of glucocorticoid therapy. Results: Glucocorticoid treatment had no effect on serum total or ionized calcium concentration or serum PTH levels, all of which remained at higher than normal levels. In contrast, on prednisone, urinary calcium excretion increased from overtly hypocalciuric levels to normal values. Anti-CaSR autoantibodies were detected at similar levels in the patient's serum before, during, and after glucocorticoid treatment. Functional testing of these antibodies showed that they inhibited the stimulatory effect of extracellular Ca2+ on ERK1/2 but did not suppress the calcium-induced accumulation of inositol-1-phosphate. Conclusions: We report a patient with AHH with frankly elevated PTH levels who was found to have autoantibodies against the CaSR. The hypercalcemia and CaSR autoantibody titers failed to respond to glucocorticoid therapy, unlike a previously reported patient with similar clinical and biochemical features. The anti-CaSR antibody-mediated inhibition of CaSR-stimulated ERK1/2 activity, but not of inositol-1-phosphate accumulation, suggests that ERK1/2 may mediate, at least in part, the regulation of PTH secretion and urinary calcium excretion by the CaSR. (J Clin Endocrinol Metab 96: 672-680, 2011) C1 [Pallais, J. Carl; Bergwitz, Clemens; Slovik, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. [Kemp, E. Helen; Weetman, Anthony P.] Univ Sheffield, Sch Med, Dept Human Metab, Sheffield S10 2JF, S Yorkshire, England. [Kantham, Lakshmi; Brown, Edward M.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Kantham, Lakshmi; Brown, Edward M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Pallais, JC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. EM jpallais@partners.org RI Kemp, Elizabeth Helen/D-1665-2011 OI Kemp, Elizabeth Helen/0000-0002-0313-8916 FU National Institutes of Health [DK078331]; Athena Diagnostics, Inc.; calcimimetic, cinacalcet, through NPS Pharmaceuticals, Inc. FX E.M.B. is supported by Grant DK078331 from the National Institutes of Health.; J.C.P., E.H.K., C.B., L.K., D.M.S., and A.P.W. have nothing to declare. E.M.B. has received lecture fees from Athena Diagnostics, Inc. and has a financial interest in the calcimimetic, cinacalcet, through NPS Pharmaceuticals, Inc. NR 27 TC 7 Z9 7 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2011 VL 96 IS 3 BP 672 EP 680 DI 10.1210/jc.2010-1739 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 730GA UT WOS:000288020600036 PM 21159843 ER PT J AU Makimura, H Stanley, TL Sun, N Hrovat, MI Systrom, DM Grinspoon, SK AF Makimura, Hideo Stanley, Takara L. Sun, Noelle Hrovat, Mirko I. Systrom, David M. Grinspoon, Steven K. TI The Association of Growth Hormone Parameters with Skeletal Muscle Phosphocreatine Recovery in Adult Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; FAT-FREE MASS; MITOCHONDRIAL RESPIRATION; FACTOR-I; EXERCISE; INSULIN; GH; PROTECTION; TURNOVER; CHILDREN AB Context: Previous studies have suggested a relationship between GH and mitochondrial function. However, little is known about the relationship of specific GH indices and in vivo measures of mitochondrial function in humans. Objective: The objective of this study was to determine the association between GH, IGF-I, and phosphocreatine (PCr) recovery, a measure of mitochondrial function, in otherwise healthy adults. Design: Thirty-seven healthy men and women were studied at a single university medical center. Subjects underwent GH stimulation testing with GH releasing hormone-arginine and measurement of IGF-I. Mitochondrial function was determined by PCr recovery after submaximal exercise by (31)Phosphorous magnetic resonance spectroscopy. Subjects underwent assessment of lean and fat mass with use of dual energy X-ray absorptiometry. Results: There were no differences in PCr recovery between men and women (men 20.7 +/- 1.5 vs. women 24.8 +/- 1.4 mM/min; P > 0.05). IGF-I (r = 0.33; P = 0.04) was associated with PCr recovery in all subjects. Among men, IGF-I (r = 0.69; P = 0.003), peak stimulated GH (r = 0.52; P = 0.04), and GH area under the curve (AUC) (r = 0.53; P = 0.04) were significantly associated with PCr recovery. However, neither IGF-I, peak stimulated GH, nor GH AUC (all P > 0.05) were associated with PCr recovery in women. After adjusting for age, race, and physical activity, IGF-I remained significantly associated with PCr recovery (beta = 0.10; P = 0.02) among men. Conclusions: IGF-I, peak stimulated GH, and GH AUC are associated with skeletal muscle PCr recovery in men. (J Clin Endocrinol Metab 96: 817-823, 2011) C1 [Makimura, Hideo; Stanley, Takara L.; Sun, Noelle; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Makimura, Hideo; Stanley, Takara L.; Sun, Noelle; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Stanley, Takara L.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hrovat, Mirko I.; Systrom, David M.] Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. [Hrovat, Mirko I.] Mirtech Inc, Brockton, MA 02301 USA. RP Makimura, H (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 211, Boston, MA 02114 USA. EM hmakimura@partners.org OI Systrom, David/0000-0002-9610-6330 FU National Institutes of Health [1R01HL085268-01A1, K24DK064545-06, K23DK087857-01A1]; Boston Nutrition Obesity Research Center [3P30DK046200, UL1RR025758]; National Center for Research Resources; Center for Functional Neuroimaging Technologies [P41RR14075] FX This work was supported by National Institutes of Health Grant 1R01HL085268-01A1 (to S. G.), K24DK064545-06 (to S. G.), K23DK087857-01A1 (to H. M.), Boston Nutrition Obesity Research Center Pilot and Feasibility Grant 3P30DK046200 (to H. M.), UL1RR025758 to the Harvard Clinical and Translational Science Center from the National Center for Research Resources, and P41RR14075 from the Center for Functional Neuroimaging Technologies to the Athinoula A. Martinos Center for Biomedical Imaging where the 31P-MRS imaging studies were conducted. The content is solely the responsibility of the authors and does not necessarily represent the offical views of the National Center for Research Resources or the National Institutes of Health. NR 26 TC 9 Z9 10 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2011 VL 96 IS 3 BP 817 EP 823 DI 10.1210/jc.2010-2264 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 730GA UT WOS:000288020600053 PM 21177784 ER PT J AU Hegedus, L Moses, AC Zdravkovic, M Tu, LT Daniels, GH AF Hegedus, Laszlo Moses, Alan C. Zdravkovic, Milan Tu Le Thi Daniels, Gilbert H. TI GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MEDULLARY-THYROID CARCINOMA; C-CELL HYPERPLASIA; OPEN-LABEL TRIAL; JAPANESE PATIENTS; GLYCEMIC CONTROL; PARALLEL-GROUP; METFORMIN; EFFICACY; SAFETY; SULFONYLUREA AB Background: Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. Aim: The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. Methods: Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy. Results: Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. Conclusions: These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies. (J Clin Endocrinol Metab 96: 853-860, 2011) C1 [Hegedus, Laszlo] Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense, Denmark. [Moses, Alan C.] Novo Nordisk Inc, Princeton, NJ 08540 USA. [Zdravkovic, Milan; Tu Le Thi] Novo Nordisk AS, DK-2880 Bagsvaerd, Denmark. [Daniels, Gilbert H.] Massachusetts Gen Hosp, Thyroid Unit, Endocrine Tumor Ctr, Boston, MA 02114 USA. [Daniels, Gilbert H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Daniels, Gilbert H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Hegedus, L (reprint author), Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense, Denmark. EM Laszlo.Hegedus@ouh.regionsyddanmark.dk FU Novo Nordisk A/S FX Writing assistance for this manuscript was provided by Watermeadow Medical, which was sponsored by Novo Nordisk A/S.; L. H. has received consulting fees from and has served on an advisory council for Novo Nordisk A/S. A.C.M., M.Z., and T.L.T. are employees of and shareholders in Novo Nordisk. G. H. D. has acted as a consultant for Novo Nordisk, currently serves on a steering committee, has received honoraria as a consultant, and has provided Food and Drug Administration testimony as a consultant. NR 22 TC 92 Z9 96 U1 0 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2011 VL 96 IS 3 BP 853 EP 860 DI 10.1210/jc.2010-2318 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 730GA UT WOS:000288020600058 PM 21209033 ER PT J AU Shaw, ND Seminara, SB Welt, CK Au, MG Plummer, L Hughes, VA Dwyer, AA Martin, KA Quinton, R Mericq, V Merino, PM Gusella, JF Crowley, WF Pitteloud, N Hall, JE AF Shaw, Natalie D. Seminara, Stephanie B. Welt, Corrine K. Au, Margaret G. Plummer, Lacey Hughes, Virginia A. Dwyer, Andrew A. Martin, Kathryn A. Quinton, Richard Mericq, Veronica Merino, Paulina M. Gusella, James F. Crowley, William F., Jr. Pitteloud, Nelly Hall, Janet E. TI Expanding the Phenotype and Genotype of Female GnRH Deficiency SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; FOLLICLE-STIMULATING-HORMONE; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; RECEPTOR MUTATIONS; GENE-MUTATIONS; SECRETION; SPECTRUM; PROKINETICIN-2 AB Context: GnRH deficiency is a rare genetic disorder of absent or partial pubertal development. The clinical and genetic characteristics of GnRH-deficient women have not been well-described. Objective: Todetermine the phenotypic and genotypic spectrum of a large series of GnRH-deficient women. Design, Setting, and Subjects: Retrospective study of 248 females with GnRH deficiency evaluated at an academic medical center between 1980 and 2010. Main Outcome Measures: Clinical presentation, baseline endogenous GnRH secretory activity, and DNA sequence variants in 11 genes associated with GnRH deficiency. Results: Eighty-eight percent had undergone pubarche, 51% had spontaneous thelarche, and 10% had 1-2 menses. Women with spontaneous thelarche were more likely to demonstrate normal pubarche (P = 0.04). In 27% of women, neuroendocrine studies demonstrated evidence of some endogenous GnRH secretory activity. Thirty-six percent (a large excess relative to controls) harbored a rare sequence variant in a gene associated with GnRH deficiency (87% heterozygous and 13% biallelic), with variants in FGFR1 (15%), GNRHR (6.6%), and PROKR2 (6.6%) being most prevalent. One woman had a biallelic variant in the X-linked gene, KAL1, and nine women had heterozygous variants. Conclusions: The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation. (J Clin Endocrinol Metab 96: E566-E576, 2011) C1 [Hall, Janet E.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Shaw, Natalie D.; Seminara, Stephanie B.; Welt, Corrine K.; Au, Margaret G.; Plummer, Lacey; Hughes, Virginia A.; Dwyer, Andrew A.; Martin, Kathryn A.; Crowley, William F., Jr.; Pitteloud, Nelly; Hall, Janet E.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Shaw, Natalie D.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Mericq, Veronica] Univ Chile, Fac Med, Inst Maternal & Child Res, Santiago 7, Chile. [Merino, Paulina M.] Univ Chile, Fac Med, Dept Pediat, Santiago 7, Chile. RP Hall, JE (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, BHX-5,55 Fruit St, Boston, MA 02114 USA. EM jehall@partners.org RI Mericq, Veronica/F-3927-2010; Dwyer, Andrew/D-8099-2012; PITTELOUD, Nelly/K-2709-2014; OI Dwyer, Andrew/0000-0002-7023-6794; Welt, Corrine/0000-0002-8219-5504; Mericq, Veronica/0000-0003-2287-0181; Shaw, Natalie/0000-0002-0847-9170 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health [R01 HD42708, U54 HD028138]; National Institutes of Health/National Center for Research Resources, General Clinical Research Centers [M01-RR-01066]; Developmental Genome Anatomy Project [GM061354]; National Institutes of Health [5T32 HD007396]; Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health through R01 HD42708 and cooperative agreement U54 HD028138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and M01-RR-01066 National Institutes of Health/National Center for Research Resources, General Clinical Research Centers Program. Dr. Gusella received support from the Developmental Genome Anatomy Project (GM061354). Dr. Shaw received fellowship support from the National Institutes of Health (5T32 HD007396) and from the Scholars in Clinical Science program of Harvard Catalyst [The Harvard Clinical and Translational Science Center (Award #UL1 RR 025758) and financial contributions from Harvard University and its affiliated academic health care centers]. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. NR 57 TC 32 Z9 32 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2011 VL 96 IS 3 BP E566 EP E576 DI 10.1210/jc.2010-2292 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 730GA UT WOS:000288020600019 PM 21209029 ER PT J AU Kim, HY Eyheramonho, MB Pichavant, M Cambaceres, CG Matangkasombut, P Cervio, G Kuperman, S Moreiro, R Konduru, K Manangeeswaran, M Freeman, GJ Kaplan, GG DeKruyff, RH Umetsu, DT Rosenzweig, SD AF Kim, Hye Young Belen Eyheramonho, Maria Pichavant, Muriel Gonzalez Cambaceres, Carlos Matangkasombut, Ponpan Cervio, Guillermo Kuperman, Silvina Moreiro, Rita Konduru, Krishnamurthy Manangeeswaran, Mohanraj Freeman, Gordon J. Kaplan, Gerardo G. DeKruyff, Rosemarie H. Umetsu, Dale T. Rosenzweig, Sergio D. TI A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID KILLER T-CELLS; ACUTE LIVER-FAILURE; AIRWAY HYPERREACTIVITY; MUCIN DOMAIN; NKT CELLS; PHOSPHATIDYLSERINE RECEPTOR; FULMINANT-HEPATITIS; APOPTOTIC CELLS; HIV-1 INFECTION; ATOPIC DISEASE AB During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However,, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy. C1 [Kim, Hye Young; Pichavant, Muriel; Matangkasombut, Ponpan; DeKruyff, Rosemarie H.; Umetsu, Dale T.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Pediat,Div Immunol, Boston, MA 02115 USA. [Belen Eyheramonho, Maria; Gonzalez Cambaceres, Carlos; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Rosenzweig, Sergio D.] Hosp Nacl Pediat JP Garrahan, Div Immunol, Buenos Aires, DF, Argentina. [Belen Eyheramonho, Maria; Gonzalez Cambaceres, Carlos; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Rosenzweig, Sergio D.] Hosp Nacl Pediat JP Garrahan, Div Liver Transplantat, Buenos Aires, DF, Argentina. [Belen Eyheramonho, Maria; Gonzalez Cambaceres, Carlos; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Rosenzweig, Sergio D.] Hosp Nacl Pediat JP Garrahan, Div Transfus Med, Buenos Aires, DF, Argentina. [Belen Eyheramonho, Maria; Gonzalez Cambaceres, Carlos; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Rosenzweig, Sergio D.] Hosp Nacl Pediat JP Garrahan, Div Lab Med, Buenos Aires, DF, Argentina. [Konduru, Krishnamurthy; Manangeeswaran, Mohanraj; Kaplan, Gerardo G.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rosenzweig, Sergio D.] NIAID, Infect Dis Susceptibil Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Umetsu, DT (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Div Immunol,Karp Labs, Rm 10127,1 Blackfan Circle, Boston, MA 02115 USA. EM dale.umetsu@childrens.harvard.edu; srosenzweig@niaid.nih.gov FU Fortabat Endowment of the David Rockefeller Center for Latin American Studies at Harvard University; NIH [P01 AI054456]; FDA FX We thank Leslie Kalish for help with the statistical analysis; and Mirta Ciocca, Miriam Cuarterolo, Oscar Imventarza, Javier Goni, Ana Del Pozo, Jorge Sasbon, Stefania Pittaluga, and Maria T. de Davila for valuable comments and support. These studies were supported by the de Fortabat Endowment of the David Rockefeller Center for Latin American Studies at Harvard University, by a grant from the NIH (P01 AI054456), and with FDA intramural funds. The findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy. NR 47 TC 36 Z9 38 U1 1 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2011 VL 121 IS 3 BP 1111 EP 1118 DI 10.1172/JCI44182 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 729YQ UT WOS:000287991000029 PM 21339644 ER PT J AU Pardanani, A Gotlib, JR Jamieson, C Cortes, JE Talpaz, M Stone, RM Silverman, MH Gilliland, DG Shorr, J Tefferi, A AF Pardanani, Animesh Gotlib, Jason R. Jamieson, Catriona Cortes, Jorge E. Talpaz, Moshe Stone, Richard M. Silverman, Michael H. Gilliland, D. Gary Shorr, Jolene Tefferi, Ayalew TI Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERNATIONAL-WORKING-GROUP; PROGNOSTIC SCORING SYSTEM; MYELOPROLIFERATIVE NEOPLASMS; POLYCYTHEMIA-VERA; MYELOID METAPLASIA; ESSENTIAL THROMBOCYTHEMIA; MUTATIONS; JAK2V617F; CRITERIA; CELLS AB Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high-or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis. J Clin Oncol 29:789-796. (C) 2011 by American Society of Clinical Oncology C1 [Tefferi, Ayalew] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Calif San Diego, San Diego, CA 92103 USA. TargeGen, San Diego, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Biostrateg Consulting, Marblehead, MA USA. Merck, N Wales, PA USA. RP Tefferi, A (reprint author), Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM tefferi.ayalew@mayo.edu FU TargeGen; Cytopia FX Research Funding: Animesh Pardanani, TargeGen, Cytopia; Jason R. Gotlib, TargeGen; Catriona Jamieson, TargeGen; Jorge E. Cortes, TargeGen; Moshe Talpaz, TargeGen; Ayalew Tefferi, TargeGen. NR 26 TC 226 Z9 233 U1 1 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 MAR 1 PY 2011 VL 29 IS 7 BP 789 EP 796 DI 10.1200/JCO.2010.32.8021 PG 8 WC Oncology SC Oncology GA 726NO UT WOS:000287729900018 PM 21220608 ER PT J AU Horan, JT Logan, BR Agovi-Johnson, MA Lazarus, HM Bacigalupo, AA Ballen, KK Bredeson, CN Carabasi, MH Gupta, V Hale, GA Khoury, HJ Juckett, MB Litzow, MR Martino, R McCarthy, PL Smith, FO Rizzo, JD Pasquini, MC AF Horan, John T. Logan, Brent R. Agovi-Johnson, Manza-A. Lazarus, Hillard M. Bacigalupo, Andrea A. Ballen, Karen K. Bredeson, Christopher N. Carabasi, Matthew H. Gupta, Vikas Hale, Gregory A. Khoury, Hanna Jean Juckett, Mark B. Litzow, Mark R. Martino, Rodrigo McCarthy, Philip L. Smith, Franklin O. Rizzo, J. Douglas Pasquini, Marcelo C. TI Reducing the Risk for Transplantation-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; ACUTE MYELOID-LEUKEMIA; ACUTE GRAFT; FLUCONAZOLE PROPHYLAXIS; PERIPHERAL-BLOOD; RECIPIENTS; METHOTREXATE; INFECTIONS; CHILDREN AB Purpose Transplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT). Patients and Methods We assessed changes in the incidence of TRM and overall survival from 1985 through 2004 in 5,972 patients younger than age 50 years who received myeloablative conditioning and HCT for acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2). Results Among HLA-matched sibling donor transplantation recipients, the relative risks (RRs) for TRM were 0.5 and 0.3 for 2000 to 2004 compared with those for 1985 to 1989 in patients in CR1 and CR2, respectively (P < .001). The RRs for all causes of mortality in the latter period were 0.73 (P < .001) and 0.60 (P = .005) for the CR1 and CR2 groups, respectively. Among unrelated donor transplantation recipients, the RRs for TRM were 0.73 (P = .095) and 0.58 (P < .001) for 2000 to 2004 compared with those in 1990 to 1994 in the CR1 and CR2 groups, respectively. Reductions in mortality were observed in the CR2 group (RR, 0.74; P = .03) but not in the CR1 group. Conclusion Our results suggest that innovations in transplantation care since the 1980s and 1990s have reduced the risk of TRM in patients undergoing allogeneic HCT for AML and that this reduction has been accompanied by improvements in overall survival. J Clin Oncol 29:805-813. (C) 2011 by American Society of Clinical Oncology C1 [Pasquini, Marcelo C.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. Emory Univ Hosp, Childrens Healthcare Atlanta Egleston, Atlanta, GA 30322 USA. Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. Univ Hosp Case Med Ctr, Cleveland, OH USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Osped San Martino Genova, Genoa, Italy. Massachusetts Gen Hosp, Boston, MA 02114 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. Mayo Clin Rochester, Rochester, MN USA. Hosp Santa Creu & Sant Pau, Barcelona, Spain. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Pasquini, MC (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM mpasquin@mcw.edu NR 35 TC 62 Z9 63 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 MAR 1 PY 2011 VL 29 IS 7 BP 805 EP 813 DI 10.1200/JCO.2010.32.5001 PG 9 WC Oncology SC Oncology GA 726NO UT WOS:000287729900020 PM 21220593 ER PT J AU Aplenc, R Blaney, SM Strauss, LC Balis, FM Shusterman, S Ingle, AM Agrawal, S Sun, JF Wright, JJ Adamson, PC AF Aplenc, Richard Blaney, Susan M. Strauss, Lewis C. Balis, Frank M. Shusterman, Suzanne Ingle, Ashish Mark Agrawal, Shruti Sun, Junfeng Wright, John J. Adamson, Peter C. TI Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CYTOGENETIC RESPONSES; IMATINIB-RESISTANT AB Purpose Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-beta receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. Patients and Methods A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m(2)/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. Results A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m(2) dose levels. At 110 mg/m(2), two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m(2)), grade 3 diarrhea (85 mg/m(2)), and grade 2 creatinine elevation (50 mg/m(2)) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. Conclusion Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients. J Clin Oncol 29:839-844. (C) 2011 by American Society of Clinical Oncology C1 [Aplenc, Richard] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. Baylor Coll Med, Houston, TX 77030 USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. Harvard Univ, Sch Med, Dana Farber Canc Ctr, Boston, MA USA. Stat & Data Ctr, Childrens Oncol Grp, Arcadia, CA USA. Univ Nebraska Med Ctr, Omaha, NE USA. NCI, Canc Therapeut & Evaluat Program, Bethesda, MD 20892 USA. RP Aplenc, R (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, 4018 CTRB,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM raplenc@mail.med.upenn.edu FU National Cancer Institute [U01 CA97452]; NCRR [M01 RR00188] FX Supported by National Cancer Institute Grants No. U01 CA97452 and NCRR M01 RR00188. NR 12 TC 41 Z9 45 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 MAR 1 PY 2011 VL 29 IS 7 BP 839 EP 844 DI 10.1200/JCO.2010.30.7231 PG 6 WC Oncology SC Oncology GA 726NO UT WOS:000287729900024 PM 21263099 ER PT J AU Kulke, MH Siu, LL Tepper, JE Fisher, G Jaffe, D Haller, DG Ellis, LM Benedetti, JK Bergsland, EK Hobday, TJ Van Cutsem, E Pingpank, J Oberg, K Cohen, SJ Posner, MC Yao, JC AF Kulke, Matthew H. Siu, Lillian L. Tepper, Joel E. Fisher, George Jaffe, Deborah Haller, Daniel G. Ellis, Lee M. Benedetti, Jacqueline K. Bergsland, Emily K. Hobday, Timothy J. Van Cutsem, Eric Pingpank, James Oberg, Kjell Cohen, Steven J. Posner, Mitchell C. Yao, James C. TI Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROGRESSION-FREE SURVIVAL; NUCLEOTIDE POLYMORPHISM ANALYSIS; METASTATIC CARCINOID-TUMORS; PANCREATIC ENDOCRINE TUMORS; PHASE-II; SOMATOSTATIN ANALOG; ALLELIC ALTERATIONS; PROGNOSTIC-FACTORS; GRADING SYSTEM; OCTREOTIDE LAR AB Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses. J Clin Oncol 29: 934-943. (C) 2011 by American Society of Clinical Oncology C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. NCI, Coordinating Ctr Clin Trials, Off Director, Rockville, MD USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Unit 426, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, SW Oncol Grp, Ctr Stat, Seattle, WA 98104 USA. Mayo Clin, Coll Med, Rochester, MN USA. Univ Chicago, Chicago, IL 60637 USA. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Hosp, Uppsala, Sweden. RP Yao, JC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Unit 426, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jyao@mdanderson.org FU National Cancer Institute, Bethesda, MD; Novartis; Pfizer; Genentech; Ipsen; sanofi-aventis; Lexicon FX Supported in part by a grant from the National Cancer Institute, Bethesda, MD.; Research Funding: Lillian L. Siu, Novartis, Pfizer; George Fisher, Genentech, Ipsen, Novartis, sanofi-aventis; Emily K. Bergsland, Novartis, Genentech, Lexicon; Timothy J. Hobday, Novartis; Eric Van Cutsem, Novartis, Pfizer; James C. Yao, Novartis, Genentech NR 49 TC 129 Z9 135 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 BP 934 EP 943 DI 10.1200/JCO.2010.33.2056 PG 10 WC Oncology SC Oncology GA 726NO UT WOS:000287729900037 PM 21263089 ER PT J AU Alharbi, H Choueiri, TK Kollmannsberger, CK North, S MacKenzie, MJ Knox, JJ Rini, BI Heng, DY AF Alharbi, H. Choueiri, T. K. Kollmannsberger, C. K. North, S. MacKenzie, M. J. Knox, J. J. Rini, B. I. Heng, D. Y. TI Brain metastases in patients treated with targeted therapy for metastatic renal cell carcinoma (mRCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. London Reg Canc Program, London, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 326 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700325 PM 27968642 ER PT J AU Arvold, ND Catalano, PJ Sweeney, C Hoffman, KE Nguyen, PL Balboni, TA Fossa, SD Travis, LB Beard, C AF Arvold, N. D. Catalano, P. J. Sweeney, C. Hoffman, K. E. Nguyen, P. L. Balboni, T. A. Fossa, S. D. Travis, L. B. Beard, C. TI Physician and patient factors influencing management recommendations in stage I testicular seminoma: A survey among radiation oncologists in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Oslo Univ Hosp, Div Canc Med & Radiotherapy, Oslo, Norway. Univ Rochester, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 225 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700226 PM 27968685 ER PT J AU Arvold, ND Chen, M Moul, JW Moran, BJ Dosoretz, DE Banez, LL Katin, MJ Braccioforte, MH D'Amico, AV AF Arvold, N. D. Chen, M. Moul, J. W. Moran, B. J. Dosoretz, D. E. Banez, L. L. Katin, M. J. Braccioforte, M. H. D'Amico, A. V. TI Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low-or intermediate-risk disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Univ Connecticut, Storrs, CT USA. Duke Univ, Med Ctr, Durham, NC USA. Prostate Canc Fdn Chicago, Westmont, IL USA. 21st Century Oncol, Ft Myers, FL USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 198 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700199 PM 27968470 ER PT J AU Baskin-Bey, ES Holtkamp, GM Smith, MR Ouatas, T Phung, D Tombal, B AF Baskin-Bey, E. S. Holtkamp, G. M. Smith, M. R. Ouatas, T. Phung, D. Tombal, B. TI A phase II, open-label, single-arm, efficacy, and safety study of MDV3100 in patients with hormone-naive prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Astellas Pharma Europe, Staines, Surrey, England. Astellas Pharma Europe BV, Leiderdorp, Netherlands. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Clin Univ St Luc, B-1200 Brussels, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 177 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700178 PM 27968436 ER PT J AU Beard, C Chen, M Arvold, ND Nguyen, PL Ng, AK Hoffman, KE AF Beard, C. Chen, M. Arvold, N. D. Nguyen, P. L. Ng, A. K. Hoffman, K. E. TI Long-term survival and competing causes of death in men with stage I seminoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Harvard Radiat Oncol Program, Boston, MA USA. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 226 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700227 PM 27968699 ER PT J AU Campbell, MT Jung, J Philips, S Mohammadi, Y Carr, KA Davis, TL Li, L Sweeney, C Skaar, TC Hahn, NM AF Campbell, M. T. Jung, J. Philips, S. Mohammadi, Y. Carr, K. A. Davis, T. L. Li, L. Sweeney, C. Skaar, T. C. Hahn, N. M. TI Germ-line single nucleotide polymorphism (SNP) predictors of progression-free survival and overall survival in patients with advanced prostate cancer treated with androgen-deprivation therapy (ADT). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Indiana Univ, Indianapolis, IN 46204 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 51 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700052 PM 27968396 ER PT J AU Choueiri, TK Vaishampayan, UN Yu, EY Quinn, DI Hahn, NM Hutson, TE Ross, RW Rosenberg, JE Jacobus, SJ Kantoff, PW AF Choueiri, T. K. Vaishampayan, U. N. Yu, E. Y. Quinn, D. I. Hahn, N. M. Hutson, T. E. Ross, R. W. Rosenberg, J. E. Jacobus, S. J. Kantoff, P. W. TI A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Univ Washington, Seattle, WA 98195 USA. Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Texas Oncol PA, Baylor Sammons Canc Ctr, Dallas, TX USA. Dana Farber Canc Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA LBA239 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700240 PM 27968416 ER PT J AU Coen, J Paly, JJ Weyman, EA Rodrigues, A Shipley, WU Zietman, AL Efstathiou, JA Talcott, JA AF Coen, J. Paly, J. J. Weyman, E. A. Rodrigues, A. Shipley, W. U. Zietman, A. L. Efstathiou, J. A. Talcott, J. A. TI Long-term QOL outcome after proton beam monotherapy for localized prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Ctr Outcomes Res, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 68 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700069 PM 27968351 ER PT J AU Davis, TL Jung, J Carr, KA Philips, S Mohammadi, Y Campbell, MT Li, L Sweeney, C Skaar, TC Hahn, NM AF Davis, T. L. Jung, J. Carr, K. A. Philips, S. Mohammadi, Y. Campbell, M. T. Li, L. Sweeney, C. Skaar, T. C. Hahn, N. M. TI Androgen pathway constitutional polymorphism predictors of progression-free and overall survivals in advanced castrate-resistant prostate cancer (CRPC) patients treated with ketoconazole (KC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Indiana Univ, Indianapolis, IN 46204 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 54 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700055 PM 27968400 ER PT J AU Efstathiou, JA Paly, JJ Lu, H Athar, BS Niemierko, A Bekelman, JE Coen, J Shipley, WU Zietman, AL Paganetti, H AF Efstathiou, J. A. Paly, J. J. Lu, H. Athar, B. S. Niemierko, A. Bekelman, J. E. Coen, J. Shipley, W. U. Zietman, A. L. Paganetti, H. TI Adjuvant radiation therapy for early-stage seminoma: Proton-photon comparison and second cancer risk SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 228 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700229 PM 27968695 ER PT J AU Galsky, MD Hahn, NM Rosenberg, JE Sonpavde, G Oh, WK Dreicer, R Vogelzang, NJ Sternberg, CN Bajorin, DF Bellmunt, J AF Galsky, M. D. Hahn, N. M. Rosenberg, J. E. Sonpavde, G. Oh, W. K. Dreicer, R. Vogelzang, N. J. Sternberg, C. N. Bajorin, D. F. Bellmunt, J. CA Cisplatin Ineligibility Bladder TI Defining "cisplatin ineligible" patients with metastatic bladder cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Baylor Coll Med, Texas Oncol, Houston, TX 77030 USA. Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. San Camillo Hosp, Rome, Italy. Forlanini Hosp, Rome, Italy. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Hosp del Mar, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 238 PG 2 WC Oncology SC Oncology GA V31JU UT WOS:000208880700239 PM 27968673 ER PT J AU Hahn, NM Jung, J Philips, S Patel, YR Carr, KA Mohammadi, Y Magjuka, D Li, L Sweeney, C Skaar, TC AF Hahn, N. M. Jung, J. Philips, S. Patel, Y. R. Carr, K. A. Mohammadi, Y. Magjuka, D. Li, L. Sweeney, C. Skaar, T. C. TI Use of germ-line single nucleotide polymorphisms (SNPs) in drug transporters (ABCG2/ABCB1) and tubulin (TUBB4) to predict survival in patients with metastatic castrate-resistant prostate cancer (CRPC) receiving docetaxel SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Publ Hlth, Indianapolis, IN 46204 USA. Indiana Univ, Indianapolis, IN 46204 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 58 PG 2 WC Oncology SC Oncology GA V31JU UT WOS:000208880700059 PM 27968403 ER PT J AU Harzstark, AL Beer, TM Weinberg, VK Higano, CS Nordquist, LT Rosenberg, JE Alumkal, JJ Yu, EY Mi, J Small, EJ AF Harzstark, A. L. Beer, T. M. Weinberg, V. K. Higano, C. S. Nordquist, L. T. Rosenberg, J. E. Alumkal, J. J. Yu, E. Y. Mi, J. Small, E. J. TI Intermittent chemotherapy (ICh) for metastatic castration-resistant prostate cancer (mCRPC): Results of a prospective randomized phase II trial of the DoD Prostate Cancer Clinical Trials Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Univ Washington, Sch Med, Seattle, WA USA. Oncol Hematol West PC, Omaha, NE USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 133 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700134 PM 27968494 ER PT J AU Heng, DY MacKenzie, MJ Vaishampayan, UN Knox, JJ Bjarnason, GA Tan, M Wood, L Donskov, F Rini, BI Choueiri, TK AF Heng, D. Y. MacKenzie, M. J. Vaishampayan, U. N. Knox, J. J. Bjarnason, G. A. Tan, M. Wood, L. Donskov, F. Rini, B. I. Choueiri, T. K. CA Int mRCC Database Consortium TI Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): Clinical characteristics, risk factors, and subsequent therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. London Reg Canc Program, London, ON, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Natl Canc Ctr Singapore, Singapore, Singapore. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 305 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700305 ER PT J AU Higano, CS Beer, TM Taplin, M Efstathiou, E Anand, A Hirmand, M Fleisher, M Scher, HI AF Higano, C. S. Beer, T. M. Taplin, M. Efstathiou, E. Anand, A. Hirmand, M. Fleisher, M. Scher, H. I. CA Prostate Canc Clinical Trials Cons TI Antitumor activity of MDV3100 in pre- and post-docetaxel advanced prostate cancer: Long-term follow-up of a phase I/II study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Washington, Sch Med, Seattle, WA USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Medivation Inc, San Francisco, CA USA. RI Anand, Aseem/P-1214-2014 OI Anand, Aseem/0000-0002-3606-540X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 134 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700135 PM 27968506 ER PT J AU Hoffman, KE Chen, M Nguyen, PL Bennett, CL Sartor, AO Stein, K Kuban, DA D'Amico, AV AF Hoffman, K. E. Chen, M. Nguyen, P. L. Bennett, C. L. Sartor, A. O. Stein, K. Kuban, D. A. D'Amico, A. V. TI Factors associated with a delay in diagnosis of recurrent prostate cancer after radical prostatectomy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Univ Connecticut, Storrs, CT USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. South Carolina Coll Pharm, Charleston, SC USA. Hollings Canc Ctr, Charleston, SC USA. Tulane Univ, New Orleans, LA 70118 USA. Eisai Pharmaceut, Woodcliff Lake, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 208 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700209 PM 27968624 ER PT J AU Jardim, DLF Je, Y Schutz, FA Choueiri, TK AF Jardim, D. L. Fontes Je, Y. Schutz, F. A. Choueiri, T. K. TI Hematologic toxicities in renal cell carcinoma and other malignancies treated with bevacizumab: A meta-analysis of clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 336 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700335 ER PT J AU Khambati, H Choueiri, TK Kollmannsberger, CK North, S Bjarnason, GA Vaishampayan, UN Wood, L MacKenzie, MJ Rini, BI Heng, DY AF Khambati, H. Choueiri, T. K. Kollmannsberger, C. K. North, S. Bjarnason, G. A. Vaishampayan, U. N. Wood, L. MacKenzie, M. J. Rini, B. I. Heng, D. Y. CA Int mRCC Database Consortium TI Efficacy of targeted drug therapy for metastatic renal cell carcinoma in the elderly patient population SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. London Reg Canc Program, London, ON, Canada. Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 318 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700317 PM 27968644 ER PT J AU Lu-Yao, GL Kim, S Moore, D Shih, W Lin, Y DiPaola, RS Zietman, AL Yao, S AF Lu-Yao, G. L. Kim, S. Moore, D. Shih, W. Lin, Y. DiPaola, R. S. Zietman, A. L. Yao, S. TI Is radiation therapy superior to conservative management in men with localized prostate cancer? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. Univ Med & Dent New Jersey, Sch Publ Hlth, Canc Inst New Jersey, New Brunswick, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 73 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700074 PM 27968334 ER PT J AU Martin, NE Chen, M Nguyen, PL Beard, C Kantoff, PW D'Amico, AV AF Martin, N. E. Chen, M. Nguyen, P. L. Beard, C. Kantoff, P. W. D'Amico, A. V. TI Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and six months of combined androgen blockade SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 191 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700192 PM 27968475 ER PT J AU Michaelson, MD Cohen, DP Li, S Motzer, RJ Escudier, B Barrios, CH Burnett, PE Puzanov, I AF Michaelson, M. D. Cohen, D. P. Li, S. Motzer, R. J. Escudier, B. Barrios, C. H. Burnett, P. E. Puzanov, I. TI Hand-foot syndrome (HFS) as a potential biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Pfizer Oncol, La Jolla, CA USA. Pfizer Oncol, Shanghai, Peoples R China. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Inst Gustave Roussy, Villejuif, France. Pontificia Univ Catolica Rio Grande do Sul, Hosp Sao Lucas, Porto Alegre, RS, Brazil. Vanderbilt Univ, Med Ctr, Nashville, TN USA. RI Barrios, Carlos/G-8525-2015 NR 0 TC 3 Z9 3 U1 0 U2 1 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 320 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700319 ER PT J AU Mitin, T Chen, M Moran, BJ Dosoretz, DE Katin, MJ Braccioforte, MH Salenius, S D'Amico, AV AF Mitin, T. Chen, M. Moran, B. J. Dosoretz, D. E. Katin, M. J. Braccioforte, M. H. Salenius, S. D'Amico, A. V. TI Diabetes mellitus, race, and the odds of high-grade prostate cancer in men diagnosed with prostate cancer in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Prostate Canc Fdn Chicago, Westmont, IL USA. 21st Century Oncol, Ft Myers, FL USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 180 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700181 PM 27968485 ER PT J AU Morgans, AK Hancock, ML Barnette, G Steiner, MS Morton, RA Smith, MR AF Morgans, A. K. Hancock, M. L. Barnette, G. Steiner, M. S. Morton, R. A. Smith, M. R. TI Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. GTx Inc, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 212 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700213 PM 27968614 ER PT J AU Nguyen, PL Chen, M Chen, RC Hoffman, KE Hu, JC Bennett, CL Kattan, MW Sartor, AO Stein, K D'Amico, AV AF Nguyen, P. L. Chen, M. Chen, R. C. Hoffman, K. E. Hu, J. C. Bennett, C. L. Kattan, M. W. Sartor, A. O. Stein, K. D'Amico, A. V. CA COMPARE Registry Steering Comm TI Comorbidity and treatment regret in men with recurrent prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Univ N Carolina, Chapel Hill, NC USA. Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. South Carolina Coll Pharm, Charleston, SC USA. Hollings Canc Ctr, Charleston, SC USA. Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. Tulane Univ, New Orleans, LA 70118 USA. Eisai Pharmaceut, Woodcliff Lake, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 187 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700188 PM 27968480 ER PT J AU Petrylak, DP Kantoff, PW Rotshteyn, Y Israel, RJ Olson, WC Ramakrishna, T Morris, S AF Petrylak, D. P. Kantoff, P. W. Rotshteyn, Y. Israel, R. J. Olson, W. C. Ramakrishna, T. Morris, S. TI Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in taxane-refractory prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Columbia Univ, Med Ctr, New York, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Progen Pharmaceut Inc, New York, NY USA. Progen Pharmaceut Inc, Tarrytown, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 158 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700159 PM 27968566 ER PT J AU Prasad, SM Gu, X Lipsitz, SR Nguyen, PL Hu, JC AF Prasad, S. M. Gu, X. Lipsitz, S. R. Nguyen, P. L. Hu, J. C. TI Inappropriate utilization of radiographic imaging in men with newly diagnosed prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 120 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700121 PM 27968524 ER PT J AU Psutka, SP Daha, A Gervais, D Feldman, AS AF Psutka, S. P. Daha, A. Gervais, D. Feldman, A. S. TI Effect of salvage radiofrequency ablation on local control of recurrent renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 355 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700353 PM 27968664 ER PT J AU Richards, CJ Je, Y Schutz, FA Dallabrida, SM Moslehi, JJ Choueiri, TK AF Richards, C. J. Je, Y. Schutz, F. A. Dallabrida, S. M. Moslehi, J. J. Choueiri, T. K. TI Incidence and risk of congestive heart failure risk in renal cell cancer (RCC) and non-RCC patients treated with sunitinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Childrens Hosp, Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Cardiol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 316 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700315 PM 27968315 ER PT J AU Saylor, PJ Hancock, ML Barnette, G Steiner, MS Morton, RA Smith, MR AF Saylor, P. J. Hancock, M. L. Barnette, G. Steiner, M. S. Morton, R. A. Smith, M. R. TI Factors associated with vertebral fractures in men treated with androgen-deprivation therapy (ADT) for prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. GTx Inc, Memphis, TN USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 205 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700206 PM 27968643 ER PT J AU Schutz, FA Je, Y Choueiri, TK AF Schutz, F. A. Je, Y. Choueiri, T. K. TI Hematologic toxicities in cancer patients treated with the multityrosine Kinase sorafenib: A meta-analysis of clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 352 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700350 PM 27968648 ER PT J AU Schutz, FA Xie, W Heng, DY Donskov, F Wood, L Vaishampayan, UN Tan, M MacKenzie, MJ Kollmannsberger, CK Choueiri, TK AF Schutz, F. A. Xie, W. Heng, D. Y. Donskov, F. Wood, L. Vaishampayan, U. N. Tan, M. MacKenzie, M. J. Kollmannsberger, C. K. Choueiri, T. K. TI The effect of low serum sodium on treatment outcome to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma: Results from a large international collaboration SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Canc Ctr Singapore, Singapore, Singapore. London Reg Canc Program, London, ON, Canada. British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 322 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700321 PM 27968635 ER PT J AU Shipley, WU Hunt, D Lukka, HR Major, P Heney, NM Grignon, D Patel, M Bahary, J Lawton, CA Sandler, HM AF Shipley, W. U. Hunt, D. Lukka, H. R. Major, P. Heney, N. M. Grignon, D. Patel, M. Bahary, J. Lawton, C. A. Sandler, H. M. TI Initial report of RTOG 9601, a phase III trial in prostate cancer: Effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2-3,N0 disease and elevated PSA levels SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Amer Coll Radiol, Philadelphia, PA USA. McMaster Univ, Juravinski Canc Ctr, Hamilton, ON, Canada. Hamilton Reg Canc Ctr, Hamilton, ON L8V 1C3, Canada. Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Univ Montreal, Dept Radiat Oncol, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 1 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700002 ER PT J AU Smith, DC Smith, MR Small, EJ Sweeney, C Kurzrock, R Gordon, MS Vogelzang, NJ Scheffold, C Ballinger, MD Hussain, M AF Smith, D. C. Smith, M. R. Small, E. J. Sweeney, C. Kurzrock, R. Gordon, M. S. Vogelzang, N. J. Scheffold, C. Ballinger, M. D. Hussain, M. TI Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Pinnacle Oncol Arizona, Scottsdale, AZ USA. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. Exelixis, San Francisco, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 127 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700128 PM 27968542 ER PT J AU Smith, MR Klotz, L van der Meulen, E Colli, E Tanko, LB AF Smith, M. R. Klotz, L. van der Meulen, E. Colli, E. Tanko, L. B. TI Association of baseline risk factors with cardiovascular (CV) events during long-term degarelix therapy in men with prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. Ferring Pharmaceut, Copenhagen, Denmark. NR 0 TC 2 Z9 2 U1 0 U2 0 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 MAR 1 PY 2011 VL 29 IS 7 SU S MA 190 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700191 PM 27968474 ER PT J AU Talcott, JA Zietman, AL Kaplan, ID Clark, JA D'Amico, AV AF Talcott, J. A. Zietman, A. L. Kaplan, I. D. Clark, J. A. D'Amico, A. V. TI Evaluation of a prostate brachytherapy technique designed to reduce short- and long-term urinary dysfunction: 5-year results of a multi-institutional comparative cohort study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Ctr Outcomes Res, Charlestown, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2011 VL 29 IS 7 SU S MA 70 PG 1 WC Oncology SC Oncology GA V31JU UT WOS:000208880700071 PM 27968332 ER PT J AU Gallucci, GO Grutter, L Chuang, SK Belser, UC AF Gallucci, German O. Gruetter, Linda Chuang, Sung-Kiang Belser, Urs C. TI Dimensional changes of peri-implant soft tissue over 2 years with single-implant crowns in the anterior maxilla SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE dental implants; DIM; emergence profile; interproximal papilla; peri-implant soft tissue; single-implant crown ID TITANIUM IMPLANTS; TOOTH IMPLANTS; TEETH; ABUTMENTS; BONE; AESTHETICS; HUMANS; MUCOSA; PINK AB P>Objective To compare the peri-implant soft tissue dimensions after insertion of single-implant crowns in the anterior maxilla. Materials and Methods Twenty patients were accepted according to well-defined inclusion criteria and randomized to porcelain-fused-to-metal (PFM) or all-ceramic groups. Follow-up was at: Baseline (B), Crown Insertion (CI), 1-year (1Y), and 2-year (2Y). The following parameters were statistically analysed: distance implant shoulder to marginal peri-implant mucosa (DIM), papilla height (PH), width of keratinized mucosa (KM), crestal bone level (CBL), full mouth plaque score (FMPS), full mouth bleeding score (FMBS), and probing pocket depth. Results Between groups measurements for DIM, PH, KM, CBL, FMPS, and FMBS showed no statistically significant differences except the distal CBLs to adjacent tooth. DIM (mid-facial) decreased from B to CI remaining stable at 1Y and 2Y (p-value 0.0014). DIM mesial and distal aspects significantly increased from B to CI showing signs of stability at the 2Y. PH between B and CI increased at the mesial site and at the distal site, thereafter, peri-implant soft tissues were stable at the 2Y. Conclusion The insertion of an implant crown affects the peri-implant mucosa morphology by an apical displacement at the mid-facial aspect and coronal at mesial and distal sites. C1 [Gallucci, German O.] Harvard Univ, Dept Restorat Dent & Biomat Sci, Sch Dent Med, Boston, MA 02115 USA. [Chuang, Sung-Kiang] Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. [Gruetter, Linda; Belser, Urs C.] Univ Geneva, Sch Dent Med, Dept Fixed Prosthodont & Occlus, Geneva, Switzerland. RP Gallucci, GO (reprint author), Harvard Univ, Dept Restorat Dent & Biomat Sci, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. EM german_gallucci@hsdm.harvard.edu RI Gallucci, German/H-4505-2011 FU ITI Foundation, Basel, Switzerland [362] FX This study was funded by the ITI Foundation, Grant 362, Basel, Switzerland. NR 26 TC 18 Z9 19 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD MAR PY 2011 VL 38 IS 3 BP 293 EP 299 DI 10.1111/j.1600-051X.2010.01686.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 715MD UT WOS:000286887700013 PM 21219391 ER PT J AU Caroff, SN Davis, VG Miller, DD Davis, SM Rosenheck, RA McEvoy, JP Campbell, EC Saltz, BL Riggio, S Chakos, MH Swartz, MS Keefe, RSE Stroup, TS Lieberman, JA AF Caroff, Stanley N. Davis, Vicki G. Miller, Del D. Davis, Sonia M. Rosenheck, Robert A. McEvoy, Joseph P. Campbell, E. Cabrina Saltz, Bruce L. Riggio, Silvana Chakos, Miranda H. Swartz, Marvin S. Keefe, Richard S. E. Stroup, T. Scott Lieberman, Jeffrey A. CA CATIE Investigators TI Treatment Outcomes of Patients With Tardive Dyskinesia and Chronic Schizophrenia SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID OUTPATIENT HEALTH OUTCOMES; FOLLOW-UP; 2ND-GENERATION ANTIPSYCHOTICS; RANDOMIZED-TRIAL; HALOPERIDOL; CATIE; OLANZAPINE; CLOZAPINE; BLIND; RISPERIDONE AB Objective: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. Method: This analysis compared 200 patients with DSM-IV defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with chi(2) tests. Data were collected from January 2001 to December 2004. Results: Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (chi(2)(1) = 0.11, P=.743). Changes in PANSS scores were not significantly different (F-1,F-974 = 0.82, P=.366), but patients with TD showed less improvement in neurocognitive scores (F-1,F-359=6.53, P=.011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F-3,F-151 = 0.32, P=.811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a >= 50% decrease in AIMS score, and 7% showed a >= 50% increase in AIMS score. Conclusions: Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT00014001 J Clin Psychiatry 2011;72(3):295-303 (C) Copyright 2010 Physicians Postgraduate Press, Inc. C1 [Caroff, Stanley N.; Campbell, E. Cabrina] Dept Vet Affairs Med Ctr, Dept Psychiat, Philadelphia, PA 19104 USA. [Caroff, Stanley N.; Campbell, E. Cabrina] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Davis, Vicki G.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Miller, Del D.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Davis, Sonia M.] Quintiles Inc, Res Triangle Pk, NC USA. [Davis, Sonia M.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. [McEvoy, Joseph P.] Duke Univ, Med Ctr, Dept Biol Psychiat, John Umstead Hosp, Durham, NC USA. [McEvoy, Joseph P.; Swartz, Marvin S.; Keefe, Richard S. E.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Saltz, Bruce L.] Mental Hlth Advocates Inc, Boca Raton, FL USA. [Riggio, Silvana] James J Peter Vet Affairs Med Ctr, New York, NY USA. [Riggio, Silvana] Mt Sinai Sch Med, New York, NY USA. [Chakos, Miranda H.] SUNY Hlth Sci Ctr, Dept Psychiat, Brooklyn, NY 11203 USA. [Stroup, T. Scott; Lieberman, Jeffrey A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. RP Caroff, SN (reprint author), Vet Affairs Med Ctr 116A, Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM stanley.caroff@va.gov RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU National Institute of Mental Health [NO1 MH90001]; Department of Veterans Affairs, Veterans Health Administration, Office of Research Development; Pfizer; Bristol-Myers Squibb; Ortho-McNeil Neurologics; National Institute of Mental Health; Foundation for the National Institute of Health; Eli Lilly; Janssen; AstraZeneca; Wyeth; Forest; Dainippon Sumitomo; Indevus; Cephalon; Novartis; Solvay; Roche; Organon; Allon; Singapore National Medical Research Council FX Dr Caroff has been a consultant for Eli Lilly and has received grant/research support from Pfizer, Bristol-Myers Squibb, and Ortho-McNeil Neurologics. Dr V. G. Davis is an employee of the Collaborative Studies Coordinating Center in the Department of Biostatistics, University of North Carolina. Dr Miller has been a consultant for Otsuka, Hoffmann-La Roche, and Schering Plough and has received research funds from the National Institute of Mental Health and the Foundation for the National Institute of Health. Dr S. M. Davis is an employee of Quintiles. Dr Rosenheck has been a consultant for Eli Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Organon, and Janssen; has received research support from Bristol-Myers Squibb, Eli Lilly, Janssen, AstraZeneca, and Wyeth; and provided expert testimony for the plaintiffs in UFCW Local 1776 and Participating Employers Health and Welfare Fund, et al vs Eli Lilly and Company; for the respondent in Eli Lilly Canada Inc vs Novapharm Ltd and Minister of Health, respondent; and for the Patent Medicines Prices Review Board, Canada, in the matter of Janssen Ortho Inc. and "Risperdal Consta." Dr McEvoy has received research funding from AstraZeneca, Forest, Eli Lilly, Janssen, Pfizer, Sanofi-Aventis, and Dainippon Sumitomo; consulting or advisory board fees from Pfizer, Bristol-Myers Squibb, Indevus, and Eli Lilly; lecture fees from Janssen and Bristol-Myers Squibb; and honoraria from Eli Lilly. Dr Saltz has received research funds from Cephalon, AstraZeneca, and Novartis and lecture fees from Janssen and Novartis. Dr Chakos has been a consultant for Roche and has received grant/research support from Pfizer, Solvay, AstraZeneca, Janssen, Roche, and Organon. Dr Swartz has received consulting and education fees from AstraZeneca, Bristol-Myers Squibb, Pfizer, Eli Lilly, and Comprehensive Neuroscience and has received grant/research support and honoraria from Eli Lilly. Dr Keefe is currently receiving or in the past 12 months has received investigator-initiated research funding support from the National Institute of Mental Health, Allon, Novartis, and the Singapore National Medical Research Council and an unrestricted educational grant from AstraZeneca; and has received honoraria from or served as a consultant or advisory board member for Abbott, AstraZeneca, BiolineRx, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo, Eli Lilly, Johnson & Johnson, Lundbeck, Memory, Merck, Neurosearch, Orion, Orexigen, Otsuka, Pfizer, Roche, Targacept, Sanofi-Aventis, Shire, Wyeth, and Xenoport. In the past, he has received honoraria from or served as a consultant or advisory board member for Acadia, Cortex, Cyberonics, Forest, Gabriel, GlaxoSmithKline, Repligen, Saegis, and Schering Plough and has received research funding from AstraZeneca, Eli Lilly, Janssen, and Pfizer. He receives royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the MATRICS Battery (BACS Symbol Coding). Dr Stroup has received research funding from Eli Lilly and consulting fees from Janssen, Eli Lilly, Lundbeck, Solvay, GlaxoSmithKline, and Bristol-Myers Squibb. Dr Lieberman has received research funding from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, and Pfizer and consulting and educational fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, Pfizer, and Solvay. Drs Campbell and Riggio report no financial or other relationship relevant to the subject of this article.; Supported by the Clinical Antipsychotic Trials of Intervention Effectiveness project, National Institute of Mental Health (NO1 MH90001). This article was based on results from the Clinical Antipsychotic Trials of Intervention Effectiveness project, supported by the National Institute of Mental Health (NO1 MH90001). The aim of this project is to examine the comparative effectiveness of antipsychotic drugs in conditions for which their use is clinically indicated including schizophrenia and Alzheimer's disease. The project was carried out by principal investigators from Columbia University, the University of North Carolina, Duke University, the University of Southern California, the University of Rochester, and Yale University in association with Quintiles, Inc.; the program staff of the Division of Interventions and Services Research of the National Institute of Mental Health; and investigators from 57 sites in the United States (CATIE Investigators Group). AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Forest Pharmaceuticals, Inc., Janssen Pharmaceutics Products, L.P., Eli Lilly and Company, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., and Zenith Goldline Pharmaceuticals, Inc., provided medications for the studies. This material is based upon work also supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research Development, with resources and the use of facilities at the Philadelphia Veterans Affairs Medical Center. NR 53 TC 10 Z9 10 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2011 VL 72 IS 3 BP 295 EP 303 DI 10.4088/JCP.09m05793yel PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 741BM UT WOS:000288838100004 PM 20816031 ER PT J AU Klein, RL Carter, RE Jenkins, AJ Lyons, TJ Baker, NL Gilbert, GE Virella, G Lopes-Virella, MF AF Klein, Richard L. Carter, Rickey E. Jenkins, Alicia J. Lyons, Timothy J. Baker, Nathaniel L. Gilbert, Gregory E. Virella, Gabriel Lopes-Virella, Maria F. CA DCCT-EDIC Res Grp TI LDL-containing immune complexes in the DCCT/EDIC cohort: associations with lipoprotein subclasses SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Diabetes; Lipoprotein subclasses; LDL autoantibodies; Intima-media thickness; Statistical mediation analysis ID INTIMA-MEDIA THICKNESS; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; OXIDIZED LDL; ATHEROSCLEROTIC LESIONS; DIABETES-MELLITUS; HUMAN MACROPHAGES; COMPLICATIONS; ANTIBODIES; GLYCOXIDATION AB Immune complexes containing modified LDL (LDL-IC) and NMR-detennined Total LDL particle concentrations are significantly associated with intima-media thickness (IMT). We analyzed the associations between concentrations of NMR-determined lipoprotein subclasses and LDL-IC in the DCCT/EDIC cohort. LDL-IC concentrations in women and men of the DCCT/EDIC cohort did not differ significantly and were positively associated with Total LDL particle concentrations in men and women (r=0.34, r=0.32, respectively; P<.01) and with Small LDL concentration (r=0.22, r=0.13, respectively; P<.01). In women, Large LDL concentrations were also associated with LDL-IC (r=0.20, P<.01) while in men, the association was more modest (r=0.11, P<.05). Thus, both Small and Large LDL are associated with LDL-IC formation. Based on the results from statistical mediation analyses, we concluded that plasma concentrations of LDL-1C may provide a physiological link between the statistically significant association of Total LDL particle concentration with carotid artery IMT in subjects with Type 1 diabetes. Furthermore, after adjusting for conventional risk factors, there was a decrease in LDL-1C concentration even in the presence of high Total LDL particle concentrations in those women with high concentrations of Large HDL, but the association was not evident in men. This suggests that the associations between Large HDL and Total LDL particle concentrations, and their associations with LDL-IC levels, differ by gender and suggest that LDL-1C partially mediate the contribution of Total LDL particle concentration to increased carotid IMT in diabetic men. Published by Elsevier Inc. C1 [Klein, Richard L.; Jenkins, Alicia J.; Lopes-Virella, Maria F.] Med Univ S Carolina, Div Endocrinol Metab & Med Genet, Dept Med, Charleston, SC 29403 USA. [Klein, Richard L.; Lopes-Virella, Maria F.] Vet Affairs Med Ctr, Res Serv, Ralph H Johnson Dept, Charleston, SC 29403 USA. [Carter, Rickey E.; Baker, Nathaniel L.; Gilbert, Gregory E.] Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29403 USA. [Jenkins, Alicia J.] Univ Melbourne, Dept Med, St Vincents Hosp, Fitzroy, Vic 3065, Australia. [Jenkins, Alicia J.; Lyons, Timothy J.] Univ Oklahoma, Hlth Sci Ctr, Endocrinol Sect, Oklahoma City, OK USA. [Jenkins, Alicia J.; Lyons, Timothy J.] Univ Oklahoma, Hlth Sci Ctr, Harold Hamm Diabet Ctr, Oklahoma City, OK USA. [Virella, Gabriel] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29403 USA. [DCCT-EDIC Res Grp] Box NDIC DCCT, Bethesda, MD USA. RP Klein, RL (reprint author), Med Univ S Carolina, Div Endocrinol Metab & Med Genet, Dept Med, 114 Doughty St,STB 501, Charleston, SC 29403 USA. EM kleinrl@musc.edu RI Jenkins, Alicia/N-2482-2015; Gilbert, Gregory/C-7735-2016 OI Gilbert, Gregory/0000-0003-0879-5496 FU American Diabetes Association; Juvenile Diabetes Research Foundation [4-1998-272, 996001]; National Institutes of Health [PO1 HL55782]; Diabetes Research and Wellness Foundation (Fairfax, VA, USA); Department of Veterans Affairs; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by funding by the American Diabetes Association, Juvenile Diabetes Research Foundation (4-1998-272, 996001), National Institutes of Health (PO1 HL55782), The Diabetes Research and Wellness Foundation (Fairfax, VA, USA), and the Merit Review Program of the Department of Veterans Affairs. The DCCT/EDIC Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institutes of Health. NR 30 TC 6 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD MAR-APR PY 2011 VL 25 IS 2 BP 73 EP 82 DI 10.1016/j.jdiacomp.2010.03.001 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 736WH UT WOS:000288525200001 PM 20605479 ER PT J AU Truong, QA Charipar, EM Ptaszek, LM Taylor, C Fontes, JD Kriegel, M Irlbeck, T Mahabadi, AA Blankstein, R Hoffmann, U AF Truong, Quynh A. Charipar, Elizabeth M. Ptaszek, Leon M. Taylor, Carolyn Fontes, Joao D. Kriegel, Matthias Irlbeck, Thomas Mahabadi, Amir A. Blankstein, Ron Hoffmann, Udo TI Usefulness of electrocardiographic parameters as compared with computed tomography measures of left atrial volume enlargement: from the ROMICAT trial SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article; Proceedings Paper CT 37th International Congress on Electrocardiology CY JUN, 2010 CL Lund, SWEDEN DE Left atrium; Left atrial volume; Left atrial enlargement; Computed tomography; Electrocardiogram ID P-WAVE; MYOCARDIAL-INFARCTION; DIAGNOSIS; ECHOCARDIOGRAPHY; CRITERIA; FORCE; HEART; PREDICTOR; SIZE AB Introduction: The 12-lead surface electrocardiogram (ECG) is commonly used as a noninvasive modality to assess for left atrial enlargement (LAE), but data comparing ECG against cardiac computed tomography (CT) for LAE is lacking. We aimed to determine the diagnostic performance of 6 ECG criteria for LAE as compared with CT left atrial volume (LAV) and index to body surface area (LAVI) as the reference standard. Materials and Methods: In 339 patients (age: mean +/- mean, 53 +/- 12 years; 63% male), we evaluated the quantitative ECG parameters of P duration, P to PR segment ratio, P wave area, and P terminal force in lead VI. We also assessed qualitatively the morphology of bifid and biphasic P waves. Patients were stratified into top and lowest quartile of LAV and LAVI by CT. Results: Of the 6 ECG criteria, patients with P duration greater than 110 milliseconds had a 2 1/2-fold increase likelihood of being in the top quartile of LAV (adjusted odds ratio [OR], 2.51; P = .01) and LAVI (adjusted OR, 2.74; P = .007) as measured by CT. For this ECG criterion, the sensitivity and specificity were 71% and 55% for CT LAE by LAV and 61% and 55% for LAVI. The remaining ECG parameters of LAE assessed (P to PR segment ratio, P terminal force in lead VI, P wave area, bifid, and biphasic P wave) were not associated with LAE by CT-based LAV or LAVI (all P >= .20). Discussion: Only P duration greater than 110 milliseconds was independently associated with LAE based on CT-derived LA volume and index. However, none of the established ECG parameters of LAE have sufficient diagnostic accuracies for predicting volumetric enlargement by CT, thus limiting its clinical utility. (C) 2011 Elsevier Inc. All rights reserved. C1 [Truong, Quynh A.; Charipar, Elizabeth M.; Taylor, Carolyn; Fontes, Joao D.; Kriegel, Matthias; Irlbeck, Thomas; Mahabadi, Amir A.; Blankstein, Ron; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol,Med Sch, Boston, MA 02114 USA. [Truong, Quynh A.; Ptaszek, Leon M.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, Boston, MA 02114 USA. [Blankstein, Ron] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Truong, QA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol,Med Sch, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NHLBI NIH HHS [L30HL093896, K23 HL098370, K24 HL113128, L30 HL093806, L30 HL093806-01, R01 HL080053, R01 HL080053-03, T32 HL076136, T32 HL076136-05, T32HL076136] NR 27 TC 8 Z9 9 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD MAR-APR PY 2011 VL 44 IS 2 BP 257 EP 264 DI 10.1016/j.jelectrocard.2010.04.011 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 733SK UT WOS:000288282900032 PM 20537347 ER PT J AU Sarkar, U Schillinger, D Lopez, A Sudore, R AF Sarkar, Urmimala Schillinger, Dean Lopez, Andrea Sudore, Rebecca TI Validation of Self-Reported Health Literacy Questions Among Diverse English and Spanish-Speaking Populations SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE health literacy; limited English proficiency; Hispanic American; validation studies ID VULNERABLE PATIENTS; HOSPITAL ADMISSION; MANAGEMENT SUPPORT; DIABETES PATIENTS; IDENTIFY PATIENTS; LIMITED LITERACY; GLYCEMIC CONTROL; PRIMARY-CARE; KNOWLEDGE; RISK AB Limited health literacy (HL) contributes to poor health outcomes and disparities, and direct measurement is often time-intensive. Self-reported HL questions have not been validated among Spanish-speaking and diverse English-speaking populations. To evaluate three self-reported questions:1 "How confident are you filling out medical forms?";2 "How often do you have problems learning about your medical condition because of difficulty understanding written information?"; and3 "How often do you have someone help you read hospital materials?" Answers were based on a 5-point Likert scale. This was a validation study nested within a trial of diabetes self-management support in the San Francisco Department of Public Health. English and Spanish-speaking adults with type 2 diabetes receiving primary care. Using the Test of Functional Health Literacy in Adults (s-TOFHLA) in English and Spanish as the reference, we classified HL as inadequate, marginal, or adequate. We calculated the C-index and test characteristics of the three questions and summative scale compared to the s-TOFHLA and assessed variations in performance by language, race/ethnicity, age, and education. Of 296 participants, 48% were Spanish-speaking; 9% were White, non-Hispanic; 47% had inadequate HL and 12% had marginal HL. Overall, 57% reported being confident with forms "somewhat" or less. The "confident with forms" question performed best for detecting inadequate (C-index = 0.82, (0.77-0.87)) and inadequate plus marginal HL (C index = 0.81, (0.76-0.86); p < 0.01 for differences from other questions), and performed comparably to the summative scale. The "confident with forms" question and scale also performed best across language, race/ethnicity, educational attainment, and age. A single self-reported HL question about confidence with forms and a summative scale of three questions discriminated between Spanish and English speakers with adequate HL and those with inadequate and/or inadequate plus marginal HL. The "confident with forms" question or the summative scale may be useful for estimating HL in clinical research involving Spanish-speaking and English-speaking, chronically-ill, diverse populations. C1 [Sarkar, Urmimala; Schillinger, Dean; Lopez, Andrea] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Sarkar, Urmimala; Schillinger, Dean; Lopez, Andrea] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco Ctr Vulnerable Populat, San Francisco, CA 94143 USA. [Sudore, Rebecca] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Div Geriatr, San Francisco, CA 94143 USA. RP Sarkar, U (reprint author), Univ Calif San Francisco, Dept Med, Div Gen Internal Med, Box 1364,1001 Potrero,Bldg 10,3rd Floor, San Francisco, CA 94143 USA. EM usarkar@medsfgh.ucsf.edu FU San Francisco Veterans' Affairs Medical Center; National Center for Research Resources [KL2RR024130]; Agency for Healthcare Research and Quality [R18 HS01726101, K08 HS017594]; NIH [ULRR024131]; Veterans Affairs; Pfizer FX We gratefully acknowledge the data analysis performed by Kathy Z. Fung, MS, (funded by the San Francisco Veterans' Affairs Medical Center) and the biostatistical advice provided by John Boscardin, Ph.D (funded by the National Center for Research Resources KL2RR024130). Funds were provided by Agency for Healthcare Research and Quality R18 HS01726101 (to DS), a NIH Clinical and Translational Science Award ULRR024131 (to DS), the National Center for Research Resources KL2RR024130 (to US.) and Agency for Healthcare Research and Quality K08 HS017594 (to US), a Veterans Affairs Career Development Award and a Pfizer Fellowship in Clear Health Communication (RS). None of the funders had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. NR 37 TC 57 Z9 57 U1 2 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2011 VL 26 IS 3 BP 265 EP 271 DI 10.1007/s11606-010-1552-1 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 725QV UT WOS:000287661800013 PM 21057882 ER PT J AU Celi, LAG Tang, RJ Villarroel, MC Davidzon, GA Lester, WT Chueh, HC AF Celi, Leo Anthony G. Tang, Robin J. Villarroel, Mauricio C. Davidzon, Guido A. Lester, William T. Chueh, Henry C. TI A Clinical Database-Driven Approach to Decision Support: Predicting Mortality Among Patients with Acute Kidney Injury SO JOURNAL OF HEALTHCARE ENGINEERING LA English DT Article DE modeling; data mining; collective experience; decision support; ICU; mortality prediction; acute kidney injury ID CRITICALLY-ILL PATIENTS; ACUTE-RENAL-FAILURE; RIFLE; CLASSIFICATION; MULTICENTER AB In exploring an approach to decision support based on information extracted from a clinical database, we developed mortality prediction models of intensive care unit (ICU) patients who had acute kidney injury (AKI) and compared them against the Simplified Acute Physiology Score (SAPS). We used MIMIC, a public de-identified database of ICU patients admitted to Beth Israel Deaconess Medical Center, and identified 1400 patients with an ICD9 diagnosis of AKI and who had an ICU stay >= 3 days. Multivariate regression models were built using the SAPS variables from the first 72 hours of ICU admission. All the models developed on the training set performed better than SAPS (AUC = 0.64, Hosmer-Lemeshow p < 0.001) on an unseen test set; the best model had an AUC = 0.74 and Hosmer-Lemeshow p = 0.53. These findings suggest that local customized modeling might provide more accurate predictions. This could be the first step towards an envisioned individualized point-of-care probabilistic modeling using one's clinical database. C1 [Celi, Leo Anthony G.] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. [Tang, Robin J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Villarroel, Mauricio C.] Univ Oxford, Dept Engn Sci, Inst Biomed Engn, Oxford OX1 3PJ, England. [Davidzon, Guido A.] Stanford Univ, Med Ctr, Dept Radiol Nucl Med, Stanford, CA 94305 USA. [Lester, William T.; Chueh, Henry C.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. RP Celi, LAG (reprint author), Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, 330 Brookline Ave, Boston, MA 02215 USA. EM lceli@bidmc.harvard.edu; rjt2112@columbia.edu; villarroel@eng.ox.ac.uk; davidzon@stan-ford.edu; wlester@partners.org; hchueh@partners.org OI Lester, William/0000-0003-4086-9280; Davidzon, Guido/0000-0001-5579-6825 FU National Library of Medicine (NLM) Training Grant [2T15LM007092-16]; National Institute of Health (NIH); National Institute of Biomedical Imaging and Bioengineering (NIBIB) [2R01 EB001659] FX This work is supported by National Library of Medicine (NLM) Training Grant # 2T15LM007092-16. The MIMIC II database was funded by the National Institute of Health (NIH), and its National Institute of Biomedical Imaging and Bioengineering (NIBIB) under Grant 2R01 EB001659. NR 11 TC 11 Z9 11 U1 1 U2 6 PU MULTI-SCIENCE PUBL CO LTD PI BRENTWOOD PA 5 WATES WAY, BRENTWOOD CM15 9TB, ESSEX, ENGLAND SN 2040-2295 J9 J HEALTHC ENG JI J. Healthc. Eng. PD MAR PY 2011 VL 2 IS 1 BP 97 EP 109 DI 10.1260/2040-2295.2.1.97 PG 13 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 045BJ UT WOS:000311668900007 PM 22844575 ER PT J AU Pol, S Ghalib, RH Rustgi, VK Martorell, C Everson, GT Tatum, HA Hezode, C Lim, JK Bronowicki, JP Abrams, GA Brau, N Morris, DW Thuluvath, P Reindollar, R Yin, PD Diva, U Hindes, R McPhee, F Gao, M Thiry, A Schnittman, S Hughes, EA AF Pol, S. Ghalib, R. H. Rustgi, V. K. Martorell, C. Everson, G. T. Tatum, H. A. Hezode, C. Lim, J. K. Bronowicki, J. -P. Abrams, G. A. Brau, N. Morris, D. W. Thuluvath, P. Reindollar, R. Yin, P. D. Diva, U. Hindes, R. McPhee, F. Gao, M. Thiry, A. Schnittman, S. Hughes, E. A. TI FIRST REPORT OF SVR12 FOR A NS5A REPLICATION COMPLEX INHIBITOR, BMS-790052 IN COMBINATION WITH PEG-IFN alpha-2A AND RBV: PHASE 2A TRIAL IN TREATMENT-NAIVE HCV-GENOTYPE-1 SUBJECTS SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Pol, S.] Hop Cochin, F-75674 Paris, France. [Ghalib, R. H.] Methodist Hlth Syst, Liver Inst, Dallas, TX USA. [Rustgi, V. K.] Metropolitan Res, Fairfax, VA USA. [Martorell, C.] Res Inst, Springfield, MA USA. [Everson, G. T.] Univ Colorado, Aurora, CO USA. [Tatum, H. A.] Opt Hlth Res LLC, Tulsa, OK USA. [Hezode, C.] CHU Henri Mondor, F-94010 Creteil, France. [Lim, J. K.] Yale Univ, Sch Med, New Haven, CT USA. [Bronowicki, J. -P.] Hop Adultes Braboios, Vandoeuvre Les Nancy, France. [Abrams, G. A.] Alabama Liver & Digest Specialists, Montgomery, AL USA. [Brau, N.] James J Peters VAMC, Bronx, NY USA. [Morris, D. W.] Healthcare Res Consultants, Tulsa, OK USA. [Thuluvath, P.] St Johns Mercy Med Ctr, Baltimore, MD USA. [Reindollar, R.] Carolinas Ctr Liver Dis Res Dept, Statesville, NC USA. [Yin, P. D.; Diva, U.; Hindes, R.; McPhee, F.; Gao, M.; Thiry, A.; Schnittman, S.; Hughes, E. A.] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. EM stanislas.pol@cch.aphp.fr NR 0 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 1373 BP S544 EP S545 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625603057 ER PT J AU Chang, LM Maheshwari, P Werth, S Schaffer, L Head, SR Kovarik, C Werth, VP AF Chang, Laura M. Maheshwari, Prateesh Werth, Sheila Schaffer, Lana Head, Steven R. Kovarik, Carrie Werth, Victoria P. TI Identification and Molecular Analysis of Glycosaminoglycans in Cutaneous Lupus Erythematosus and Dermatomyositis SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE chondroitin sulfate; cutaneous lupus erythematosus; dermatomyositis; glycosaminoglycans; hyaluronan ID CHONDROITIN-SULFATE; HUMAN SKIN; HYALURONAN METABOLISM; MONOCLONAL-ANTIBODIES; CD44; CELLS; EXPRESSION; ADHESION; INJURY; PROTEOGLYCANS AB Glycosaminoglycans (GAGs), also known histologically as dermal mucin, accumulate in several inflammatory skin conditions. Because different GAG species have distinct immunologic effects, the authors examined two GAGs, hyaluronan (HA) and chondroitin sulfate (CS), using specific stains in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). In the dermis of one CLE subtype, tumid LE (TLE), they found only increased HA, but both HA and CS were significantly elevated in another CLE subtype, discoid LE (DLE). DM lesional dermis accumulated mainly CS but not HA. The authors then used glycomic gene expression microarrays to assess the expression of HA-and CS-related genes in CLE skin. Real-time quantitative PCR confirmed significantly increased expression of HAS2, CHSY1, and C4ST1 in the combined groups of CLE lesions (n = 8) compared to healthy controls (n = 4). Thus, the increase in HA in CLE presumably results from upregulation of HAS2, whereas CHSY1 and C4ST1 appear to contribute to increased CS. Based on their known immunomodulatory effects in other systems, HA and CS may thus participate in the pathophysiology of these inflammatory skin conditions. (J Histochem Cytochem 59:336-345, 2011) C1 [Chang, Laura M.; Maheshwari, Prateesh; Werth, Sheila; Kovarik, Carrie; Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Chang, Laura M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Maheshwari, Prateesh] Univ Penn, Coll Arts & Sci, Philadelphia, PA 19104 USA. [Kovarik, Carrie; Werth, Victoria P.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Schaffer, Lana; Head, Steven R.] Consortium Funct Glyc, DNA Array Core Facil, La Jolla, CA USA. [Schaffer, Lana; Head, Steven R.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Werth, VP (reprint author), Hosp Univ Penn, Dept Dermatol, 2 Maloney Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM werth@mail.med.upenn.edu FU Lupus Foundation of American; Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; National Institutes of Health [NIH K24-AR 02207, NIH T32-AR007465-25, GM-62116] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This work was supported by the Lupus Foundation of American; in part by a Merit Review Grant from the Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; the National Institutes of Health (grant number NIH K24-AR 02207) to VPW; the National Institutes of Health training grant (grant number NIH T32-AR007465-25) to LMC; and the Consortium for Functional Glycomics Grant (grant number GM-62116) from the National Institutes of Health. NR 44 TC 10 Z9 10 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD MAR PY 2011 VL 59 IS 3 BP 336 EP 345 DI 10.1369/0022155410398000 PG 10 WC Cell Biology SC Cell Biology GA 805CC UT WOS:000293703000010 PM 21378287 ER PT J AU Zhou, XY Shapiro, L Fellingham, G Willardson, BM Burton, GF AF Zhou, Xueyuan Shapiro, Leland Fellingham, Gilbert Willardson, Barry M. Burton, Gregory F. TI HIV Replication in CD4(+) T Lymphocytes in the Presence and Absence of Follicular Dendritic Cells: Inhibition of Replication Mediated by alpha-1-Antitrypsin through Altered I kappa B alpha Ubiquitination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR NECROSIS FACTOR; TRANSCRIPTION FACTORS; INFECTION; TYPE-1; ACTIVATION; ACTIN; PATHOGENESIS; PROTEINS; NUCLEUS AB Follicular dendritic cells (FDCs) increase HIV replication and virus production in lymphocytes by increasing the activation of NF-kappa B in infected cells. Because alpha-1-antitrypsin (AAT) decreases HIV replication in PBMCs and monocytic cells and decreases NF-kappa B activity, we postulated that AAT might also block FDC-mediated HIV replication. Primary CD4(+) T cells were infected with HIV and cultured with FDCs or their supernatant with or without AAT, and ensuing viral RNA and p24 production were monitored. NF-kappa B activation in the infected cells was also assessed. Virus production was increased in the presence of FDC supernatant, but the addition of AAT at concentrations >0.5 mg/ml inhibited virus replication. AAT blocked the nuclear translocation of NF-kappa B p50/p65 despite an unexpected elevation in associated phosphorylated and ubiquitinated I kappa B alpha (Ub-I kappa B alpha). In the presence of AAT, degradation of cytoplasmic I kappa B alpha was dramatically inhibited compared with control cultures. AAT did not inhibit the proteasome; however, it altered the pattern of ubiquitination of I kappa B alpha. AAT decreased I kappa B alpha polyubiquitination linked through ubiquitin lysine residue 48 and increased ubiquitination linked through lysine residue 63. Moreover, lysine reside 63-linked Ub-I kappa B alpha degradation was substantially slower than lysine residue 48-linked Ub-I kappa B alpha in the presence of AAT, correlating altered ubiquitination with a prolonged I kappa B alpha t(1/2). Because AAT is naturally occurring and available clinically, examination of its use as an inhibitory agent in HIV-infected subjects may be informative and lead to the development of similar agents that inhibit HIV replication using a novel mechanism. The Journal of Immunology, 2011, 186: 3148-3155. C1 [Zhou, Xueyuan; Willardson, Barry M.; Burton, Gregory F.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Shapiro, Leland] Univ Colorado, Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Shapiro, Leland] Univ Colorado, Div Infect Dis, Dept Med, Denver, CO 80220 USA. [Fellingham, Gilbert] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. RP Burton, GF (reprint author), Brigham Young Univ, Dept Chem & Biochem, Room C104B BNSN, Provo, UT 84602 USA. EM gburton@chem.byu.edu FU National Institute of Allergy and Infectious Disease [AI39963, AI91517]; National Institute of General Medical Sciences [GM078550]; Campbell Foundation; College of Physical and Mathematical Sciences FX This work was supported by Public Health Service Grants AI39963 and AI91517 from the National Institute of Allergy and Infectious Disease (to G.F.B.), GM078550 from the National Institute of General Medical Sciences (to B.M.W.), the Campbell Foundation (to L.S.), and by a Brigham Young University grant from the College of Physical and Mathematical Sciences (to G.F.B.). NR 35 TC 19 Z9 20 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 MAR 1 PY 2011 VL 186 IS 5 BP 3148 EP 3155 DI 10.4049/jimmunol.1001358 PG 8 WC Immunology SC Immunology GA 721LT UT WOS:000287356900053 PM 21263074 ER PT J AU Cassol, E Rossouw, T Seebregts, C Cassol, S AF Cassol, Edana Rossouw, Theresa Seebregts, Chris Cassol, Sharon TI Microbial Translocation: A Marker of Advanced HIV-1 Infection and a Predictor of Treatment Failure? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID IMMUNE ACTIVATION; GENE-EXPRESSION; PROGRESSION; DISEASE; AFRICA C1 [Cassol, Edana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Cassol, Sharon] Univ Pretoria, Fac Hlth Sci, MRC Unit Inflammat & Immun, ZA-0002 Pretoria, South Africa. [Rossouw, Theresa] Univ Pretoria, Dept Family Med, ZA-0002 Pretoria, South Africa. [Seebregts, Chris] Med Res Counts, Ehlth Res & Innovat Platform, Biomed Informat Res, Tygerberg, South Africa. RP Cassol, E (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, CLS 1017,450 Brookline Ave, Boston, MA 02215 USA. EM edana_cassol@dfci.harvard.edu NR 12 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2011 VL 203 IS 5 BP 747 EP 748 DI 10.1093/infdis/jiq109 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 717FD UT WOS:000287028000024 PM 21278212 ER PT J AU Luo, S Chaplin, AC Langley, RGB Njauw, CN Duncan, LM Miller, RA Tsao, H AF Luo, Su Chaplin, Anna C. Langley, Richard G. B. Njauw, Ching-Ni Duncan, Lyn M. Miller, Robert A. Tsao, Hensin TI Agminated Segmental Nevi Demonstrating Intranevic Concordance of BRAF Status SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID FACIO-CUTANEOUS SYNDROME; MUTATIONS; SKIN; NRAS C1 [Luo, Su; Njauw, Ching-Ni; Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Luo, Su] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Chaplin, Anna C.; Langley, Richard G. B.; Miller, Robert A.] Dalhousie Univ, Dept Med, Div Dermatol, Halifax, NS, Canada. [Duncan, Lyn M.] Harvard Univ, Sch Med, Dept Pathol, MGH Dermatopathol Unit, Boston, MA 02115 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. RP Luo, S (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM htsao@partners.org RI Njauw, Ching-Ni/H-8046-2012 FU NCI NIH HHS [P50 CA093683-09, K24 CA149202, P50 CA-93683, K24 CA149202-01, P50 CA093683] NR 12 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2011 VL 131 IS 3 BP 788 EP 790 DI 10.1038/jid.2010.380 PG 4 WC Dermatology SC Dermatology GA 719SQ UT WOS:000287229700036 PM 21160499 ER PT J AU Warren, HS AF Warren, H. Shaw TI Control issues in sepsis: what modulates apoptosis? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material DE entotoxin shock; serum; modulation; lymphocytes; monocytes ID DEFINITIONS; MACROPHAGES; DEPLETION; HUMANS; SHOCK C1 Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Warren, HS (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, 149 13th St, Charlestown, MA 02129 USA. EM swarren1@partners.org FU PHS HHS [A1059010] NR 13 TC 1 Z9 1 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2011 VL 89 IS 3 BP 325 EP 326 DI 10.1189/jlb.1110612 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 727NL UT WOS:000287807700002 PM 21357246 ER PT J AU Gee, MS Harisinghani, MG AF Gee, Michael S. Harisinghani, Mukesh G. TI MRI in Patients With Inflammatory Bowel Disease SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Review DE MRI; MR enterography; Crohn's disease; ulcerative colitis; imaging ID MULTIDETECTOR ROW CT; ORAL CONTRAST-MEDIA; CROHNS-DISEASE; COMPUTED-TOMOGRAPHY; IMAGING EVALUATION; CAPSULE ENDOSCOPY; FOLLOW-THROUGH; CANCER-RISKS; RADIATION; ENTEROCLYSIS AB Inflammatory bowel disease (IBD) affects approximate to 1.4 million people in North America and, because of its typical early age of onset and episodic disease course, IBD patients often undergo numerous imaging studies over the course of their lifetimes. Computed tomography (CT) has become the standard imaging modality for assessment of IBD patients because of its widespread availability, rapid image acquisition, and ability to evaluate intraluminal and extraluminal disease. However, repetitive CT imaging has been associated with a significant ionizing radiation risk to patients, making MRI an appealing alternative IBD Imaging modality. Pelvic MRI is currently the imaging gold standard for detecting perianal disease, while recent studies indicate that MRI bowel-directed techniques (enteroclysis, enterography, colonography) can accurately evaluate bowel inflammation in IBD. With recent technical innovations leading to faster and higher resolution body MRI, the role of MRI in IBD evaluation is likely to continue to expand. Future applications include surveillance Imaging. detection of mural fibrosis, and early assessment of therapy response. C1 [Gee, Michael S.; Harisinghani, Mukesh G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. [Gee, Michael S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Pediat Imaging, Boston, MA 02114 USA. RP Harisinghani, MG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM mharisinghani@partners.org FU National Institutes of Health; Harvard Medical School [UL1 RR025758-02] FX Contract grant sponsor: National Institutes of Health and Harvard Medical School; Contract grant number: Clinical and translational science award UL1 RR025758-02 (to M.S.G. and M.G.H.). NR 46 TC 28 Z9 29 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2011 VL 33 IS 3 BP 527 EP 534 DI 10.1002/jmri.22504 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 729LL UT WOS:000287951100002 PM 21512607 ER PT J AU Milbury, CA Chen, CC Mamon, H Liu, PF Santagata, S Makrigiorgos, GM AF Milbury, Coren A. Chen, Clark C. Mamon, Harvey Liu, Pingfang Santagata, Sandro Makrigiorgos, G. Mike TI Multiplex Amplification Coupled with COLD-PCR and High Resolution Melting Enables Identification of Low-Abundance Mutations in Cancer Samples with Low DNA Content SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CELL LUNG-CANCER; WHOLE-GENOME AMPLIFICATION; REAL-TIME PCR; P53 MUTATIONS; GENETIC PATHWAYS; CLINICAL-IMPLICATIONS; SENSITIVE DETECTION; DYE CONCENTRATION; CODING SEQUENCES; CURVE ANALYSIS AB Thorough screening of cancer-specific biomarkers, such as DNA mutations, can require large amounts of genomic material; however, the amount of genomic material obtained from some specimens (such as biopsies, fine-needle aspirations, circulating-DNA or tumor cells, and histological slides) may limit the analyses that can be performed. Furthermore, mutant alleles may be at low-abundance relative to wild-type DNA, reducing detection ability. We present a multiplex-PCR approach tailored to amplify targets of interest from small amounts of precious specimens, for extensive downstream detection of low-abundance alleles. Using 3 ng of DNA (1000 genome-equivalents), we amplified the 1 coding exons (2-11) of TP53 via multiplex-PCR. Following multiplex-PCR, we performed COLD-PCR (co-amplification of major and minor alleles at lower denaturation temperature) to enrich low-abundance variants and high resolution melting (HRM) to screen for aberrant melting profiles. Mutation-positive samples were sequenced. Evaluation of mutation-containing dilutions revealed improved sensitivities after COLD-PCR over conventional-PCR. COLD-PCR improved HRM sensitivity by approximately threefold to sixfold. Similarly, COLD-PCR improved mutation identification in sequence-chromatograms over conventional PCR. In clinical specimens, eight mutations were detected via conventional-PCR-HRM, whereas 12 were detected by COLD-PCR-HRM, yielding a 33% improvement in mutation detection. In summary, we demonstrate an efficient approach to increase screening capabilities from limited DNA material via multiplex-PCR and improve mutation detection sensitivity via COLD-PCR amplification. (J Mol Dingo 2011, 13:220-232; DOI: 10.1016/j.jmoldx.2010.10.008) C1 [Milbury, Coren A.; Chen, Clark C.; Mamon, Harvey; Liu, Pingfang; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. [Chen, Clark C.] Beth Israel Deaconess Med Ctr, Div Neurosurg, Boston, MA 02215 USA. [Santagata, Sandro] Harvard Univ, Med Sch Boston, Brigham & Womens Hosp, Dept Pathol, Cambridge, MA 02138 USA. RP Makrigiorgos, GM (reprint author), Brigham & Womens Hosp, Dana Farber Brigham & Womens Canc Ctr, Level L2,75 Francis St, Boston, MA 02115 USA. EM mmakrigiorgos@partners.org RI Chen, Clark/C-8714-2013 OI Chen, Clark/0000-0001-6258-9277 FU NCI [T32-CA009078]; NIH [CA-138280, CA-111994] FX Supported by grants T32-CA009078 from the NCI (C.A.M.), and NIH grants CA-138280 and CA-111994. NR 62 TC 13 Z9 14 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2011 VL 13 IS 2 BP 220 EP 232 DI 10.1016/j.jmoldx.2010.10.008 PG 13 WC Pathology SC Pathology GA 865JD UT WOS:000298306300015 PM 21354058 ER PT J AU Munger, KL Chitnis, T Frazier, AL Giovannucci, E Spiegelman, D Ascherio, A AF Munger, Kassandra L. Chitnis, Tanuja Frazier, A. Lindsay Giovannucci, Edward Spiegelman, Donna Ascherio, Alberto TI Dietary intake of vitamin D during adolescence and risk of multiple sclerosis SO JOURNAL OF NEUROLOGY LA English DT Article DE Multiple sclerosis; Vitamin D; Cohort study; Epidemiology ID BREAST-CANCER; ENVIRONMENTAL-FACTORS; US WOMEN; CONSUMPTION; CHILDHOOD; MILK; MS; REPRODUCIBILITY; EXPOSURE; COHORTS AB Adolescence may be an important etiological period in the development of multiple sclerosis (MS), and studies suggest that adequate vitamin D nutrition is protective. Here, the authors examined whether dietary intake of vitamin D during adolescence decreases the risk of MS in adulthood. In 1986 in the Nurses' Health Study and in 1998 in the Nurses' Health Study II (NHSII), women completed a food frequency questionnaire regarding their dietary intake during adolescence. From this, daily intake of vitamin D was calculated. Adolescent diet was available for 379 incident MS cases confirmed over the combined 44 years of follow-up in both cohorts, and for 67 prevalent cases in the NHSII who had MS at baseline (1989). Cox proportional hazards models were used to calculate relative risk estimates and 95% confidence intervals. Total vitamin D intake during adolescence was not associated with MS risk. Intake of a parts per thousand yen400 IU/day of vitamin D from multivitamins was associated with a non-statistically significant reduced risk (RR compared to no intake = 0.73, 95% CI: 0.50-1.07, P = 0.11), whereas intake of whole milk, an important source of dietary vitamin D, was associated with an increased risk. The possibility of opposite effects of vitamin D and milk intake on MS risk should be considered in future studies. C1 [Munger, Kassandra L.; Giovannucci, Edward; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chitnis, Tanuja] Harvard Univ, Brigham & Womens Hosp, Sch Med, Partners Multiple Sclerosis Ctr,Dept Neurol, Boston, MA 02115 USA. [Frazier, A. Lindsay] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA. [Frazier, A. Lindsay; Giovannucci, Edward; Ascherio, Alberto] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward; Spiegelman, Donna; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Munger, KL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,3rd Fl, Boston, MA 02115 USA. EM kgorham@hsph.harvard.edu FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health [NS047467] FX This work was supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (grant NS047467). We thank K. Claire Simon, ScD, and Leslie Unger for technical support. The authors have no financial conflicts of interest to disclose. NR 29 TC 26 Z9 27 U1 1 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAR PY 2011 VL 258 IS 3 BP 479 EP 485 DI 10.1007/s00415-010-5783-1 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 729BZ UT WOS:000287924200018 PM 20945071 ER PT J AU Mendez, MF Shapira, JS AF Mendez, Mario F. Shapira, Jill S. TI Internet Pornography and Frontotemporal Dementia SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Letter ID SEXUAL-BEHAVIOR; DEGENERATION C1 [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Mendez, MF (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, Los Angeles, CA 90095 USA. NR 5 TC 0 Z9 0 U1 1 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SPR PY 2011 VL 23 IS 2 BP E3 EP E3 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 777VF UT WOS:000291652500093 ER PT J AU Fung, SJ Xi, MC Zhang, JH Torterolo, P Sampogna, S Morales, FR Chase, MH AF Fung, Simon J. Xi, MingChu Zhang, JianHua Torterolo, Pablo Sampogna, Sharon Morales, Francisco R. Chase, Michael H. TI Projection Neurons From the Central Nucleus of the Amygdala to the Nucleus Pontis Oralis SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE amygdalofugal projection; glutamate; cholera toxin B; retrograde; reticular formation ID VESICULAR GLUTAMATE TRANSPORTER-2; TRIGEMINAL MOTOR NUCLEUS; ACTIVE REM SLEEP; RETICULAR-FORMATION; BRAIN-STEM; HYPOGLOSSAL MOTONEURONS; MEDULLA-OBLONGATA; PARADOXICAL SLEEP; GUINEA-PIG; RAT AB The present retrograde labeling study was designed to determine the presence and pattern of projections from individual subdivisions of the central nucleus of the amygdala (CNA) to the nucleus pontis oralis (NPO), which is a critical brainstem site involved in the generation and maintenance of active (REM) sleep. Projections from the CNA were labeled with the retrograde tracer cholera toxin B-subunit (CTB), which was injected, unilaterally, via microiontophoresis, into the NPO. Sections of the amygdala were immunostained in order to identify CTB-labeled CNA neurons and CNA neurons that contained CTB plus the vesicular glutamate transporter 2 (VGLUT2), which is a marker for glutamatergic neurons. Histological analyses revealed that retrogradely labeled neurons that project to the NPO were localized, ipsilaterally, within the medial, lateral, and capsular subdivisions of the CNA. In addition, a substantial proportion (24%) of all retrogradely labeled CNA neurons also exhibited VGLUT2 immunoreactivity. The present study demonstrates that glutamatergic neurons, which are present within various subdivisions of the CNA, project directly to the NPO. These data lend credence to the hypothesis that NPO neurons that are involved in the control of active sleep are activated by glutamatergic projections from the amygdala. (C) 2010 Wiley-Liss, Inc. C1 [Fung, Simon J.; Xi, MingChu; Zhang, JianHua; Torterolo, Pablo; Sampogna, Sharon; Morales, Francisco R.; Chase, Michael H.] WebSci Int, Los Angeles, CA 90024 USA. [Fung, Simon J.; Xi, MingChu; Zhang, JianHua; Chase, Michael H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Torterolo, Pablo; Morales, Francisco R.; Chase, Michael H.] Univ Republica, Dept Fisiol, Fac Med, Montevideo, Uruguay. [Chase, Michael H.] Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90024 USA. RP Fung, SJ (reprint author), WebSci Int, 1251 Westwood Blvd, Los Angeles, CA 90024 USA. EM sfung@websciences.org FU NIH [NS 60917] FX Contract grant sponsor: NIH; Contract grant number: NS 60917. NR 51 TC 14 Z9 14 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR PY 2011 VL 89 IS 3 BP 429 EP 436 DI 10.1002/jnr.22554 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 717RG UT WOS:000287064500015 PM 21259329 ER PT J AU Morasco, BJ Corson, K Turk, DC Dobscha, SK AF Morasco, Benjamin J. Corson, Kathryn Turk, Dennis C. Dobscha, Steven K. TI Association Between Substance Use Disorder Status and Pain-Related Function Following 12 Months of Treatment in Primary Care Patients With Musculoskeletal Pain SO JOURNAL OF PAIN LA English DT Article DE Chronic pain; substance use disorder; pain functioning; treatment; collaborative care intervention ID LOW-BACK-PAIN; MORRIS DISABILITY QUESTIONNAIRE; CHRONIC NONMALIGNANT PAIN; CHRONIC NONCANCER PAIN; ABUSE SCREENING-TEST; METHADONE-MAINTENANCE; COLLABORATIVE CARE; DEPENDENT PATIENTS; RANDOMIZED-TRIAL; PERSISTENT PAIN AB The goal of this study was to examine relationships between substance use disorder (SUD) history and 12-month outcomes among primary care patients with chronic noncancer pain (CNCP). Patients were enrolled in a randomized trial of collaborative care intervention (CCI) versus treatment as usual (TAU) to improve pain-related physical and emotional function. At baseline, 72 of 362 patients (20.0%) had a history of SUD. Compared to CNCP patients without SUD, those with comorbid SUD had poorer pain-related function and were more likely to meet criteria for current major depression and post-traumatic stress disorder (all P values <.05). Logistic regression analyses were conducted to examine whether SUD status was associated with clinically significant change over 12 months in pain-related function (30% reduction in Roland Morris Disability Questionnaire Score). The overall model was not significant in the CCI group. However, within the TAU group, participants with a SUD history were significantly less likely to show improvements in pain-related function (OR = .30, 95% CI = .11-.82). CNCP patients with comorbid SUD reported greater functional impairment at baseline. Patients with SUD who received usual care were 70% less likely to have clinically significant improvements in pain-related function 12 months postbaseline, and SUD status did not impede improvement for the CCI group. Perspective: Chronic noncancer pain patients with a history of a substance use disorder (SUD) report poorer pain-related functioning and are less likely to experience clinically significant improvements from usual pain treatment. Providers should assess for SUD status and provide more intensive interventions for these patients. (C) 2011 by the American Pain Society C1 [Morasco, Benjamin J.; Dobscha, Steven K.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR USA. [Corson, Kathryn; Dobscha, Steven K.] Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Med & Psychiat, Portland, OR USA. [Morasco, Benjamin J.; Corson, Kathryn; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turk, Dennis C.] Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr R&D99, 3710 SW US Vet Hop Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU Department of Veterans Affairs, Veterans Health Administration; Health Services Research and Development Service Projects [PMI 03-195, RCD04129]; National Institute on Drug Abuse [K23DA023467]; Endo; Johnson Johnson; Philips Respironics; National Institutes of Health; Eli Lilly; Empi; Pfizer; SK Life Science; Oregon Clinical and Translational Research Institute at OHSU; National Center for Research Resources, a component of the National Institutes of Health and NIH Roadmap for Medical Research [UI1RR024140] FX Supported in part by the Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service Projects PMI 03-195 and RCD04129, awarded to Dr Dobscha. Dr Morasco also received support from award K23DA023467 from the National Institute on Drug Abuse. During the past 12 months, Dr Turk has received research support from Endo, Johnson & Johnson, Philips Respironics, and the National Institutes of Health, and consulting fees from Eli Lilly, Empi, Johnson & Johnson, Pfizer, Philips Respironics, and SK Life Science. He is also a Special Government Employee of the U.S. Food and Drug Administration. The authors also appreciate support provided from the Oregon Clinical and Translational Research Institute at OHSU, grant number UI1RR024140 from the National Center for Research Resources, a component of the National Institutes of Health and NIH Roadmap for Medical Research. NR 49 TC 14 Z9 14 U1 2 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAR PY 2011 VL 12 IS 3 BP 352 EP 359 DI 10.1016/j.jpain.2010.07.010 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 738HS UT WOS:000288631500006 PM 20851057 ER PT J AU Wood, GJ Morrison, RS AF Wood, Gordon J. Morrison, R. Sean TI Writing Abstracts and Developing Posters for National Meetings SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID STRUCTURED ABSTRACTS; PUBLICATION; PRESENTATIONS; ELABORATION; EXPLANATION; PRESENTERS; ARTICLES; CONSORT; TRIALS; IMPACT AB Presenting posters at national meetings can help fellows and junior faculty members develop a national reputation. They often lead to interesting and fruitful networking and collaboration opportunities. They also help with promotion in academic medicine and can reveal new job opportunities. Practically, presenting posters can help justify funding to attend a meeting. Finally, this process can be invaluable in assisting with manuscript preparation. This article provides suggestions and words of wisdom for palliative care fellows and junior faculty members wanting to present a poster at a national meeting describing a case study or original research. It outlines how to pick a topic, decide on collaborators, and choose a meeting for the submission. It also describes how to write the abstract using examples that present a general format as well as writing tips for each section. It then describes how to prepare the poster and do the presentation. Sample poster formats are provided as are talking points to help the reader productively interact with those that visit the poster. Finally, tips are given regarding what to do after the meeting. The article seeks to not only describe the basic steps of this entire process, but also to highlight the hidden curriculum behind the successful abstracts and posters. These tricks of the trade can help the submission stand out and will make sure the reader gets the most out of the hard work that goes into a poster presentation at a national meeting. C1 [Wood, Gordon J.] Univ Pittsburgh, Sch Med, Inst Enhance Palliat Care, Sect Palliat Care & Med Eth,Dept Med, Pittsburgh, PA 15213 USA. [Morrison, R. Sean] Mt Sinai Sch Med, Dept Geriatr & Palliat Med, New York, NY USA. [Morrison, R. Sean] James J Peters VA, Bronx, NY USA. RP Wood, GJ (reprint author), Univ Pittsburgh, Sch Med, Inst Enhance Palliat Care, Sect Palliat Care & Med Eth,Dept Med, 200 Lothrop St,Suite 933 W, Pittsburgh, PA 15213 USA. EM woodgj@upmc.edu FU National Institute on Aging [K24 AG022345]; National Palliative Care Research Center FX Dr. Morrison is supported by a Mid-Career Investigator Award in Patient Oriented Research from the National Institute on Aging (K24 AG022345). A portion of this work was funded by the National Palliative Care Research Center. NR 31 TC 5 Z9 5 U1 0 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD MAR PY 2011 VL 14 IS 3 BP 353 EP 359 DI 10.1089/jpm.2010.0171 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 728ZZ UT WOS:000287915700021 PM 21241194 ER PT J AU Rosen, AK Mull, HJ Kaafarani, H Nebeker, J Shimada, S Helwig, A Nordberg, B Long, B Savitz, LA Shanahan, CW Itani, K AF Rosen, Amy K. Mull, Hillary J. Kaafarani, Haytham Nebeker, Jonathan Shimada, Stephanie Helwig, Amy Nordberg, Brian Long, Brenna Savitz, Lucy A. Shanahan, Christopher W. Itani, Kamal TI Applying Trigger Tools to Detect Adverse Events Associated With Outpatient Surgery SO JOURNAL OF PATIENT SAFETY LA English DT Article DE patient safety; adverse events; triggers; outpatient surgery; quality AB Objective: The objective of this study is to evaluate the performance of 5 triggers to detect adverse events (AEs) associated with outpatient surgery. Triggers use surveillance algorithms derived from clinical logic to flag cases where AEs have most likely occurred. Current efforts to detect AEs have focused primarily on the inpatient setting, despite the increase in outpatient surgery in all health care settings. Methods: Using trigger logic, we retrospectively evaluated data from 3 large health care systems' electronic medical records. Patients were eligible for inclusion if they had an outpatient (same-day) surgery in 2007 and at least 1 clinical note in the 6 months after the surgery. Two nurse abstractors reviewed a sample of trigger-flagged cases from each health care system. After reaching interrater reliability targets (k > 0.60), we calculated the positive predictive value (PPV) of each trigger and the confidence interval of the estimate. Results: The surgical triggers flagged between 1% and 22% of the outpatient surgery cases, with a wide range in PPVs (6.0%-62.0%). The pulmonary embolism and deep vein thrombosis and emergency department triggers had the lowest proportion of flagged cases along with the highest PPVs, showing the most promise for screening cases with a high probability of AE occurrence. Conclusions: Triggers may be useful in identifying a narrow set of surgeries for further review to determine if a surgical AE occurred, complementing existing tools and initiatives used to detect AEs. Improved detection of AEs in outpatient surgery should help target potential areas for quality improvement. C1 [Rosen, Amy K.; Mull, Hillary J.] VA Boston Healthcare Syst, Ctr Org, Leadership, Management Res, Boston, MA USA. [Rosen, Amy K.; Mull, Hillary J.; Shimada, Stephanie] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Kaafarani, Haytham] Tufts Med Ctr, Dept Surg, Boston, MA USA. [Kaafarani, Haytham] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Nebeker, Jonathan; Nordberg, Brian; Long, Brenna] VA Salt Lake City Geriatr Res Educ & Clin Ctr, Salt Lake City, UT USA. [Nebeker, Jonathan; Savitz, Lucy A.] Univ Utah, Salt Lake City, UT USA. [Shimada, Stephanie] Bedford VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Helwig, Amy] Agcy Healthcare Res & Qual, Rockville, MD USA. [Savitz, Lucy A.] Intermt Healthcare, Salt Lake City, UT USA. [Shanahan, Christopher W.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Shanahan, Christopher W.] Boston Med Ctr, Boston, MA USA. [Itani, Kamal] VA Boston Healthcare Syst, Dept Surg, W Roxbury, MA USA. [Itani, Kamal] Harvard Univ, Sch Med, Boston, MA USA. RP Rosen, AK (reprint author), VA Boston Healthcare Syst 152M, 150 S Huntington Ave, Boston, MA 02130 USA. EM akrosen@bu.edu RI Shanahan, Christopher/H-6592-2015 OI Shanahan, Christopher/0000-0001-9067-5922 FU Agency for Healthcare Research and Quality [HHSA290200600012] FX This project was supported by the Agency for Healthcare Research and Quality (Contract No. HHSA290200600012). NR 32 TC 7 Z9 7 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1549-8417 J9 J PATIENT SAF JI J. Patient Saf. PD MAR PY 2011 VL 7 IS 1 BP 45 EP 59 DI 10.1097/PTS.0b013e31820d164b PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V27KL UT WOS:000208612000008 PM 21921867 ER PT J AU Smaldone, A Ritholz, MD AF Smaldone, Arlene Ritholz, Marilyn D. TI Perceptions of Parenting Children With Type 1 Diabetes Diagnosed in Early Childhood SO JOURNAL OF PEDIATRIC HEALTH CARE LA English DT Article DE Parenting; type 1 diabetes; teamwork; qualitative ID DIFFICULT CONVERSATIONS; HEALTH-CARE; MELLITUS; KETOACIDOSIS; TRENDS; YOUTH; HOME AB Introduction: The purpose of this study was to explore perceptions of psychosocial adaptations in parenting young children with type 1 diabetes (T1DM) from diagnosis through childhood. Method: Fourteen parents of 11 children with T1DM who were diagnosed at age five years or younger participated in semi-structured interviews. Data were analyzed using content analysis. Results: Three significant themes were identified. In the theme "Diagnostic Experiences: Frustrations, Fears, and Doubts,'' parents described inadequate diagnostic experiences with pediatricians where concerns were minimized and diagnosis was sometimes delayed. Although hospitalization occurred abruptly, communication with specialists was more satisfactory. In the theme "Adapting to Diabetes,'' parents described isolation in caring for their child's T1DM. Family and friends had minimal understanding of T1DM care. Support groups lessened mothers' isolation, but fathers were less positive about this experience. Parental adaptation was more effective when responsibility for diabetes decision making was shared. All parents reported never mastering diabetes management. The theme "Negotiating Developmental Transitions'' revealed that normative childhood events were stressful, requiring that parents balance concerns to foster their child's participation. Conclusions: Pediatric providers can improve diagnostic and treatment experiences for parents of children with T1DM by recognizing feelings of isolation and lack of mastery, providing attentive communication, encouraging parental teamwork, and offering ongoing anticipatory guidance. J Pediatr Health Care. (2011) 25, 87-95. C1 [Smaldone, Arlene] Columbia Univ, Sch Nursing, New York, NY 10032 USA. [Ritholz, Marilyn D.] Childrens Hosp Boston, Boston, MA USA. [Ritholz, Marilyn D.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Ritholz, Marilyn D.] Harvard Univ, Sch Med, Boston, MA USA. RP Smaldone, A (reprint author), Columbia Univ, Sch Nursing, 617 W 168th St, New York, NY 10032 USA. EM ams130@columbia.edu FU National Institutes of Health/National Institute of Nursing Research [5P20 NR007799] FX Supported by National Institutes of Health/National Institute of Nursing Research grant No. 5P20 NR007799 (Arlene Smaldone, DNSc, CPNP, CDE, principal investigator of project pilot). NR 35 TC 27 Z9 28 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5245 J9 J PEDIATR HEALTH CAR JI J. Pediatr. Health Care PD MAR-APR PY 2011 VL 25 IS 2 BP 87 EP 95 DI 10.1016/j.pedhc.2009.09.003 PG 9 WC Health Policy & Services; Nursing; Pediatrics SC Health Care Sciences & Services; Nursing; Pediatrics GA 797QU UT WOS:000293143200005 PM 21320680 ER PT J AU Fung, EB Humphrey, ML Gildengorin, G Goldstein, N Hoffinger, SA AF Fung, Ellen B. Humphrey, Marcie L. Gildengorin, Ginny Goldstein, Natalie Hoffinger, Scott A. TI Rapid Remineralization of the Distal Radius After Forearm Fracture in Children SO JOURNAL OF PEDIATRIC ORTHOPAEDICS LA English DT Article DE DXA; bone mineral content; bone mineral density; forearm fracture; children ID BONE-MINERAL DENSITY; REFRACTURES; ADOLESCENTS; POPULATION; CHILDHOOD; MASS AB Background: Bone mineral content (BMC) and density (BMD) have been shown to diminish after fracture and immobilization in adults. Distal radius fractures are common in children, and unlike adults, there is a low incidence of refracture. The primary aim of this study was to assess the change in radial BMC and BMD after upper extremity fracture and casting in healthy pediatric patients. Methods: Patients were recruited at the time of distal radius fractures casting. The nonfractured (non-Fx) distal radius was initially scanned by dual energy x-ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), and 4, 8, 12, 24, and 52 weeks post CastOff. Results: Twenty-one patients were enrolled (13 male, 13 Caucasian; 10.4 +/- 2.5 y) with an average length of casting of 38 +/- 11 days. Eighteen patients (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the Fx and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was + 4.2% and + 0.2%, respectively, whereas for the Fx arm, the change was + 8.3% and + 3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error; P < 0.05). However, by 52 weeks, these differences were no longer significant. The increased mineralization was unrelated to age, sex, arm dominance, or calcium intake. Conclusions: These data show that there is rapid remineralization after a simple forearm fracture in children, with a transient elevation in BMD in the Fx arm after casting. This novel finding suggests that bone may be stronger around the site of fracture and could significantly change how we counsel young patients recovering from forearm fracture. Future research should focus on children immobilized for varying lengths of time and those with repeat fractures, using volumetric techniques of bone geometry and strength assessment. C1 [Fung, Ellen B.] Childrens Hosp & Res Ctr, HEDCO Hlth Sci Ctr, Dept Hematol, Oakland, CA 94609 USA. [Humphrey, Marcie L.; Hoffinger, Scott A.] Childrens Hosp & Res Ctr, Dept Orthoped, Oakland, CA 94609 USA. [Gildengorin, Ginny] Childrens Hosp & Res Ctr, Pediat Clin Res Ctr, Oakland, CA 94609 USA. [Goldstein, Natalie] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Fung, EB (reprint author), Childrens Hosp & Res Ctr, HEDCO Hlth Sci Ctr, Dept Hematol, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. EM efung@mail.cho.org FU National Center for Research Resources [M01 RR01271, UL1-RR024131] FX This publication was supported in part by the following grants: M01 RR01271 and UL1-RR024131 from the National Center for Research Resources. NR 21 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-6798 J9 J PEDIATR ORTHOPED JI J. Pediatr. Orthop. PD MAR PY 2011 VL 31 IS 2 BP 138 EP 143 DI 10.1097/BPO.0b013e3182093ddd PG 6 WC Orthopedics; Pediatrics SC Orthopedics; Pediatrics GA 719GS UT WOS:000287190800008 PM 21307706 ER PT J AU Gutierrez, OM Isakova, T Enfield, G Wolf, M AF Gutierrez, Orlando M. Isakova, Tamara Enfield, Gwen Wolf, Myles TI Impact of Poverty on Serum Phosphate Concentrations in the Third National Health and Nutrition Examination Survey SO JOURNAL OF RENAL NUTRITION LA English DT Article ID CHRONIC KIDNEY-DISEASE; SURVEY NHANES-III; FAST-FOOD; MINERAL METABOLISM; PHOSPHORUS INTAKE; RENAL-DISEASE; UNITED-STATES; HYPERPHOSPHATEMIA; HEMODIALYSIS; ASSOCIATION AB Objective: Increased serum phosphate is associated with adverse health outcomes. High intake of inexpensive processed and fast foods is common in impoverished communities, and is linked with excessive dietary phosphorus intake and elevated serum phosphate concentrations in chronic kidney disease patients. We examined the impact of socioeconomic status on dietary phosphorus intake and serum phosphate concentrations in the general population. Design: Cross-sectional study. Participants: A total of 14,261 adult participants in the Third National Health and Nutrition Examination Survey. Predictors and Outcomes: Poverty to income ratio (PIR; family income indexed to the federal poverty level) was the primary index of socioeconomic status. Serum phosphate was the primary outcome variable. Results: Although estimated phosphorus intake decreased with decreasing quartiles of PIR (P < .001), serum phosphate was inversely associated with PIR (P = .003). The relationship between lower PIR and higher serum phosphate remained significant after adjustment for demographic, laboratory, and dietary intake characteristics (P - .02). Compared with participants in the highest PIR quartile (income >300% of the federal poverty level), participants in the lowest quartile (income < the federal poverty level) had more than twice the odds of hyperphosphatemia (>= 4.4 mg/dL) in unadjusted and multivariable-adjusted logistic regression analyses (OR, 2.2; 95% CI, 1.5 to 3.2). Conclusions: Although lower income was associated with decreased estimated phosphorus intake, increasing poverty was independently linked with increased serum phosphate and higher likelihood of hyperphosphatemia. These findings may indicate that conventional dietary instruments underestimate phosphorus intake, especially among impoverished individuals. Further studies are needed to explore these possibilities. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved. C1 [Gutierrez, Orlando M.; Wolf, Myles] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Isakova, Tamara] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Nephrol, Boston, MA USA. [Enfield, Gwen] Univ Miami, Miller Sch Med, Clin Res Ctr, Miami, FL 33136 USA. RP Gutierrez, OM (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, 1120 NW 14th St,CRB C-221,Room 815, Miami, FL 33136 USA. EM ogutierrez2@med.miami.edu FU American Kidney Fund Clinical Scientist in Nephrology Fellowship; National Institutes of Health [K23DK081673, R01DK076116, R01DK081374] FX This study was supported by the American Kidney Fund Clinical Scientist in Nephrology Fellowship (to Dr. Isakova) and grants K23DK081673 (to Dr. Gutierrez), R01DK076116 and R01DK081374 (to Dr. Wolf) from the National Institutes of Health. NR 42 TC 20 Z9 20 U1 0 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 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD MAR PY 2011 VL 21 IS 2 BP 140 EP 148 DI 10.1053/j.jrn.2010.03.001 PG 9 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 722YQ UT WOS:000287471600005 PM 20537917 ER PT J AU Crane, DA Little, JW Burns, SP AF Crane, Deborah A. Little, James W. Burns, Stephen P. TI Weight gain following spinal cord injury: a pilot study SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Spinal cord injury; Obesity ID BODY-MASS INDEX; ENERGY-EXPENDITURE; DISEASE RISK; FAT MASS; OBESITY; ADULTS; PARAPLEGIA; COMMUNITY; TIME; MEN AB Study design: Retrospective chart review. Objective: To define the temporal course of weight gain in persons with new spinal cord injury (SCI), and to identify predictors of weight gain in this population. Setting: A United States Department of Veterans Affairs (VA) SCI Unit. Methods: A retrospective chart review in a VA SCI Unit was conducted. Participants (n = 85) included all persons with new SCI completing initial rehabilitation at the center between 1998 and 2006. Outcome measures were mean change in body mass index (BMI) between rehabilitation admission and final follow-up, time of greatest BMI change, and distribution of participants by BMI classification. These measures were also examined relative to SCI level, American Spinal Injury Association Impairment Scale (AIS) grade, primary mode of mobility, and age at rehabilitation admission. Results: Mean BMI increased by 2.3 kg/m(2) between rehabilitation admission (mean 45 days post-injury) and final follow-up (mean 5 years post-injury). The distribution of participants shifted from lower BMI classifications at rehabilitation admission to higher BMI classifications at final follow-up. For participants transitioning from normal to overweight or obese, the greatest increase occurred during the first year after acute rehabilitation. Neurological level, impairment category, primary mode of mobility, and age at rehabilitation admission did not significantly predict BMI change. BMI at rehabilitation admission correlated significantly with BMI at final follow-up (P < 0.0005). Conclusions: These findings confirm a significant increase in BMI after new SCI and suggest that persons with new SCI are at greatest weight gain risk during the first year following acute rehabilitation. C1 [Crane, Deborah A.; Little, James W.; Burns, Stephen P.] Univ Washington, Harborview Med Ctr, Dept Rehabil Med, Seattle, WA 98104 USA. [Crane, Deborah A.; Little, James W.; Burns, Stephen P.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Crane, DA (reprint author), Univ Washington, Harborview Med Ctr, Dept Rehabil Med, Box 359740,325 9th Ave, Seattle, WA 98104 USA. EM dacrane@uw.edu NR 22 TC 10 Z9 10 U1 0 U2 1 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD MAR PY 2011 VL 34 IS 2 BP 227 EP 232 DI 10.1179/2045772311Y.0000000001 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 744FR UT WOS:000289080800011 PM 21675361 ER PT J AU Patti, JA AF Patti, John A. TI Radiology-Centric Medicine and the Need for Practice Transformation SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Patti, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM jpatti@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2011 VL 8 IS 3 BP 149 EP 150 DI 10.1016/j.jacr.2011.01.014 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FH UT WOS:000305449000001 PM 21371659 ER PT J AU Byers, E Gomez, MA Sheridan, RM Orr, NW Hirsch, JA AF Byers, Ernest Gomez, Max A., II Sheridan, Robert M. Orr, Nelson W. Hirsch, Joshua A. TI Radiofrequency Identification for Inventory in Neurointerventional Practice SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE RFID; interventional radiology; medical inventory; patient billing; human factor AB Implementations of radiofrequency identification (RFID) systems within hospital settings are not unique or without controversy. To date, little consideration has been given to use of this technology in clinical interventional radiologic practice. The potential financial advantages coupled with benefits to quality and safety and increases in staff satisfaction are considerable. The authors outline these advantages by enabling readers to broadly consider the systemic perspective of implementing RFID technology with art associated vision toward downstream growth. Furthermore, the authors demonstrate the benefits of RFID technology integration in reducing cost and increasing quality assurance and the on-time delivery of services. Implementing RFID requires commitment from frontline technologist staff members to work collaboratively with management and external vendors. Ultimately, the authors believe this technology can positively influence patient care. C1 [Byers, Ernest; Gomez, Max A., II; Sheridan, Robert M.; Orr, Nelson W.; Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. RP Sheridan, RM (reprint author), Massachusetts Gen Hosp, Dept Imaging, 175 Cambridge St,Suite 200, Boston, MA 02114 USA. EM rmsheridan@partners.org NR 7 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2011 VL 8 IS 3 BP 191 EP 198 DI 10.1016/j.jacr.2010.09.006 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FH UT WOS:000305449000012 PM 21371670 ER PT J AU Okura, T Plassman, BL Steffens, DC Llewellyn, DJ Potter, GG Langa, KM AF Okura, Toru Plassman, Brenda L. Steffens, David C. Llewellyn, David J. Potter, Guy G. Langa, Kenneth M. TI Neuropsychiatric Symptoms and the Risk of Institutionalization and Death: The Aging, Demographics, and Memory Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE neuropsychiatric symptoms; caregiver distress; institutionalization; mortality ID MILD COGNITIVE IMPAIRMENT; NURSING-HOME PLACEMENT; ALZHEIMERS-DISEASE; OLDER-ADULTS; DEMENTIA CARE; UNITED-STATES; FOLLOW-UP; PREVALENCE; MORTALITY; DEPRESSION AB OBJECTIVES To examine the association between neuropsychiatric symptoms and risk of institutionalization and death. DESIGN Analysis of longitudinal data. SETTING The Aging, Demographics, and Memory Study (ADAMS). PARTICIPANTS Five hundred thirty-seven adults aged 71 and older with cognitive impairment drawn from the Health and Retirement Study (HRS). MEASUREMENTS Neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, apathy, elation, anxiety, disinhibition, irritation, and aberrant motor behaviors) and caregiver distress were identified using the Neuropsychiatric Inventory. A consensus panel in the ADAMS assigned cognitive category. Date of nursing home placement and information on death, functional limitations, medical comorbidity, and sociodemographic characteristics were obtained from the HRS and ADAMS. RESULTS Overall, the presence of one or more neuropsychiatric symptoms was not associated with a significantly higher risk for institutionalization or death during the 5-year study period, although when assessing each symptom individually, depression, delusions, and agitation were each associated with a significantly higher risk of institutionalization (hazard rate (HR)=3.06, 95% confidence interval (CI)=1.09-8.59 for depression; HR=5.74, 95% CI=1.94-16.96 for clinically significant delusions; HR=4.70, 95% CI=1.07-20.70 for clinically significant agitation). Caregiver distress mediated the association between delusions and agitation and institutionalization. Depression and hallucinations were associated with significantly higher mortality (HR=1.56, 95% CI=1.08-2.26 for depression; HR=2.59, 95% CI=1.09-6.16 for clinically significant hallucinations). CONCLUSION Some, but not all, neuropsychiatric symptoms are associated with a higher risk of institutionalization and death in people with cognitive impairment, and caregiver distress also influences institutionalization. Interventions that better target and treat depression, delusions, agitation, and hallucinations, as well as caregiver distress, may help delay or prevent these negative clinical outcomes. C1 [Okura, Toru] Bajikoen Clin, Geriatr Sect, Tokyo 1580098, Japan. [Steffens, David C.] Duke Univ, Med Ctr, Div Geriatr Psychiat, Durham, NC USA. [Potter, Guy G.] Duke Univ, Med Ctr, Div Med Psychol, Durham, NC USA. [Plassman, Brenda L.; Steffens, David C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Llewellyn, David J.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Langa, Kenneth M.] Univ Michigan, Dept Internal Med, Div Gen Med, Ann Arbor, MI 48109 USA. [Langa, Kenneth M.] US Dept Vet Affairs, Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. RP Okura, T (reprint author), Bajikoen Clin, Geriatr Sect, 1-22-23 Kami Yoga Setagaya Ward, Tokyo 1580098, Japan. EM t-ohkura@t3.rim.or.jp FU National Institute on Aging (NIA) [R01 AG027010, R01 AG030155] FX Conflict of Interest: The National Institute on Aging (NIA) provided funding for the HRS and the ADAMS (U01 AG09740). Additional funding support was provided by NIA Grants R01 AG027010 and R01 AG030155. NR 45 TC 36 Z9 37 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2011 VL 59 IS 3 BP 473 EP 481 DI 10.1111/j.1532-5415.2011.03314.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 732UQ UT WOS:000288215600012 PM 21391937 ER PT J AU Rosolowsky, ET Skupien, J Smiles, AM Niewczas, M Roshan, B Stanton, R Eckfeldt, JH Warram, JH Krolewski, AS AF Rosolowsky, Elizabeth T. Skupien, Jan Smiles, Adam M. Niewczas, Monika Roshan, Bijan Stanton, Robert Eckfeldt, John H. Warram, James H. Krolewski, Andrzej S. TI Risk for ESRD in Type 1 Diabetes Remains High Despite Renoprotection SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TERM ANTIHYPERTENSIVE TREATMENT; CONVERTING ENZYME-INHIBITION; IMPROVED GRAFT-SURVIVAL; CHRONIC KIDNEY-DISEASE; RENAL-TRANSPLANTATION; NEPHROPATHY; PROGRESSION; MELLITUS; MICROALBUMINURIA; PROTEINURIA AB Historically, patients with type 1 diabetes and macroalbuminuria had high competing risks: cardiovascular death or renal failure. Here, we assessed these risks in patients receiving therapies implemented during the last 30 years. Between 1991 and 2004, we enrolled 423 white patients with type 1 diabetes who developed macroalbuminuria (albumin excretion rate, >= 300 mu g/min). With follow-up for 98% through 2008, ESRD developed in 172 patients (incidence rate, 5.8/100 person-years), and 29 died without ESRD (mortality rate, 1/100 person-years). The majority of these outcomes occurred between ages 36 and 52 years with durations of diabetes of 21 to 37 years. The 15-year cumulative risks were 52% for ESRD and 11% for pre-ESRD death. During the 15 years of follow-up, the use of renoprotective treatment increased from 56 to 82%, and BP and lipid levels improved significantly; however, the risks for both ESRD and pre-ESRD death did not change over the years analyzed. There were 70 post-ESRD deaths, and the mortality rate was very similar during the 1990s and the 2000s (11/100 person-years versus 12/100 person-years, respectively). Mortality was low in patients who received a pre-emptive kidney transplant (1/100 person-years), although these patients did not differ from dialyzed patients with regard to predialysis eGFR, sex, age at onset of ESRD, or duration of diabetes. In conclusion, despite the widespread adoption of renoprotective treatment, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD, suggesting that more effective therapies are desperately needed. C1 [Krolewski, Andrzej S.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. [Rosolowsky, Elizabeth T.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Skupien, Jan; Niewczas, Monika; Krolewski, Andrzej S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Roshan, Bijan; Stanton, Robert] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Renal, Boston, MA 02215 USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Rosolowsky, Elizabeth T.; Skupien, Jan; Smiles, Adam M.; Niewczas, Monika; Roshan, Bijan; Stanton, Robert; Warram, James H.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Clin Div, Boston, MA 02215 USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM Andrzej.Krolewski@joslin.harvard.edu FU JDRF [1-2008-1018, 3-2009-397]; National Institutes of Health [DK41526, DK067638]; National Institutes of Health Child Health Services [HS00063] FX This project was supported through JDRF research grant 1-2008-1018 (A.S.K.) and National Institutes of Health grants DK41526 (A.S.K.) and DK067638 (A.S.K.) and National Institutes of Health Child Health Services Research Training Program, grant HS00063 (E.T.R.), and JDRF fellowship grant 3-2009-397 (J.S.). NR 33 TC 84 Z9 87 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2011 VL 22 IS 3 BP 545 EP 553 DI 10.1681/ASN.2010040354 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 740GE UT WOS:000288778800022 PM 21355053 ER PT J AU Boger, CA Chen, MH Tin, A Olden, M Koettgen, A de Boer, IH Fuchsberger, C O'Seaghdha, CM Pattaro, C Teumer, A Liu, CT Glazer, NL Li, M O'Conne, JR Tanaka, T Peralta, CA Kutalik, Z Luan, J Zhao, JH Hwang, SJ Akylbekova, E Kramer, H van der Harst, P Smith, AV Lohman, K de Andrade, M Hayward, C Kollerits, B Tonjes, A Aspelund, T Ingelsson, E Eiriksdottir, G Launer, LJ Harris, TB Shuldiner, AR Mitchell, BD Arking, DE Franceschini, N Boerwinkle, E Egan, J Hernandez, D Reilly, M Townsend, RR Lumley, T Siscovick, DS Psaty, BM Kestenbaum, B Haritunians, T Bergmann, S Vollenweider, P Waeber, G Mooser, V Waterworth, D Johnson, AD Florez, JC Meigs, JB Lu, XN Turner, ST Atkinson, EJ Leak, TS Aasarod, K Skorpen, F Syvanen, AC Illig, T Baumert, J Koenig, W Kramer, BK Devuyst, O Mychaleckyj, JC Minelli, C Bakker, SJL Kedenko, L Paulweber, B Coassin, S Endlich, K Kroemer, HK Biffar, R Stracke, S Volzke, H Stumvol, M Magi, R Campbell, H Vitart, V Hastie, ND Gudnason, V Kardia, SLR Liu, YM Polasek, O Curhan, G Kronenberg, F Prokopenko, I Rudan, I Arnlov, J Hallan, S Navis, G Parsa, A Ferrucci, L Coresh, J Shlipak, MG Bul, SB Paterson, AD Wichmann, HE Wareham, NJ Loos, RJF Rotter, JI Pramstaller, PP Cupples, LA Beckmann, JS Yang, QO Heid, IM Rettig, R Dreisbach, AW Bochud, M Fox, CS Kao, WHL AF Boeger, Carsten A. Chen, Ming-Huei Tin, Adrienne Olden, Matthias Koettgen, Anna de Boer, Ian H. Fuchsberger, Christian O'Seaghdha, Conall M. Pattaro, Cristian Teumer, Alexander Liu, Ching-Ti Glazer, Nicole L. Li, Man O'Conne, Jeffrey R. Tanaka, Toshiko Peralta, Carmen A. Kutalik, Zoltan Luan, Jian'an Zhao, Jing Hua Hwang, Shih-Jen Akylbekova, Ermeg Kramer, Holly van der Harst, Pim Smith, Albert V. Lohman, Kurt de Andrade, Mariza Hayward, Caroline Kollerits, Barbara Toenjes, Anke Aspelund, Thor Ingelsson, Erik Eiriksdottir, Gudny Launer, Lenore J. Harris, Tamara B. Shuldiner, Alan R. Mitchell, Braxton D. Arking, Dan E. Franceschini, Nora Boerwinkle, Eric Egan, Josephine Hernandez, Dena Reilly, Muredach Townsend, Raymond R. Lumley, Thomas Siscovick, David S. Psaty, Bruce M. Kestenbaum, Bryan Haritunians, Talin Bergmann, Sven Vollenweider, Peter Waeber, Gerard Mooser, Vincent Waterworth, Dawn Johnson, Andrew D. Florez, Jose C. Meigs, James B. Lu, Xiaoning Turner, Stephen T. Atkinson, Elizabeth J. Leak, Tennille S. Aasarod, Knut Skorpen, Frank Syvaenen, Ann-Christine Illig, Thomas Baumert, Jens Koenig, Wolfgang Kraemer, Bernhard K. Devuyst, Olivier Mychaleckyj, Josyf C. Minelli, Cosetta Bakker, Stephan J. L. Kedenko, Lyudmyla Paulweber, Bernhard Coassin, Stefan Endlich, Karlhans Kroemer, Heyo K. Biffar, Reiner Stracke, Sylvia Voelzke, Henry Stumvol, Michael Maegi, Reedik Campbell, Harry Vitart, Veronique Hastie, Nicholas D. Gudnason, Vilmundur Kardia, Sharon L. R. Liu, Yongmei Polasek, Ozren Curhan, Gary Kronenberg, Florian Prokopenko, Inga Rudan, Igor Aernloev, Johan Hallan, Stein Navis, Gerjan Parsa, Afshin Ferrucci, Luigi Coresh, Josef Shlipak, Michael G. Bul, Shelley B. Paterson, Andrew D. Wichmann, H. -Erich Wareham, Nicholas J. Loos, Ruth J. F. Rotter, Jerome I. Pramstaller, Peter P. Cupples, L. Adrienne Beckmann, Jacques S. Yang, Qiong Heid, Iris M. Rettig, Rainer Dreisbach, Albert W. Bochud, Murielle Fox, Caroline S. Kao, W. H. L. CA CKDGen Consortium DCCT EDIC TI CUBN Is a Gene Locus for Albuminuria SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; CHRONIC KIDNEY-DISEASE; TYPE-1 DIABETES-MELLITUS; LOW-GRADE ALBUMINURIA; RENAL-FUNCTION; ALBUMIN/CREATININE RATIO; ATHEROSCLEROSIS RISK; LINKAGE ANALYSIS; PROXIMAL TUBULE; DESIGN AB Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 x 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes. C1 [Hwang, Shih-Jen; Johnson, Andrew D.; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA 01702 USA. [Boeger, Carsten A.; Olden, Matthias] Univ Med Ctr Regensburg, Dept Internal Med 2, Regensburg, Germany. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Tin, Adrienne; Koettgen, Anna; Li, Man; Kao, W. H. L.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Tin, Adrienne; Koettgen, Anna; Li, Man; Kao, W. H. L.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Olden, Matthias; Heid, Iris M.] Univ Regensburg, Dept Epidemiol & Prevent Med, Med Ctr, Regensburg, Germany. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [de Boer, Ian H.; Kestenbaum, Bryan] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Fuchsberger, Christian; Pattaro, Cristian; Minelli, Cosetta; Pramstaller, Peter P.] European Acad Bolzano Bozen EURAC, Inst Med Genet, Bolzano, Italy. [Fuchsberger, Christian; Pattaro, Cristian; Minelli, Cosetta; Pramstaller, Peter P.] Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany. [O'Seaghdha, Conall M.] Harvard Univ, Sch Med, Boston, MA USA. [O'Seaghdha, Conall M.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] NHLBIs Framingham Heart Study, Boston, MA USA. [Glazer, Nicole L.; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Glazer, Nicole L.; Lumley, Thomas] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [O'Conne, Jeffrey R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Div Nephrol, San Francisco Med Sch, San Francisco, CA 94143 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kutalik, Zoltan; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kutalik, Zoltan; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Luan, Jian'an; Zhao, Jing Hua; Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Akylbekova, Ermeg] Jackson State Univ, Jackson, MS USA. [Hwang, Shih-Jen; Johnson, Andrew D.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Kramer, Holly] Loyola Univ, Maywood, IL USA. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Holtasmara, Kopavogur, Iceland. [Lohman, Kurt; Liu, Yongmei] Wake Forest Univ, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [de Andrade, Mariza; Atkinson, Elizabeth J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Hayward, Caroline; Vitart, Veronique; Hastie, Nicholas D.] Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Kollerits, Barbara; Coassin, Stefan; Kronenberg, Florian] Innsbruck Med Univ, Div Genet Epidemiol, Innsbruck, Austria. [Toenjes, Anke; Stumvol, Michael] Univ Leipzig, Dept Med, Leipzig, Germany. [Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Geriatr Res & Educ Clin Ctr, Vet Adm Med Ctr, Baltimore, MD 21201 USA. [Arking, Dan E.] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Franceschini, Nora] Univ N Carolina, Chapel Hill, NC USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Egan, Josephine] NIA, Lab Clin Invest, Baltimore, MD 21224 USA. [Hernandez, Dena] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Reilly, Muredach] Univ Penn, Div Cardiol, Perelman Ctr Adv Med, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Dept Epidemiol, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Dept Hlth Serv, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Haritunians, Talin; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Vollenweider, Peter; Waeber, Gerard] Univ Vaudois, Ctr Hosp, Dept Internal Med, Lausanne, Switzerland. [Mooser, Vincent; Waterworth, Dawn] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Gen Internal Med, Boston, MA 02114 USA. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Leak, Tennille S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Aasarod, Knut; Hallan, Stein] St Olavs Univ Hosp, Trondheim, Norway. [Aasarod, Knut; Skorpen, Frank; Hallan, Stein] Norwegian Univ Sci & Technol, Fac Med, N-7034 Trondheim, Norway. [Syvaenen, Ann-Christine] Uppsala Univ, Sci Life Lab, Dept Med Sci, Uppsala, Sweden. [Illig, Thomas; Baumert, Jens; Wichmann, H. -Erich; Heid, Iris M.] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Koenig, Wolfgang] Univ Ulm Klinikum, Zentrum Innere Med, Med Klin Kardiol 2, Ulm, Germany. [Kraemer, Bernhard K.] Univ Med Ctr Mannheim, Dept Med 5, Mannheim, Germany. [Devuyst, Olivier] Catholic Univ Louvain, Sch Med, NEER Unit, B-1200 Brussels, Belgium. [Mychaleckyj, Josyf C.] Ctr Publ Hlth Genom, Charlottesville, VA USA. [Bakker, Stephan J. L.; Navis, Gerjan] Univ Groningen, Dept Internal Med, Univ Med Ctr, Groningen, Netherlands. [Kedenko, Lyudmyla; Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, Salzburg, Austria. [Endlich, Karlhans] Ernst Moritz Arndt Univ Greifswald, Inst Anat & Cell Biol, Greifswald, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, Greifswald, Germany. [Biffar, Reiner] Ernst Moritz Arndt Univ Greifswald, Clin Prosthodont Dent Gerostomatol & Mat Sci, Greifswald, Germany. [Stracke, Sylvia] Ernst Moritz Arndt Univ Greifswald, Nephrol Clin Internal Med A, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Maegi, Reedik; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Maegi, Reedik; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Polasek, Ozren] Gen Info Ltd, Zagreb, Croatia. [Curhan, Gary] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Edinburgh, Midlothian, Scotland. [Aernloev, Johan] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bul, Shelley B.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth, Toronto, ON M5G 1X5, Canada. [Paterson, Andrew D.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Beckmann, Jacques S.] Univ Lausanne, Lausanne, Switzerland. [Beckmann, Jacques S.] Univ Vaudois, Ctr Hosp, Serv Med Genet, Lausanne, Switzerland. [Wichmann, H. -Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Dreisbach, Albert W.] Univ Mississippi, Div Nephrol, Jackson, MS 39216 USA. [Bochud, Murielle] Univ Lausanne, IUMSP, Lausanne, Switzerland. [Bochud, Murielle] Univ Vaudois, Ctr Hosp, Univ Inst Social & Prevent Med, Lausanne, Switzerland. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov; wkao@jhsph.edu RI Singleton, Andrew/C-3010-2009; Giallauria, Francesco/B-5681-2013; Endlich, Karlhans/G-5485-2013; Johnson, Andrew/G-6520-2013; Colaus, PsyColaus/K-6607-2013; Fuchsberger, Christian/C-9646-2010; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Beckmann, Jacques S /A-9772-2008; Arnlov, Johan/N-9886-2013; Kottgen, Anna/D-2920-2012; Cavalieri, Margherita/G-8053-2012; Rudan, Igor/I-1467-2012; Kronenberg, Florian/B-1736-2008; Yang, Qiong/G-5438-2014; Pramstaller, Peter/C-2357-2008; Bakker, Stephan/J-4023-2015; Gudnason, Vilmundur/K-6885-2015; Bull, Shelley/A-1920-2013; Polasek, Ozren/B-6002-2011; Prokopenko, Inga/H-3241-2014; Paterson, Andrew/A-4088-2011; Smith, Albert/K-5150-2015; Hayward, Caroline/M-8818-2016; Feitosa, Mary/K-8044-2012; OI Mitchell, Braxton/0000-0003-4920-4744; Bergmann, Sven/0000-0002-6785-9034; Giallauria, Francesco/0000-0003-4119-9397; Aspelund, Thor/0000-0002-7998-5433; Beckmann, Jacques S /0000-0002-9741-1900; Rudan, Igor/0000-0001-6993-6884; Felix, Janine/0000-0002-9801-5774; Magi, Reedik/0000-0002-2964-6011; Kramer, Holly/0000-0002-6374-837X; Cupples, L. Adrienne/0000-0003-0273-7965; Zgaga, Lina/0000-0003-4089-9703; Kronenberg, Florian/0000-0003-2229-1120; Bakker, Stephan/0000-0003-3356-6791; Gudnason, Vilmundur/0000-0001-5696-0084; Polasek, Ozren/0000-0002-5765-1862; Prokopenko, Inga/0000-0003-1624-7457; Paterson, Andrew/0000-0002-9169-118X; Smith, Albert/0000-0003-1942-5845; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Fuchsberger, Christian/0000-0002-5918-8947 FU NIH [R01 AG18728, R01 HL088119, U01 GM074518-04, U01 HL072515-06, U01 HL084756, NIH K12RR023250, NIH P30 DK072488, NIH P60 DK079637, HHSN268200625226C]; University of Maryland General Clinical Research Center [M01 RR 16500]; Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center; Paul Beeson Physician Faculty; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652, R01 AG027002]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health and NIH Roadmap for Medical Research [ULIRR025005]; National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Medical Research Council UK; Cancer Research UK FX AMISH: The Amish studies are supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (PAPI Study), U01 HL072515-06 (HAPI Study), U01 HL084756 and NIH K12RR023250 (University of Maryland MCRDP), NIH P30 DK072488 (Clinical Nutrition Research Unit of Maryland), and NIH P60 DK079637 (Baltimore Diabetes Research and Training Center). The University of Maryland General Clinical Research Center, grant M01 RR 16500, the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center, and the Paul Beeson Physician Faculty Scholars in Aging Program. We thank our Amish research volunteers for their long-standing partnership in research, and the research staff at the Amish Research Clinic for their hard work and dedication.; ARIC: The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant numbers ULIRR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; CHS: The Cardiovascular Health Study (CHS) research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133, grants U01 HL080295 and R01 HL087652, and R01 AG027002 from the National Heart, Lung and Blood Institute, with additional contribution from the National Institute of Neurologic Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; CoLaus: The CoLaus authors thank Mande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramie, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, and 310000-112552), the Swiss School of Public Health Plus, the Giorgi-Cavaglieri Foundation, and the European Framework Project 6 (EuroDia, AnEuploidy, and Hypergenes projects).; EPIC: The EPIC Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK, and by additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and the Wellcome Trust. NR 81 TC 85 Z9 87 U1 5 U2 13 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2011 VL 22 IS 3 BP 555 EP 570 DI 10.1681/ASN.2010060598 PG 16 WC Urology & Nephrology SC Urology & Nephrology GA 740GE UT WOS:000288778800023 PM 21355061 ER PT J AU Salanitro, AH Safford, MM Houston, TK Williams, JH Ovalle, F Payne-Foster, P Allison, JJ Estrada, CA AF Salanitro, Amanda H. Safford, Monika M. Houston, Thomas K. Williams, Jessica H. Ovalle, Fernando Payne-Foster, Pamela Allison, Jeroan J. Estrada, Carlos A. TI Patient Complexity and Diabetes Quality of Care in Rural Settings SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE diabetes; quality of care; primary care AB Purpose: Even though pay-for-performance programs are being rapidly implemented, little is known about how patient complexity affects practice-level performance assessment in rural settings. We sought to determine the association between patient complexity and practice-level performance in the rural United States. Basic procedures: Using baseline data from a trial aimed at improving diabetes care, we determined factors associated with a practice's proportion of patients having controlled diabetes (hemoglobin A(lc) <= 7%): patient socioeconomic factors, clinical factors, difficulty with self-testing of blood glucose, and difficulty with keeping appointments. We used linear regression to adjust the practice-level proportion with A(lc) controlled for these factors. We compared practice rankings using observed and expected performance and classified practices into hypothetical pay-for-performance categories. Main Findings: Rural primary care practices (n = 135) in 11 southeastern states provided information for 1641 patients with diabetes. For practices in the best quartile of observed control, 76.1% of patients had controlled diabetes vs 19.3% of patients in the worst quartile. After controlling for other variables, proportions of diabetes control were 10% lower in those practices whose patients had the greatest difficulty with either self testing or appointment keeping (p < .05 for both). Practice rankings based on observed and expected proportion of AI, control showed only moderate agreement in pay-for-performance categories (kappa = 0.47; 95% confidence interval, 0.32-0.56; p < .001). Principal Conclusions: Basing public reporting and resource allocation on quality assessment that does not account for patient characteristics may further harm this vulnerable group of patients and physicians. C1 [Salanitro, Amanda H.] Vanderbilt Univ, VA Tennessee Valley Geriatr Res Educ & Clin Ctr, Nashville, TN USA. [Salanitro, Amanda H.] Vanderbilt Univ, Sect Hosp Med, Nashville, TN USA. [Estrada, Carlos A.] Univ Alabama, Vet Affairs Natl Qual Scholars Program, Birmingham, AL USA. [Estrada, Carlos A.] Univ Alabama, Ctr Surg Med Acute Care Res & Transit CSMART, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Houston, Thomas K.; Allison, Jeroan J.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Payne-Foster, Pamela] Univ Alabama, Tuscaloosa, AL USA. RP Salanitro, AH (reprint author), Room A-414,1310 24th Ave S, Nashville, TN 37212 USA. EM amanda.salanitro@vanderbilt.edu RI Houston, Thomas/F-2469-2013; OI Allison, Jeroan/0000-0003-4472-2112 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [5R18DK065001]; Veterans Affairs FX Dr Allison was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, 5R18DK065001). Dr Salanitro was supported by a Veterans Affairs National Quality Scholars fellowship. NR 1 TC 3 Z9 3 U1 1 U2 2 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD MAR PY 2011 VL 103 IS 3 BP 234 EP 240 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 755UO UT WOS:000289964400006 PM 21671526 ER PT J AU Reiner, AP Kahn, A Eisner, BH Pletcher, MJ Sadetsky, N Williams, OD Polak, JF Jacobs, DR Stoller, ML AF Reiner, Alexander P. Kahn, Arnold Eisner, Brian H. Pletcher, Mark J. Sadetsky, Natalia Williams, O. Dale Polak, Joseph F. Jacobs, David R., Jr. Stoller, Marshall L. TI Kidney Stones and Subclinical Atherosclerosis in Young Adults: The CARDIA Study SO JOURNAL OF UROLOGY LA English DT Article DE urolithiasis; atherosclerosis ID UNITED-STATES; NEPHROLITHIASIS; HYPERTENSION; RISK; ASSOCIATION; POPULATION; OBESITY AB Purpose: Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. To our knowledge there has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease. We studied the relationship between nephrolithiasis, and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from the CARDIA study. Materials and Methods: The CARDIA study is a United States, population based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985 to 1986. Results: By the year 20 examination 200 (3.9%) CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 examination, particularly of the internal carotid/bulb region. Using a composite dichotomous end point of carotid stenosis and/or the upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (OR 1.6, 95% CI 1.1-2.3, p = 0.01), even after adjusting for major atherosclerotic risk factors. Conclusions: The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology. C1 [Pletcher, Mark J.; Sadetsky, Natalia; Stoller, Marshall L.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. [Pletcher, Mark J.; Sadetsky, Natalia; Stoller, Marshall L.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Polak, Joseph F.] Tufts Univ New England Med Ctr, Dept Radiol, Boston, MA USA. [Eisner, Brian H.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Kahn, Arnold] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Williams, O. Dale] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Stoller, ML (reprint author), Univ Calif San Francisco, Dept Urol, Box 0738, San Francisco, CA 94143 USA. EM mstoller@urology.ucsf.edu FU CARDIA [N01-HC-48047 - N01-HC-48050, N01-HC-95095]; CARDIA Ultrasound Reading Center [HHSN268200425204C]; CARDIA Computed Tomography Reading Center [N01-HC-05187, HHSN268200425205C]; Boston Scientific Corporation; PercSys; Ravine Group FX Supported by the CARDIA contract (N01-HC-48047 - N01-HC-48050 and N01-HC-95095), CARDIA Ultrasound Reading Center HHSN268200425204C, and CARDIA Computed Tomography Reading Center N01-HC-05187 and HHSN268200425205C.; Financial interest and/or other relationship with Boston Scientific Corporation, PercSys and the Ravine Group. NR 19 TC 41 Z9 42 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2011 VL 185 IS 3 BP 920 EP 925 DI 10.1016/j.juro.2010.10.086 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 718OM UT WOS:000287133900056 PM 21251678 ER PT J AU Lim, CS Qiao, XY Reslan, OM Xia, Y Raffetto, JD Paleolog, E Davies, AH Khalil, RA AF Lim, Chung S. Qiao, Xiaoying Reslan, Ossama M. Xia, Yin Raffetto, Joseph D. Paleolog, Ewa Davies, Alun H. Khalil, Raouf A. TI Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the American-Venous-Forum CY FEB 10-13, 2010 CL Amelia Isl, FL SP Amer Venous Forum ID SMOOTH-MUSCLE-CELLS; VARICOSE-VEIN FORMATION; FACTOR-KAPPA-B; NITRIC-OXIDE; MATRIX METALLOPROTEINASES; SUPEROXIDE-PRODUCTION; INDUCED ANGIOGENESIS; VASCULAR-DISEASE; MMP-9 EXPRESSION; SKELETAL-MUSCLE AB Background: Decreased venous tone and vein wall dilation may contribute to varicose vein formation. We have shown that prolonged vein wall stretch is associated with upregulation of matrix metalloproteases (MMPs) and decreased contraction. Because hypoxia-inducible factors (HIFs) expression also increases with mechanical stretch, this study tested whether upregulation of HIFs is an intermediary mechanism linking prolonged vein wall stretch to the changes in MMP expression and venous contraction. Methods: Segments of rat inferior vena cava (IVC) were suspended in tissue bath under 0.5-g basal tension for 1 hour, and a control contraction to phenylephrine (PHE, 10(-5)M) and KCl (96mM) was elicited. The veins were then exposed to prolonged 18 hours of tension at 0.5 g, 2 g, 2 g plus HIF inhibitor U0126 (10(-5)M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG, 10(-5)M), or echinomycin (10(-6)M), or 2 g plus dimethyloxallyl glycine (DMOG; 10(-4)M), a prolyl-hydroxylase inhibitor that stabilizes HIF. The fold-change in PHE and KCl contraction was compared with the control contraction at 0.5-g tension for 1 hour. Vein tissue homogenates were analyzed for HIF-1 alpha, HIF-2 alpha, MMF-2, and MMP-9 messenger RNA (mRNA) and protein amount using real-time reverse transcription polymerase chain reaction and Western blots. Results: Compared with control IVC contraction at 0.5-g tension for 1 hour, the PHE and KCl contraction after prolonged 0.5-g tension was 2.0 +/- 0.35 and 1.1 +/- 0.06, respectively. Vein contraction to PHE and KCl after prolonged 2-g tension was significantly reduced (0.87 +/- 0.13 and 0.72 +/- 0.05, respectively). PHE-induced contraction was restored in IVC exposed to prolonged 2-g tension plus the HIF inhibitor U0126 (1.38 +/- 0.15) or echinomycin (1.99 +/- 0.40). U0126 and echinomycin also restored KCl-induced contraction in NC exposed to prolonged 2-g tension (1.14 +/- 0.05 and 1.11 +/- 0.15, respectively). Treatment with DMOG further reduced PHE- and KCl-induced contraction in veins subjected to prolonged 2-g tension (0.47 +/- 0.06 and 0.57 +/- 0.01, respectively). HIF-1 alpha and HIF-2 alpha inRNA were overexpressed in NC exposed to prolonged 2-g tension, and the overexpression was reversed by U0126. The overexpression of HIF-1 alpha and HIF-2 alpha in stretched NC was associated with increased MMP-2 and MMP-9 mRNA. The protein amount of HIf-1 alpha, HIF-2 alpha, MMP-2, and MMP-9 was also increased in NC exposed to prolonged 2-g wall tension. Conclusions:Prolonged increases in vein wall tension are associated with overexpression of HIF-1 alpha and HIF-2 alpha, increased MMP-2 and MMP-9 expression, and reduced venous contraction in rat IVC. Together with our report that MMP-2 and MMP-9 inhibit NC contraction, the data suggest that increased vein wall tension induces HIF overexpression and causes an increase in MMP expression and reduction of venous contraction, leading to progressive venous dilation and varicose vein formation. (J Vase Surg 2011;53:764-73.) C1 [Lim, Chung S.; Paleolog, Ewa; Davies, Alun H.] Univ London Imperial Coll Sci Technol & Med, Imperial Vasc Unit, London SW7 2AZ, England. [Lim, Chung S.; Paleolog, Ewa; Davies, Alun H.] Univ London Imperial Coll Sci Technol & Med, Cytokine Biol Vessels Grp, Dept Surg & Canc, London SW7 2AZ, England. [Lim, Chung S.; Paleolog, Ewa; Davies, Alun H.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Kennedy Inst Rheumatol, London SW7 2AZ, England. [Lim, Chung S.; Qiao, Xiaoying; Reslan, Ossama M.; Xia, Yin; Raffetto, Joseph D.; Khalil, Raouf A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA 02115 USA. [Raffetto, Joseph D.] VA Boston Healthcare Syst, W Roxbury, MA USA. RP Khalil, RA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Vasc Surg, 75 Francis St, Boston, MA 02115 USA. EM raouf_khalil@hms.harvard.edu FU NHLBI NIH HHS [HL-70659, R01 HL065998-10, R01 HL065998, R01 HL070659-05, R01 HL070659, HL-65998]; NICHD NIH HHS [HD-60702, R03 HD060702-02, R03 HD060702] NR 48 TC 21 Z9 21 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAR PY 2011 VL 53 IS 3 BP 764 EP 773 DI 10.1016/j.jvs.2010.09.018 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 727HF UT WOS:000287788200036 PM 21106323 ER PT J AU Jones, EG AF Jones, Elizabeth Geiger TI Recognizing Hospital-Acquired Burn Injury in Patients After Coronary Artery Bypass Surgery SO JOURNAL OF WOUND OSTOMY AND CONTINENCE NURSING LA English DT Article AB BACKGROUND: Nosocomial injury is a constant threat in the hospital setting. While there is growing awareness surrounding hospital-acquired pressure ulcers, little information is available on burns associated with intraoperative procedures. CASES: We identified perineal lesions on 4 patients who underwent coronary artery bypass with grafting. These injuries were initially classified as pressure ulcers but subsequent investigation revealed that the injuries were intraoperative burns attributable to pooling of isopropyl alcohol underneath patients who were placed on intraoperative heating pads. CONCLUSIONS: Differentiating between hospital-acquired pressure ulcers and burns can be difficult. Our facility's experience with intraoperative burn injuries now mandates that this etiologic factor be considered in the differential diagnosis of postoperative patients with atypical cutaneous injuries. C1 Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Jones, EG (reprint author), Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. EM Gwammyliz@heavi.tv NR 12 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1071-5754 J9 J WOUND OSTOMY CONT JI J. Wound Ostomy Cont. Nurs. PD MAR-APR PY 2011 VL 38 IS 2 BP 193 EP 195 DI 10.1097/WON.0b013e31820bc479 PG 3 WC Nursing SC Nursing GA 732PZ UT WOS:000288201900014 PM 21389831 ER PT J AU Davies, JK Barbon, CM Voskertchian, AR Nadler, LM Guinan, EC AF Davies, Jeff K. Barbon, Christine M. Voskertchian, Annie R. Nadler, Lee M. Guinan, Eva C. TI Induction of Alloantigen-specific Anergy in Human Peripheral Blood Mononuclear Cells by Alloantigen Stimulation with Co-stimulatory Signal Blockade SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 49; Allogeneic stem cell transplantation; alloreactivity; Graft-versus-Host Disease; T cell costimulation; anergy; mixed lymphocyte reaction AB Allogeneic hematopoietic stem cell transplantation (AHSCT) offers the best chance of cure for many patients with congenital and acquired hematologic diseases. Unfortunately, transplantation of alloreactive donor T cells which recognize and damage healthy patient tissues can result in Graft-versus-Host Disease (GvHD)(1). One challenge to successful AHSCT is the prevention of GvHD without associated impairment of the beneficial effects of donor T cells, particularly immune reconstitution and prevention of relapse. GvHD can be prevented by non-specific depletion of donor T cells from stem cell grafts or by administration of pharmacological immunosuppression. Unfortunately these approaches increase infection and disease relapse(2-4). An alternative strategy is to selectively deplete alloreactive donor T cells after allostimulation by recipient antigen presenting cells (APC) before transplant. Early clinical trials of these allodepletion strategies improved immune reconstitution after HLA-mismatched HSCT without excess GvHD(5, 6). However, some allodepletion techniques require specialized recipient APC production(6,7)and some approaches may have off-target effects including depletion of donor pathogen-specific T cells(8)and CD4 T regulatory cells(9). One alternative approach is the inactivation of alloreactive donor T cells via induction of alloantigen-specific hyporesponsiveness. This is achieved by stimulating donor cells with recipient APC while providing blockade of CD28-mediated co-stimulation signals(10). This "alloanergization" approach reduces alloreactivity by 1-2 logs while preserving pathogen-and tumor-associated antigen T cell responses in vitro(11). The strategy has been successfully employed in 2 completed and 1 ongoing clinical pilot studies in which alloanergized donor T cells were infused during or after HLA-mismatched HSCT resulting in rapid immune reconstitution, few infections and less severe acute and chronic GvHD than historical control recipients of unmanipulated HLA-mismatched transplantation(12). Here we describe our current protocol for the generation of peripheral blood mononuclear cells (PBMC) which have been alloanergized to HLA-mismatched unrelated stimulator PBMC. Alloanergization is achieved by allostimulation in the presence of monoclonal antibodies to the ligands B7.1 and B7.1 to block CD28-mediated costimulation. This technique does not require the production of specialized stimulator APC and is simple to perform, requiring only a single and relatively brief ex vivo incubation step. As such, the approach can be easily standardized for clinical use to generate donor T cells with reduced alloreactivity but retaining pathogen-specific immunity for adoptive transfer in the setting of AHSCT to improve immune reconstitution without excessive GvHD. C1 [Davies, Jeff K.; Barbon, Christine M.; Voskertchian, Annie R.; Nadler, Lee M.; Guinan, Eva C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Davies, Jeff K.; Nadler, Lee M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Guinan, Eva C.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. RP Guinan, EC (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. EM eva_guinan@dfci.harvard.edu FU National Institutes of Health [U19 CA100625, R21 CA137645]; Leukemia & Lymphoma Society; American Society of Blood and Marrow Transplantation/OtsukaNew Investigator Award FX Supported by the National Institutes of Health (U19 CA100625 and R21 CA137645). JKD was supported by the Leukemia & Lymphoma Society and the American Society of Blood and Marrow Transplantation/OtsukaNew Investigator Award. NR 12 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD MAR PY 2011 IS 49 AR UNSP e2673 DI 10.3791/2673 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36LY UT WOS:000209214600048 ER PT J AU Villablanca, EJ Mora, JR AF Villablanca, Eduardo J. Mora, J. Rodrigo TI Competitive Homing Assays to Study Gut-tropic T Cell Migration SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Editorial Material C1 [Villablanca, Eduardo J.; Mora, J. Rodrigo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Cambridge, MA 02138 USA. RP Mora, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Cambridge, MA 02138 USA. EM j_rodrigo_mora@hms.harvard.edu RI Villablanca, Eduardo/E-1380-2016 OI Villablanca, Eduardo/0000-0001-9522-9729 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD MAR PY 2011 IS 49 DI 10.3791/2619 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36LY UT WOS:000209214600014 ER PT J AU Ratnam, KK Feng, XB Chuang, PY Verma, V Lu, TC Wang, JS Jin, YM Farias, EF Napoli, JL Chen, N Kaufman, L Takano, T D'Agati, VD Klotman, PE He, JC AF Ratnam, Krishna K. Feng, Xiaobei Chuang, Peter Y. Verma, Vikram Lu, Ting-Chi Wang, Jinshan Jin, Yuanmeng Farias, Eduardo F. Napoli, Joseph L. Chen, Nan Kaufman, Lewis Takano, Tomoko D'Agati, Vivette D. Klotman, Paul E. He, John C. TI Role of the retinoic acid receptor-alpha in HIV-associated nephropathy SO KIDNEY INTERNATIONAL LA English DT Article DE HIV; kidney disease; podocytes; proteinuria; retinoic acid receptor ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; IN-VITRO; HIV-1-ASSOCIATED NEPHROPATHY; PATHOLOGICAL CLASSIFICATION; PODOCYTE PROLIFERATION; ANTIRETROVIRAL THERAPY; GLOMERULAR-DISEASE; EXPRESSION; MICE; DIFFERENTIATION AB All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-alpha (RAR alpha). Here, we report that Am580, a water-soluble RAR alpha-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RAR alpha-/- Tg26 mice developed more severe kidney and podocyte injury than did RAR alpha-/- Tg26 mice. Am580 failed to ameliorate kidney injury in RAR alpha-/- Tg26 mice, confirming our hypothesis that Am580 acts through RAR alpha. Although the expression of RAR alpha-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RAR alpha in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RAR alpha agonists may be potential agents for the treatment of HIVAN. Kidney International (2011) 79, 624-634; doi: 10.1038/ki.2010.470; published online 8 December 2010 C1 [He, John C.] Mt Sinai Sch Med, Dept Med Nephrol, Div Nephrol, New York, NY 10029 USA. [Feng, Xiaobei; Jin, Yuanmeng; Chen, Nan] Shanghai Jiao Tong Univ, RuiJin Hosp, Sch Med, Shanghai 200030, Peoples R China. [Wang, Jinshan; Napoli, Joseph L.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Farias, Eduardo F.] Mt Sinai Sch Med, Dept Med, Div Hematol, New York, NY 10029 USA. [Takano, Tomoko] McGill Univ, Ctr Hlth, Div Nephrol, Montreal, PQ, Canada. [D'Agati, Vivette D.] Columbia Univ, Dept Pathol, New York, NY USA. [He, John C.] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [He, John C.] James J Peters VA Med Ctr, New York, NY USA. RP He, JC (reprint author), Mt Sinai Sch Med, Dept Med Nephrol, Div Nephrol, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. EM cijiang.he@mssm.edu FU National Institutes of Health [R01 DK078897, K08DK082760]; VA [1I01BX000345] FX This work was supported by National Institutes of Health grant R01 DK078897 to JCH. JCH is also supported by a VA Merit Award (1I01BX000345). PYC is a recipient of the NIH career development award (K08DK082760). NR 42 TC 31 Z9 31 U1 0 U2 3 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 MAR PY 2011 VL 79 IS 6 BP 624 EP 634 DI 10.1038/ki.2010.470 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 727MO UT WOS:000287804600007 PM 21150871 ER PT J AU Mollenhauer, B Locascio, JJ Schulz-Schaeffer, W Sixel-Doring, F Trenkwalder, C Schlossmacher, MG AF Mollenhauer, Brit Locascio, Joseph J. Schulz-Schaeffer, Walter Sixel-Doering, Friederike Trenkwalder, Claudia Schlossmacher, Michael G. TI alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study SO LANCET NEUROLOGY LA English DT Article ID MULTIPLE SYSTEM ATROPHY; ALZHEIMERS-DISEASE; LEWY BODIES; CLINICAL-DIAGNOSIS; RESEARCH CRITERIA; TASK-FORCE; DEMENTIA; CSF; BIOMARKERS; QUANTIFICATION AB Background Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular alpha-synuclein deposits. We aimed to assess whether reduction of alpha-synudein concentrations in CSF was a marker for alpha-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies. Methods We assessed potential extracellular-fluid markers of alpha-synuclein deposition in the brain (total alpha-synuclein and total tau in CSF, and total alpha-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics. Findings In our training set, people with Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF alpha-synuclein concentrations than patients with Alzheimer's disease and other neurological disorders. CSF alpha-synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0.0001; area under the receiver operating characteristic curve [AUC]=0.908). In the autopsy-confirmed cases, CSF alpha-synuclein discriminated between dementia with Lewy bodies and Alzheimer's disease (p=0-0190; AUC=0.687); in the validation cohort, CSF alpha-synuclein discriminated Parkinson's disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0.0001; AUC=0.711). Other predictor variables tested in this cohort included CSF tau (p=0.0798), serum alpha-synuclein (p=0.0502), and age (p=0.0335). CSF alpha-synuclein concentrations of 1.6 pg/p.I. or lower showed 70.72% sensitivity (95% CI 65-3-76.1%) and 52.83% specificity (39.4-66.3%) for the diagnosis of Parkinson's disease. At this cutoff, the positive predictive value for any synucleinopathy was 90.7% (95% CI 87.3-94.2%) and the negative predictive value was 20.4% (13.7-27.2%). Interpretation Mean CSF alpha-synuclein concentrations as measured by ELISA are significantly lower in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF alpha-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials. C1 [Mollenhauer, Brit; Sixel-Doering, Friederike; Trenkwalder, Claudia] Paracelsus Elena Klin, D-34128 Kassel, Germany. [Mollenhauer, Brit; Trenkwalder, Claudia] Georg August Univ Goettingen, Dept Neurol, Gottingen, Germany. [Mollenhauer, Brit; Trenkwalder, Claudia] Georg August Univ Goettingen, Dept Clin Neurophysiol, Gottingen, Germany. [Locascio, Joseph J.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schulz-Schaeffer, Walter] Univ Gottingen, Dept Neuropathol, Gottingen, Germany. [Schlossmacher, Michael G.] Ottawa Hosp, Div Neurosci, Res Inst, Dept Med, Ottawa, ON, Canada. [Schlossmacher, Michael G.] Univ Ottawa, Dept Cellular & Mol Med, OHRI Neurosci, Ottawa, ON K1H 8M5, Canada. [Mollenhauer, Brit; Schlossmacher, Michael G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis,Dept Neurol, Boston, MA 02115 USA. RP Mollenhauer, B (reprint author), Paracelsus Elena Klin, Klin Str 16, D-34128 Kassel, Germany. EM brit.mollenhauer@pk-mx.de; mschlossmacher@ohri.ca FU TEVA-Pharma; Desitin; Boehringer Ingelheim; GE Healthcare; TEVA Neuroscience; VolkswagenStiftung; Deutsche Forschungsgemeinschaft; Alberta Prion Research Institut, Canada; European Union; Bayer Schering Pharma; German Parkinson Patient Foundation; Orion Phamia; UCB/Schwarz Pharma; Solvay FX BM has received grants from TEVA-Pharma, Desitin, Boehringer Ingelheim and GE Healthcare and honoraria for consultancy from Bayer Schering Pharma AG and for presentations from GlaxoSmithKline and Orion Pharma as well as travel and meeting expenses from Boehringer-Ingelheim and Novartis. MGS has served as an ad hoc, paid consultant for FoldRx, Genzyme, Johnson and Johnson, Amicus Therapeutics, Elan Pharmaceuticals, Novartis, and LINK Medicine, has received payment for a lecture from TEVA Neuroscience, and has a scientific collaboration with Covance, Epitomics, and the Michael J Fox Foundation. CT is employed by Paracelsus, provides expert testimony for Axxonis, serves as a consultant for TEVA Pharma, Boerhinger-Ingelheim, UCB, Solvay, Novartis, Mundipharm, Viofor Pharma, and Cephalon, and has received honoraria for presentations and lectures from TEVA Pharma, Boehringer-Ingelheim, UCB, Viofor Pharma, and Cephalon. WS-S serves as consultant for Bayer Schering Pharma; he has received grants from the VolkswagenStiftung, Deutsche Forschungsgemeinschaft, Alberta Prion Research Institut, Canada, and the European Union, and has received payment for lectures from Bayer Schering Pharma. FS-D has received a grant from the German Parkinson Patient Foundation and honoraria from advisory board meetings from Orion Pharma, as well as payment for lectures by Boehringer-Ingelheim, Orion Phamia, UCB/Schwarz Pharma, and Solvay. JJL declares no conflicts of interest. BM and MGS are listed as co-inventors in a patent application to the US Patent Office related to the quantification of alpha-synuclein in biological fluids for the purpose of improved diagnosis. NR 42 TC 213 Z9 223 U1 2 U2 19 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 MAR PY 2011 VL 10 IS 3 BP 230 EP 240 DI 10.1016/S1474-4422(11)70014-X PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 736HR UT WOS:000288482200011 PM 21317042 ER PT J AU Gianni, L Dafni, U Gelber, RD Azambuja, E Muehlbauer, S Goldhirsch, A Untch, M Smith, I Baselga, J Jackisch, C Cameron, D Mano, M Pedrini, JL Veronesi, A Mendiola, C Pluzanska, A Semiglazov, V Vrdoljak, E Eckart, MJ Shen, ZZ Skiadopoulos, G Procter, M Pritchard, KI Piccart-Gebhart, MJ Bell, R AF Gianni, Luca Dafni, Urania Gelber, Richard D. Azambuja, Evandro Muehlbauer, Susanne Goldhirsch, Aron Untch, Michael Smith, Ian Baselga, Jose Jackisch, Christian Cameron, David Mano, Max Pedrini, Jose Luiz Veronesi, Andrea Mendiola, Cesar Pluzanska, Anna Semiglazov, Vladimir Vrdoljak, Eduard Eckart, Michael J. Shen, Zhenzhou Skiadopoulos, George Procter, Marion Pritchard, Kathleen I. Piccart-Gebhart, Martine J. Bell, Richard CA Herceptin Adjuvant HERA Trial Stud TI Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial SO LANCET ONCOLOGY LA English DT Article ID 1ST-LINE TREATMENT; CLINICAL-TRIALS; OVARIAN-CANCER; PHASE-II; EFFICACY; SAFETY; ONCOGENE; ANTIBODY; PLUS AB Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48.4 months (IQR 42.0-56.5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78.6%) compared with the observation group (4-year disease-free survival 72.2%; hazard ratio [HR] 0.76; 95% CI 0.66-0.87; p<0.0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89.3% vs 87.7%, respectively; HR 0.85; 95% CI 0.70-1.04; p=0.11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22.8 months (range 4.5-52.7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0.68; 95% CI 0.51-0.90; p=0.0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. C1 [Gianni, Luca] San Raffaele Inst, Dept Med Oncol, Milan, Italy. [Dafni, Urania] Univ Athens, Lab Biostat, Athens, Greece. [Dafni, Urania; Skiadopoulos, George] Frontier Sci Fdn Hellas, Athens, Greece. [Gelber, Richard D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Azambuja, Evandro] Univ Libre Bruxelles, Med Oncol Clin, Inst Jules Bordet, Brussels, Belgium. [Azambuja, Evandro] Univ Libre Bruxelles, Breast European Adjuvant Study Team BrEAST, Ctr Data, Inst Jules Bordet, Brussels, Belgium. [Muehlbauer, Susanne] F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. [Goldhirsch, Aron] European Inst Oncol, Dept Med, Milan, Italy. [Goldhirsch, Aron] Oncol Inst So Switzerland, Bellinzona, Switzerland. [Untch, Michael] Helios Klinikum Berlin Buch, Dept Obstet & Gynaecol, Berlin, Germany. [Untch, Michael] Helios Klinikum Berlin Buch, Multidisciplinary Breast Canc Ctr, Berlin, Germany. [Smith, Ian] Royal Marsden Hosp, Breast Unit, London SW3 6JJ, England. [Smith, Ian] Inst Canc Res, London SW3 6JB, England. [Baselga, Jose] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA USA. [Jackisch, Christian] Klinikum Offenbach, Dept Gynecol & Obstet, Offenbach, Germany. [Cameron, David] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Cameron, David] Western Gen Hosp, Dept Oncol, Edinburgh EH4 2XU, Midlothian, Scotland. [Mano, Max] Univ Sao Paulo, Dept Med Oncol, Inst Canc Estado Sao Paulo, BR-05508 Sao Paulo, Brazil. [Pedrini, Jose Luiz] Hosp Nossa Senhora Conceicao, Minist Saude, Unity Mastol, Porto Alegre, RS, Brazil. [Veronesi, Andrea] Natl Canc Inst, Ctr Riferimento Oncol, Div Med Oncol C, Aviano, Italy. [Mendiola, Cesar] Hosp Ruber Int, Madrid, Spain. [Pluzanska, Anna] Reg Oncol Ctr, Oncol Chemotherapy Clin, Lodz, Poland. [Semiglazov, Vladimir] Petrov Res Inst Oncol, St Petersburg, Russia. [Vrdoljak, Eduard] Univ Hosp Split, Split, Croatia. [Eckart, Michael J.] Onkol Schwerpunktpraxis & Tagesklin, Erlangen, Germany. [Shen, Zhenzhou] Fudan Univ, Canc Hosp, Shanghai 200433, Peoples R China. [Procter, Marion] Frontier Sci Scotland, Kingussie, Kincraig, Scotland. [Pritchard, Kathleen I.] Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Piccart-Gebhart, Martine J.] Univ Libre Bruxelles, Dept Med, Inst Jules Bordet, Brussels, Belgium. [Piccart-Gebhart, Martine J.] Univ Libre Bruxelles, BrEAST Data Ctr, Inst Jules Bordet, Brussels, Belgium. [Bell, Richard] Geelong Hosp, Andrew Love Canc Ctr, Geelong, Vic, Australia. RP Gianni, L (reprint author), Fdn San Raffaele, Via Olgettina 68, I-20132 Milan, Italy. EM gianni.luca@hsr.it RI Mano, Max /C-6917-2012; Pritchard, Kathleen/I-2184-2014 OI Semiglazov, Vladimir/0000-0003-0077-9619; Pritchard, Kathleen/0000-0003-0758-9666 FU Roche; Michelangelo Foundation FX LG has received payments for membership of advisory boards for Roche. RDG was provided with financial support through Roche's support for the International Breast Cancer Study Group and Breast International Group. IS has received speaker's honoraria from Roche. CJ has received consultancy fees from Roche in relation to the HERA trial, and travel expenses and speaker's honoraria. EA has received consultancy fees from Roche in relation to the HERA trial and speaker's honoraria. MM has received travel expenses from Roche in relation to the HERA trial and speaker's honoraria. CM and EV have received consultancy fees from Roche in relation to the HERA trial, and travel expenses and speaker's honoraria. EV has received consultancy fees and payments for advisory board membership, speaking engagements, and related travel expenses. CM has received consultancy fees, payment for speaking engagements, and related travel expenses. GS's institution received funding from Roche in relation to the HERA study. JP received travel expenses from Roche to attend HERA-related meetings. AV has received research funding and travel expenses from Roche. DC and RB have received research funding from Roche in relation to the HERA trial, honoraria for speaking engagements, and consultancy fees and travel expenses from Roche. MJP-G and JB have received consultancy fees from Roche for work unrelated to this study. KIP has received consultancy fees from Roche in relation to the HERA trial. SM is an employee of F Hoffmann-La Roche and has stock options in the company. The other authors declare that they have no conflicts of interest.; We thank the women who participated in the study; the Breast European Adjuvant Study Team Data Centre; the Frontier Science Team; the Breast International Group Secretariat; the HERA steering committee; the Independent Data Monitoring Committee; the Cardiac Advisory Board; the Pathology Laboratory, Kassel, Germany; F Hoffmann-La Roche; and all the doctors who participated in HERA. Medical writing assistance was provided by Alan Russell of Complete HealthVizion and funded by the Michelangelo Foundation. NR 25 TC 290 Z9 304 U1 7 U2 38 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2011 VL 12 IS 3 BP 236 EP 244 DI 10.1016/S1470-2045(11)70033-X PG 9 WC Oncology SC Oncology GA 736HY UT WOS:000288483500022 PM 21354370 ER PT J AU Ghobrial, IM Weller, E Vij, R Munshi, NC Banwait, R Bagshaw, M Schlossman, R Leduc, R Chuma, S Kunsman, J Laubach, J Jakubowiak, AJ Maiso, P Roccaro, A Armand, P Dollard, A Warren, D Harris, B Poon, T Sam, A Rodig, S Anderson, KC Richardson, PG AF Ghobrial, Irene M. Weller, Edie Vij, Ravi Munshi, Nikhil C. Banwait, Ranjit Bagshaw, Meghan Schlossman, Robert Leduc, Renee Chuma, Stacey Kunsman, Janet Laubach, Jacob Jakubowiak, Andrzej J. Maiso, Patricia Roccaro, Aldo Armand, Philippe Dollard, Akari Warren, Diane Harris, Brianna Poon, Tiffany Sam, Amy Rodig, Scott Anderson, Kenneth C. Richardson, Paul G. TI Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study SO LANCET ONCOLOGY LA English DT Article ID MAMMALIAN TARGET; SYNERGISTIC ACTIVITY; INHIBITOR RAPAMYCIN; AKT ACTIVITY; II TRIAL; MTOR; CCI-779; CELLS; PATHWAYS; KINASE AB Background Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma. Methods We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1.3 or 1.6 mg/m(2) once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262. Findings 20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1.6 mg/m(2) bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21-47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less). Interpretation mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids. C1 [Ghobrial, Irene M.; Weller, Edie; Munshi, Nikhil C.; Banwait, Ranjit; Bagshaw, Meghan; Schlossman, Robert; Leduc, Renee; Chuma, Stacey; Kunsman, Janet; Laubach, Jacob; Maiso, Patricia; Roccaro, Aldo; Armand, Philippe; Warren, Diane; Harris, Brianna; Poon, Tiffany; Sam, Amy; Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Vij, Ravi] Washington Univ, Sch Med, Sect Bone Marrow Transplant & Leukemia, St Louis, MO USA. [Munshi, Nikhil C.] Boston Veteran Affairs Hlth Care Syst, Dept Med, Boston, MA USA. [Jakubowiak, Andrzej J.] Univ Michigan, Dept Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Dollard, Akari] MMRC, Norwalk, CT USA. [Rodig, Scott] Brigham & Women Hosp, Dept Pathol, Boston, MA USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM irene_ghobrial@dfci.hatvard.edu OI Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; Harris, Brianna/0000-0001-6229-9907 FU Millennium; Bristol-Myers Squibb; Celgene; Onyx FX IMG has received payment as a member of advisory boards for Millennium, Celgene, Novartis, Genzyme, and Onyx; and has received research support from Millennium and Bristol-Myers Squibb. RV has received payment for being a member of speaker bureaus for Celgene and Millennium; advisory boards for Millennium, Celgene, and Onyx; and has received research support from Celgene and Onyx. NCM has received payment for being a member of advisory boards for Millennium, Celgene, Onyx, and Novartis. At has been a consultant without honoraria for Millennium, Bristol-Myers Squibb, and Onyx. KCA has received payment for being a member of advisory boards for Millennium, Celgene, Johnson get Johnson, Bristol-Myers Squibb, Onyx, and Novartis; and is the founder and a share holder of Acetylon Inc. PGR has received payment for being a member of advisory boards for Millennium, Celgene, Johnson & Johnson, Bristol-Myers Squibb, and Novartis. The other authors declare no conflicts of interest. NR 33 TC 45 Z9 46 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2011 VL 12 IS 3 BP 263 EP 272 DI 10.1016/S1470-2045(11)70028-6 PG 10 WC Oncology SC Oncology GA 736HY UT WOS:000288483500025 PM 21345726 ER PT J AU Tanaka, M Kinoshita, M Yoshihara, Y Shinomiya, N Seki, S Nemoto, K Hamblin, MR Morimoto, Y AF Tanaka, Masamitsu Kinoshita, Manabu Yoshihara, Yasuo Shinomiya, Nariyoshi Seki, Shuhji Nemoto, Koichi Hamblin, Michael R. Morimoto, Yuji TI Photodynamic Therapy Using Intra-Articular Photofrin for Murine MRSA Arthritis: Biphasic Light Dose Response for Neutrophil-Mediated Antibacterial Effect SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE photoinactivation; antimicrobial effect; neutrophil-mediated host defense; chemokine; macrophage inflammatory protein-2 ID RESISTANT STAPHYLOCOCCUS-AUREUS; IN-VIVO; INFECTIONS; MICE; MODEL AB Background and Objective: Bacterial arthritis does not respond well to antibiotics and moreover multidrug resistance is spreading. We previously tested photodynamic therapy (PDT) mediated by systemic Photofrin (R) in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) arthritis, but found that neutrophils were killed by PDT and therefore the infection was potentiated. Study Design/Materials and Methods: The present study used an intra-articular injection of Photofrin (R) and optimized the light dosimetry in order to maximize bacterial killing and minimize killing of host neutrophils. MRSA (5 x 10(7) CFU) was injected into the mouse knee followed 3 days later by 1 mu g of Photofrin (R) and 635-nm diode laser illumination with a range of fluences within 5 minutes. Synovial fluid was sampled 6 hours or 1-3, 5, and 7 days after PDT to determine MRSA colony-forming units (CFU), neutrophil numbers, and levels of cytokines. Results: A biphasic light dose response was observed with the greatest reduction of MRSA CFU seen with a fluence of 20 J cm(-2), whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. Consistent with these results, a significantly higher concentration of macrophage inflammatory protein-2, a CXC chemokine, and greater accumulation of neutrophils were seen in the infected knee joint after PDT with a fluence of 20 J cm(-2) compared to fluences of 5 or 70 J cm(-2). Conclusion: PDT for murine MRSA arthritis requires appropriate light dosimetry to simultaneously maximize bacterial killing and neutrophil accumulation into the infected site, while too little light does not kill sufficient bacteria and too much light kills neutrophils and damages host tissue as well as bacteria and allows bacteria to grow unimpeded by host defense. Lasers Surg. Med. 43:221-229, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Shinomiya, Nariyoshi; Morimoto, Yuji] Natl Def Med Coll, Dept Integrat Physiol & Bionano Med, Tokorozawa, Saitama 3598513, Japan. [Tanaka, Masamitsu; Yoshihara, Yasuo; Nemoto, Koichi] Natl Def Med Coll, Dept Orthoped Surg, Tokorozawa, Saitama 3598513, Japan. [Kinoshita, Manabu; Seki, Shuhji] Natl Def Med Coll, Dept Immunol & Microbiol, Tokorozawa, Saitama 3598513, Japan. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Morimoto, Y (reprint author), Natl Def Med Coll, Dept Integrat Physiol & Bionano Med, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan. EM moyan@ndmc.ac.jp OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH [RO1AI050875]; US Air Force MFEL program [FA9550-04-1-0079]; Center for Integration of Medicine and Innovative Technology [DAMD17-02-2-0006]; Congressionally Directed Medical Research Program [W81XWH-09-1-0514]; Young Scholar Encouragement Program of National Defense Medical College FX This work was supported by the Young Scholar Encouragement Program of National Defense Medical College. M. R. H. was supported by US NIH (grant RO1AI050875), US Air Force MFEL program (contract FA9550-04-1-0079), Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006), Congressionally Directed Medical Research Program (W81XWH-09-1-0514). NR 34 TC 17 Z9 19 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD MAR PY 2011 VL 43 IS 3 BP 221 EP 229 DI 10.1002/lsm.21037 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 735EC UT WOS:000288395200006 PM 21412806 ER PT J AU Grabher, C Payne, EM Johnston, AB Bolli, N Lechman, E Dick, JE Kanki, JP Look, AT AF Grabher, C. Payne, E. M. Johnston, A. B. Bolli, N. Lechman, E. Dick, J. E. Kanki, J. P. Look, A. T. TI Zebrafish microRNA-126 determines hematopoietic cell fate through c-Myb SO LEUKEMIA LA English DT Article DE miR-126; miR-150; c-myb; thrombocyte; hematopoiesis; zebrafish ID ACUTE MYELOID-LEUKEMIA; STEM-CELLS; TRANSCRIPTIONAL REGULATION; DEFINITIVE HEMATOPOIESIS; AORTIC ENDOTHELIUM; T-ALL; EXPRESSION; TARGET; PROGENITOR; MEGAKARYOPOIESIS AB Precise regulatory mechanisms are required to appropriately modulate the cellular levels of transcription factors controlling cell fate decisions during blood cell development. In this study, we show that miR-126 is a novel physiological regulator of the proto-oncogene c-myb during definitive hematopoiesis. We show that knockdown of miR-126 results in increased c-Myb levels and promotes erythropoiesis at the expense of thrombopoiesis in vivo. We further provide evidence that specification of thrombocyte versus erythrocyte cell lineages is altered by the concerted activities of the microRNAs (miRNAs) miR-126 and miR-150. Both miRNAs are required but not sufficient individually to precisely regulate the cell fate decision between erythroid and megakaryocytic lineages during definitive hematopoiesis in vivo. These results support the notion that miRNAs not only function to provide precision to developmental programs but also are essential determinants in the control of variable potential functions of a single gene during hematopoiesis. Leukemia (2011) 25, 506-514; doi:10.1038/leu.2010.280; published online 16 November 2010 C1 [Grabher, C.; Payne, E. M.; Johnston, A. B.; Bolli, N.; Kanki, J. P.; Look, A. T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Payne, E. M.] Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, Inst Canc, London, England. [Lechman, E.; Dick, J. E.] Univ Hlth Network, Ontario Canc Inst, Campbell Family Inst Canc Res, Div Stem Cell & Dev Biol, Toronto, ON, Canada. [Lechman, E.; Dick, J. E.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Look, A. T.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol,Dept Pediat, Boston, MA 02115 USA. RP Grabher, C (reprint author), Karlsruhe Inst Technol, Inst Toxicol & Genet, Hermann von Helmholtz Pl 1, D-76344 Eggenstein Leopoldshafen, Germany. EM clemens.grabher@kit.edu RI Grabher, Clemens/H-2064-2013; Bolli, Niccolo/D-4057-2011; OI Bolli, Niccolo/0000-0002-1018-5139; Dick, John/0000-0002-9527-8317 FU NIH [CA93152]; Leukemia and Lymphoma Research UK FX We thank R Hoffmans, U Pyati and N Bushati for critical comments on the manuscript and L Zon for the Tg(c-myb:EGFP) zebrafish line. This work was supported by the NIH grant CA93152 (ATL). EMP is the recipient of a Clinical Research Training Fellowship from Leukemia and Lymphoma Research UK. NB is a Special Fellow of the Leukemia and Lymphoma Society. NR 52 TC 30 Z9 33 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2011 VL 25 IS 3 BP 506 EP 514 DI 10.1038/leu.2010.280 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 732CB UT WOS:000288159500014 PM 21079614 ER PT J AU Stone, RM Moser, B Sanford, B Schulman, P Kolitz, JE Allen, S Stock, W Galinsky, I Vij, R Marcucci, G Hurd, D Larson, RA AF Stone, Richard M. Moser, Barry Sanford, Ben Schulman, Philip Kolitz, Jonathan E. Allen, Steven Stock, Wendy Galinsky, Ilene Vij, Ravi Marcucci, Guido Hurd, David Larson, Richard A. CA Canc & Leukemia Grp B TI High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: Cancer and Leukemia Group B study 19902 SO LEUKEMIA RESEARCH LA English DT Article DE Gemtuzumab ozogamicin; Acute myeloid leukemia; Cytarabine; Relapse ID ACUTE MYELOGENOUS LEUKEMIA; STEM-CELL TRANSPLANTATION; DISEASE-FREE SURVIVAL; INDUCTION CHEMOTHERAPY; FINAL REPORT; PHASE-I; G-CSF; MITOXANTRONE; COMBINATION; ADULTS AB Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, was combined with high dose cytarabine (HiDAC; cytarabine 3 g/m(2) over 3 h daily for 5 days) for adults with relapsed or refractory AML. HiDAC plus GO 9mg/m(2) on day 7 and 4.5mg/m(2) on day 14 was not tolerated, but HiDAC followed by GO 9mg/m(2) on day 7 was safe: 12/37 (32%) patients with relapsed AML achieved complete remission. Median overall survival was 8.9 months. No grade 4 hepatic veno-occlusive disease was observed. This regimen merits further study, both in this setting and as a remission consolidation therapy. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Stone, Richard M.; Galinsky, Ilene] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moser, Barry; Sanford, Ben] Duke Univ, Med Ctr, CALGB Stat Ctr, Durham, NC USA. [Schulman, Philip] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kolitz, Jonathan E.; Allen, Steven] N Shore Long Isl Jewish Hlth Syst, New Hyde Pk, NY USA. [Stock, Wendy; Larson, Richard A.] Univ Chicago, Chicago, IL 60637 USA. [Vij, Ravi] Washington Univ, Sch Med, St Louis, MO USA. [Marcucci, Guido] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Hurd, David] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, 44 Binney St,M1B-17, Boston, MA 02115 USA. EM rstone@partners.org OI Allen, Steven/0000-0002-3482-3182; Larson, Richard/0000-0001-9168-3203 FU National Cancer Institute [CA31946]; Cancer and Leukemia Group B; CALGB Statistical Center [CA33601] FX The research for CALGB 19902 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and to the CALGB Statistical Center (Stephen George, PhD, CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: Christiana Care Health Services, Inc. CCOP, Wilmington, DE - Stephen Grubbs, MD, supported by CA45418; Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY - Jeffrey Kirshner, MD, supported by CA45389; Kansas City Community Clinical Oncology Program CCOP, Kansas City, MO - Rakesh Gaur, MD; Dana-Farber Cancer Institute, Boston, MA Harold J. Burstein, MD, supported by CA32291; North Shore Long Island Jewish Health System, New Hyde Park, NY - Daniel Budman, MD, supported by CA35279; Rhode Island Hospital, Providence, RI - William Sikov, MD, supported by CA08025; The Ohio State University Medical Center, Columbus, OH - Clara D. Bloomfield, MD, supported by CA77658; University of Chicago, Chicago, IL - Hedy L Kindler, MD, supported by CA41287; University of Illinois MBCCOP, Chicago, IL - David J. Peace, MD, supported by CA74811; University of Iowa, Iowa City, IA - Daniel A. Vaena, MD, supported by CA47642; University of Vermont, Burlington, VT - Hyman B. Muss, MD, supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC - David D. Hurd, MD, supported by CA03927; Washington University School of Medicine, St. Louis, MO - Nancy Bartlett, MD, supported by CA77440; and Western Pennsylvania Cancer Institute, Pittsburgh, PA - Richard K. Shadduck, MD. NR 28 TC 19 Z9 19 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD MAR PY 2011 VL 35 IS 3 BP 329 EP 333 DI 10.1016/j.leukres.2010.07.017 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 729QH UT WOS:000287965100017 PM 20688393 ER PT J AU Rogal, SS Landsittel, D Surman, O Chung, RT Rutherford, A AF Rogal, Shari S. Landsittel, Douglas Surman, Owen Chung, Raymond T. Rutherford, Anna TI Pretransplant Depression, Antidepressant Use, and Outcomes of Orthotopic Liver Transplantation SO LIVER TRANSPLANTATION LA English DT Article ID RENAL-TRANSPLANTATION; HEART-TRANSPLANTATION; MORBIDITY; PREDICTORS; MORTALITY; DISEASE; RISK AB Depression is a common problem among patients awaiting organ transplantation, but little is known about the impact of depression and its treatment on the outcomes of liver transplantation. In this retrospective cohort analysis, we studied all patients over 18 years of age who underwent liver transplantation during a 5-year period (2004-2008) at a single center. Among 179 recipients, 65 patients had depression, as defined by a health care provider assessment, before transplantation. Depression was defined as past or active depression or an adjustment disorder. The associations between pretransplant depression and various outcomes (time to death, graft failure, first acute cellular rejection episode, first infection, and first rehospitalization) were assessed. In the entire sample, more patients with depression required posttransplant psychiatric care (37% versus 18%); the adjusted hazard ratio was 2.28 (1.27-4.11). The rates of other outcomes, including hospital readmission, acute cellular rejection, graft failure, mortality, and infection, were similar for patients with depression and patients without depression. Among those with depression, patients on antidepressants at the time of transplantation had acute cellular rejection less frequently than those not taking antidepressants (13% versus 40%); the adjusted hazard ratio was 0.14 (0.03-0.62). The rates of other outcomes were similar between these 2 groups. These data indicate that depression affects posttransplant psychiatric morbidity but not other medical outcomes of liver transplantation. Pharmacological treatment of depression may significantly reduce the incidence of acute cellular rejection in patients undergoing liver transplantation. However, future prospective studies of mental health and liver transplantation are required to definitively assess the effects of antidepressant medications on medical outcomes. Liver Transpl 17:251-260, 2011. (C) 2011 AASLD. C1 [Rogal, Shari S.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Rutherford, Anna] Brigham & Womens Hosp, Div Gastroenterol & Hepatol, Boston, MA 02115 USA. [Landsittel, Douglas] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Surman, Owen] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Div Gastroenterol & Hepatol, Boston, MA 02114 USA. RP Rogal, SS (reprint author), Univ Pittsburgh, Med Ctr, Presbyterian Univ Hosp, Div Gastroenterol Hepatol & Nutr, C Wing,200 Lothrop St, Pittsburgh, PA 15261 USA. EM shari.rogal@gmail.com FU National Center for Research Resources a component of the National Institutes of Health [5UL1 RR024153-04]; Roadmap for Medical Research FX Contributions from Douglas Landsittel were made possible by grant 5UL1 RR024153-04 from the National Center for Research Resources (a component of the National Institutes of Health) and the Roadmap for Medical Research. NR 20 TC 19 Z9 20 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD MAR PY 2011 VL 17 IS 3 BP 251 EP 260 DI 10.1002/lt.22231 PG 10 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 732IL UT WOS:000288178100005 PM 21384507 ER PT J AU Paulus, JK Zhou, W Kraft, P Johnson, BE Lin, XH Christiani, DC AF Paulus, Jessica K. Zhou, Wei Kraft, Peter Johnson, Bruce E. Lin, Xihong Christiani, David C. TI Haplotypes of estrogen receptor-beta and risk of non-small cell lung cancer in women SO LUNG CANCER LA English DT Article DE Non-small cell lung cancer; Estrogen receptor-beta (ESR2); Molecular epidemiology; Tobacco; Parity; Women ID HORMONE REPLACEMENT THERAPY; CIGARETTE-SMOKING; UNRELATED INDIVIDUALS; POSTMENOPAUSAL WOMEN; REPRODUCTIVE FACTORS; PROSTATE-CANCER; SEX-DIFFERENCES; BREAST-CANCER; EXPRESSION; COHORT AB Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the estrogen receptor-beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 to 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved (CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)). Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes versus no), age (< 50 years versus >= 50 years) or smoking history (current-, former-, never-smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Paulus, Jessica K.; Kraft, Peter; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Zhou, Wei] Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Boston, MA 02115 USA. [Kraft, Peter; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Paulus, JK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM jpaulus@hsph.harvard.edu FU NIH [R01CA98924, R01CA74386, T32ES07069]; MGH; HSPH FX This study was funded by NIH grants: R01CA98924, R01CA74386 and T32ES07069. We are indebted to the Lung Cancer Susceptibility and Survival Study participants and the assistance of the study support teams at MGH and HSPH. NR 52 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD MAR PY 2011 VL 71 IS 3 BP 258 EP 263 DI 10.1016/j.lungcan.2010.06.011 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 735LS UT WOS:000288416700003 PM 20655613 ER PT J AU Lane, MA McDonald, JR Zeringue, AL Caplan, L Curtis, JR Ranganathan, P Eisen, SA AF Lane, Michael A. McDonald, Jay R. Zeringue, Angelique L. Caplan, Liron Curtis, Jeffrey R. Ranganathan, Prabha Eisen, Seth A. TI TNF-alpha Antagonist Use and Risk of Hospitalization for Infection in a National Cohort of Veterans With Rheumatoid Arthritis SO MEDICINE LA English DT Article ID ANTITUMOR-NECROSIS-FACTOR; MODIFYING ANTIRHEUMATIC DRUGS; SERIOUS BACTERIAL-INFECTIONS; BRITISH-SOCIETY; ELDERLY-PATIENTS; FACTOR THERAPY; AFFAIRS; BIOLOGICS; PNEUMONIA; MORTALITY AB Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-alpha antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA. A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88Y2.43) and TNF-alpha antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-alpha antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy. We conclude that patients with RA who are treated with TNF-alpha antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection. C1 [Lane, Michael A.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [McDonald, Jay R.; Zeringue, Angelique L.] St Louis Vet Affairs Med Ctr, St Louis, MO USA. [Caplan, Liron] Denver Vet Affairs Med Ctr, Denver, CO USA. [Curtis, Jeffrey R.] Univ Alabama, Ctr Educ & Res Therapeut, Birmingham, AL USA. [Eisen, Seth A.] Vet Affairs Hlth Serv Res & Dev, Washington, DC USA. RP Lane, MA (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave,Campus Box 8051, St Louis, MO 63110 USA. EM mlane@dom.wustl.edu RI Zeringue, Angelique/I-1755-2012; OI Lane, Michael/0000-0003-2426-8186 FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development [IAF 06-026]; Goldfarb Patient Safety & Quality Fellowship; Barnes-Jewish Hospital Foundation; NIH [K12RR023249, KL2RR024994]; VA [07-221] FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service project number IAF 06-026 (PI: Dr. McDonald). Dr. Lane has received career development support from the Goldfarb Patient Safety & Quality Fellowship program and the Barnes-Jewish Hospital Foundation. The career development of Dr. McDonald has been supported by NIH K12RR023249 and KL2RR024994. Dr. Caplan is supported by VA HSR&D Career Development Award 07-221. NR 35 TC 39 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD MAR PY 2011 VL 90 IS 2 BP 139 EP 145 DI 10.1097/MD.0b013e318211106a PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 729BC UT WOS:000287920600007 PM 21358439 ER PT J AU Ren, XF Akiyoshi, K Vandenbark, AA Hurn, PD Offner, H AF Ren, Xuefang Akiyoshi, Kozaburo Vandenbark, Arthur A. Hurn, Patricia D. Offner, Halina TI CD4(+)FoxP3(+) regulatory T-cells in cerebral ischemic stroke SO METABOLIC BRAIN DISEASE LA English DT Article DE Cerebral ischemia; T lymphocyte; T regulatory cells; Middle cerebral artery occlusion; Stroke AB Experimental cerebral ischemic stroke is exacerbated by inflammatory T-cells and is accompanied by systemic increases in CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Treg). To determine their effect on ischemic brain injury, Treg were depleted in Foxp3(DTR) mice prior to stroke induction. In contrast to a recent Nature Medicine report, our results demonstrate unequivocally that Treg depletion did not affect stroke infarct volume, thus failing to implicate this regulatory pathway in limiting stroke damage. C1 [Ren, Xuefang; Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, R&D 31, Portland, OR 97239 USA. [Ren, Xuefang; Akiyoshi, Kozaburo; Hurn, Patricia D.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Vandenbark, Arthur A.; Hurn, Patricia D.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu RI wu, peihua/F-8818-2012 FU NIH [NR03521]; Biomedical Laboratory R&D Service, Department of Veterans Affairs FX The authors wish to thank Dr. Sushmita Sinha, Ms. Sandhya Subramanian and Dr. Suzan Dziennis for helpful discussions and Ms. Eva Niehaus and Heather Hoem for assistance in preparing the manuscript. This work was supported by NIH grant NR03521 and the Biomedical Laboratory R&D Service, Department of Veterans Affairs. NR 7 TC 55 Z9 56 U1 2 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD MAR PY 2011 VL 26 IS 1 BP 87 EP 90 DI 10.1007/s11011-010-9226-6 PG 4 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 745DR UT WOS:000289146100010 PM 21082336 ER PT J AU Spires-Jones, TL de Calignon, A Meyer-Luehmann, M Bacskai, BJ Hyman, BT AF Spires-Jones, Tara L. de Calignon, Alix Meyer-Luehmann, Melanie Bacskai, Brian J. Hyman, Bradley T. TI Monitoring protein aggregation and toxicity in Alzheimer's disease mouse models using in vivo imaging SO METHODS LA English DT Article DE Alzheimer; Tau; Plaque; Multiphoton; In vivo imaging ID AMYLOID PRECURSOR PROTEIN; TANGLE-BEARING NEURONS; A-BETA-PLAQUES; TRANSGENIC MICE; MULTIPHOTON MICROSCOPY; NEURITE TRAJECTORIES; CASPASE ACTIVATION; SPINE LOSS; TAU; PATHOLOGY AB Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer's disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer's disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions. (C) 2010 Elsevier Inc. All rights reserved. C1 [Spires-Jones, Tara L.; de Calignon, Alix; Meyer-Luehmann, Melanie; Bacskai, Brian J.; Hyman, Bradley T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Spires-Jones, TL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM tspires@partners.org OI Spires-Jones, Tara/0000-0003-2530-0598; Meyer-Luehmann, Melanie/0000-0003-3661-2220 FU Alzheimer's Association; NIH [AG08487, K99AG33670, EB000768, AG026249] FX We gratefully acknowledge funding from the Alzheimer's Association Zenith Award, NIH Grants AG08487, K99AG33670, EB000768, and AG026249. NR 45 TC 13 Z9 13 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR PY 2011 VL 53 IS 3 BP 201 EP 207 DI 10.1016/j.ymeth.2010.12.009 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 736VN UT WOS:000288523200004 PM 21163350 ER PT J AU Berra, L Sampson, J Fumagalli, J Panigada, M Kolobow, T AF Berra, L. Sampson, J. Fumagalli, J. Panigada, M. Kolobow, T. TI Alternative approaches to ventilator-associated pneumonia prevention SO MINERVA ANESTESIOLOGICA LA English DT Review DE Pneumonia, ventilator-associated; Respiration, artificial; Cross infection ID COATED ENDOTRACHEAL-TUBES; BACTERIAL-COLONIZATION; TRACHEAL TUBE; MINERVA ANESTESIOLOGICA; MUCUS SHAVER; ASPIRATION; TRIAL; FEASIBILITY; ORIENTATION; INTUBATION AB Ventilator-associated pneumonia (VAP), which develops in patients receiving mechanical ventilation, is the most common nosocomial infection in patients with acute respiratory failure. The major mechanism of lower respiratory tract colonization is aspiration of bacteria-colonized secretions from the oropharynx into the lower airways. The hydrostatic pressure of the secretions that collect in the subglottic space, which is the area above the endotracheal tube (ETT) cuff, or aerosolization of bacteria from the secretions collected within the respiratory tubing may facilitate the leakage into the lower airways. Ideally, the elimination of the mechanisms responsible for aspiration would decrease the incidence of VAP. Several preventive measures have been tested in clinical trials with little success.Here we present the results of our efforts to develop novel approaches for the prevention of VAP Specifically, we found that keeping ventilated patients in a lateral position, which eliminates gravitational forces, is feasible and possibly advantageous. Additionally, several novel medical devices have been recently developed to prevent bacterial biofilm formation from the ETT and breathing tubing. These devices include coated ETTs, mucus shavers and mucus slurpers. Prevention of ETT bacterial colonization showed decreased bacterial colonization of the respiratory circuit and of the lower respiratory tract in laboratory studies and clinical trials. Future large studies should be designed to test the hypothesis that VAP can be prevented with these novel strategies. While there is a current focus on the use of respiratory devices to prevent biofilm formation and microaspiration, it is important to remember that lower respiratory tract colonization is multifactorial. Prevention of VAP cannot be achieved solely by eliminating bacterial biofilm on respiratory devices, and more comprehensive care of the intubated patient needs to be implemented. (Minerva Anestesiol 2011;77:323-33) C1 [Berra, L.; Sampson, J.; Fumagalli, J.; Panigada, M.; Kolobow, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Berra, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM lberra@partners.org RI Lee, H/E-7918-2010; Panigada, Mauro/K-4650-2014 OI Panigada, Mauro/0000-0003-4841-9794 NR 30 TC 12 Z9 15 U1 0 U2 5 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0375-9393 EI 1827-1596 J9 MINERVA ANESTESIOL JI Minerva Anestesiol. PD MAR PY 2011 VL 77 IS 3 BP 323 EP 333 PG 11 WC Anesthesiology; Critical Care Medicine SC Anesthesiology; General & Internal Medicine GA 751CA UT WOS:000289593900012 PM 21150848 ER PT J AU Liu, W Hasserjian, RP Hu, Y Zhang, LP Miranda, RN Medeiros, LJ Wang, SA AF Liu, Wei Hasserjian, Robert P. Hu, Ying Zhang, Liping Miranda, Roberto N. Medeiros, L. Jeffrey Wang, Sa A. TI Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification SO MODERN PATHOLOGY LA English DT Article DE acute erythroleukemia; cytogenetics; erythroid predominance; myelodysplastic syndromes; pure erythroid leukemia; survival ID ACUTE ERYTHROLEUKEMIA; E-CADHERIN; AML; PROERYTHROBLASTS; CYTOGENETICS; GLYCOPHORIN; EXPRESSION; CRITERIA; VARIANT; CELLS AB Pure erythroid leukemia (PEL) is rare, characterized by a neoplastic proliferation of erythroblasts. Given recent incorporation of molecular genetic findings and clinical features in the revised 2008 World Health Organization classification scheme of acute myeloid leukemia, we questioned if PEL still remains as a distinct subtype of acute myeloid leukemia. In this retrospective study, we identified 18 cases of acute leukemia with morphologic and immunophenotypic features of PEL. Following the current World Health Organization classification algorithm, these cases were classified as: 13 acute myeloid leukemia with myelodysplasia-related changes, 3 therapy-related acute myeloid leukemia, and 1 chronic myelogenous leukemia blast crisis, and one unclassifiable due to insufficient clinical information. All 16 cases with cytogenetic data harbored an extremely complex karyotype and the median overall survival of the 18 patients was 3 months (range, 1-7 months). This survival was significantly shorter than that of patients with acute erythroid leukemia, erythroid/myeloid subtype, or acute myeloid leukemia with myelodysplasia-related changes with erythroid predominance (P < 0.001). PEL is characterized as a neoplastic erythroid hyperproliferation with maturation arrest. E-cadherin emerged as the most sensitive and specific marker for immature erythroblasts, and was helpful in distinguishing PEL from other erythroid proliferations. Our study showed that the criteria for acute myeloid leukemia in the 2008 World Health Organization system facilitate reclassification of PEL cases into other acute myeloid leukemia categories, mainly of acute myeloid leukemia with myelodysplasia-related changes. These new assigned categories fail to capture the distinct features of PEL, where the phenotype of PEL correlates with a very complex karyotype and an extremely aggressive clinical course. Modern Pathology (2011) 24, 375-383; doi:10.1038/modpathol.2010.194; published online 19 November 2010 C1 [Liu, Wei; Hu, Ying; Miranda, Roberto N.; Medeiros, L. Jeffrey; Wang, Sa A.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zhang, Liping] Univ Massachusetts, Med Ctr, Dept Pathol, Worcester, MA USA. RP Liu, W (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM swang5@mdanderson.org OI Miranda, Roberto/0000-0002-8467-5464 FU NCI NIH HHS [P30 CA016672] NR 27 TC 19 Z9 20 U1 0 U2 2 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 MAR PY 2011 VL 24 IS 3 BP 375 EP 383 DI 10.1038/modpathol.2010.194 PG 9 WC Pathology SC Pathology GA 729XC UT WOS:000287986600005 PM 21102413 ER PT J AU Seward, RJ Drouin, EE Steere, AC Costello, CE AF Seward, Robert J. Drouin, Elise E. Steere, Allen C. Costello, Catherine E. TI Peptides Presented by HLA-DR Molecules in Synovia of Patients with Rheumatoid Arthritis or Antibiotic-Refractory Lyme Arthritis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID CYCLIC CITRULLINATED PEPTIDE; T-CELL RECOGNITION; MASS-SPECTROMETRY; BOUND PEPTIDES; CLASS-I; ANTIGENIC DETERMINANTS; HLA-DRB1 ALLELES; ASSOCIATION; CYSTEINE; DISEASE AB Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New in-sights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.002477, 1-14, 2011. C1 [Seward, Robert J.; Costello, Catherine E.] Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Dept Biochem, Boston, MA 02118 USA. [Seward, Robert J.; Drouin, Elise E.; Steere, Allen C.] Harvard Univ, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Med Sch, Boston, MA 02114 USA. RP Costello, CE (reprint author), Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Dept Biochem, 670 Albany St,Rm 511, Boston, MA 02118 USA. EM cecmsms@bu.edu OI Costello, Catherine/0000-0003-1594-5122 FU National Institutes of Health [P41 RR010888, S10 RR015942, S10 RR020946, N01 HV028178, R01 AR020358]; Dana Foundation; Mathers Foundation; English, Bonter, Mitchell Foundation; Eshe Fund; Massachusetts General Hospital FX This work was supported, in whole or in part, by National Institutes of Health Grants P41 RR010888, S10 RR015942, and S10 RR020946 and Contract N01 HV028178 (to C. E. C.) and by Grant R01 AR020358 (to A. C. S.). This work was also supported by a grant from the Dana Foundation (to A. C. S. and C. E. C.) and grants from the Mathers Foundation; the English, Bonter, Mitchell Foundation; the Eshe Fund; and the Lyme/Arthritis Research Fund at Massachusetts General Hospital (to A. C. S.). NR 56 TC 9 Z9 9 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD MAR PY 2011 VL 10 IS 3 AR M110.002477 DI 10.1074/mcp.M110.002477 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 728AY UT WOS:000287847200010 PM 21081667 ER PT J AU Whiteman, NK Groen, SC Chevasco, D Bear, A Beckwith, N Gregory, TR Denoux, C Mammarella, N Ausubel, FM Pierce, NE AF Whiteman, Noah K. Groen, Simon C. Chevasco, Daniela Bear, Ashley Beckwith, Noor Gregory, T. Ryan Denoux, Carine Mammarella, Nicole Ausubel, Frederick M. Pierce, Naomi E. TI Mining the plant-herbivore interface with a leafmining Drosophila of Arabidopsis SO MOLECULAR ECOLOGY LA English DT Review DE Arabidopsis; Drosophila; gene expression; herbivory; jasmonate; model system ID CARDAMINE-CORDIFOLIA GRAY,A.; HOST PLANTS; INSECT INTERACTIONS; MOLECULAR-PATTERNS; DEFENSE RESPONSES; HAWAIIAN DROSOPHILIDAE; PSEUDOMONAS-SYRINGAE; LARVAL PERFORMANCE; PARKINSONS-DISEASE; NATIVE CRUCIFER AB Experimental infections of Arabidopsis thaliana (Arabidopsis) with genomically characterized plant pathogens such as Pseudomonas syringae have facilitated the dissection of canonical eukaryotic defence pathways and parasite virulence factors. Plants are also attacked by herbivorous insects, and the development of an ecologically relevant genetic model herbivore that feeds on Arabidopsis will enable the parallel dissection of host defence and reciprocal resistance pathways such as those involved in xenobiotic metabolism. An ideal candidate is Scaptomyza flava, a drosophilid fly whose leafmining larvae are true herbivores that can be found in nature feeding on Arabidopsis and other crucifers. Here, we describe the life cycle of S. flava on Arabidopsis and use multiple approaches to characterize the response of Arabidopsis to S. flava attack. Oviposition choice tests and growth performance assays on different Arabidopsis ecotypes, defence-related mutants, and hormone and chitin-treated plants revealed significant differences in host preference and variation in larval performance across Arabidopsis accessions. The jasmonate and glucosinolate pathways in Arabidopsis are important in mediating quantitative resistance against S. flava, and priming with jasmonate or chitin resulted in increased resistance. Expression of xenobiotic detoxification genes was reduced in S. flava larvae reared on Arabidopsis jasmonate signalling mutants and increased in plants pretreated with chitin. These results and future research directions are discussed in the context of developing a genetic model system to analyse insect-plant interactions. C1 [Whiteman, Noah K.; Groen, Simon C.; Chevasco, Daniela; Bear, Ashley; Beckwith, Noor; Pierce, Naomi E.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02478 USA. [Whiteman, Noah K.] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA. [Gregory, T. Ryan] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [Denoux, Carine; Mammarella, Nicole; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Denoux, Carine; Mammarella, Nicole; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Whiteman, NK (reprint author), Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02478 USA. EM whiteman@email.arizona.edu RI Groen, Simon/G-2443-2012; OI Beckwith, Noor/0000-0001-6025-8642 FU National Institutes of Health [F32AI069732, GM48707]; National Science Foundation [MCB-0519898, SES-0750480]; Harvard University; Harvard University Science and Engineering Committee FX NKW was supported by a Kirschstein National Research Service Award (NRSA) from the National Institutes of Health (F32AI069732 to NKW), FMA was supported by a grant from the National Science Foundation (grant MCB-0519898 to FMA) and a grant from the National Institutes of Health (grant GM48707 to FMA), and NEP was supported by a grant from the National Science Foundation (grant SES-0750480 to NEP). NKW, SCG, FMA and NEP were supported by a grant from the Harvard University's Provost Fund for Interfaculty Collaboration and a grant from the Harvard University Science and Engineering Committee Seed Fund for Interdisciplinary Science. We thank Jen Bush for advice on culturing of Arabidopsis, Andrew Brownjohn, Benjamin Goldman-Huertas, Sondra Lavigne, Christopher Meehan and Matan Shelomi for assistance with laboratory work and culturing of Scaptomyza flava. We thank Mark Beilstein for advice on the phylogenetic analyses and William Gelbart, Patrick O'Grady and Therese Markow for useful discussions of Drosophila biology. We thank Gabe Miller for photographs of Arabidopsis. We thank Paul H. Williams for telling NEP about leafmining flies of Arabidopsis in a meeting hosted by Ed and Kyoko Jones as part of the Japan Fulbright Masters Teacher Program in 2004. NR 132 TC 30 Z9 30 U1 3 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD MAR PY 2011 VL 20 IS 5 BP 995 EP 1014 DI 10.1111/j.1365-294X.2010.04901.x PG 20 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 721ZN UT WOS:000287397600013 PM 21073583 ER PT J AU Ko, S Ahn, J Song, CS Kim, S Knapczyk-Stwora, K Chatterjee, B AF Ko, Soyoung Ahn, Jungmi Song, Chung S. Kim, Soyoung Knapczyk-Stwora, Katarzyna Chatterjee, Bandana TI Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROSTATE-CANCER; COACTIVATOR COMPLEX; HISTONE H3; ACETYLATION; EXPRESSION; BINDING; ALPHA; AKT; P53; MYB AB Lysine methyltransferases modulate activities of transcription factors and transcription coregulators by methylating specific lysine residue(s). We report that the androgen receptor (AR) is methylated at lysine-630 by Set9, which was originally identified as a histone H3K4 monomethyltransferase. Alanine substitution of lysine-630 prevented AR methylation in vitro and in vivo. Set9 methylated the nuclear and cytoplasmic AR utilizing the cofactor S-adenosyl-methionine. A panmethyllysine antibody recognized endogenous AR, and Set9 coimmunoprecipitated with nuclear and cytoplasmic AR. Set9 overexpression potentiated AR-mediated transactivation of the probasin promoter, whereas Set9 depletion inhibited AR activity and target gene expression. Similar to AR, chromatin occupancy of Set9 at androgen response elements (AREs) was androgen dependent, and associated with methylated histone H3K4 chromatin activation marks and p300/CBP associated factor acetyltransferase recruitment. Set9 depletion increased the histone H3K9-dimethyl repressive mark at AREs and reduced histone activation marks and occupancy of p300/CBP associated factor. K630A mutation reduced amino-and carboxy-terminal (N-C) interaction in Set9-intact cells, whereas N-C interaction for wild-type AR was reduced upon Set9 depletion. The K630A mutant was resistant to loss of activity from Set9 silencing and to increase of activity from Set9 overexpression. The K630 dependence of Set9-regulated N-C interaction and AR activity suggests that Set9 directly acts on AR at the amino acid level. Chromatin recruitment of Set9 to AREs is suggestive of its additional role as a transcriptional coactivator. Because the cellular metabolic state determines the level of S-adenosylmethionine and consequently the activity of Set9, the enhanced activity of methylated AR may have special significance in certain metabolic contexts. (Molecular Endocrinology 25: 433-444, 2011) C1 [Ko, Soyoung; Ahn, Jungmi; Song, Chung S.; Kim, Soyoung; Knapczyk-Stwora, Katarzyna; Chatterjee, Bandana] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Inst Biotechnol, San Antonio, TX 78245 USA. [Chatterjee, Bandana] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Chatterjee, B (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Inst Biotechnol, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM chatterjee@uthscsa.edu FU National Institutes of Health [R01-AG10486, R01-AG19660]; Veterans Affairs; Department of Defense [XWH-08-1-0067]; Clinical and Translational Science Award-Translational Science Training predoctoral fellowship FX The study was supported by National Institutes of Health Grants R01-AG10486 and R01-AG19660; a Veterans Affairs Merit-Review grant, a Department of Defense predoctoral fellowship, XWH-08-1-0067 (to S. Ko.); and a Clinical and Translational Science Award-Translational Science Training predoctoral fellowship (to J.A.). NR 26 TC 34 Z9 35 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2011 VL 25 IS 3 BP 433 EP 444 DI 10.1210/me.2010-0482 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 726CX UT WOS:000287697500006 PM 21273441 ER PT J AU Rosenquist, JN Fowler, JH Christakis, NA AF Rosenquist, J. N. Fowler, J. H. Christakis, N. A. TI Social network determinants of depression SO MOLECULAR PSYCHIATRY LA English DT Article DE depression; social networks; sociology; social norms; mood ID HEALTH; SYMPTOMS; SPREAD AB The etiology of depression has long been thought to include social environmental factors. To quantitatively explore the novel possibility of person-to-person spread and network-level determination of depressive symptoms, analyses were performed on a densely interconnected social network of 12 067 people assessed repeatedly over 32 years as part of the Framingham Heart Study. Longitudinal statistical models were used to examine whether depressive symptoms in one person were associated with similar scores in friends, co-workers, siblings, spouses and neighbors. Depressive symptoms were assessed using CES-D scores that were available for subjects in three waves measured between 1983 and 2001. Results showed both low and high CES-D scores (and classification as being depressed) in a given period were strongly correlated with such scores in one's friends and neighbors. This association extended up to three degrees of separation (to one's friends' friends' friends). Female friends appear to be especially influential in the spread of depression from one person to another. The results are robust to multiple network simulation and estimation methods, suggesting that network phenomena appear relevant to the epidemiology of depression and would benefit from further study. Molecular Psychiatry (2011) 16, 273-281; doi:10.1038/mp.2010.13; published online 16 March 2010 C1 [Rosenquist, J. N.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Rosenquist, J. N.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fowler, J. H.] Univ Calif San Diego, Dept Polit Sci, San Diego, CA 92103 USA. [Christakis, N. A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. [Christakis, N. A.] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. RP Rosenquist, JN (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jrosenqu@gmail.com RI Fowler, James/C-2750-2008 OI Fowler, James/0000-0001-7795-1638 FU NIA NIH HHS [P01 AG031093, P01 AG031093-01]; NIGMS NIH HHS [P41 GM103504] NR 44 TC 86 Z9 88 U1 3 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2011 VL 16 IS 3 BP 273 EP 281 DI 10.1038/mp.2010.13 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 723AT UT WOS:000287479100008 PM 20231839 ER PT J AU Osborn, MJ McElmurry, RT Lees, CJ DeFeo, AP Chen, ZY Kay, MA Naldini, L Freeman, G Tolar, J Blazar, BR AF Osborn, Mark J. McElmurry, Ron T. Lees, Christopher J. DeFeo, Anthony P. Chen, Zhi-Ying Kay, Mark A. Naldini, Luigi Freeman, Gordon Tolar, Jakub Blazar, Bruce R. TI Minicircle DNA-based Gene Therapy Coupled With Immune Modulation Permits Long-term Expression of alpha-L-Iduronidase in Mice With Mucopolysaccharidosis Type I SO MOLECULAR THERAPY LA English DT Article ID EPISOMAL TRANSGENE EXPRESSION; NAKED PLASMID DNA; ENDOGENOUS MICRORNA; HUMAN GENOME; FACTOR-VIII; VECTOR; VIVO; LIVER; TOLERANCE; ELEMENTS AB Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease characterized by mutations to the alpha-L-iduronidase (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results in the progressive accumulation of glycosaminoglycans within the lysosomes resulting in severe, multi-organ system pathology. Gene replacement strategies have relied on the use of viral or nonviral gene delivery systems. Drawbacks to these include laborious production procedures, poor efficacy due to plasmid-borne gene silencing, and the risk of insertional mutagenesis. This report demonstrates the efficacy of a nonintegrating, minicircle (MC) DNA vector that is resistant to epigenetic gene silencing in vivo. To achieve sustained expression of the immunogenic IDUA protein we investigated the use of a tissue-specific promoter in conjunction with microRNA target sequences. The inclusion of microRNA target sequences resulted in a slight improvement in long-term expression compared to their absence. However, immune modulation by costimulatory blockade was required and permitted for IDUA expression in MPS I mice that resulted in the biochemical correction of pathology in all of the organs analyzed. MC gene delivery combined with costimulatory pathway blockade maximizes safety, efficacy, and sustained gene expression and is a new approach in the treatment of lysosomal storage disease. C1 [Osborn, Mark J.; McElmurry, Ron T.; Lees, Christopher J.; DeFeo, Anthony P.; Tolar, Jakub; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Bone Marrow Transplant, Minneapolis, MN 55455 USA. [Osborn, Mark J.; McElmurry, Ron T.; Lees, Christopher J.; DeFeo, Anthony P.; Tolar, Jakub; Blazar, Bruce R.] Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. [Chen, Zhi-Ying; Kay, Mark A.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Chen, Zhi-Ying; Kay, Mark A.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Naldini, Luigi] San Raffaele Telethon Inst Gene Therapy, Milan, Italy. [Naldini, Luigi] Univ Vita Salute San Raffaele, Milan, Italy. [Freeman, Gordon] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA. RP Osborn, MJ (reprint author), Univ Minnesota, Dept Pediat, Div Bone Marrow Transplant, 420 Delaware St SE,MMC 366, Minneapolis, MN 55455 USA. EM osbor026@umn.edu RI Naldini, Luigi/E-9083-2012; OI Tolar, Jakub/0000-0002-0957-4380 FU National MPS Society; Minnesota Medical Foundation; Children's Cancer Research Fund; Fondazione Telethon FX We are grateful to Katherine P. Ponder (Washington University) for helpful discussions in developing the IDUA enzymatic assay. We thank Andrew P. Price and John Oleksowicz (University of Minnesota) for excellent technical assistance. M.J.O. is supported by a grant from the National MPS Society. M.J.O., J.T., & B.R.B. are also supported by the Minnesota Medical Foundation and the Children's Cancer Research Fund. NR 47 TC 49 Z9 50 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2011 VL 19 IS 3 BP 450 EP 460 DI 10.1038/mt.2010.249 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 728YY UT WOS:000287911600004 PM 21081900 ER PT J AU Boulting, GL Kiskinis, E Croft, GF Amoroso, MW Oakley, DH Wainger, BJ Williams, DJ Kahler, DJ Yamaki, M Davidow, L Rodolfa, CT Dimos, JT Mikkilineni, S MacDermott, AB Woolf, CJ Henderson, CE Wichterle, H Eggan, K AF Boulting, Gabriella L. Kiskinis, Evangelos Croft, Gist F. Amoroso, Mackenzie W. Oakley, Derek H. Wainger, Brian J. Williams, Damian J. Kahler, David J. Yamaki, Mariko Davidow, Lance Rodolfa, Christopher T. Dimos, John T. Mikkilineni, Shravani MacDermott, Amy B. Woolf, Clifford J. Henderson, Christopher E. Wichterle, Hynek Eggan, Kevin TI A functionally characterized test set of human induced pluripotent stem cells SO NATURE BIOTECHNOLOGY LA English DT Article ID MOTOR-NEURONS; DIRECTED DIFFERENTIATION; NEURAL CONVERSION; IPS CELLS; HUMAN ES; DISEASE; BLASTOCYSTS; TISSUE; LINES; ALS AB Human induced pluripotent stem cells (iPSCs) present exciting opportunities for studying development and for in vitro disease modeling. However, reported variability in the behavior of iPSCs has called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate. Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise to functional motor neurons with a range of efficiencies similar to that of human embryonic stem cells (ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescued their performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despite variations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSC and ESC test set is a robust resource for those interested in the basic biology of stem cells and their applications. C1 [Boulting, Gabriella L.; Kiskinis, Evangelos; Yamaki, Mariko; Eggan, Kevin] Howard Hughes Med Inst, Cambridge, MA USA. [Boulting, Gabriella L.; Kiskinis, Evangelos; Yamaki, Mariko; Davidow, Lance; Mikkilineni, Shravani; Eggan, Kevin] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Boulting, Gabriella L.; Rodolfa, Christopher T.; Dimos, John T.; Mikkilineni, Shravani; Eggan, Kevin] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Croft, Gist F.; Amoroso, Mackenzie W.; Oakley, Derek H.; Henderson, Christopher E.; Wichterle, Hynek] Columbia Univ, Jenifer Estess Lab Stem Cell Res, Project ALS, New York, NY USA. [Croft, Gist F.; Amoroso, Mackenzie W.; Oakley, Derek H.; Henderson, Christopher E.; Wichterle, Hynek] Columbia Univ, Ctr Motor Neuron Biol & Dis MNC, Dept Pathol, New York, NY USA. [Croft, Gist F.; Amoroso, Mackenzie W.; Oakley, Derek H.; Henderson, Christopher E.; Wichterle, Hynek] Columbia Univ, Ctr Motor Neuron Biol & Dis MNC, Dept Neurol & Neurosci, New York, NY USA. [Croft, Gist F.; Amoroso, Mackenzie W.; Oakley, Derek H.; Henderson, Christopher E.; Wichterle, Hynek] Columbia Stem Cell Initiat CSCI, New York, NY USA. [Wainger, Brian J.; Woolf, Clifford J.] Childrens Hosp, Program Neurobiol, Boston, MA 02115 USA. [Wainger, Brian J.; Woolf, Clifford J.] Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Wainger, Brian J.; Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Williams, Damian J.; MacDermott, Amy B.] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY USA. [Williams, Damian J.; MacDermott, Amy B.] Columbia Univ, Dept Neurosci, New York, NY USA. [Kahler, David J.] New York Stem Cell Fdn Inc, New York, NY USA. RP Eggan, K (reprint author), Howard Hughes Med Inst, Cambridge, MA USA. EM hw350@columbia.edu; keggan@scrb.harvard.edu RI Williams, Damian/K-4023-2014; OI Weygandt Amoroso, Mackenzie/0000-0001-7368-4456; Henderson, Christopher/0000-0002-9936-3279 FU A.L.S.; P2ALS; NYSTEM; National Institutes of Health (NIH) [1RC2 NS069395-01, 5T32GM007592]; National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Development FX We thank H. Mitsumoto, J. Montes, P. Kaufmann and J. Andrews for collecting skin biopsies; K. Koszka, A. Sproul, A. Hon and A. Garcia-Diaz for technical assistance; M. Park, A. Meissner and C. Bock for manuscript assistance, as well as S. Brenner-Morton and T. Jessell for providing Islet antibodies. This work was funded by Project A.L.S., P2ALS, NYSTEM and the National Institutes of Health (NIH) GO grant 1RC2 NS069395-01. G. L. B. is a Harvard Stem Cell Institute/NIH Trainee. E. K. is an EMBO Postdoctoral Fellow. B.J.W. is supported by NIH Training Grant 5T32GM007592. C.J.W. is supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development. K. E. is a Howard Hughes Medical Institute early career scientist. NR 24 TC 238 Z9 248 U1 4 U2 47 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 2011 VL 29 IS 3 BP 279 EP U147 DI 10.1038/nbt.1783 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 732RL UT WOS:000288206700024 PM 21293464 ER PT J AU Anderson, CA Boucher, G Lees, CW Franke, A D'Amato, M Taylor, KD Lee, JC Goyette, P Imielinski, M Latiano, A Lagace, C Scott, R Amininejad, L Bumpstead, S Baidoo, L Baldassano, RN Barclay, M Bayless, TM Brand, S Buning, C Colombel, JF Denson, LA De Vos, M Dubinsky, M Edwards, C Ellinghaus, D Fehrmann, RSN Floyd, JAB Florin, T Franchimont, D Franke, L Georges, M Glas, J Glazer, NL Guthery, SL Haritunians, T Hayward, NK Hugot, JP Jobin, G Laukens, D Lawrance, I Lemann, M Levine, A Libioulle, C Louis, E McGovern, DP Milla, M Montgomery, GW Morley, KI Mowat, C Ng, A Newman, W Ophoff, RA Papi, L Palmieri, O Peyrin-Biroulet, L Panes, J Phillips, A Prescott, NJ Proctor, DD Roberts, R Russell, R Rutgeerts, P Sanderson, J Sans, M Schumm, P Seibold, F Sharma, Y Simms, LA Seielstad, M Steinhart, AH Targan, SR van den Berg, LH Vatn, M Verspaget, H Walters, T Wijmenga, C Wilson, DC Westra, HJ Xavier, RJ Zhao, ZZ Ponsioen, CY Andersen, V Torkvist, L Gazouli, M Anagnou, NP Karlsen, TH Kupcinskas, L Sventoraityte, J Mansfield, JC Kugathasan, S Silverberg, MS Halfvarson, J Rotter, JI Mathew, CG Griffiths, AM Gearry, R Ahmad, T Brant, SR Chamaillard, M Satsangi, J Cho, JH Schreiber, S Daly, MJ Barrett, JC Parkes, M Annese, V Hakonarson, H Radford-Smith, G Duerr, RH Vermeire, S Weersma, RK Rioux, JD AF Anderson, Carl A. Boucher, Gabrielle Lees, Charlie W. Franke, Andre D'Amato, Mauro Taylor, Kent D. Lee, James C. Goyette, Philippe Imielinski, Marcin Latiano, Anna Lagace, Caroline Scott, Regan Amininejad, Leila Bumpstead, Suzannah Baidoo, Leonard Baldassano, Robert N. Barclay, Murray Bayless, Theodore M. Brand, Stephan Buening, Carsten Colombel, Jean-Frederic Denson, Lee A. De Vos, Martine Dubinsky, Marla Edwards, Cathryn Ellinghaus, David Fehrmann, Rudolf S. N. Floyd, James A. B. Florin, Timothy Franchimont, Denis Franke, Lude Georges, Michel Glas, Juergen Glazer, Nicole L. Guthery, Stephen L. Haritunians, Talin Hayward, Nicholas K. Hugot, Jean-Pierre Jobin, Gilles Laukens, Debby Lawrance, Ian Lemann, Marc Levine, Arie Libioulle, Cecile Louis, Edouard McGovern, Dermot P. Milla, Monica Montgomery, Grant W. Morley, Katherine I. Mowat, Craig Ng, Aylwin Newman, William Ophoff, Roel A. Papi, Laura Palmieri, Orazio Peyrin-Biroulet, Laurent Panes, Julian Phillips, Anne Prescott, Natalie J. Proctor, Deborah D. Roberts, Rebecca Russell, Richard Rutgeerts, Paul Sanderson, Jeremy Sans, Miquel Schumm, Philip Seibold, Frank Sharma, Yashoda Simms, Lisa A. Seielstad, Mark Steinhart, A. Hillary Targan, Stephan R. van den Berg, Leonard H. Vatn, Morten Verspaget, Hein Walters, Thomas Wijmenga, Cisca Wilson, David C. Westra, Harm-Jan Xavier, Ramnik J. Zhao, Zhen Z. Ponsioen, Cyriel Y. Andersen, Vibeke Torkvist, Leif Gazouli, Maria Anagnou, Nicholas P. Karlsen, Tom H. Kupcinskas, Limas Sventoraityte, Jurgita Mansfield, John C. Kugathasan, Subra Silverberg, Mark S. Halfvarson, Jonas Rotter, Jerome I. Mathew, Christopher G. Griffiths, Anne M. Gearry, Richard Ahmad, Tariq Brant, Steven R. Chamaillard, Mathias Satsangi, Jack Cho, Judy H. Schreiber, Stefan Daly, Mark J. Barrett, Jeffrey C. Parkes, Miles Annese, Vito Hakonarson, Hakon Radford-Smith, Graham Duerr, Richard H. Vermeire, Severine Weersma, Rinse K. Rioux, John D. TI Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 SO NATURE GENETICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; COMMON VARIANTS; GENE-EXPRESSION; CELLS; MULTIPLE; PROTEIN; ENRICHMENT AB Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. C1 [Anderson, Carl A.; Bumpstead, Suzannah; Floyd, James A. B.; Morley, Katherine I.; Barrett, Jeffrey C.] Wellcome Trust Sanger Inst, Cambridge, England. [Boucher, Gabrielle; Goyette, Philippe; Lagace, Caroline; Jobin, Gilles; Rioux, John D.] Univ Montreal, Montreal, PQ, Canada. [Boucher, Gabrielle; Goyette, Philippe; Lagace, Caroline; Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Lees, Charlie W.; Satsangi, Jack] Univ Edinburgh, Western Gen Hosp, Gastrointestinal Unit, Mol Med Ctr, Edinburgh, Midlothian, Scotland. [Franke, Andre; Ellinghaus, David; Schreiber, Stefan] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [D'Amato, Mauro] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden. [Taylor, Kent D.; McGovern, Dermot P.; Targan, Stephan R.] Cedars Sinai Med Ctr, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA. [Lee, James C.; Parkes, Miles] Univ Cambridge, Addenbrookes Hosp, Gastroenterol Res Unit, Cambridge CB2 2QQ, England. [Imielinski, Marcin; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Latiano, Anna; Palmieri, Orazio; Annese, Vito] IRCCS CSS Hosp, Gastroenterol Unit, San Giovanni Rotondo, Italy. [Scott, Regan; Baidoo, Leonard; Duerr, Richard H.] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Amininejad, Leila; Franchimont, Denis] Free Univ Brussels, Erasmus Hosp, Dept Gastroenterol, Brussels, Belgium. [Baldassano, Robert N.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Dept Pediat, Ctr Pediat Inflammatory Bowel Dis, Philadelphia, PA 19104 USA. [Barclay, Murray; Roberts, Rebecca; Gearry, Richard] Univ Otago, Dept Med, Christchurch, New Zealand. [Bayless, Theodore M.; Brant, Steven R.] Johns Hopkins Univ, Sch Med, Dept Med, Meyerhoff Inflammatory Bowel Dis Ctr, Baltimore, MD 21205 USA. [Brand, Stephan; Glas, Juergen] Univ Hosp Munich, Dept Med 2, Munich, Germany. [Buening, Carsten] Univ Med Berlin, Dept Gastroenterol, Charite, Berlin, Germany. [Colombel, Jean-Frederic] Univ Lille, Dept Hepatogastroenterol, Lille, France. [Denson, Lee A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [De Vos, Martine; Laukens, Debby] Ghent Univ Hosp, Dept Gastroenterol & Hepatol, B-9000 Ghent, Belgium. [Dubinsky, Marla] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. [Edwards, Cathryn] Torbay Hosp, Dept Gastroenterol, Torquay, Devon, England. [Fehrmann, Rudolf S. N.; Franke, Lude; Wijmenga, Cisca; Westra, Harm-Jan] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Florin, Timothy] Dept Gastroenterol, Mater Hlth Serv, Brisbane, Qld, Australia. [Georges, Michel] Univ Liege, Dept Genet, Fac Vet Med, Liege, Belgium. [Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Internal Med, Seattle, WA 98195 USA. [Guthery, Stephen L.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Haritunians, Talin; McGovern, Dermot P.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Hayward, Nicholas K.] Queensland Inst Med Res, Oncogenom Lab, Brisbane, Qld 4006, Australia. [Lemann, Marc] Univ Paris Diderot, GETAID Grp, Paris, France. [Jobin, Gilles] Hop Maison Neuve Rosemont, Dept Gastroenterol, Montreal, PQ H1T 2M4, Canada. [Lawrance, Ian] Univ Western Australia, Sch Med & Pharmacol, Fremantle, WA, Australia. [Levine, Arie] Tel Aviv Univ, Pediat Gastroenterol Unit, Wolfson Med Ctr, IL-69978 Tel Aviv, Israel. [Levine, Arie] Sackler Sch Med, Tel Aviv, Israel. [Libioulle, Cecile; Louis, Edouard] Ctr Hosp Univ Univ Liege, Div Gastroenterol, Liege, Belgium. [Milla, Monica; Annese, Vito] Azienda Ospeda Univ AOU Careggi, Unit Gastroenterol SOD2, Florence, Italy. [Montgomery, Grant W.; Zhao, Zhen Z.] Queensland Inst Med Res, Mol Epidemiol, Brisbane, Qld 4006, Australia. [Mowat, Craig; Phillips, Anne] Univ Dundee, Ninewells Hosp & Med Sch, Dept Med, Dundee DD1 9SY, Scotland. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol Unit, Boston, MA USA. [Ng, Aylwin; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Newman, William] Univ Manchester, Dept Med Genet, Manchester, Lancs, England. [Ophoff, Roel A.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Papi, Laura] Univ Florence, Inst Human Genet, Florence, Italy. [Peyrin-Biroulet, Laurent] Univ Hosp Nancy, Dept Hepatogastroenterol, Vandoeuvre Les Nancy, France. [Panes, Julian; Sans, Miquel] Hosp Clin Barcelona, Dept Gastroenterol, IDIBAPS, CIBERehd, Barcelona, Spain. [Prescott, Natalie J.; Mathew, Christopher G.] Kings Coll London, Sch Med, Dept Med & Mol Genet, Guys Hosp, London WC2R 2LS, England. [Proctor, Deborah D.; Sharma, Yashoda; Cho, Judy H.] Yale Univ, Dept Med, Sect Digest Dis, New Haven, CT 06520 USA. [Russell, Richard; Wilson, David C.] Royal Hosp Sick Children, Glasgow G3 8SJ, Lanark, Scotland. [Rutgeerts, Paul; Vermeire, Severine] Univ Hosp Gasthuisberg, Div Gastroenterol, B-3000 Louvain, Belgium. [Sanderson, Jeremy] St Thomas Hosp, Dept Gastroenterol, Guys & St Thomas NHS Fdn Trust, London, England. [Schumm, Philip] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Seibold, Frank] Univ Bern, Inselspital, Div Gastroenterol, CH-3010 Bern, Switzerland. [Simms, Lisa A.; Radford-Smith, Graham] Queensland Inst Med Res, Inflammatory Bowel Dis, Brisbane, Qld 4006, Australia. [Seielstad, Mark] Genome Inst Singapore, Singapore, Singapore. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Steinhart, A. Hillary; Silverberg, Mark S.] Univ Toronto, Mt Sinai Hosp, Ctr Inflammatory Bowel Dis, Toronto, ON M5G 1X5, Canada. [van den Berg, Leonard H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands. [Vatn, Morten; Karlsen, Tom H.] Univ Hosp, Rikshosp, Dept Med, Oslo, Norway. [Verspaget, Hein] Leiden Univ, Med Ctr, Leiden, Netherlands. [Walters, Thomas; Griffiths, Anne M.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Wilson, David C.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Ponsioen, Cyriel Y.] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol, NL-1105 AZ Amsterdam, Netherlands. [Andersen, Vibeke] Viborg Reg Hosp, Dept Med, Viborg, Denmark. [Torkvist, Leif] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Gazouli, Maria; Anagnou, Nicholas P.] Univ Athens, Dept Biol, Sch Med, GR-15701 Athens, Greece. [Kupcinskas, Limas; Sventoraityte, Jurgita] Kaunas Univ Med, Dept Gastroenterol, Kaunas, Lithuania. [Mansfield, John C.] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Kugathasan, Subra] Emory Sch Med, Dept Genet, Atlanta, GA USA. [Kugathasan, Subra] Emory Sch Med, Dept Pediat, Atlanta, GA USA. [Halfvarson, Jonas] Orebro Univ Hosp, Dept Med, Orebro, Sweden. [Ahmad, Tariq] Peninsula Coll Med & Dent, Exeter, Devon, England. [Chamaillard, Mathias] INSERM, U1019, F-59045 Lille, France. [Cho, Judy H.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Schreiber, Stefan] Univ Kiel, Dept Gen Internal Med, Kiel, Germany. [Daly, Mark J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Duerr, Richard H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Weersma, Rinse K.] Univ Med Ctr Groningen, Dept Gastroenterol, NL-9713 AV Groningen, Netherlands. RP Anderson, CA (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. EM carl.anderson@sanger.ac.uk; john.david.rioux@umontreal.ca RI Mathew, Christopher/G-3434-2015; Palmieri, Orazio/J-7697-2012; Morley, Katherine/A-2986-2011; Franke, Lude/P-7036-2016; Latiano, Anna/R-1965-2016; Franke, Andre/B-2151-2010; Ellinghaus, David/G-4467-2012; Anderson, Carl/B-8327-2013; Silverberg, Mark/B-4183-2008; Wijmenga, Cisca/D-2173-2009; hayward, nicholas/C-1367-2015; Chamaillard, Mathias/L-6542-2013; Rioux, John/A-9599-2015; Schreiber, Stefan/B-6748-2008; Fehrmann, Rudolf/E-2551-2011; Prescott, Natalie/F-6490-2011; Hugot, Jean-Pierre/F-6594-2012; D'Amato, Mauro/F-2450-2010; Montgomery, Grant/B-7148-2008 OI Gearry, Richard/0000-0002-2298-5141; Halfvarson, Jonas/0000-0003-0122-7234; Andersen, Vibeke/0000-0002-0127-2863; Newman, William/0000-0002-6382-4678; Papi, Laura/0000-0003-4552-9517; Panes, Julian/0000-0002-4971-6902; Wijmenga, Cisca/0000-0002-5635-1614; Barrett, Jeffrey/0000-0002-1152-370X; Lee, James/0000-0001-5711-9385; Mathew, Christopher/0000-0003-4178-1838; Palmieri, Orazio/0000-0002-0019-7929; Morley, Katherine/0000-0002-2725-5535; Franke, Lude/0000-0002-5159-8802; Latiano, Anna/0000-0003-3719-2061; Franke, Andre/0000-0003-1530-5811; Duerr, Richard/0000-0001-6586-3905; Laukens, Debby/0000-0002-1984-5850; Seielstad, Mark/0000-0001-5783-1401; Vermeire, Severine/0000-0001-9942-3019; Anderson, Carl/0000-0003-1719-7009; hayward, nicholas/0000-0003-4760-1033; Chamaillard, Mathias/0000-0002-0243-9717; Rioux, John/0000-0001-7560-8326; Schreiber, Stefan/0000-0003-2254-7771; Fehrmann, Rudolf/0000-0002-7516-315X; Prescott, Natalie/0000-0002-5901-7371; D'Amato, Mauro/0000-0003-2743-5197; Montgomery, Grant/0000-0002-4140-8139 FU German Ministry of Education and Research through the National Genome Research Network; Italian Group for IBD; Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition; Royal Brisbane and Women's Hospital Foundation; University of Queensland; National Health and Medical Research Council, Australia; European Community; National Association for Colitis and Crohn's disease; Medical Research Council UK; Peninsular College of Medicine and Dentistry, Exeter; Wellcome Trust [083948/Z/07/Z, WT091745/Z/10/Z, WT089120/Z/09/Z]; Crohn's and Colitis Foundation of America; US National Institutes of Health (NIH)/NIDDK [DK064869]; National Center for Research Resources (NCRR) [M01-RR00425]; NIH/NIDDK [P01-DK046763, DK 063491]; Cedars-Sinai Medical Center; Deutsche Forschungsgemeinschaft (DFG) [BR 1912/5-1]; Else Kroner-Fresenius-Stiftung [P50/05/EKMS05/62]; Programme Hospitalier de Recherche Clinique; Netherlands Organization for Scientific Research (NWO) [90.700.281, 918.66.620]; Celiac Disease Consortium [BSIK03009]; Prinses Beatrix Fonds; Adessium Foundation; Amyotrophic Lateral Sclerosis Association; Netherlands Genomics Initiative [93519031]; NWO (ZonMW) [916.10.135]; National Institute for Health Research (NIHR) Biomedical Research Centre; Helmsley Foundation; Primary Children's Medical Center Foundation; [DK062431]; [DK062422]; [DK062420]; [DK062432]; [DK062423]; [DK062413]; [DK076984]; [DK084554]; [DK062429]; [DK069513]; [DK83756]; [AI062773]; [DK043351] FX We thank all the subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. This study was supported by the German Ministry of Education and Research through the National Genome Research Network, the Popgen biobank and infrastructure support through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence 'Inflammation at Interfaces'. Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition. We acknowledge funding provided by the Royal Brisbane and Women's Hospital Foundation, University of Queensland (Ferguson Fellowship), National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). UK case collections were supported by the National Association for Colitis and Crohn's disease, Wellcome Trust, Medical Research Council UK and Peninsular College of Medicine and Dentistry, Exeter. Activities in Sweden were supported by the Swedish Society of Medicine, the Bengt Ihre Foundation, the Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, the Swedish Medical Research Council, the Soderbergh Foundation and the Swedish Cancer Foundation. Support for genotyping and genetic data analysis was provided by the Agency for Science Technology and Research (A*STAR), Singapore. We are grateful to the funders and investigators of the Epidemiological Investigation of Rheumatoid Arthritis for providing genotype data from healthy Swedish individuals.; The Wellcome Trust Case Control Consortium 2 project was supported by Wellcome Trust grant 083948/Z/07/Z. We also acknowledge the National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy's & St. Thomas' National Health Service (NHS) Trust, King's College London and to Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S. R. B.), DK062422 (J.H.C.), DK062420 (R. H. D.), DK062432 (J.D.R.), DK062423 (M. S. S.), DK062413 (D. P. M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D. P. M.) and DK062429 (J.H.C.). J.H.C. is also funded by the Crohn's and Colitis Foundation of America; S. L. G. by DK069513 and Primary Children's Medical Center Foundation; and J.D.R. by US National Institutes of Health (NIH)/NIDDK grant DK064869. Cedars-Sinai is supported by National Center for Research Resources (NCRR) grant M01-RR00425, NIH/NIDDK grant P01-DK046763, DK 063491 and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. E. L., D. F. and S. V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. S. Brand was supported by Deutsche Forschungsgemeinschaft (DFG BR 1912/5-1) and Else Kroner-Fresenius-Stiftung (P50/05/EKMS05/62). M. C. was supported by the Programme Hospitalier de Recherche Clinique. C. A. A. is supported by Wellcome Trust grant WT091745/Z/10/Z. J.C.B. is supported by Wellcome Trust grant WT089120/Z/09/Z. R. K. W. is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research (NWO). C. W. is supported by grants from the Celiac Disease Consortium (BSIK03009) and The Netherlands Organization for Scientific Research (NWO, VICI grant 918.66.620). L.H.v.d.B. acknowledges funding from the Prinses Beatrix Fonds, the Adessium Foundation and the Amyotrophic Lateral Sclerosis Association. L. F. received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). R.J.X. and A.N. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation. NR 53 TC 609 Z9 614 U1 4 U2 66 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2011 VL 43 IS 3 BP 246 EP U94 DI 10.1038/ng.764 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 726BR UT WOS:000287693800016 PM 21297633 ER PT J AU Nakahira, K Haspel, JA Rathinam, VAK Lee, SJ Dolinay, T Lam, HC Englert, JA Rabinovitch, M Cernadas, M Kim, HP Fitzgerald, KA Ryter, SW Choi, AMK AF Nakahira, Kiichi Haspel, Jeffrey Adam Rathinam, Vijay A. K. Lee, Seon-Jin Dolinay, Tamas Lam, Hilaire C. Englert, Joshua A. Rabinovitch, Marlene Cernadas, Manuela Kim, Hong Pyo Fitzgerald, Katherine A. Ryter, Stefan W. Choi, Augustine M. K. TI Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome SO NATURE IMMUNOLOGY LA English DT Article ID FRANCISELLA-TULARENSIS; AIM2 INFLAMMASOME; INTRACELLULAR DNA; OXIDATIVE STRESS; ENDOTOXIC-SHOCK; HOST-DEFENSE; ACTIVATION; IL-1-BETA; DISEASE; MECHANISMS AB Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. Here we demonstrate that depletion of the autophagic proteins LC3B and beclin 1 enhanced the activation of caspase-1 and secretion of interleukin 1 (IL-1 beta) and IL-18. Depletion of autophagic proteins promoted the accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial reactive oxygen species (ROS). Cytosolic mtDNA contributed to the secretion of IL-1 beta and IL-18 in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity. C1 [Nakahira, Kiichi; Haspel, Jeffrey Adam; Lee, Seon-Jin; Dolinay, Tamas; Lam, Hilaire C.; Englert, Joshua A.; Cernadas, Manuela; Kim, Hong Pyo; Ryter, Stefan W.; Choi, Augustine M. K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Haspel, Jeffrey Adam] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Boston, MA USA. [Rathinam, Vijay A. K.; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA USA. [Rabinovitch, Marlene] Stanford Univ, Sch Med, Wall Ctr Pulm Vasc Dis, Stanford, CA 94305 USA. [Kim, Hong Pyo] Univ Ulsan, Coll Nat Sci, Sch Biol Sci, Ulsan 680749, South Korea. RP Choi, AMK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. EM amchoi@rics.bwh.harvard.edu FU National Institutes of Health [HL079904-12, HL08554, HL060234-10, HL097005, AI083713, AI067497]; New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (National Institute of Allergy and Infectious Diseases of the National Institutes of Health) [AI057159] FX We thank B. Levine (University of Texas Southwestern Medical Center) for Becn1+/-mice; and E. Ifedigbo for technical assistance. Supported by National Institutes of Health (HL079904-12, HL08554, HL060234-10 and HL097005 to A. M. K. C., and AI083713 and AI067497 to K. A. F.) and the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (National Institute of Allergy and Infectious Diseases of the National Institutes of Health; AI057159 to V.A.K.R). NR 48 TC 789 Z9 831 U1 29 U2 156 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 MAR PY 2011 VL 12 IS 3 BP 222 EP U57 DI 10.1038/ni.1980 PG 10 WC Immunology SC Immunology GA 721KZ UT WOS:000287354400009 PM 21151103 ER PT J AU Chin, L Andersen, JN Futreal, PA AF Chin, Lynda Andersen, Jannik N. Futreal, P. Andrew TI Cancer genomics: from discovery science to personalized medicine SO NATURE MEDICINE LA English DT Article ID CELL LUNG-CANCER; GROWTH-FACTOR RECEPTOR; ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; SOMATIC MUTATIONS; ALK KINASE; ACTIVATING MUTATIONS; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; RENAL-CARCINOMA AB Recent advances in genome technologies and the ensuing outpouring of genomic information related to cancer have accelerated the convergence of discovery science and clinical medicine. Successful examples of translating cancer genomics into therapeutics and diagnostics reinforce its potential to make possible personalized cancer medicine. However, the bottlenecks along the path of converting a genome discovery into a tangible clinical endpoint are numerous and formidable. In this Perspective, we emphasize the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential and discuss some of the major obstacles to moving from the bench to the bedside. C1 [Chin, Lynda; Andersen, Jannik N.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Chin, Lynda] Broad Inst MIT & Harvard, Cambridge, MA USA. [Futreal, P. Andrew] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England. RP Chin, L (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu OI Andersen, Jannik/0000-0003-4528-2120 NR 67 TC 207 Z9 211 U1 11 U2 76 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 MAR PY 2011 VL 17 IS 3 BP 297 EP 303 DI 10.1038/nm.2323 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 730XF UT WOS:000288070000040 PM 21383744 ER PT J AU Namekawa, SH Lee, JT AF Namekawa, Satoshi H. Lee, Jeannie T. TI Detection of nascent RNA, single-copy DNA and protein localization by immunoFISH in mouse germ cells and preimplantation embryos SO NATURE PROTOCOLS LA English DT Article ID X-CHROMOSOME INACTIVATION; HISTONE MODIFICATIONS; CHROMATIN; MICE; METHYLATION AB Dynamic reprogramming of the genome takes place during the gamete-to-embryo transition. This transition defines a period of continuous and global change but has been difficult to study because of extremely limited material and varying degrees of chromatin compaction. Improved methods of detecting chromatin and gene expression changes in the germ line and in the preimplantation embryo would greatly enhance the understanding of this crucial developmental transition. Here we describe a protocol developed and used by us that improves the sensitivity of existing fluorescence in situ hybridization ( FISH) methods; the protocol described here has enabled us to visualize single-copy DNA targets and corresponding nascent RNA transcripts in preimplantation embryos and during spermatogenesis. Major improvements over alternative methods involve fixation and permeabilization steps. Chromatin epitopes can be visualized simultaneously by combining FISH with immunofluorescence; multicopy and repetitive element expression can also be reliably measured. This procedure ( sample preparation and staining) requires 1-1.5 d to complete and will facilitate detailed examination of spatial relationships between chromatin epitopes, DNA and RNA during the dynamic transition from gamete to embryo. C1 [Namekawa, Satoshi H.; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Namekawa, Satoshi H.; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. EM satoshi.namekawa@cchmc.org; lee@molbio.mgh.harvard.edu FU National Institutes of Health [R01-GM58839]; Japan Society for the Promotion of Science (JSPS); Charles King Trust FX We thank K. Hyunh, B. Payer and L.- F. Zhang for their assistance to optimize experimental conditions during the initial phases of these works. The studies have been supported by National Institutes of Health grant R01-GM58839 to J.T.L. S.H.N. was supported by the research fellowships of the Japan Society for the Promotion of Science (JSPS) and the Charles King Trust. J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 34 TC 27 Z9 27 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD MAR PY 2011 VL 6 IS 3 DI 10.1038/nprot.2010.195 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 729PA UT WOS:000287961700002 PM 21372809 ER PT J AU Altfeld, M Fadda, L Frleta, D Bhardwaj, N AF Altfeld, Marcus Fadda, Lena Frleta, Davor Bhardwaj, Nina TI DCs and NK cells: critical effectors in the immune response to HIV-1 SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-KILLER-CELLS; PLASMACYTOID-DENDRITIC-CELLS; CD4(+) T-CELLS; MHC CLASS-I; INTERFERON-ALPHA EXPRESSION; HIV-1-INFECTED PATIENTS; INHIBITORY RECEPTORS; TYPE-1 INFECTION; HLA-B AB Dendritic cells (DCs) and natural killer (NK) cells have central roles in antiviral immunity by shaping the quality of the adaptive immune response to viruses and by mediating direct antiviral activity. HIV-1 infection is characterized by a severe dysregulation of the antiviral immune response that starts during early infection. This Review describes recent insights into how HIV-1 infection affects DC and NK cell function, and the roles of these innate immune cells in HIV-1 pathogenesis. The importance of understanding DC and NK cell crosstalk during HIV infection for the development of effective antiviral strategies is also discussed. C1 [Altfeld, Marcus; Fadda, Lena] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Charlestown, MA 02129 USA. [Frleta, Davor; Bhardwaj, Nina] NYU, Langone Med Ctr, Inst Canc, New York, NY 10016 USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Charlestown, MA 02129 USA. EM maltfeld@partners.org; Nina.Bhardwaj@nyumc.org FU Science Foundation Ireland; Irish Research Council for Science, Engineering Technology; Health Research Board Ireland FX The authors would like to thank their respective funding bodies: L.A.O'N. is supported by Science Foundation Ireland, F.J.S. was supported by the Irish Research Council for Science, Engineering & Technology and C.E.M. is supported by a Health Research Board Ireland/Marie Curie fellowship. NR 127 TC 104 Z9 107 U1 2 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD MAR PY 2011 VL 11 IS 3 BP 176 EP 186 DI 10.1038/nri2935 PG 11 WC Immunology SC Immunology GA 726OG UT WOS:000287732500011 PM 21350578 ER PT J AU Neuwelt, EA Bauer, B Fahlke, C Fricker, G Iadecola, C Janigro, D Leybaert, L Molnar, Z O'Donnell, ME Povlishock, JT Saunders, NR Sharp, F Stanimirovic, D Watts, RJ Drewes, LR AF Neuwelt, Edward A. Bauer, Bjoern Fahlke, Christoph Fricker, Gert Iadecola, Constantino Janigro, Damir Leybaert, Luc Molnar, Zoltan O'Donnell, Martha E. Povlishock, John T. Saunders, Norman R. Sharp, Frank Stanimirovic, Danica Watts, Ryan J. Drewes, Lester R. TI Engaging neuroscience to advance translational research in brain barrier biology SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; BINDING CASSETTE TRANSPORTERS; P-GLYCOPROTEIN EXPRESSION; HUMAN BLOOD-BRAIN; HEREDITARY CEREBRAL-HEMORRHAGE; GREEN FLUORESCENT PROTEIN; AMINO-ACID TRANSPORTERS; NECROSIS-FACTOR-ALPHA; INDUCED UP-REGULATION; MULTIPLE-SCLEROSIS AB The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, of which the most well known are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, in the control of cerebral blood flow, and-when barrier integrity is impaired-in the pathology of many common CNS disorders such as Alzheimer's disease, Parkinson's disease and stroke. C1 [Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Neuwelt, Edward A.] Portland VA Med Ctr, Portland, OR 97239 USA. [Bauer, Bjoern] Univ Minnesota, Coll Pharm, Duluth, MN 55812 USA. [Fahlke, Christoph] Hannover Med Sch, Inst Neurophysiol, OE 4230, D-30625 Hannover, Germany. [Fricker, Gert] Univ Heidelberg, Abt Pharmazeut Technol & Pharmakol Neuenheimer, D-69120 Heidelberg, Germany. [Iadecola, Constantino] Weill Cornell Med Coll, Div Neurobiol, New York, NY 10065 USA. [Janigro, Damir] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Leybaert, Luc] Univ Ghent, Dept Basic Med Sci, B-9000 Ghent, Belgium. [Molnar, Zoltan] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [O'Donnell, Martha E.] Univ Calif Davis, Sch Med, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. [Povlishock, John T.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23298 USA. [Saunders, Norman R.] Univ Melbourne, Dept Pharmacol Parkville, Melbourne, Vic 3010, Australia. [Sharp, Frank] Univ Calif Davis, UC Davis MIND Inst, Sacramento, CA 95817 USA. [Stanimirovic, Danica] Natl Res Council Canada, Inst Biol Sci, Ottawa, ON K1A 0R7, Canada. [Watts, Ryan J.] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA. [Drewes, Lester R.] Univ Minnesota, Sch Med, Duluth, MN 55812 USA. RP Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,L603, Portland, OR 97239 USA. EM neuwelte@ohsu.edu RI Fahlke, Christoph/G-3635-2013; Leybaert, Luc/F-4079-2015; OI Fahlke, Christoph/0000-0001-8602-9952; Janigro, Damir/0000-0003-2165-5826; Leybaert, Luc/0000-0001-6452-6982; Molnar, Zoltan/0000-0002-6852-6004; Saunders, Norman/0000-0001-6660-7639 FU US National Institutes of Health [5 R13 CA086959-10] FX The meeting on which this report was based was partially funded by an R13 grant from the US National Institutes of Health (Grant 5 R13 CA086959-10). We would like to thank all of the people who attended the Engaging Neuroscience to Advance Brain Barriers Translational Research meeting (March 19-21, 2009), Gleneden Beach, Oregon, USA. Special thanks to Lester Drewes, Martha O'Donnell, Leslie Muldoon and Aliana Kim who were instrumental in the development of this report. NR 218 TC 192 Z9 197 U1 2 U2 58 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD MAR PY 2011 VL 12 IS 3 BP 169 EP 182 DI 10.1038/nrn2995 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 722ZM UT WOS:000287474900004 PM 21331083 ER PT J AU Upadhyay, A Larson, MG Guo, CY Vasan, RS Lipinska, I O'Donnell, CJ Kathiresan, S Meigs, JB Keaney, JF Rong, JA Benjamin, EJ Fox, CS AF Upadhyay, Ashish Larson, Martin G. Guo, Chao-Yu Vasan, Ramachandran S. Lipinska, Izabella O'Donnell, Christopher J. Kathiresan, Sekar Meigs, James B. Keaney, John F., Jr. Rong, Jian Benjamin, Emelia J. Fox, Caroline S. TI Inflammation, kidney function and albuminuria in the Framingham Offspring cohort SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; chronic kidney disease; C-reactive protein; inflammation ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; CARDIOVASCULAR MORTALITY; RENAL-INSUFFICIENCY; TISSUE DISTRIBUTION; OXIDATIVE STRESS; ALL-CAUSE; BIOMARKERS; RISK; ASSOCIATION AB Background. Inflammation and chronic kidney disease (CKD) are both associated with cardiovascular disease (CVD). Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood. Methods. The sample comprised Framingham Offspring cohort participants (n = 3294, mean age 61, 53% women) who attended the seventh examination cycle (1998-2001). Inflammatory biomarkers [C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha, interleukin-6, TNF receptor 2 (TNFR2), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD-40 ligand, osteoprotegerin, urinary isoprostanes, myeloperoxidase and fibrinogen] were measured on fasting blood samples. Serum creatinine-based estimated glomerular filtration rate (eGFR) and serum cystatin C concentration were used to assess kidney function. Urinary albumin-to-creatinine ratio (UACR) was used to assess albuminuria. Linear or logistic regression was used to test associations between biomarkers and kidney measures. Results. Chronic kidney disease (CKD), defined as eGFR < 59/64 mL/min/1.73 m(2) in women/men, was present in 8.8% (n = 291) of participants. TNF-alpha, interleukin-6, TNFR2, MCP-1, osteoprotegerin, myeloperoxidase and fibrinogen were higher among individuals with CKD; all biomarkers except for urinary isoprostanes were elevated in higher cystatin C quartiles; and TNF-alpha, interleukin-6, TNFR2, ICAM-1 and osteoprotegerin were elevated in higher UACR quartiles-all assessed after multivariable adjustment. Almost 6% and 17% of variability in TNFR2 were explained by CKD status and higher cystatin C quartiles, respectively. Conclusions. Biomarkers of inflammation are associated with kidney function and albuminuria. In particular, substantial variability in soluble TNFR2 is explained by CKD and cystatin C. C1 [Upadhyay, Ashish] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Upadhyay, Ashish] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Larson, Martin G.; Guo, Chao-Yu; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Rong, Jian; Benjamin, Emelia J.; Fox, Caroline S.] Boston Univ, Framingham, MA USA. [Larson, Martin G.; Guo, Chao-Yu; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Rong, Jian; Benjamin, Emelia J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Lipinska, Izabella] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Lipinska, Izabella; O'Donnell, Christopher J.; Kathiresan, Sekar; Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Keaney, John F., Jr.] UMass Mem Hlth Care, Div Cardiovasc Med, Worcester, MA USA. [Rong, Jian; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. RP Upadhyay, A (reprint author), Tufts Med Ctr, Div Nephrol, Boston, MA USA. EM aupadhyay@tuftsmedicalcenter.org OI Larson, Martin/0000-0002-9631-1254; Upadhyay, Ashish/0000-0002-0536-5776; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01 HL064753, N01 HC025195, N01-HC-25195, R01 HL043302-10, R01 HL064753-01, R01 HL076784, R01 HL076784-01, R01-HL-076784, R01-HL-64753, R01-HL04334, R01-HL70139]; NIA NIH HHS [AG028321, R01 AG028321, R01 AG028321-01]; NIDDK NIH HHS [K24 DK080140, K24 DK080140-01, K24-DK080140] NR 32 TC 56 Z9 59 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAR PY 2011 VL 26 IS 3 BP 920 EP 926 DI 10.1093/ndt/gfq471 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 726SN UT WOS:000287746500024 PM 20682604 ER PT J AU Reardon, DA Galanis, E DeGroot, JF Cloughesy, TF Wefel, JS Lamborn, KR Lassman, AB Gilbert, MR Sampson, JH Wick, W Chamberlain, MC Macdonald, DR Mehta, MP Vogelbaum, MA Chang, SM Van den Bent, MJ Wen, PY AF Reardon, David A. Galanis, Evanthia DeGroot, John F. Cloughesy, Timothy F. Wefel, Jeffrey S. Lamborn, Kathleen R. Lassman, Andrew B. Gilbert, Mark R. Sampson, John H. Wick, Wolfgang Chamberlain, Marc C. Macdonald, David R. Mehta, Minesh P. Vogelbaum, Michael A. Chang, Susan M. Van den Bent, Martin J. Wen, Patrick Y. TI Clinical trial end points for high-grade glioma: the evolving landscape SO NEURO-ONCOLOGY LA English DT Review DE clinical trials; malignant glioma; end point ID PROGRESSION-FREE SURVIVAL; QUALITY-OF-LIFE; RECURRENT MALIGNANT GLIOMA; PHASE-II TRIAL; GLIOBLASTOMA-MULTIFORME; TUMOR PROGRESSION; BRAIN-TUMORS; NEUROCOGNITIVE FUNCTION; DISEASE PROGRESSION; RESPONSE ASSESSMENT AB To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being. C1 [Reardon, David A.; Sampson, John H.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Galanis, Evanthia] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [DeGroot, John F.; Wefel, Jeffrey S.; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, David Geffen Sch Med, Neurooncol Program, Los Angeles, CA 90095 USA. [Lamborn, Kathleen R.; Chang, Susan M.] Univ Calif San Francisco, Dept Neurol Surg, Div Neurooncol, San Francisco, CA 94143 USA. [Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA. [Wick, Wolfgang] Univ Heidelberg, Dept Neurooncol, Heidelberg, Germany. [Chamberlain, Marc C.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Macdonald, David R.] Univ Western Ontario, Dept Oncol, London, ON N6A 3K7, Canada. [Macdonald, David R.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON N6A 3K7, Canada. [Macdonald, David R.] London Reg Canc Program, London, ON, Canada. [Mehta, Minesh P.] Univ Wisconsin, Sch Med, Dept Human Oncol, Madison, WI 53706 USA. [Vogelbaum, Michael A.] Cleveland Clin Fdn, Brain Tumor & NeuroOncol Ctr, Cleveland, OH 44195 USA. [Van den Bent, Martin J.] Erasmus Univ Hosp Rotterdam, Neurooncol Unit, Dr Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Div Neurol, Boston, MA 02115 USA. RP Reardon, DA (reprint author), Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Box 3624, Durham, NC 27710 USA. EM reard003@mc.duke.edu RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 NR 73 TC 54 Z9 56 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD MAR PY 2011 VL 13 IS 3 BP 353 EP 361 DI 10.1093/neuonc/noq203 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 732AA UT WOS:000288151400010 PM 21310734 ER PT J AU Leung, E Guo, L Bu, J Maloof, M El Khoury, J Geula, C AF Leung, Elaine Guo, Ling Bu, Jing Maloof, Marie El Khoury, Joseph Geula, Changiz TI Microglia activation mediates fibrillar amyloid-beta toxicity in the aged primate cortex SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyloid toxicity; Microglia; Fibrillar; Neuronal loss; Non-human primate ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; SCAVENGER RECEPTOR; BONE-MARROW; IN-VITRO; HUMAN MONOCYTES; PROTEIN; NEUROTOXICITY; TUFTSIN AB The amyloid-beta peptide (A beta) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of A beta (fA beta) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fA beta toxicity at low concentrations. In addition to neuronal loss, fA beta induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fA beta toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fA beta. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fA beta, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fA beta-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fA beta when compared with young microglia. (C) 2009 Elsevier Inc. All rights reserved. C1 [Leung, Elaine; Guo, Ling; Bu, Jing; Maloof, Marie; Geula, Changiz] Northwestern Univ, Feinberg Sch Med, Lab Cognit & Mol Morphometry, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Leung, Elaine; Bu, Jing; Maloof, Marie; El Khoury, Joseph; Geula, Changiz] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Leung, Elaine; Bu, Jing; Maloof, Marie; Geula, Changiz] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [El Khoury, Joseph] Massachusetts Gen Hosp, Div Infect Dis, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Geula, C (reprint author), Northwestern Univ, Feinberg Sch Med, Lab Cognit & Mol Morphometry, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60611 USA. EM c-geula@northwestern.edu FU Alzheimer's Association; Dana Foundation; Illinois Department of Public Health Alzheimer's Disease; Northwestern University Alzheimer's Disease Center [P30 AGO 13854] FX We thank Naima Gedi and Nicholas Nagykery for expert technical assistance. This work was supported in part by grants from the Alzheimer's Association, the Dana Foundation Neuroimmunology Program and the Illinois Department of Public Health Alzheimer's Disease Fund and the Northwestern University Alzheimer's Disease Center (P30 AGO 13854). NR 59 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2011 VL 32 IS 3 BP 387 EP 397 DI 10.1016/j.neurobiolaging.2009.02.025 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 755PE UT WOS:000289944800004 PM 19349094 ER PT J AU Rozkalne, A Hyman, BT Spires-Jones, TL AF Rozkalne, Anete Hyman, Bradley T. Spires-Jones, Tara L. TI Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Alzheimer; Dendritic spine; FK506; Tacrolimus; Synapse; Transgenic ID PROTEIN TRANSGENIC MICE; DISEASE MOUSE MODEL; AMYLOID-BETA; IN-VIVO; LIVER-TRANSPLANTATION; SYNAPTIC PLASTICITY; EXPERIMENTAL STROKE; MEMORY; OLIGOMERS; IMMUNOSUPPRESSION AB Synapse loss is the strongest correlate of cognitive decline in Alzheimer's disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques that dendrites surrounding plaques become dystrophic and lose postsynaptic dendritic spines. Furthermore, we found strong evidence that plaque-associated dendritic changes are mediated by calcineurin, a calcium-dependent phosphatase involved in cell signaling, using in vitro models and genetically encoded inhibitors in mouse models. In this study, we pharmacologically inhibited calcineurin with FK506 treatment to test the hypothesis that calcineurin inhibition will allow recovery of plaque-associated synapse loss. We found that in plaque bearing transgenic mice, short term (1 week) FK506 treatment results in an amelioration of dendritic spine loss. We also observe an effect on spine morphology in wild-type mice with FK506 treatment. These data show that systemic FK506 administration, and hence calcineurin inhibition, may be neuroprotective for amyloid beta induced synaptic alterations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Rozkalne, Anete; Hyman, Bradley T.; Spires-Jones, Tara L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), 114 16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org OI Spires-Jones, Tara/0000-0003-2530-0598 FU Alzheimer's disease Drug Discovery Foundation/Association for Frontotemporal Dementias [P50 AG005134, AG08487]; [K99 AG033670-01A1] FX This work was supported by K99 AG033670-01A1, Alzheimer's disease Drug Discovery Foundation/Association for Frontotemporal Dementias, P50 AG005134, AG08487. NR 34 TC 32 Z9 35 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2011 VL 41 IS 3 BP 650 EP 654 DI 10.1016/j.nbd.2010.11.014 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 718JZ UT WOS:000287118700007 PM 21134458 ER PT J AU Greenberg, SM Frosch, MP AF Greenberg, Steven M. Frosch, Matthew P. TI Life imitates art Anti-amyloid antibodies and inflammatory cerebral amyloid angiopathy SO NEUROLOGY LA English DT Editorial Material ID BETA C1 [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM sgreenberg@partners.org NR 10 TC 13 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 1 PY 2011 VL 76 IS 9 BP 772 EP 773 DI 10.1212/WNL.0b013e31820e7bce PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 728JE UT WOS:000287869600004 PM 21357829 ER PT J AU Gao, XA Chen, HL Schwarzschild, MA Ascherio, A AF Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Ascherio, Alberto TI Use of ibuprofen and risk of Parkinson disease SO NEUROLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NONNARCOTIC ANALGESIC USE; WOMEN; METAANALYSIS; NSAIDS; QUESTIONNAIRE; CONSUMPTION; CAFFEINE; SMOKING; TARGET AB Background: Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies. Methods: We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations. Results: We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42-0.93; p = 0.02). There was a dose-response relationship between tablets of ibuprofen taken per week and PD risk (p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78-1.26), other NSAIDs (RR = 1.26; 95% CI 0.86-1.84), or acetaminophen (RR = 0.86; 95% CI 0.62-1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63-0.85; p < 0.0001) for ibuprofen use, whereas use of other types of analgesics was not associated with lower PD risk. Conclusions: The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD. Neurology (R) 2011; 76: 863-869 C1 [Gao, Xiang; Ascherio, Alberto] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Gao, Xiang] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gao, XA (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM xiang.gao@channing.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU NIH/NINDS [R01 NS048517]; NIH [K24NS060991]; US Department of Defense; Michael J. Fox Foundation; Parkinson Disease Foundation; RJG Parkinson's Disease Foundation; American Parkinson Disease Association; American Federation for Aging Research FX Supported by NIH/NINDS grant R01 NS048517, NIH K24NS060991, and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. None of the sponsors participated in the design of this study or in the collection, analysis, or interpretation of the data.; Dr. Gao has received research support from the NIH/NINDS. Dr. Chen has received intramural funding from the NIH. Dr. Schwarzschild has received research support from the NIH/NINDS, the US Department of Defense, the Michael J. Fox Foundation, the Parkinson Disease Foundation, the RJG Parkinson's Disease Foundation, the American Parkinson Disease Association, and the American Federation for Aging Research. Dr. Ascherio serves on a scientific advisory board for the Michael J. Fox Foundation; serves on the editorial boards of Neurology (R), Annals of Neurology, and the American Journal of Epidemiology; has received speaker honoraria from Merck Serono; and receives research support from the NIH, the US Department of Defense, and the Michael J. Fox Foundation. NR 41 TC 101 Z9 103 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2011 VL 76 IS 10 BP 863 EP 869 DI 10.1212/WNL.0b013e31820f2d79 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 731NZ UT WOS:000288117500007 PM 21368281 ER PT J AU Numis, AL Major, P Montenegro, MA Muzykewicz, DA Pulsifer, MB Thiele, EA AF Numis, A. L. Major, P. Montenegro, M. A. Muzykewicz, D. A. Pulsifer, M. B. Thiele, E. A. TI Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex SO NEUROLOGY LA English DT Article ID MRI FINDINGS; CHILDREN; TSC1; ABNORMALITIES; IMPAIRMENT; MUTATIONS; LOCATION; FAMILIES; EPILEPSY; SEIZURES AB Objective: The purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC). Methods: A total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden. Results: Of the 103 patients with TSC, 40% were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers. Conclusions: The development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed. Neurology (R) 2011;76:981-987 C1 [Numis, A. L.; Major, P.; Muzykewicz, D. A.; Thiele, E. A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychol Assessment Ctr, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Carol & James Herscot Ctr Tuberous Sclerosis Comp, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Carol and James Herscot Center for Tuberous Sclerosis Complex [NIH 5P01NS024279]; Doris Duke Charitable Foundation; Lundbeck Inc.; NIH; Tuberous Sclerosis Alliance; UCB FX Supported by the Carol and James Herscot Center for Tuberous Sclerosis Complex, NIH 5P01NS024279, and the Doris Duke Charitable Foundation (A.L.N.).; Dr. Numis, Dr. Major, Dr. Montenegro, D. A. Muzykewicz, and Dr. Pulsifer report no disclosures. Dr. Thiele serves on the Board of Directors of the Tuberous Sclerosis Alliance and on scientific advisory boards for the Angelman Syndrome Foundation and the Charlie Foundation; serves on the speakers' bureau for and has received funding for travel and speaker honoraria from UCB; serves as a consultant for Lundbeck Inc.; and receives research support from Lundbeck Inc., the NIH, and the Tuberous Sclerosis Alliance. NR 40 TC 71 Z9 72 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2011 VL 76 IS 11 BP 981 EP 987 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 734WK UT WOS:000288371800012 PM 21403110 ER PT J AU Montine, TJ Peskind, ER Quinn, JF Wilson, AM Montine, KS Galasko, D AF Montine, Thomas J. Peskind, Elaine R. Quinn, Joseph F. Wilson, Angela M. Montine, Kathleen S. Galasko, Douglas TI Increased Cerebrospinal Fluid F-2-Isoprostanes are Associated with Aging and Latent Alzheimer's Disease as Identified by Biomarkers SO NEUROMOLECULAR MEDICINE LA English DT Article DE Alzheimer's disease; Cerebrospinal fluid; Biomarkers; A beta(42); Tau; F-2-isoprostanes ID MILD COGNITIVE IMPAIRMENT; IN-VIVO; AMYLOID DEPOSITION; LIPID-PEROXIDATION; OXIDATIVE STRESS; OLDER-ADULTS; BRAIN; AD; F-4-NEUROPROSTANES; NEUROPATHOLOGY AB Alzheimer's disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F-2-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) beta(42) and tau, we defined normality using results from 28 clinically normal individuals < 50 years old, and then stratified 74 clinically normal subjects a parts per thousand yen60 years into those with CSF that had normal CSF A beta(42) and tau (n = 37); abnormal CSF A beta(42) and tau, the biomarker signature of AD (n = 24); decreased A beta(42) only (n = 4); or increased tau only (n = 9). Increased CSF F-2-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F-2-IsoPs for those clinically normal adults with normal CSF (n = 37) and those with abnormal CSF A beta(42) and/or tau (n = 37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F-2-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD. C1 [Montine, Thomas J.; Wilson, Angela M.; Montine, Kathleen S.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Peskind, Elaine R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Peskind, Elaine R.] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Portland, OR USA. [Galasko, Douglas] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Montine, TJ (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98195 USA. EM tmontine@u.washington.edu FU NIH [AG05131, AG05136]; Fidelity Foundation; Nancy and Buster Alvord Endowment FX This work was supported by grants from the NIH (AG05131 and AG05136), the Fidelity Foundation, and the Nancy and Buster Alvord Endowment. NR 41 TC 32 Z9 32 U1 1 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2011 VL 13 IS 1 BP 37 EP 43 DI 10.1007/s12017-010-8126-6 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 726VB UT WOS:000287753400012 PM 20632131 ER PT J AU Ritchey, M Bessette-Symons, B Hayes, SM Cabeza, R AF Ritchey, Maureen Bessette-Symons, Brandy Hayes, Scott M. Cabeza, Roberto TI Emotion processing in the aging brain is modulated by semantic elaboration SO NEUROPSYCHOLOGIA LA English DT Article DE Affective; Valence; Functional MRI; Neuroimaging; Elderly; Levels of processing ID AGE-RELATED DIFFERENCES; EVENT-RELATED FMRI; OLDER-ADULTS; PREFRONTAL CORTEX; FUNCTIONAL NEUROANATOMY; NEURAL MECHANISMS; COGNITIVE CONTROL; NEGATIVE IMAGES; SOURCE MEMORY; ANGRY FACES AB The neural correlates of emotion processing have been shown to vary with age: older adults (OAs) exhibit increased frontal activations and, under some circumstances, decreased amygdala activations relative to young adults (YAs) during emotion processing. Some of these differences are additionally modulated by valence, with age-related biases toward positive versus negative stimuli, and are thought to depend on OAs' capacity for controlled elaboration. However, the role of semantic elaboration in mediating valence effects in the aging brain has not yet been explicitly tested. In the present study, YAs and OAs were scanned while they viewed negative, neutral, and positive pictures during either a deep, elaborative task or a shallow, perceptual task. fMRI results reveal that emotion-related activity in the amygdala is preserved in aging and insensitive to elaboration demands. This study provides novel evidence that differences in valence processing are modulated by elaboration: relative to YAs, OAs show enhanced activity in the medial prefrontal cortex (PFC) and ventrolateral PFC in response to positive versus negative stimuli, but only during elaborative processing. These positive valence effects are predicted by individual differences in executive function in OAs for the deep but not shallow task. Finally, psychophysiological interaction analyses reveal age effects on valence-dependent functional connectivity between medial PFC and ventral striatum, as well as age and task effects on medial PFC-retrosplenial cortex interactions. Altogether, these findings provide support for the hypothesis that valence shifts in the aging brain are mediated by controlled processes such as semantic elaboration, self-referential processing, and emotion regulation. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ritchey, Maureen; Cabeza, Roberto] Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA. [Ritchey, Maureen; Cabeza, Roberto] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27708 USA. [Bessette-Symons, Brandy] Ithaca Coll, Dept Psychol, Ithaca, NY USA. [Hayes, Scott M.] VA Boston Healthcare Syst, Neuroimaging Ctr, Boston, MA USA. [Hayes, Scott M.] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA USA. [Hayes, Scott M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Ritchey, M (reprint author), Duke Univ, Ctr Cognit Neurosci, Box 90999,LSRC Bldg, Durham, NC 27708 USA. EM maureen.ritchey@duke.edu RI Frank, David/E-8213-2012; OI Ritchey, Maureen/0000-0002-5957-3642 FU National Institute on Aging [R01 AG019731, R01 AG23770, R01 AG34580, F32 AG029738]; National Institute of Mental Health [F31 MH085384]; National Institute of Neurological Disorders and Stroke [R01 NS41328] FX This work was supported by the National Institute on Aging [grant numbers R01 AG019731, R01 AG23770, and R01 AG34580 awarded to RC and F32 AG029738 awarded to SMH], the National Institute of Mental Health [F31 MH085384 awarded to MR], and the National Institute of Neurological Disorders and Stroke [R01 NS41328]. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH, NIA, NINDS, or NIMH. NR 65 TC 23 Z9 25 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD MAR PY 2011 VL 49 IS 4 SI SI BP 640 EP 650 DI 10.1016/j.neuropsychologia.2010.09.009 PG 11 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 753GZ UT WOS:000289761600008 PM 20869375 ER PT J AU Morse, L AF Morse, Linda TI Henry Kaplan and the Story of Hodgkin's Disease SO ONCOLOGY NURSING FORUM LA English DT Book Review C1 [Morse, Linda] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. RP Morse, L (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2011 VL 38 IS 2 BP 239 EP 240 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 736DM UT WOS:000288470700019 ER PT J AU Stacy, RC Jakobiec, FA Sutula, FC AF Stacy, Rebecca C. Jakobiec, Frederick A. Sutula, Francis C. TI Recurrent Conjunctival Dermoid Cyst With Reactive Lymphoid Hyperplasia SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID CLASSIFICATION; MANAGEMENT AB Conjunctival dermoid cysts are a rare subtype of dermoid cyst usually presenting in adulthood. The authors report a case of a recurrent conjunctival dermoid cyst with reactive lymphoid hyperplasia that was immunohistochemically demonstrated to be polyclonal. Follicular centers that were present within the cyst wall were negative for Bcl-2 and positive for the immunohistochemical markers CD20, Bcl-6, CD10, and Ki67, which helped to differentiate the lesion from a follicular lymphoma. The lesion did not recur after 14 months of follow-up. C1 [Stacy, Rebecca C.; Jakobiec, Frederick A.; Sutula, Francis C.] Massachusetts Eye & Ear Infirm, Boston, MA 02116 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02116 USA. EM fred_jakobiec@meei.harvard.edu FU Heed Foundation FX Supported in part by the Heed Foundation (to R.C.S.). NR 7 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAR-APR PY 2011 VL 27 IS 2 BP E28 EP E30 DI 10.1097/IOP.0b013e3181c6873a PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 730BL UT WOS:000288003800029 PM 20562661 ER PT J AU Brauner, SC Berry, JL Pye, J Lee, EG Rhee, DJ AF Brauner, Stacey C. Berry, Jesse L. Pye, James Lee, Edwin G. Rhee, Douglas J. TI Effect of Saline Conditions on the Tensile Strength of Ophthalmic Sutures SO OPHTHALMIC SURGERY LASERS & IMAGING LA English DT Article ID ABSORBABLE SUTURES; STRABISMUS SURGERY; MUSCLE SURGERY AB BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the tensile strength of sutures commonly used for ophthalmic surgery and the role of physiologically balanced saline comparable to the ocular environment to material failure. MATERIALS AND METHODS: Ophthalmic sutures (9-0 and 10-0 nylon, 7-0 and 8-0 polyglactin 910, and 10-0 polypropylene) were tested using a tensiometer. Wet conditions were defined by soaking the suture in balanced salt solution for 24 hours or 7 days prior to testing. RESULTS: The 9-0 nylon was approximately 30% stronger than 10-0 nylon (P < .01), whereas 7-0 polyglactin was 60% and 85% stronger than 8-0 polyglactin under dry and 24 hours of wet conditions (P = .0014 and .004), respectively. There was no difference in tensile strength between 10-0 nylon and polypropylene sutures. The 8-0 polyglactin suture lost 11% of tensile strength after 7 days of saline exposure. CONCLUSION: The relative difference of suture strength between the difference gauge sutures is not a simple relationship to differences in the diameter. Tensile strength was not affected by saline conditions for the nylon, polypropylene, and 7-0 polyglactin sutures. The 8-0 polyglactin suture had a decrease in tensile strength after 7 days of exposure to saline. Surgeons should be aware of this limitation with 8-0 polyglactin. C1 [Brauner, Stacey C.; Rhee, Douglas J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Berry, Jesse L.] LAC USC Med Ctr, Doheny Eye Inst, Los Angeles, CA USA. [Pye, James; Lee, Edwin G.] Beaver Visitec Int, Waltham, MA USA. RP Rhee, DJ (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Dougrhee@aol.com OI Berry, Jesse/0000-0002-8907-9100 NR 10 TC 0 Z9 0 U1 0 U2 4 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1542-8877 J9 OPHTHAL SURG LAS IM JI Ophthalmic Surg. Lasers Imaging PD MAR-APR PY 2011 VL 42 IS 2 DI 10.3928/15428877-20101124-01 PG 4 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 959PS UT WOS:000305325900009 ER PT J AU Sun, JK Aiello, LP Cavallerano, JD Stockman, M Miller, KM Qin, HJ Beck, RW Glassman, AR AF Sun, Jennifer K. Aiello, Lloyd Paul Cavallerano, Jerry D. Stockman, Margaret Miller, Kellee M. Qin, Haijing Beck, Roy W. Glassman, Adam R. CA Diabetic Retinopathy Clinical Res TI Visual Acuity Testing Using Autorefraction or Pinhole Occluder Compared with a Manual Protocol Refraction in Individuals with Diabetes SO OPHTHALMOLOGY LA English DT Article ID COMPUTERIZED METHOD; POWER VECTORS; REPEATABILITY; RETINOPATHY; ADAPTATION; ERROR AB Purpose: To compare visual acuity (VA) scores obtained after autorefraction or using a pinhole occluder to scores obtained after refraction according to a standard clinical research protocol. Design: Prospective, comparative case series. Participants: One hundred ten study participants (209 eyes) with diabetes mellitus and a broad range of diabetic retinopathy severity and VA. Methods: We measured VA after autorefraction by a Topcon KR-8000 autorefractor as well as after a Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol manual refraction. The order of testing was randomized and examiners were masked to the source of each refraction. A second VA measurement, utilizing an identical DRCR.net manual refraction, was made in a subset of eyes (n = 144; 69%) to establish test-retest variability for comparison purposes. All eyes underwent VA testing using a pinhole occluder. Main Outcome Measures: Best corrected VA as measured by the Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Test (E-ETDRS). Results: In all eyes, the median E-ETDRS VA letter score (EVA) obtained after manual refraction (MR-EVA) was 69 (Snellen equivalent 20/40), ranging from 4 to 93 (20/800 to 20/16). The median MR-EVA was slightly better than the median EVA obtained after autorefraction (AR-EVA), with a median difference (AR-EVA - MR-EVA) of -1 letter (25th, 75th percentiles, -4, 2 letters). The absolute difference between AR-EVA and MR-EVA was similar to the test-retest variability of MR-EVA alone. In contrast, MR-EVA was better than EVA obtained using a pinhole occluder (PH-EVA; median PH-EVA - MR-EVA, -4 letters [-9, 0]), and had significantly less test-retest variability (P < 0.001). Generally, the spherical equivalent of autorefraction was slightly more hyperopic (or less myopic) than the spherical equivalent of manual refraction (median difference, +0.25 diopters [0, +0.63]). Conclusions: Given the substantial time and effort required for training and certification of study protocol refractionists, and the similarity between AR-EVA and MR-EVA, further evaluation of autorefraction, but not pinhole occluder testing, as an alternative to the current clinical research gold standard of ETDRS protocol manual refraction in study participants with diabetic retinopathy is warranted. C1 [Miller, Kellee M.; Qin, Haijing; Beck, Roy W.; Glassman, Adam R.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Sun, Jennifer K.; Aiello, Lloyd Paul; Cavallerano, Jerry D.; Stockman, Margaret] Harvard Univ, Sch Med, Beetham Eye Inst, Boston, MA USA. [Sun, Jennifer K.; Aiello, Lloyd Paul; Cavallerano, Jerry D.; Stockman, Margaret] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Ophthalmol,Eye Res Sect, Boston, MA 02115 USA. RP Miller, KM (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat4@jaeb.org FU National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [EY14231, EY14229, EY018817] FX Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817. NR 16 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2011 VL 118 IS 3 BP 537 EP 542 DI 10.1016/j.ophtha.2010.07.022 PG 6 WC Ophthalmology SC Ophthalmology GA 729QA UT WOS:000287964400018 PM 20947171 ER PT J AU Litvack, JR Mace, J Smith, TL AF Litvack, Jamie R. Mace, Jess Smith, Timothy L. TI Role of Depression in Outcomes of Endoscopic Sinus Surgery SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE sinusitis; depression; quality of life; disease severity; endoscopic sinus surgery; outcomes ID QUALITY-OF-LIFE; PATIENT HEALTH QUESTIONNAIRE; CHRONIC RHINOSINUSITIS; MYOCARDIAL-INFARCTION; HEART-FAILURE; PRIME-MD; SYMPTOMS; DISEASE; IMPACT; SEVERITY AB Objective. To prospectively measure the prevalence and effect of symptomatic depression on chronic rhinosinusitis (CRS) patients' quality of life (QOL), disease severity, and outcomes of endoscopic sinus surgery (ESS). Study Design. Prospective cohort study. Setting. Academic, tertiary care center. Subjects and Methods. Seventy-six patients with CRS were enrolled prior to ESS and followed postoperatively for a mean (SD) of 13.3 (5.4) months. Lund-Mackay computed tomography score, Lund-Kennedy endoscopy score, Patient Health Questionnaire-9 (PHQ-9), 2 disease-specific QOL instruments (Rhinosinusitis Disability Index [RSDI] and Chronic Sinusitis Survey [CSS]), and 1 general QOL instrument (Medical Outcomes Study Short Form-36 [SF-36]) were measured. Differences in outcome scores were analyzed using univariate and multivariate analyses. Results. Only 7 (9.2%) patients reported a history of depression, but 19 (25.0%) patients scored in the range of moderate or severe depression on the PHQ-9. Mean (SD) preoperative scores were significantly worse in depressed patients on the RSDI (62.7 [18.2] vs 45.3 [16.3]; P < .001) and 7 of 8 SF-36 domains (all P <= .011). Patients with depression significantly improved on both disease-specific QOL instruments (mean [SD] change; RSDI: 33.5 [24.7], P = .017; CSS: 25.0 [20.9], P = .012) and 3 SF-36 domains (all P <= .050). Postoperative change scores were not significantly different from patients without depression on the RSDI, CSS, or SF-36. Severity of depression significantly improved postoperatively in depressed patients (preoperative PHQ-9 scores: 13.4 [2.0] vs 6.1 [4.5], P = .017). Conclusion. CRS patients with depression had worse baseline QOL than other CRS patients but experienced comparable postoperative improvement in QOL after ESS. Interestingly, depression severity significantly improved after ESS. C1 [Mace, Jess; Smith, Timothy L.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Div Rhinol & Sinus Surg, Oregon Sinus Ctr, Portland, OR 97239 USA. [Litvack, Jamie R.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Smith, TL (reprint author), Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Div Rhinol & Sinus Surg, Oregon Sinus Ctr, 3181 SW Sam Jackson Pk Rd,PV-01, Portland, OR 97239 USA. EM smithtim@ohsu.edu FU Oregon Health & Science University [T32 DC5945]; American Academy of Otolaryngology-Head & Neck Surgery Foundation; NIH/NIDCD [R01 DC005805] FX Dr. Litvack was supported by a T32 NIH Training Grant at Oregon Health & Science University during this study (T32 DC5945). Partial funding was supported for this project by the American Academy of Otolaryngology-Head & Neck Surgery Foundation Health Service Research Grant, 2008-09. Dr Smith and Mr Mace were grant funded by the NIH/NIDCD R01 DC005805 (principal investigator: T.L. Smith). NR 27 TC 31 Z9 32 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2011 VL 144 IS 3 BP 446 EP 451 DI 10.1177/0194599810391625 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808RZ UT WOS:000293997400020 PM 21493211 ER PT J AU Morasco, BJ Gritzner, S Lewis, L Oldham, R Turk, DC Dobscha, SK AF Morasco, Benjamin J. Gritzner, Susan Lewis, Lynsey Oldham, Robert Turk, Dennis C. Dobscha, Steven K. TI Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder SO PAIN LA English DT Review DE Chronic pain; Substance use disorder; Treatment outcomes; Opioids; Systematic review; Quality of life ID LOW-BACK-PAIN; CHRONIC NONMALIGNANT PAIN; TERM OPIOID THERAPY; DRUG-RELATED BEHAVIORS; PRIMARY-CARE; IMMPACT RECOMMENDATIONS; MEDICATION MISUSE; CLINICAL-TRIALS; ALCOHOL-ABUSE; RISK-FACTORS AB Recent data suggest that comorbid substance use disorders (SUDs) are common among chronic non-cancer pain (CNCP) patients; however, prevalence rates vary across studies and findings are limited regarding treatment options for CNCP patients with comorbid SUD. The purpose of this systematic review is to assess the prevalence, associated demographic and clinical characteristics, and treatment outcomes for CNCP patients with comorbid SUD. We conducted searches from Ovid MEDLINE, PsychINFO, and PubMED from 1950 through February 2010 and retrieved the references. Thirty-eight studies met inclusion criteria and provided data that addressed our key questions. Three to forty-eight percent of CNCP patients have a current SUD. There are no demographic or clinical factors that consistently differentiate CNCP patients with comorbid SUD from patients without SUD, though SUD patients appear to be at greater risk for aberrant medication-related behaviors. CNCP patients with SUD are more likely to be prescribed opioid medications and at higher doses than CNCP patients without a history of SUD. CNCP patients with comorbid SUD do not significantly differ in their responses to treatment compared to CNCP patients without SUD, though the quality of this evidence is low. Limited data are available to identify predictors of treatment outcome. Although clinical experience and research suggests that SUDs are common among CNCP patients, only limited data are available to guide clinicians who treat this population. Research is needed to increase understanding of the prevalence, correlates, and responses to treatment of CNCP patients with comorbid SUDs. Published by Elsevier B. V. on behalf of International Association for the Study of Pain. C1 [Morasco, Benjamin J.; Gritzner, Susan; Lewis, Lynsey; Oldham, Robert; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Morasco, Benjamin J.; Oldham, Robert; Dobscha, Steven K.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR USA. [Gritzner, Susan] Univ Pacific, Sch Profess Psychol, Stockton, CA 95211 USA. [Turk, Dennis C.] Univ Washington Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA USA. [Dobscha, Steven K.] Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Med & Psychiat, Portland, OR USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr R&D99, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU National Institute on Drug Abuse [K23DA023467]; Endo; Johnson Johnson; Philips Respironics; National Institutes of Health; Eli Lilly; Empi; Pfizer; SK LifeScience FX This study was supported in part by award K23DA023467 from the National Institute on Drug Abuse to Dr. Morasco. During the past 12 months, Dr. Turk has received research support from Endo, Johnson & Johnson, Philips Respironics, and the National Institutes of Health, and consulting fees from Eli Lilly, Empi, Johnson & Johnson, Pfizer, Philips Respironics, and SK LifeScience. He is also a Special Government Employee of the US Food and Drug Administration. We appreciate the assistance of Mark Helfand, M. D., Devan Kansagara, M. D., and Roger Chou, M. D., for help in drafting or editing the key questions, Michele Freeman, M. P. H. for technical assistance, and research librarians Rose Campbell and Andrew Hamilton for developing the literature search strategies. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Department of Veterans Affairs, US Food and Drug Administration, or another private entity. NR 65 TC 48 Z9 50 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD MAR PY 2011 VL 152 IS 3 BP 488 EP 497 DI 10.1016/j.pain.2010.10.009 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 719GZ UT WOS:000287192200009 PM 21185119 ER PT J AU Sosenko, JM Mahon, J Rafkin, L Lachin, JM Krause-Steinrauf, H Krischer, JP Cuthbertson, D Palmer, JP Thompson, C Greenbaum, CJ Skyler, JS AF Sosenko, Jay M. Mahon, Jeffrey Rafkin, Lisa Lachin, John M. Krause-Steinrauf, Heidi Krischer, Jeffrey P. Cuthbertson, David Palmer, Jerry P. Thompson, Clinton Greenbaum, Carla J. Skyler, Jay S. CA Diabet Prevention Trial-Type 1 Grp TrialNet Study Grp TI A comparison of the baseline metabolic profiles between Diabetes Prevention Trial-Type 1 and TrialNet Natural History Study participants SO PEDIATRIC DIABETES LA English DT Article DE C-peptide; glucose; prevention; trials; T1D ID ISLET-CELL ANTIBODIES; INSULIN; MELLITUS; RISK; AUTOANTIBODIES; SPECIFICITIES; RELATIVES; ANTIGEN; ONSET AB Objective: We assessed whether differing autoantibody screening criteria for type 1 diabetes (T1D) prevention trials result in different baseline metabolic profiles of those who screen positive. Methods: Diabetes Prevention Trial-Type 1 (DPT-1) participants were screened for islet cell autoantibodies, whereas TrialNet Natural History Study (TNNHS) participants were screened for biochemical autoantibodies. In both studies, those determined to be autoantibody positive underwent baseline oral glucose tolerance tests (OGTTs) in which glucose and C-peptide were measured. Results: The percentage of those with an OGTT in the diabetic range was higher among the DPT-1 participants (10.0% of 956 vs. 6.4% of 645, p < 0.01). In a logistic regression analysis with adjustments for age and gender, the difference persisted (p < 0.01). Among those in the non-diabetic range (n = 860 for DPT-1 and n = 604 for the TNNHS), glucose levels were similar at all time points, except for higher fasting glucose levels in the TNNHS participants (p < 0.001). There was a higher percentage of impaired fasting glucose (IFG) in the TNNHS participants (10.9 vs. 6.7%, p < 0.01); however, with adjustments for age and gender, there was no longer a significant difference. There was no significant difference in the percentages with impaired glucose tolerance. C-peptide levels were much lower in the DPT-1 cohort at all OGTT time points (p < 0.001 for all). Discussion: Differing criteria for autoantibody screening can result in marked differences in the baseline metabolic profiles of prospective participants of T1D prevention trials. C1 [Sosenko, Jay M.] Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol, Miami, FL 33101 USA. [Mahon, Jeffrey] Univ Western Ontario, Dept Epidemiol & Biostat, London, ON N6A 3K7, Canada. [Lachin, John M.; Krause-Steinrauf, Heidi; Thompson, Clinton] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Krischer, Jeffrey P.] Univ S Florida, Div Informat & Biostat, Tampa, FL USA. [Cuthbertson, David] Univ S Florida, Pediatr Epidemiol Ctr, Tampa, FL USA. [Palmer, Jerry P.] Univ Washington, Div Endocrinol & Metab, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Greenbaum, Carla J.] Benaroya Res Inst, Seattle, WA USA. RP Sosenko, JM (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol, POB 016960, Miami, FL 33101 USA. EM jsosenko@med.miami.edu RI Skyler, Jay/F-4211-2016; OI Lachin, John/0000-0001-9838-2841 FU National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; General Clinical Research Centers; Juvenile Diabetes Research Foundation International; ADA FX TrialNet is funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and General Clinical Research Centers Program; the Juvenile Diabetes Research Foundation International; and the ADA. NR 17 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD MAR PY 2011 VL 12 IS 2 BP 85 EP 90 DI 10.1111/j.1399-5448.2010.00662.x PG 6 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 726DZ UT WOS:000287700300003 PM 20522170 ER PT J AU Rouhani, S Meloney, L Ahn, R Nelson, BD Burke, TF AF Rouhani, Shada Meloney, Laura Ahn, Roy Nelson, Brett D. Burke, Thomas F. TI Alternative Rehydration Methods: A Systematic Review and Lessons for Resource-Limited Care SO PEDIATRICS LA English DT Review DE dehydration; critically ill children; diarrhea; international child health; intravenous rehydration ID INTRAOSSEOUS INFUSION; NASOGASTRIC REHYDRATION; INTRAVENOUS REHYDRATION; ACUTE DIARRHEA; ACUTE GASTROENTERITIS; SEVERE DEHYDRATION; RANDOMIZED-TRIAL; ORAL REHYDRATION; CHILDREN; RESUSCITATION AB OBJECTIVE: Dehydration is a significant threat to the health of children worldwide and a major cause of death in resource-scarce settings. Although multiple studies have revealed that oral and intravenous (IV) methods for rehydration in nonsevere dehydration are nearly equally effective, little is known about effectiveness beyond these 2 techniques. With this systematic review we analyzed the effectiveness of nonoral and nonintravenous methods of rehydration. METHODS: The Medline, Cochrane, Global Health, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases were searched for articles on intraosseous (IO), nasogastric (NG), intraperitoneal (IP), subcutaneous (hypodermoclysis), and rectal (proctoclysis) rehydration through December 2009. Only human pediatric studies that included data on the effectiveness or complications of these methods were included. RESULTS: The search identified 38 articles that met the inclusion criteria: 12 articles on NG, 16 on IO, 7 on IP, 3 on subcutaneous, and none on rectal rehydration. NG rehydration was as effective as IV rehydration for moderate-to-severe dehydration. IO rehydration was effective and easy to obtain, although only 1 randomized trial was identified. IP rehydration had some benefit for moderate dehydration, although none of the trials had control groups. Limited data were available on subcutaneous rehydration, and only 1 case series showed benefit. CONCLUSIONS: NG rehydration should be considered second-line therapy, after oral rehydration, particularly in resource-limited environments. IO rehydration seems to be an effective alternative when IV access is not readily obtainable. Additional evidence is needed before IP and subcutaneous rehydration can be endorsed. Pediatrics 2011;127:e748-e757 C1 [Rouhani, Shada; Meloney, Laura; Ahn, Roy; Nelson, Brett D.; Burke, Thomas F.] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, Boston, MA 02114 USA. [Rouhani, Shada] Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency Progra, Boston, MA 02115 USA. [Ahn, Roy; Burke, Thomas F.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Nelson, Brett D.; Burke, Thomas F.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Nelson, Brett D.; Burke, Thomas F.] MassGen Hosp Children, Div Global Hlth, Boston, MA USA. RP Rouhani, S (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 5 Emerson Pl,Suite 100, Boston, MA 02114 USA. EM srouhani@partners.org OI Nelson, Brett/0000-0002-5049-1798 NR 48 TC 13 Z9 13 U1 1 U2 4 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 MAR PY 2011 VL 127 IS 3 BP E748 EP E757 DI 10.1542/peds.2010-0952 PG 10 WC Pediatrics SC Pediatrics GA 728AI UT WOS:000287845400027 PM 21321023 ER PT J AU Dai, TH Kharkwal, GB Zhao, J St Denis, TG Wu, QH Xia, YM Huang, LY Sharma, SK d'Enfert, C Hamblin, MR AF Dai, Tianhong Kharkwal, Gitika B. Zhao, Jie St Denis, Tyler G. Wu, Qiuhe Xia, Yumin Huang, Liyi Sharma, Sulbha K. d'Enfert, Christophe Hamblin, Michael R. TI Ultraviolet-C Light for Treatment of Candida albicans Burn Infection in Mice SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA; WOUND-INFECTION; MICROORGANISMS; ONYCHOMYCOSIS; COLONIZATION; DISINFECTION; INACTIVATION; BIOFILMS AB Burn patients are at high risk of invasive fungal infections, which are a leading cause of morbidity, mortality, and related expense exacerbated by the emergence of drug resistant fungal strains. In this study, we investigated the use of UVC light (254 nm) for the treatment of yeast Candida albicans infection in mouse third degree burns. In vitro studies demonstrated that UVC could selectively kill the pathogenic C. albicans compared with a normal mouse keratinocyte cell line in a light exposure dependent manner. A mouse model of chronic C. albicans infection in non-lethal third degree burns was developed. The C. albicans strain was stably transformed with a version of the Gaussia princeps luciferase gene that allowed real-time bioluminescence imaging of the progression of C. albicans infection. UVC treatment with a single exposure carried out on day 0 (30 min postinfection) gave an average 2.16-log(10)-unit (99.2%) loss of fungal luminescence when 2.92 J cm-2 UVC had been delivered, while UVC 24 h postinfection gave 1.94-log(10)-unit (95.8%) reduction of fungal luminescence after 6.48 J cm-2. Statistical analysis demonstrated that UVC treatment carried out on both day 0 and day 1 significantly reduced the fungal bioburden of infected burns. UVC was found to be superior to a topical antifungal drug, nystatin cream. UVC was tested on normal mouse skin and no gross damage was observed 24 h after 6.48 J cm-2. DNA lesions (cyclobutane pyrimidine dimers) were observed by immunofluorescence in normal mouse skin immediately after a 6.48 J cm-2 UVC exposure, but the lesions were extensively repaired at 24 h after UVC exposure. C1 [Dai, Tianhong; Kharkwal, Gitika B.; Zhao, Jie; St Denis, Tyler G.; Wu, Qiuhe; Xia, Yumin; Huang, Liyi; Sharma, Sulbha K.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Dai, Tianhong; Kharkwal, Gitika B.; Wu, Qiuhe; Huang, Liyi; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [St Denis, Tyler G.] John Jay High Sch, Cross River, NY USA. [Wu, Qiuhe] Shandong Univ, Jinan Cent Hosp, Jinan 250100, Peoples R China. [Huang, Liyi] Guangxi Med Univ, Affiliated Coll & Hosp 1, Dept Infect Dis, Nanning, Peoples R China. [d'Enfert, Christophe] Unite Biol & Pathogenicite Fong, Paris, France. [d'Enfert, Christophe] USC2019, INRA, Paris, France. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI d'Enfert, Christophe/0000-0002-6235-3886; Hamblin, Michael/0000-0001-6431-4605 FU NIH [RO1 AI050875]; US Air Force [FA9550-04-1-0079]; Bullock-Wellman Fellowship Award; Airlift Research Foundation [109421] FX This work was supported by the NIH (grant RO1 AI050875 to M. R. H.) and US Air Force MFEL Program (FA9550-04-1-0079). T. D. was partially supported by a Bullock-Wellman Fellowship Award and an Airlift Research Foundation Extremity Trauma Research Grant (grant 109421). NR 33 TC 12 Z9 13 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAR-APR PY 2011 VL 87 IS 2 BP 342 EP 349 DI 10.1111/j.1751-1097.2011.00886.x PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 728JU UT WOS:000287871200012 PM 21208209 ER PT J AU Goebel, M Stengel, A Lambrecht, NWG Sachs, G AF Goebel, M. Stengel, A. Lambrecht, N. W. G. Sachs, G. TI Selective gene expression by rat gastric corpus epithelium SO PHYSIOLOGICAL GENOMICS LA English DT Article DE transcriptome; stomach ID PROTEIN DISULFIDE-ISOMERASE; ACID-SECRETION; HELICOBACTER-PYLORI; PARIETAL-CELLS; MESSENGER-RNA; MOLECULAR CHARACTERIZATION; ALCOHOL-DEHYDROGENASE; OXYNTIC MUCOSA; MOUSE STOMACH; ECL CELLS AB Goebel M, Stengel A, Lambrecht NW, Sachs G. Selective gene expression by rat gastric corpus epithelium. Physiol Genomics 43: 237-254, 2011. First published December 21, 2010; doi:10.1152/physiolgenomics.00193.2010.-The gastrointestinal (GI) tract is divided into several segments that have distinct functional properties, largely absorptive. The gastric corpus is the only segment thought of as largely secretory. Microarray hybridization of the gastric corpus mucosal epithelial cells was used to compare gene expression with other segments of the columnar GI tract followed by statistical data subtraction to identify genes selectively expressed by the rat gastric corpus mucosa. This provides a means of identifying less obvious specific functions of the corpus in addition to its secretion-related genes. For example, important properties found by this GI tract comparative transcriptome reflect the energy demand of acid secretion, a role in lipid metabolism, the large variety of resident neuroendocrine cells, responses to damaging agents and transcription factors defining differentiation of its epithelium. In terms of overlap of gastric corpus genes with the rest of the GI tract, the distal small bowel appears to express many of the gastric corpus genes in contrast to proximal small and large bowel. This differential map of gene expression by the gastric corpus epithelium will allow a more detailed description of major properties of the gastric corpus and may lead to the discovery of gastric corpus cell differentiation genes and those mis-regulated in gastric carcinomas. C1 [Goebel, M.; Stengel, A.; Sachs, G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lambrecht, N. W. G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Lambrecht, N. W. G.; Sachs, G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Sachs, G.] W Los Angeles Vet Affairs Med Ctr, Membrane Biol Lab, Los Angeles, CA 90073 USA. RP Lambrecht, NWG (reprint author), VA Long Beach Hlth Care Syst, Bldg 1,Rm 200M,E 7th St 09-113, Long Beach, CA 90822 USA. EM Nils.Lambrecht2@va.gov OI Lambrecht, Nils/0000-0002-1275-1384 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-058333, DK-053642]; US Department of Veterans Affairs; German Research Foundation [STE 1765/1-1, GO 1718/1-1] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-058333 (G. Sachs) and DK-053642 (G. Sachs), the US Department of Veterans Affairs (G. Sachs), and German Research Foundation Grants STE 1765/1-1 (A. Stengel) and Grant GO 1718/1-1 (M. Goebel). NR 92 TC 5 Z9 5 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAR PY 2011 VL 43 IS 5 BP 237 EP 254 DI 10.1152/physiolgenomics.00193.2010 PG 18 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 735ZI UT WOS:000288458900001 PM 21177383 ER PT J AU Kim, S Putrino, D Ghosh, S Brown, EN AF Kim, Sanggyun Putrino, David Ghosh, Soumya Brown, Emery N. TI A Granger Causality Measure for Point Process Models of Ensemble Neural Spiking Activity SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TRAIN DATA-ANALYSIS; SPATIOTEMPORAL CORRELATIONS; STATISTICAL ASSESSMENT; NEURONS; NETWORK; CONNECTIVITY; CORTEX AB The ability to identify directional interactions that occur among multiple neurons in the brain is crucial to an understanding of how groups of neurons cooperate in order to generate specific brain functions. However, an optimal method of assessing these interactions has not been established. Granger causality has proven to be an effective method for the analysis of the directional interactions between multiple sets of continuous-valued data, but cannot be applied to neural spike train recordings due to their discrete nature. This paper proposes a point process framework that enables Granger causality to be applied to point process data such as neural spike trains. The proposed framework uses the point process likelihood function to relate a neuron's spiking probability to possible covariates, such as its own spiking history and the concurrent activity of simultaneously recorded neurons. Granger causality is assessed based on the relative reduction of the point process likelihood of one neuron obtained excluding one of its covariates compared to the likelihood obtained using all of its covariates. The method was tested on simulated data, and then applied to neural activity recorded from the primary motor cortex (MI) of a Felis catus subject. The interactions present in the simulated data were predicted with a high degree of accuracy, and when applied to the real neural data, the proposed method identified causal relationships between many of the recorded neurons. This paper proposes a novel method that successfully applies Granger causality to point process data, and has the potential to provide unique physiological insights when applied to neural spike trains. C1 [Kim, Sanggyun; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Putrino, David; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Ghosh, Soumya] Univ Western Australia, QEII Med Ctr, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia. [Brown, Emery N.] Harvard Univ, MIT, Sch Med, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Kim, S (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM sgkim@neurostat.mit.edu OI Putrino, David/0000-0002-2232-3324 FU NIH [DP1-OD003646, R01-EB006385] FX This work was supported by NIH Grants DP1-OD003646 and R01-EB006385(http://www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 55 Z9 55 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2011 VL 7 IS 3 AR e1001110 DI 10.1371/journal.pcbi.1001110 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 743CU UT WOS:000288995500017 PM 21455283 ER PT J AU Krishnaswamy, P Brown, EN Herr, HM AF Krishnaswamy, Pavitra Brown, Emery N. Herr, Hugh M. TI Human Leg Model Predicts Ankle Muscle-Tendon Morphology, State, Roles and Energetics in Walking SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID SKELETAL-MUSCLE; MOTOR; BIOMECHANICS; ELECTROMYOGRAPHY; EXOSKELETONS; LOCOMOTION; EFFICIENCY; SIGNAL AB A common feature in biological neuromuscular systems is the redundancy in joint actuation. Understanding how these redundancies are resolved in typical joint movements has been a long-standing problem in biomechanics, neuroscience and prosthetics. Many empirical studies have uncovered neural, mechanical and energetic aspects of how humans resolve these degrees of freedom to actuate leg joints for common tasks like walking. However, a unifying theoretical framework that explains the many independent empirical observations and predicts individual muscle and tendon contributions to joint actuation is yet to be established. Here we develop a computational framework to address how the ankle joint actuation problem is resolved by the neuromuscular system in walking. Our framework is founded upon the proposal that a consideration of both neural control and leg muscle-tendon morphology is critical to obtain predictive, mechanistic insight into individual muscle and tendon contributions to joint actuation. We examine kinetic, kinematic and electromyographic data from healthy walking subjects to find that human leg muscle-tendon morphology and neural activations enable a metabolically optimal realization of biological ankle mechanics in walking. This optimal realization (a) corresponds to independent empirical observations of operation and performance of the soleus and gastrocnemius muscles, (b) gives rise to an efficient load-sharing amongst ankle muscle-tendon units and (c) causes soleus and gastrocnemius muscle fibers to take on distinct mechanical roles of force generation and power production at the end of stance phase in walking. The framework outlined here suggests that the dynamical interplay between leg structure and neural control may be key to the high walking economy of humans, and has implications as a means to obtain insight into empirically inaccessible features of individual muscle and tendons in biomechanical tasks. C1 [Krishnaswamy, Pavitra; Brown, Emery N.; Herr, Hugh M.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Herr, Hugh M.] MIT, Media Lab, Cambridge, MA 02139 USA. RP Krishnaswamy, P (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM hherr@mit.edu FU NIH [DP1 OD003646]; MIT Media Lab [2736448, 6895867] FX This work was supported by the NIH Pioneer Award DP1 OD003646 (to ENB) and the MIT Media Lab (Consortia Accounts 2736448 and 6895867). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 14 Z9 14 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2011 VL 7 IS 3 AR e1001107 DI 10.1371/journal.pcbi.1001107 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 743CU UT WOS:000288995500014 PM 21445231 ER PT J AU Neale, BM Rivas, MA Voight, BF Altshuler, D Devlin, B Orho-Melander, M Kathiresan, S Purcell, SM Roeder, K Daly, MJ AF Neale, Benjamin M. Rivas, Manuel A. Voight, Benjamin F. Altshuler, David Devlin, Bernie Orho-Melander, Marju Kathiresan, Sekar Purcell, Shaun M. Roeder, Kathryn Daly, Mark J. TI Testing for an Unusual Distribution of Rare Variants SO PLOS GENETICS LA English DT Article ID AMINO-ACID SUBSTITUTIONS; GENOME-WIDE ASSOCIATION; COMMON DISEASES; PLASMA-LEVELS; CHOLESTEROL; ALLELES; PCSK9; POLYMORPHISMS; MUTATIONS; GENES AB Technological advances make it possible to use high-throughput sequencing as a primary discovery tool of medical genetics, specifically for assaying rare variation. Still this approach faces the analytic challenge that the influence of very rare variants can only be evaluated effectively as a group. A further complication is that any given rare variant could have no effect, could increase risk, or could be protective. We propose here the C-alpha test statistic as a novel approach for testing for the presence of this mixture of effects across a set of rare variants. Unlike existing burden tests, C-alpha, by testing the variance rather than the mean, maintains consistent power when the target set contains both risk and protective variants. Through simulations and analysis of case/control data, we demonstrate good power relative to existing methods that assess the burden of rare variants in individuals. C1 [Neale, Benjamin M.; Rivas, Manuel A.; Voight, Benjamin F.; Kathiresan, Sekar; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Rivas, Manuel A.; Voight, Benjamin F.; Altshuler, David; Kathiresan, Sekar; Purcell, Shaun M.; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Devlin, Bernie] Univ Pittsburgh Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Orho-Melander, Marju] Malmo Univ Hosp, Dept Clin Sci Malmo Diabet & Cardiovasc Dis, Genet Epidemiol CRC, Malmo, Sweden. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Purcell, Shaun M.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. RP Neale, BM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM bneale@broadinstitute.org; Kathryn.roeder@gmail.com; mjdaly@chgr.mgh.harvard.edu RI Voight, Benjamin/F-1775-2011; Sincan, Murat /A-3794-2010; Altshuler, David/A-4476-2009 OI Altshuler, David/0000-0002-7250-4107 FU NIH [HL087676, EY11309, NS059727, DK072041]; NIH/NEIHS [NS059727]; NIH/NHBLI [HL087676, DK072041]; NIH/NIMH [NS059727, MH057881, MH089025, MH089208]; Autism Speaks FX This work was supported by NIH grants HL087676, EY11309, NS059727, and DK072041; NIH/NEIHS grant NS059727; NIH/NHBLI grants DK072041 and HL087676; NIH/NIMH grants NS059727, MH057881, MH089025, and MH089208; and Autism Speaks grant for the Autism Genome Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 258 Z9 269 U1 4 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2011 VL 7 IS 3 AR e1001322 DI 10.1371/journal.pgen.1001322 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 743DD UT WOS:000288996600004 PM 21408211 ER PT J AU Speliotes, EK Yerges-Armstrong, LM Wu, J Hernaez, R Kim, LJ Palmer, CD Gudnason, V Eiriksdottir, G Garcia, ME Launer, LJ Nalls, MA Clark, JM Mitchell, BD Shuldiner, AR Butler, JL Tomas, M Hoffmann, U Hwang, SJ Massaro, JM O'Donnell, CJ Sahani, DV Salomaa, V Schadt, EE Schwartz, SM Siscovick, DS Voight, BF Carr, JJ Feitosa, MF Harris, TB Fox, CS Smith, AV Kao, WHL Hirschhorn, JN Borecki, IB AF Speliotes, Elizabeth K. Yerges-Armstrong, Laura M. Wu, Jun Hernaez, Ruben Kim, Lauren J. Palmer, Cameron D. Gudnason, Vilmundur Eiriksdottir, Gudny Garcia, Melissa E. Launer, Lenore J. Nalls, Michael A. Clark, Jeanne M. Mitchell, Braxton D. Shuldiner, Alan R. Butler, Johannah L. Tomas, Marta Hoffmann, Udo Hwang, Shih-Jen Massaro, Joseph M. O'Donnell, Christopher J. Sahani, Dushyant V. Salomaa, Veikko Schadt, Eric E. Schwartz, Stephen M. Siscovick, David S. Voight, Benjamin F. Carr, J. Jeffrey Feitosa, Mary F. Harris, Tamara B. Fox, Caroline S. Smith, Albert V. Kao, W. H. Linda Hirschhorn, Joel N. Borecki, Ingrid B. CA NASH CRN GIANT Consortium MAGIC Investigators GOLD Consortium TI Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits SO PLOS GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; TRIGLYCERIDE LEVELS; LOCI; HEART; RISK; DESIGN; ADULTS; STEATOHEPATITIS; PNPLA3; SUSCEPTIBILITY AB Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (similar to 26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and similar to 2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<56 10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. C1 [Speliotes, Elizabeth K.; Butler, Johannah L.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.; Butler, Johannah L.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Speliotes, Elizabeth K.; Voight, Benjamin F.; Hirschhorn, Joel N.] Broad Inst, Cambridge, MA USA. [Yerges-Armstrong, Laura M.; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD USA. [Wu, Jun; Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Hernaez, Ruben; Clark, Jeanne M.; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hernaez, Ruben; Clark, Jeanne M.] Johns Hopkins Univ Hosp, Div Gen Internal Med, Baltimore, MD 21287 USA. [Hernaez, Ruben] Washington Hosp Ctr, Dept Internal Med, Washington, DC USA. [Kim, Lauren J.; Garcia, Melissa E.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Palmer, Cameron D.; Butler, Johannah L.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Butler, Johannah L.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.; Butler, Johannah L.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Gudnason, Vilmundur; Eiriksdottir, Gudny; Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Clark, Jeanne M.; Kao, W. H. Linda] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, GRECC, Baltimore, MD 21218 USA. [Tomas, Marta] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Tomas, Marta] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Hoffmann, Udo; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Salomaa, Veikko] Natl Publ Hlth Inst, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Schadt, Eric E.] Pacific Biosci, Menlo Pk, CA USA. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Carr, J. Jeffrey] Wake Forest Univ Sch Med, Dept Radiol Sci, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Speliotes, EK (reprint author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM espeliot@med.umich.edu; iborecki@wustl.edu RI Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Macciardi, Fabio/N-3768-2014; Aben, Katja/G-9686-2016; Carr, John/A-1938-2012; Smith, Albert/K-5150-2015; kinnunen, leena/B-7059-2012; Bochud, Murielle/A-3981-2010; Visvikis-Siest, Sophie/H-2324-2014; Schwarz, Peter/B-5127-2013; Naitza, Silvia/D-5620-2017; Feitosa, Mary/K-8044-2012; Colaus, PsyColaus/K-6607-2013; Hernaez, Ruben/C-4039-2014; Kiemeney, Lambertus/D-3357-2009; Singleton, Andrew/C-3010-2009; Voight, Benjamin/F-1775-2011; Brunner, Eric/H-2114-2011; Ridderstrale, Martin/F-7678-2012; Elliott, Amanda/G-5120-2012; Rudan, Igor/I-1467-2012; Palmer, Lyle/K-3196-2014; Witte, Daniel/C-1722-2008; Gudnason, Vilmundur/K-6885-2015; OI Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Prokopenko, Inga/0000-0003-1624-7457; Macciardi, Fabio/0000-0003-0537-4266; Aben, Katja/0000-0002-0214-2147; Carr, John/0000-0002-4398-8237; Smith, Albert/0000-0003-1942-5845; kinnunen, leena/0000-0001-8739-4812; Bochud, Murielle/0000-0002-5727-0218; Visvikis-Siest, Sophie/0000-0001-8104-8425; Schwarz, Peter/0000-0001-6317-7880; Feitosa, Mary/0000-0002-0933-2410; Seedorf, Udo/0000-0003-4652-5358; Massaro, Joseph/0000-0002-2682-4812; Thiering, Elisabeth/0000-0002-5429-9584; Lango Allen, Hana/0000-0002-7803-8688; Willems van Dijk, Ko/0000-0002-2172-7394; Esko, Tonu/0000-0003-1982-6569; Pichler, Irene/0000-0001-8251-0757; Magi, Reedik/0000-0002-2964-6011; Kivimaki, Mika/0000-0002-4699-5627; Hernaez, Ruben/0000-0002-1518-4020; Kiemeney, Lambertus/0000-0002-2368-1326; Rudan, Igor/0000-0001-6993-6884; Palmer, Lyle/0000-0002-1628-3055; Witte, Daniel/0000-0002-0769-2922; Gudnason, Vilmundur/0000-0001-5696-0084; Zgaga, Lina/0000-0003-4089-9703; Zeggini, Eleftheria/0000-0003-4238-659X; Luben, Robert/0000-0002-5088-6343; Scherag, Andre/0000-0002-9406-4704; Melzer, David/0000-0002-0170-3838; Forouhi, Nita/0000-0002-5041-248X; John, Ulrich/0000-0003-0587-5298; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Visscher, Peter/0000-0002-2143-8760; Marmot, Michael/0000-0002-2431-6419; Mitchell, Braxton/0000-0003-4920-4744; Ouwehand, Willem/0000-0002-7744-1790; Lawlor, Debbie A/0000-0002-6793-2262; Johansson, Asa/0000-0002-2915-4498; de Geus, Eco/0000-0001-6022-2666 FU NIH [T32 DK07191-32, F32 DK079466-01, NIH K23DK080145-01, R01DK075787, N01-AG-12100, K01 DK067207, R01 AG18728, R01HL088119, U01 HL72515, U01 HL084756, T32AG000262, F32AR059469]; Icelandic Heart Association; Althingi (the Icelandic Parliament); Diabetes Research and Training Center of Maryland [P60 DK079637]; Nutrition and Obesity Research Center of Maryland [P30DK072488]; American Diabetes Association [7-07-MN-08]; NIDDK [R01DK075681]; NHLBI [R01HL087700]; National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713]; General Clinical Research Centers or Clinical and Translational Science [UL1RR024989, M01RR000750, M01RR00188, ULRR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359]; US National Institutes of Health (NIH); National Heart, Lung, and Blood Institute; Generalitat de Catalunya [2007BP-B100068]; Red HERACLES, ISCIII [RD06/0009] FX This work was partially supported by NIH grants T32 DK07191-32 to Daniel Podolsky (for EKS), F32 DK079466-01 to EKS, NIH K23DK080145-01 to EKS, and R01DK075787 to JNH. The AGES-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Old Order Amish Study was supported by NIH research grants K01 DK067207, R01 AG18728, R01HL088119, U01 HL72515, and U01 HL084756. Partial funding was also provided by the Diabetes Research and Training Center of Maryland (P60 DK079637) and the Nutrition and Obesity Research Center of Maryland (P30DK072488). LMY-A was supported by NIH training grants T32AG000262 and F32AR059469. RH was supported by the American Diabetes Association Mentor-Based Postdoctoral Fellowship Program (7-07-MN-08). The NHLBI Family Heart Study was supported by NIDDK R01DK075681 (to IBB) and NHLBI R01HL087700. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Several clinical centers use support from General Clinical Research Centers or Clinical and Translational Science Awards in conduct of NASH CRN Studies (grants UL1RR024989, M01RR000750, M01RR00188, ULRR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359). The MIGen study was funded by the US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute's STAMPEED genomics research program. MT was supported by the Beatriu de Pinos postdoctoral fellowship, Generalitat de Catalunya (2007BP-B100068, MT), and Red HERACLES, ISCIII (RD06/0009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 266 Z9 275 U1 2 U2 49 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2011 VL 7 IS 3 AR e1001324 DI 10.1371/journal.pgen.1001324 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 743DD UT WOS:000288996600006 PM 21423719 ER PT J AU Colantonio, AD Bimber, BN Neidermyer, WJ Reeves, RK Alter, G Altfeld, M Johnson, RP Carrington, M O'Connor, DH Evans, DT AF Colantonio, Arnaud D. Bimber, Benjamin N. Neidermyer, William J., Jr. Reeves, R. Keith Alter, Galit Altfeld, Marcus Johnson, R. Paul Carrington, Mary O'Connor, David H. Evans, David T. TI KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand with a Bw6 Motif SO PLOS PATHOGENS LA English DT Article ID NATURAL-KILLER-CELLS; IMMUNOGLOBULIN-LIKE RECEPTOR; SIMIAN IMMUNODEFICIENCY VIRUS; SELECTIVE DOWN-REGULATION; HLA-B; INHIBITORY RECEPTORS; RHESUS MACAQUES; CRYSTAL-STRUCTURE; CUTTING EDGE; HEPATITIS-C AB Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05(+) macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets. C1 [Colantonio, Arnaud D.; Neidermyer, William J., Jr.; Evans, David T.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. [Bimber, Benjamin N.; O'Connor, David H.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Dept Pathol & Lab Med, Madison, WI USA. [Reeves, R. Keith; Johnson, R. Paul] New England Primate Res Ctr, Div Immunol, Southborough, MA USA. [Alter, Galit; Altfeld, Marcus; Johnson, R. Paul; Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Alter, Galit; Altfeld, Marcus; Johnson, R. Paul; Carrington, Mary] Harvard Univ, Boston, MA 02115 USA. [Carrington, Mary] NCI Frederick, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. RP Colantonio, AD (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. EM devans@hms.harvard.edu OI o'connor, david/0000-0003-2139-470X FU Public Health Service [AI063993, AI071306, RR000168]; Elizabeth Glaser Pediatric AIDS Foundation; NIH [HHSN261200800001E] FX This work was supported by Public Health Service grants AI063993, AI071306 and RR000168. DTE is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation. This project was also supported in part by intramural NIH funding to the NCI under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 24 Z9 25 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2011 VL 7 IS 3 AR e1001316 DI 10.1371/journal.ppat.1001316 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 743CQ UT WOS:000288994900010 PM 21423672 ER PT J AU Chan, WM Dicianno, BE AF Chan, Wendy M. Dicianno, Brad E. TI Virtual Socialization in Adults With Spina Bifida SO PM&R LA English DT Article ID QUALITY-OF-LIFE; YOUNG-ADULTS; HYDROCEPHALUS; ADOLESCENTS; ADJUSTMENT; DISABILITY; MOBILITY; CHILDREN; HEALTH; WORLD AB Objective: To use spina bifida (SB) as a model of chronic physical disability to study the associations of virtual socialization, friendships, and quality of life (QOL) in adults. Design: Cross-sectional survey. Setting: Subjects were recruited from residential living facilities, outpatient clinics, and the University of Pittsburgh Medical Center (UPMC) research registry. Patients: Inclusion criteria were age between 18 and 80 years and clinical diagnoses of SB cystica (myelomeningocele) and hydrocephalus. The exclusion criterion was the diagnosis of SB occulta. Sixty-three eligible adults were enrolled, and all completed the study. Methods: The survey via questionnaire was performed in person or over the telephone. Main Outcome Measurements: Data collected included the World Health Organization's Medical Outcomes Study 26-item Short Form, Economic Self-Sufficiency from the Craig Handicap Assessment and Reporting Technique Short Form, virtual socializing habits, and number of friends. Three linear regression models were performed, each with a unique dependent variable: number of friends, psychological QOL, or social QOL. The following independent variables were included in all models: age, gender, ethnicity, economic self-sufficiency, marital status, education level, lesion level, health status, user group, collection method, and time spent virtually socializing. In addition, each regression model included the dependent variables from the other 2 models in its independent variables. Results: Increased degree of virtual socialization (VS) was associated with a greater number of friends (P = .003, r = .684). Mean (standard deviation) numbers of friends by VS groups were the following: users, n = 4.9 +/- 2.7; semi-users, n = 3.8 +/- 2.7; and nonusers, n = 2.1 +/- 2.3, which represent a 2.3 times greater number of friends between the users and nonusers. The effect of virtual socialization on QOL was also positive, however, not statistically significant. Conclusions: People with chronic physical disabilities, such as SB, are at high risk for peer rejection and long-term social avoidance. Users of the most immersive forms of virtual socialization, have more real world friends than both semi-users and nonusers. Any form of VS, whether immersive or real time, may improve the opportunity for meaningful social encounters. Prospective intervention studies are needed to elucidate whether a causal positive relationship between virtual socialization and friendships exists. Further research is needed to clarify virtual socialization's impact on QOL; however, the upward trend in all 4 domains of QOL across user groups suggests similar potential benefits. PM R 2011;3:219-225 C1 [Dicianno, Brad E.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Adult Spina Bifida Clin, Pittsburgh, PA 15260 USA. [Dicianno, Brad E.] VA Pittsburgh HealthCare Syst, Pittsburgh, PA USA. [Chan, Wendy M.] SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. RP Dicianno, BE (reprint author), Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Adult Spina Bifida Clin, 201 Kaufmann Bldg,3471 5th Ave, Pittsburgh, PA 15260 USA. EM dicianno@pitt.edu OI Dicianno, Brad/0000-0003-0738-0192 FU Human Engineering Research Laboratories FX This research benefited from the support of Annmarie Kelleher MS, OTR/L, ATP, CCRP, and Stacy Eckstein BS, MT(ASCP) from the Human Engineering Research Laboratories. NR 38 TC 4 Z9 4 U1 3 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD MAR PY 2011 VL 3 IS 3 BP 219 EP 225 DI 10.1016/j.pmrj.2010.12.002 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961AX UT WOS:000305437400006 PM 21402368 ER PT J AU Nguyen, RT Borg-Stein, J McInnis, K AF Nguyen, Rosalyn T. Borg-Stein, Joanne McInnis, Kelly TI Applications of Platelet-Rich Plasma in Musculoskeletal and Sports Medicine: An Evidence-Based Approach SO PM&R LA English DT Review ID ANTERIOR CRUCIATE LIGAMENT; AUTOLOGOUS BLOOD INJECTION; TOTAL KNEE ARTHROPLASTY; BIODEGRADABLE GELATIN HYDROGEL; RANDOMIZED CONTROLLED-TRIAL; HEPATOCYTE GROWTH-FACTOR; HUMAN ENDOTHELIAL-CELLS; IN-VITRO; CONDITIONED SERUM; ACHILLES-TENDON AB This article aims to provide a comprehensive review of the current literature that pertains to the therapeutic use of autologous platelet-rich plasma (PRP). The basic science literature regarding the role of growth factors in mediating the healing process and the laboratory data from in vitro and in vivo studies that evaluated PRP are reviewed. Subsequently, the current evidence regarding PRP efficacy from animal models, human surgical studies, and human clinical studies is presented. A critical analysis of the literature follows, and the article concludes with the authors' perspectives on the state of PRP as a potentially efficacious bioregenerative treatment option for musculoskeletal and sports medicine applications. The relevant articles in this review were obtained via PubMed literature searches for PRP publications that pertain to musculoskeletal and sports medicine conditions. This article is not intended to be a formal meta-analysis. PM R 2011;3:226-250 C1 [Nguyen, Rosalyn T.] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Newton Wellesley Hosp,Dept Phys Med & Rehabil, Boston, MA 02115 USA. [Nguyen, Rosalyn T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Borg-Stein, Joanne] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Wellesley & Newton Wellesley Hosp, Wellesley, MA USA. [McInnis, Kelly] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Sachusetts Gen Hosp, Boston, MA USA. RP Nguyen, RT (reprint author), Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Newton Wellesley Hosp,Dept Phys Med & Rehabil, Boston, MA 02115 USA. EM rtnsportsmd@gmail.com NR 118 TC 45 Z9 49 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD MAR PY 2011 VL 3 IS 3 BP 226 EP 250 DI 10.1016/j.pmrj.2010.11.007 PG 25 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961AX UT WOS:000305437400007 PM 21402369 ER PT J AU Hiratsuka, S Goel, S Kamoun, WS Maru, Y Fukumura, D Duda, DG Jain, RK AF Hiratsuka, Sachie Goel, Shom Kamoun, Walid S. Maru, Yoshiro Fukumura, Dai Duda, Dan G. Jain, Rakesh K. TI Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE metastasis; permeability ID GROWTH-FACTOR; BONE-MARROW; METASTASIS FORMATION; BREAST-CANCER; MYELOID CELLS; IN-VIVO; ANGIOGENESIS; MICE; VEGF; INFLAMMATION AB Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs. C1 [Hiratsuka, Sachie; Goel, Shom; Kamoun, Walid S.; Fukumura, Dai; Duda, Dan G.; Jain, Rakesh K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab Tumor Biol,Dept Radiat Oncol, Boston, MA 02114 USA. [Maru, Yoshiro] Tokyo Womens Med Univ, Dept Pharmacol, Tokyo 1628666, Japan. RP Fukumura, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab Tumor Biol,Dept Radiat Oncol, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu; duda@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu FU Dyax; AstraZeneca; MedImmune; AstraZeneca/MedImmune; Astellas-Fibrogen; SynDevRx; Regeneron; Genzyme; Morphosys; Noxxon Pharma; National Institutes of Health [R01-CA085140, R01-CA115767, P01-CA080124, R01-CA126642]; Federal Share/National Cancer Institute; R01-CA096915; The Scholarship Fund; Fulbright Postgraduate Award; American Society of Clinical Oncology; Susan G. Komen Postdoctoral Research Fellowship; Department of Defence [W81XWH-10-1-0016] FX R.K.J. received commercial research grants from Dyax, AstraZeneca, and MedImmune; consultant fees from AstraZeneca/MedImmune, Dyax, Astellas-Fibrogen, SynDevRx, Regeneron, Genzyme, Morphosys, and Noxxon Pharma; and a speaker honorarium from Genzyme. R.K.J. owns stock in SynDevRx. No reagents or funding from these companies was used in these studies. There is no significant financial or other competing interest in the work.; We thank B. Seed and I. Garkavstev for helpful comments; L. Benjamin for providing VE-cadherin-tTA mice; R. Lee for providing the FRNK vector; L. Wu for help with transgenic mice; M. Dawson, P. Huang, M. Lee, C. Smith, and K. Kinzel for help in performing these experiments; and M. Ancukiewicz for statistical analysis. This study was supported by National Institutes of Health Grants R01-CA085140, R01-CA115767, P01-CA080124, R01-CA126642, and Federal Share/National Cancer Institute Proton Beam Program Income (to R.K.J.), and R01-CA096915 (to D.F.). S.H. is supported by The Scholarship Fund to Study Abroad, Japan. S.G. is supported by a Fulbright Postgraduate Award and an American Society of Clinical Oncology Young Investigator Award. W.S.K. is the recipient of a Susan G. Komen Postdoctoral Research Fellowship. R.K.J. is the recipient of the Department of Defence Breast Cancer Research Innovator Award W81XWH-10-1-0016. NR 43 TC 48 Z9 50 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 MAR 1 PY 2011 VL 108 IS 9 BP 3725 EP 3730 DI 10.1073/pnas.1100446108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 728AD UT WOS:000287844400054 PM 21321210 ER PT J AU Reddy, R Fleet-Michaliszyn, S Condray, R Yao, JK Keshavan, MS Reddy, R AF Reddy, R. Fleet-Michaliszyn, S. Condray, R. Yao, J. K. Keshavan, M. S. Reddy, R. TI Reduction in perseverative errors with adjunctive ethyl-eicosapentaenoic acid in patients with schizophrenia: Preliminary study SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Schizophrenia; Omega-3 fatty acid; Eicosapentaenoic acid; WCST; Executive function ID PLACEBO-CONTROLLED TRIAL; CELL MEMBRANE DYNAMICS; COGNITIVE DYSFUNCTION; FATTY-ACIDS; ANTIPSYCHOTIC MEDICATIONS; 1ST-EPISODE SCHIZOPHRENIA; NEUROCOGNITIVE DEFICITS; MEMORY PERFORMANCE; EXECUTIVE FUNCTION; OMEGA-3-FATTY-ACIDS AB Introduction: Patients with schizophrenia have significant cognitive deficits, generally resistant to conventional treatment. This preliminary study examined the effects of ethyl-eicosapentanoate (EPA) on an executive function in early course patients. Patients and methods: Patients with schizophrenia were given, after an informed consent, 2 g of an EPA daily for 24 weeks, in an open-label study. The Wisconsin Card Sort Test (WCST) was administered at baseline, weeks 4, 12 and 24. Results: The 27 patients, with a mean duration of illness of 4.2 years, were all receiving atypical antipsychotics; treatment remained unchanged for the study. Perseverative errors - the key measure derived from WCST - were significantly reduced from the baseline mean of 28.2 to 18.4 errors at week 24. Positive symptoms also improved significantly. There were no correlations between EPA levels and any clinical or other neuropsychological measures. Conclusion: These findings suggest that an EPA has procognitive effects for patients with schizophrenia, but controlled trials are required. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Reddy, R.; Condray, R.; Yao, J. K.; Reddy, R.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Reddy, R.] Univ Toledo, Sch Med, Toledo, OH 43606 USA. [Fleet-Michaliszyn, S.] Univ Arizona, Tucson, AZ USA. [Condray, R.; Yao, J. K.; Reddy, R.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Keshavan, M. S.] Harvard Univ, Boston, MA 02115 USA. RP Reddy, R (reprint author), Univ Pittsburgh, 3811 OHara St, Pittsburgh, PA 15213 USA. EM reddyr@upmc.edu FU NIMH [MH-46118, MH-58141, MH-45203]; VA Research Career Scientist Award; NIH/NCRR/GCRC [M01 RR00056] FX Sources of support: this publication was supported by funds received from NIMH Grants MH-46118 (RR), MH-58141 (JKY) and MH-45203 (MSK), VA Research Career Scientist Award (JKY), and the NIH/NCRR/GCRC Grant #M01 RR00056. NR 54 TC 9 Z9 9 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 EI 1532-2823 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD MAR-APR PY 2011 VL 84 IS 3-4 BP 79 EP 83 DI 10.1016/j.plefa.2010.12.001 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 727EJ UT WOS:000287780100002 PM 21211955 ER PT J AU Hermanrud, CE Lucas, CL Sykes, M Huang, CA Wang, ZR AF Hermanrud, Christina E. Lucas, Carrie L. Sykes, Megan Huang, Christene A. Wang, Zhirui TI Expression and purification of soluble murine CD40L monomers and polymers in yeast Pichia pastoris SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Murine CD40L; Pichia pastoris; Yeast expression; Purification ID T CELL IMMUNOTOXIN; LIGAND; RECIPIENTS; TRIMER AB The anti-murine CD40L monoclonal antibody MR1 has been widely used in immunology research to block the CD40-CD40L interaction for induction of transplantation tolerance and to abrogate autoimmune diseases. The availability of recombinant CD40L with high binding capacity for MR1 would provide a valuable immunologic research tool. In this study, we constructed the single chain murine soluble CD40L monomer, dimer, trimer and successfully expressed them in yeast Pichia pastoris under the control of the alcohol oxidase promoter. The secreted single chain murine soluble CD40L monomers, dimers, and trimers were initially enriched through histidine tag capture by Ni-Sepharose 6 fast flow resin and further purified on a cation exchange resin. Purity reached more than 95% for the monomer and dimer forms and more than 90% for the trimer. Protein yield following purification was 16 mg/L for the monomer and dimer, and 8 mg/L for the trimer. ELISA analysis demonstrated that the CD40L dimers and trimers correctly folded in conformations exposing the MR1 antigenic determinant. (C) 2010 Elsevier Inc. All rights reserved. C1 [Huang, Christene A.] Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Sch Med,MGH E, Boston, MA 02129 USA. [Hermanrud, Christina E.; Huang, Christene A.; Wang, Zhirui] MGH DF HCC Recombinant Prot Express & Purificat C, Boston, MA USA. RP Huang, CA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Sch Med,MGH E, Bldg 149-6117C,13th St, Boston, MA 02129 USA. EM christene.huang@tbrc.mgh.harvard.edu; zhirui.wang@tbrc.mgh.harvard.edu FU Massachusetts General Hospital (MGH); Department of Surgery; Amelia Peabody Foundation; MGH Executive Committee on Research; Dana-Farber/Harvard Cancer Center (DF/HCC); NIH [R01HL049915] FX The authors would like to gratefully acknowledge the Massachusetts General Hospital (MGH), Department of Surgery, Amelia Peabody Foundation and MGH Executive Committee on Research for equipment funding; and the Dana-Farber/Harvard Cancer Center (DF/HCC) for start up funds to establish a new Recombinant Protein Expression and Purification (RPrEP) Core Facility. We also acknowledge the support and guidance of Dr. David H. Sachs, Scientific Co-Director of the newly formed DF/HCC RPrEP Core Facility at MGH. The work was supported by NIH Grant R01HL049915 (MS). NR 19 TC 4 Z9 4 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2011 VL 76 IS 1 BP 115 EP 120 DI 10.1016/j.pep.2010.11.006 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 705WH UT WOS:000286170900017 PM 21074618 ER PT J AU Rajagopal, MU Hathout, Y MacDonald, TJ Kieran, MW Gururangan, S Blaney, SM Phillips, P Packer, R Gordish-Dressman, H Rood, BR AF Rajagopal, Meena U. Hathout, Yetrib MacDonald, Tobey J. Kieran, Mark W. Gururangan, Sri Blaney, Susan M. Phillips, Peter Packer, Roger Gordish-Dressman, Heather Rood, Brian R. TI Proteomic profiling of cerebrospinal fluid identifies prostaglandin D2 synthase as a putative biomarker for pediatric medulloblastoma: A pediatric brain tumor consortium study SO PROTEOMICS LA English DT Article DE 2-DE; Biomedicine; CSF proteomics; Medulloblastoma; Prostaglandin synthase ID CENTRAL-NERVOUS-SYSTEM; BETA-TRACE PROTEIN; BIOLOGICAL VARIATION; MASS-SPECTROMETRY; APOLIPOPROTEIN-E; CANCER; QUANTIFICATION; CLUSTERIN; MARKER; CSF AB The aims of this study were to demonstrate the feasibility of centrally collecting and processing high-quality cerebrospinal fluid (CSF) samples for proteomic studies within a multi-center consortium and to identify putative biomarkers for medulloblastoma in CSF. We used 2-DE to investigate the CSF proteome from 33 children with medulloblastoma and compared it against the CSF proteome from 25 age-matched controls. Protein spots were subsequently identified by a combination of in-gel tryptic digestion and MALDI-TOF TOF MS analysis. On average, 160 protein spots were detected by 2-DE and 76 protein spots corresponding to 25 unique proteins were identified using MALDI-TOF. Levels of prostaglandin D2 synthase (PGD2S) were found to be six-fold decreased in the tumor samples versus control samples (p < 0.00001). These data were further validated using ELISA. Close examination of PGD2S spots revealed the presence of complex sialylated carbohydrates at residues Asn(78) and Asn(87). Total PGD2S levels are reduced six-fold in the CSF of children with medulloblastoma most likely representing a host response to the presence of the tumor. In addition, our results demonstrate the feasibility of performing proteomic studies on CSF samples collected from patients at multiple institutions within the consortium setting. C1 [MacDonald, Tobey J.; Rood, Brian R.] Childrens Natl Med Ctr, Ctr Canc & Immunol, Washington, DC 20010 USA. [Rajagopal, Meena U.; Hathout, Yetrib; Gordish-Dressman, Heather] Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC 20010 USA. [Kieran, Mark W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. RP Rood, BR (reprint author), Childrens Natl Med Ctr, Ctr Canc & Immunol, Washington, DC 20010 USA. EM brood@cnmc.org RI MacDonald, Tobey/D-4554-2013; OI Gordish-Dressman, Heather/0000-0002-2330-5427; Kieran, Mark/0000-0003-2184-7692 FU NIH [U01 CA81457, 1P30HD40677, 5R24 HD050846]; American Lebanese Syrian Associated Charities; The Childhood Brain Tumor Foundation; The Becca's Run Fund; The Schlobohm Family; Friends of Ian FX The authors acknowledge the support of James M. Boyett PhD, Executive Director of the Operations and Biostatistics Center for the PBTC, Larry E. Kun MD, Chair of the PBTC, Dana Wallace MS, Stacye Richardson MS, Stewart Goldman MD, Ian Pollack MD, and Andreas Ekefjard of Ludesi. This work was supported in part by NIH grant U01 CA81457 for the PBTC, the American Lebanese Syrian Associated Charities, The Childhood Brain Tumor Foundation, The Becca's Run Fund, The Schlobohm Family, and Friends of Ian. This work was also partially supported by NIH core grants 1P30HD40677 and 5R24 HD050846. NR 40 TC 19 Z9 22 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD MAR PY 2011 VL 11 IS 5 BP 935 EP 943 DI 10.1002/pmic.201000198 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 731VK UT WOS:000288137300010 PM 21271676 ER PT J AU Reise, SP Ventura, J Keefe, RSE Baade, LE Gold, JM Green, MF Kern, RS Mesholam-Gately, R Nuechterlein, KH Seidman, LJ Bilder, R AF Reise, Steven P. Ventura, Joseph Keefe, Richard S. E. Baade, Lyle E. Gold, James M. Green, Michael F. Kern, Robert S. Mesholam-Gately, Raquelle Nuechterlein, Keith H. Seidman, Larry J. Bilder, Robert TI Bifactor and Item Response Theory Analyses of Interviewer Report Scales of Cognitive Impairment in Schizophrenia SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE item response theory; CGI-CogS; SCoRS; schizophrenia and cognitive deficits; computerized adaptive testing ID CLINICAL-TRIALS; RATING-SCALE; DIMENSIONALITY; RELIABILITY; VALIDITY; BATTERY; MODELS AB A psychometric analysis of 2 interview-based measures of cognitive deficits was conducted: the 21-item Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS; Ventura et al., 2008), and the 20-item Schizophrenia Cognition Rating Scale (SCoRS; Keefe et al., 2006), which were administered on 2 occasions to a sample of people with schizophrenia. Traditional psychometrics, bifactor analysis, and item response theory methods were used to explore item functioning and dimensionality and to compare instruments. Despite containing similar item content, responses to the CGI-CogS demonstrated superior psychometric properties (e.g., higher item intercorrelations, better spread of ratings across response categories) relative to the SCoRS. The authors argue that these differences arise mainly from the differential use of prompts and how the items are phrased and scored. Bifactor analysis demonstrated that although both measures capture a broad range of cognitive functioning (e.g., working memory, social cognition), the common variance on each is overwhelmingly explained by a single general factor. Item response theory analyses of the combined pool of 41 items showed that measurement precision is peaked in the mild to moderate range of cognitive impairment. Finally, simulated adaptive testing revealed that only about 10 to 12 items are necessary to achieve latent trait level estimates with reasonably small standard errors for most individuals. This suggests that these interview-based measures of cognitive deficits could be shortened without loss of measurement precision. C1 [Reise, Steven P.; Nuechterlein, Keith H.; Bilder, Robert] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Ventura, Joseph; Green, Michael F.; Kern, Robert S.; Nuechterlein, Keith H.; Bilder, Robert] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Keefe, Richard S. E.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [Baade, Lyle E.] Univ Kansas, Sch Med, Lawrence, KS 66045 USA. [Gold, James M.] Univ Maryland, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21201 USA. [Green, Michael F.; Kern, Robert S.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mesholam-Gately, Raquelle; Seidman, Larry J.] Harvard Univ, Massachusetts Mental Hlth Ctr, Publ Psychiat Div, Beth Israel Deaconess Med Ctr,Dept Psychiat,Med S, Cambridge, MA 02138 USA. RP Reise, SP (reprint author), Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. EM reise@psych.ucla.edu RI Bilder, Robert/A-8894-2008 OI Bilder, Robert/0000-0001-5085-7852 FU NIDA NIH HHS [RL1 DA024853, RL1 DA024853-04, RL1DA024853]; NIDCR NIH HHS [UL1 DE019580-05, UL1 DE019580, UL1-DE019580]; NIMH NIH HHS [1R21MH073971, MH37705, N01MH22006, P50 MH066286, R01 MH037705, R21 MH073971, R21 MH073971-01A2, R21 MH073971-02] NR 34 TC 21 Z9 23 U1 2 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 EI 1939-134X J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD MAR PY 2011 VL 23 IS 1 BP 245 EP 261 DI 10.1037/a0021501 PG 17 WC Psychology, Clinical SC Psychology GA 729KT UT WOS:000287949200021 PM 21381848 ER PT J AU Kranick, SM Gorrindo, T Hallett, M AF Kranick, Sarah M. Gorrindo, Tristan Hallett, Mark TI Psychogenic Movement Disorders and Motor Conversion: A Roadmap for Collaboration Between Neurology and Psychiatry SO PSYCHOSOMATICS LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; CLINICAL-FEATURES; DISSOCIATIVE DISORDER; SYMPTOMS; TREMOR; TRIAL; PHENOMENOLOGY; PARKINSONISM; MANAGEMENT; PROGNOSIS AB Background: There are a host of vague terms to describe psychologically-mediated symptoms that mimic neurological disease, such as "functional," "non-organic," "psychogenic," or "medically unexplained." None of these terms has a direct translation in psychiatric classification, and psychiatrists are often fixed with patients who do not believe in a psychological origin for their symptoms. Objective: Within the framework of psychogenic movement disorders, we discuss the roadblocks to effective collaboration and treatment in these patients and the current state of the literature regarding diagnosis and treatment. Results: We describe the approach to these patients from the perspective of neurology and psychiatry illustrating the differences in terminology and categorization. Conclusion: Psychogenic movement disorders represent a unique opportunity for these fields to collaborate in the care of a potentially curable but significantly disabling disorder. (Psychosomatics 2011: 52:109-116) C1 [Kranick, Sarah M.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Gorrindo, Tristan] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Kranick, SM (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10-7D42,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM sarah.kranick@nih.gov FU NINDS FX This research was supported in part by the NINDS Intramural Program. NR 51 TC 13 Z9 13 U1 1 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2011 VL 52 IS 2 BP 109 EP 116 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 741RF UT WOS:000288881100002 PM 21397102 ER PT J AU Lindsay, AC Sussner, KM Greaney, ML Peterson, KE AF Lindsay, Ana C. Sussner, Katarina M. Greaney, Mary L. Peterson, Karen E. TI Latina Mothers' Beliefs and Practices Related to Weight Status, Feeding, and the Development of Child Overweight SO PUBLIC HEALTH NURSING LA English DT Article DE beliefs; childhood overweight; feeding practices; Latino ID LOW-INCOME MOTHERS; MEXICAN-AMERICAN MOTHERS; PRESCHOOL-AGED CHILDREN; PHYSICAL-ACTIVITY; EATING BEHAVIOR; OBESIGENIC FAMILIES; IMMIGRANT STATUS; SOCIAL-CONTEXT; OBESITY; HEALTH AB Objective To examine maternal beliefs and practices related to weight status, child feeding, and child overweight in the Latino culture that may contribute to the rising rates of overweight among preschool Latino children in the United States. Design and Sample This 2-phase qualitative study relies on data obtained in 6 focus groups with a total of 31 primarily Spanish-speaking, low-income mothers, followed by 20 individual, in-depth interviews with women participating in a health promotion educational program. Measures Child-feeding beliefs, practices, and weight status perceptions were elicited. Results The findings indicated that most respondents reported personal struggles with weight gain, particularly during and after pregnancy, and were concerned that their children would become obese. Although subjects understood the health and social consequences related to overweight, many discussed the pressures of familial and cultural influences endorsing a "chubby child." Conclusions Education and interventions that incorporate "culturally mediated" pathways to address mothers' feeding practices are essential for the prevention and control of childhood overweight among low-income Latinos. Nurses should be aware of the social and cultural influences on Latina mothers' beliefs and practices related to weight status and feeding practices and address these in their education approaches to prevent childhood overweight and obesity with this population group. C1 [Lindsay, Ana C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sussner, Katarina M.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Greaney, Mary L.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Peterson, Karen E.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth, Ann Arbor, MI 48109 USA. RP Lindsay, AC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2, Boston, MA 02115 USA. EM alindsay@hsph.harvard.edu FU National Cancer Institute [R03 CA108347-01] FX We are thankful to the staff of the WIC Program at the Massachusetts Department of Public Health and the mothers who participated in this study. This study was supported by a grant from the National Cancer Institute, R03 CA108347-01, for which Ana Lindsay, D. D. S., M. P. H., Dr.P.H., is Principal Investigator. NR 53 TC 36 Z9 38 U1 1 U2 19 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0737-1209 J9 PUBLIC HEALTH NURS JI Public Health Nurs. PD MAR-APR PY 2011 VL 28 IS 2 BP 107 EP 118 DI 10.1111/j.1525-1446.2010.00906.x PG 12 WC Public, Environmental & Occupational Health; Nursing SC Public, Environmental & Occupational Health; Nursing GA 726QA UT WOS:000287740000002 PM 21442018 ER PT J AU Ding, A Eisenberg, JD Pandharipande, PV AF Ding, Alexander Eisenberg, Jonathan D. Pandharipande, Pari V. TI The Economic Burden of Incidentally Detected Findings SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Economic burden; Incidental findings; Imaging; CT colonography ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; EXTRACOLONIC FINDINGS; CT COLONOGRAPHY; COST-EFFECTIVENESS; COLORECTAL-CANCER; LUNG-CANCER; EXTRACARDIAC FINDINGS; MUTATION CARRIERS; IMPACT; MR AB Practitioners in all medical disciplines recognize the high frequency of incidentally detected findings. Although some findings are discovered on physical examination, an increasing majority are detected at imaging performed for another indication. With increasing federal scrutiny on the net value of imaging services, the costs and benefits of incidental findings need to be more rigorously quantified. In this article, the authors examine current related work on imaging expenditures for incidental findings and provide a framework for future investigations that will efficiently and substantially advance the knowledge in this field. C1 [Eisenberg, Jonathan D.; Pandharipande, Pari V.] Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, Boston, MA 02114 USA. [Pandharipande, Pari V.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org FU NCI NIH HHS [K07 CA133097, K07 CA133097-02] NR 42 TC 17 Z9 17 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD MAR PY 2011 VL 49 IS 2 BP 257 EP + DI 10.1016/j.rcl.2010.11.004 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738EX UT WOS:000288623500004 PM 21333777 ER PT J AU Shanbhogue, AK Prasad, SR Takahashi, N Vikram, R Sahani, DV AF Shanbhogue, Alampady K. Prasad, Srinivasa R. Takahashi, Naoki Vikram, Raghunandan Sahani, Dushyant V. TI Recent Advances in Cytogenetics and Molecular Biology of Adult Hepatocellular Tumors: Implications for Imaging and Management SO RADIOLOGY LA English DT Review ID FOCAL NODULAR HYPERPLASIA; GLYCOGEN-STORAGE-DISEASE; GROWTH-FACTOR-II; HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; ORAL-CONTRACEPTIVE USE; PRIMARY LIVER-CANCER; C VIRUS-INFECTION; MAGNETIC-RESONANCE; FIBROLAMELLAR CARCINOMA; UNITED-STATES AB Focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) compose hepatocellular neoplasms that occur in adults. These tumors demonstrate characteristic epidemiologic and histopathologic features and clinical and imaging manifestations. HCAs are monoclonal neoplasms characterized by increased predilection to hemorrhage or rupture and occasional transformation to HCC. On the other hand, FNH is a polyclonal tumorlike lesion that occurs in response to increased perfusion and has an indolent clinical course. Up to 90% of HCCs occur in the setting of cirrhosis. Chronic viral hepatitis (hepatitis B and hepatitis C) infection and metabolic syndrome are major risk factors that can induce HCCs in nonfibrotic liver. Recent advances in pathology and genetics have led to better understanding of the histogenesis, natural history, and molecular events that determine specific oncologic pathways used by these neoplasms. HCAs are now believed to result from specific genetic mutations involving TCF1 (transcription factor 1 gene), IL6ST (interleukin 6 signal transducer gene), and CTNNB1 (beta catenin-1 gene); FNHs are characterized by an "imbalance" of angiopoietin. While the beta catenin signaling pathway is associated with well-and moderately differentiated HCCs, mutations involving p53 (tumor protein 53 gene), MMP14 (matrix metalloproteinase 14 gene), and RhoC (Ras homolog gene family, member C) are associated with larger tumor size, higher tumor grade with resultant shortened tumor-free survival, and poor prognosis. Fibrolamellar carcinoma (FLC), a unique HCC subtype, exhibits genomic homogeneity that partly explains its better overall prognosis. On the basis of recent study results involving cytogenetics and oncologic pathways of HCCs, novel drugs that act against molecular targets are being developed. Indeed, sorafenib (a multikinase inhibitor) is currently being used in the successful treatment of patients with advanced HCC. Characterization of genetic abnormalities and genotype-phenotype correlations in adult hepatocellular tumors provides better understanding of tumor pathology and biology, imaging findings, prognosis, and response to molecular therapeutics. (C)RSNA, 2011 C1 [Shanbhogue, Alampady K.; Prasad, Srinivasa R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Vikram, Raghunandan] Univ Texas MD Anderson Canc Ctr, Dept Radiol, Houston, TX 77030 USA. [Takahashi, Naoki] Mayo Clin, Dept Radiol, Rochester, MN USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Prasad, SR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM prasads@uthscsa.edu FU GE Healthcare; Bracco Diagnostics FX A.K.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. S.R.P. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. N.T. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. R.V. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. D.V.S. Financial activities related to the present article: Institution received a grant from GE Healthcare; received consulting fee or honorarium from Bracco Diagnostics. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. NR 156 TC 26 Z9 30 U1 0 U2 5 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 MAR PY 2011 VL 258 IS 3 BP 673 EP 693 DI 10.1148/radiol.10100376 PG 21 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 724JX UT WOS:000287573100004 PM 21339346 ER PT J AU Uppal, R Catana, C Ay, I Benner, T Sorensen, AG Caravan, P AF Uppal, Ritika Catana, Ciprian Ay, Ilknur Benner, Thomas Sorensen, A. Gregory Caravan, Peter TI Bimodal Thrombus Imaging: Simultaneous PET/MR Imaging with a Fibrin-targeted Dual PET/MR Probe-Feasibility Study in Rat Model SO RADIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IRON-OXIDE NANOPARTICLES; MR CONTRAST AGENT; IN-VIVO; CORONARY-THROMBOSIS; PULMONARY EMBOLI; SWINE MODEL; EP-2104R; SCANNER AB Purpose: To image thrombus by using magnetic resonance (MR) imaging and positron emission tomography (PET) simultaneously in a rat arterial thrombus model with a dual PET/MR probe. Materials and Methods: Animal studies were approved by the institutional animal use committee. A dual PET/MR probe was synthesized by means of partial exchange of gadolinium for copper 64 ((64)Cu) in the fibrin-targeted MR probe EP-2104R. A preformed 25-mm thrombus was injected into the right internal carotid artery of a rat. Imaging was performed with a clinical 3.0-T MR imager with an MR-compatible human PET imager. Rats (n = 5) were imaged prior to and after systemic administration of the dual probe by using simultaneous PET/MR. The organ distribution of (64)Cu and gadolinium was determined ex vivo (n = 8), 2 hours after injection by using well counting and inductively coupled plasma mass spectrometry, respectively. Signal intensity ratios (SIRs) between the thrombus-containing and contralateral vessel were computed from PET images and MR data before and after probe administration. Results: The dual probe was synthesized with greater than 98% radiochemical purity. Thrombus enhancement was observed in all five animals at both MR (SIR([postprobe])/SIR([preprobe]) = 1.71 +/- 0.35, P = .0053) and PET (SIR = 1.85 +/- 0.48, P = .0087) after injection of the dual PET/MR probe. Ex vivo analysis at 2 hours after injection showed the highest (64)Cu and gadolinium concentrations, after the excretory organs (kidney and liver), to be in the thrombus. Conclusion: A fibrin-targeted dual PET/MR probe enables simultaneous, direct MR and PET imaging of thrombus. (C)RSNA, 2010 C1 [Uppal, Ritika; Catana, Ciprian; Ay, Ilknur; Benner, Thomas; Sorensen, A. Gregory; Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU MIND Institute; T32 Ruth L. Kirschstein National Research Service [5T32CA009502]; National Institutes of Health [5T32CA009502, EB009062, EB009783, NS38477, P41-RR14075]; NIH; National Cancer Institute; Medical Research Council; Massachusetts General Hospital FX Supported in part by the MIND Institute. I.A. supported by a T32 Ruth L. Kirschstein National Research Service Award (5T32CA009502).; This research was supported by the National Institutes of Health (grants EB009062, EB009783, NS38477, 5T32CA009502, and P41-RR14075).; R.U. No potential conflicts of interest to disclose. C.C. No potential conflicts of interest to disclose. I.A. No potential conflicts of interest to disclose. T.B. Financial activities related to the present article: institution received an NIH grant. Financial activities not related to the present article: is a consultant for Siemens Medical. Other relationships: none to disclose. A.G.S. Financial activities related to the present article: institution received grant from National Cancer Institute. Financial activities not related to the present article: money paid to institution for board membership for ACR-Image Metrix (no compensation); author is a consultant for BayerScheringPharma, Bristol Meyers Squibb, Biogenldec, Merrimack Pharmaceuticals, Olea Medical, Mitsubishi Pharm, GE Healthcare, Regeneron, Siemens Medical, and NIH; author and institution are consultants for Novartis, Roche, Takeda, and AstraZeneca; author provides expert testimony for Kit; institution receives grants from NIH and Medical Research Council; author receives payment for lectures from New York University and ACR-Image Metrix; institution has patent with Massachusetts General Hospital; author and institution receive royalties from Massachusetts General Hospital; author has Catalyst Medical and Breakaway Imaging stock; author receives travel accommodations from Oxford University and Aarhus University. Other relationships: none to disclose. A full listing of A.G.S.'s competing interests is available at http://www.biomarkers.org/. P.C. Financial activities related to the present article: institution received NIH grant. Financial activities not related to the present article: is a consultant for Lantheus Medical Imaging and Epix Pharmaceuticals; has Catalyst Medical stock. Other relationships: none to disclose. NR 37 TC 40 Z9 42 U1 1 U2 13 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 MAR PY 2011 VL 258 IS 3 BP 812 EP 820 DI 10.1148/radiol.10100881 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 724JX UT WOS:000287573100018 PM 21177389 ER PT J AU Spampinato, MV Rumboldt, Z Hosker, RJ Mintzer, JE AF Spampinato, Maria Vittoria Rumboldt, Zoran Hosker, Robert J. Mintzer, Jacobo E. CA Alzheimer's Dis Neuroimaging TI Apolipoprotein E and Gray Matter Volume Loss in Patients with Mild Cognitive Impairment and Alzheimer Disease SO RADIOLOGY LA English DT Article ID VOXEL-BASED MORPHOMETRY; CEREBROSPINAL-FLUID TAU; E EPSILON-4 ALLELE; E GENOTYPE; TRANSGENIC MICE; CHOLINERGIC DEFICITS; CORTICAL THICKNESS; AMYLOID DEPOSITION; CLINICAL-DIAGNOSIS; TACRINE THERAPY AB Purpose: To examine the influence of apoliprotein E epsilon 4 allele (APOE 4) carrier status on disease progression by evaluating the rate of regional gray matter (GM) volume loss and disease severity in patients with newly diagnosed Alzheimer disease (AD) and stable amnestic mild cognitive impairment (MCI). Materials and Methods: This study was approved by the institutional review board and was HIPAA compliant. All subjects or their legal representatives gave informed consent for participation. Ninety-five subjects (63 male; average age, 77.1 years; age range, 58-91 years; 51 APOE4 carriers; 44 noncarriers) with either documented MCI to AD conversion or stable amnestic MCI underwent three yearly magnetic resonance imaging examinations. Voxel-based morphometry for image postprocessing and Clinical Dementia Rating (CDR) scale for cognitive assessment were used. Results: In APOE 4 carriers, GM volume loss affected the hippocampi, temporal and parietal lobes, right caudate nucleus, and insulae in patients with MCI to AD conversion and the insular and temporal lobes in patients in whom MCI was stable. In subjects who were not APOE 4 carriers, there was no significant GM volume change. There were no differences in CDR scores between APOE 4 carriers and noncarriers. Conclusion: APOE 4 carriers with cognitive decline undergo faster GM atrophy than do noncarriers. The involvement of APOE 4 in the progression of hippocampal atrophy, neocortical atrophy, or both has potential important implications for diagnosis and therapeutic approaches in patients with AD and should be considered in clinical trials. The present results and the results of prior studies indicate that the rate of hippocampal and neocortical atrophy is greater in association with APOE 4 in nondemented elderly subjects, subjects with MCI, and those with AD. (C)RSNA, 2010 C1 [Spampinato, Maria Vittoria; Rumboldt, Zoran; Hosker, Robert J.] Med Univ S Carolina, Dept Radiol & Radiol Sci, Charleston, SC 29425 USA. [Mintzer, Jacobo E.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Mintzer, Jacobo E.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Spampinato, MV (reprint author), Med Univ S Carolina, Dept Radiol & Radiol Sci, 96 Jonathan Lucas St,MSC 323, Charleston, SC 29425 USA. EM spampin@musc.edu RI Scharre, Douglas/E-4030-2011 FU Bracco Diagnostics; Bayer; Siemens; National Institute on Aging FX M.V.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: institution received compensation from Bayer HealthCare and Bracco Diagnostics. Z.R. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: none to disclose. Other relationships: is a consultant for Bracco Diagnostics; provides research support for Bracco Diagnostics, Bayer, and Siemens. R.J.H. No potential conflicts of interest to disclose. J.E.M. Financial activities related to the present article: institution received funding from National Institute on Aging. Financial activities not related to the present article: is on the board of ADNI. Other relationships: none to disclose. NR 53 TC 25 Z9 27 U1 0 U2 3 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 MAR PY 2011 VL 258 IS 3 BP 843 EP 852 DI 10.1148/radiol.10100307 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 724JX UT WOS:000287573100021 PM 21163916 ER PT J AU Hricak, H Brenner, DJ Adelstein, SJ Frush, DP Hall, EJ Howell, RW McCollough, CH Mettler, FA Pearce, MS Suleiman, OH Thrall, JH Wagner, LK AF Hricak, Hedvig Brenner, David J. Adelstein, S. James Frush, Donald P. Hall, Eric J. Howell, Roger W. McCollough, Cynthia H. Mettler, Fred A. Pearce, Mark S. Suleiman, Orhan H. Thrall, James H. Wagner, Louis K. TI Managing Radiation Use in Medical Imaging : A Multifaceted Challenge SO RADIOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; CARDIAC COMPUTED-TOMOGRAPHY; FLUOROSCOPICALLY GUIDED PROCEDURES; CORONARY-ARTERY-DISEASE; MULTISLICE HELICAL CT; MULTIDETECTOR-ROW CT; LOW-DOSE RADIATION; BREAST-CANCER; IONIZING-RADIATION; DECISION-SUPPORT AB This special report aims to inform the medical community about the many challenges involved in managing radiation exposure in a way that maximizes the benefit-risk ratio. The report discusses the state of current knowledge and key questions in regard to sources of medical imaging radiation exposure, radiation risk estimation, dose reduction strategies, and regulatory options. C1 [Hricak, Hedvig] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Brenner, David J.; Hall, Eric J.] Columbia Univ, Ctr Radiol Res, Med Ctr, New York, NY 10032 USA. [Adelstein, S. James] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frush, Donald P.] Duke Med Ctr, Div Pediat Radiol, Durham, NC USA. [Howell, Roger W.] UMDNJ New Jersey Med Sch Canc Ctr, Dept Radiol, Newark, NJ USA. [McCollough, Cynthia H.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Mettler, Fred A.] Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. [Pearce, Mark S.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Suleiman, Orhan H.] US FDA, Off New Drugs, Silver Spring, MD USA. [Thrall, James H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wagner, Louis K.] Univ Texas Med Sch Houston, Dept Diagnost & Intervent Imaging, Houston, TX USA. RP Hricak, H (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave,Suite C-278, New York, NY 10021 USA. EM mullnea@mskcc.org RI Frush, Donald/M-6457-2015 OI Frush, Donald/0000-0002-6928-4465 FU NASA [NNJO5H138G]; DOE [SC0001634]; Siemens Medical Solutions; American College of Radiology FX E.J.H. Financial activities related to the present article: institutional grants from NASA NNJO5H138G and DOE-SC0001634. Financial activities not related to the present article: is paid for consultancy (teaching) elsewhere, is paid for employment as professor emeritus at Columbia University, is paid for expert testimony for several court cases, and receives payment for lectures including service on speakers bureaus teaching residents, receives royalties for textbook, receives institutional grants for payment for development of educational presentations, receives money for stock or stock options as part of retirement portfolio, receives money for travel, accommodations, meeting expenses for resident lectures. Other relationships: none to disclose.; C.H.M. Financial activities related to the present article: received institutional payment for travel expenses to the National Academies of Science sponsored Beebe Symposium in December 2009. Financial activities not related to the present article: received research grant related to CT imaging from Siemens Medical Solutions. Other relationships: none to disclose.; Financial activities not related to the present article: receives a stipend for service as board chair from American College of Radiology NR 122 TC 117 Z9 125 U1 3 U2 16 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 MAR PY 2011 VL 258 IS 3 BP 889 EP 905 DI 10.1148/radiol.10101157 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 724JX UT WOS:000287573100026 PM 21163918 ER PT J AU Sparks, TN Ecker, JE Janakiraman, V AF Sparks, Teresa N. Ecker, Jeff E. Janakiraman, Vanitha TI How Do Global Cesarean Rates Compare to Those in Massachusetts by Ethnicity SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Sparks, Teresa N.] Brigham & Womens Hosp, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA T058 BP 88A EP 88A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721700063 ER PT J AU Selesniemi, K Lee, HJ Tilly, JL AF Selesniemi, Kaisa Lee, Ho-Joon Tilly, Jonathan L. TI Aging-Related Increases in Oocyte Aneuploidy and Spindle Assembly Defects Are Prevented by Dietary Caloric Restriction (CR) or Pgc-1-alpha Gene Inactivation SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Selesniemi, Kaisa; Lee, Ho-Joon; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA T-099 BP 100A EP 100A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721700104 ER PT J AU Kulkarni-Datar, K Guo, LK Zhang, L Zuckerberg, LR Foster, R Rueda, BR AF Kulkarni-Datar, Kashmira Guo, Lankai Zhang, Ling Zuckerberg, Lawrence R. Foster, Rosemary Rueda, Bo R. TI Comparing Stem Cell Populations in Normal, Hyperplastic and Carcinomatous Endometrium in Wild Type and PTEN Deficient Mice SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Kulkarni-Datar, Kashmira; Guo, Lankai; Zhang, Ling; Foster, Rosemary; Rueda, Bo R.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Zuckerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kulkarni-Datar, Kashmira; Zuckerberg, Lawrence R.; Foster, Rosemary; Rueda, Bo R.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA T127 BP 108A EP 108A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721700130 ER PT J AU White, YAR Woods, DC Guo, L Rueda, BR Tilly, JL AF White, Yvonne A. R. Woods, Dori C. Guo, Lankai Rueda, Bo R. Tilly, Jonathan L. TI The Cables1 Gene Is a Key Regulator of Oogonial Stem Cell (OSC) Mitotic Activity in Adult Mouse Ovaries SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [White, Yvonne A. R.; Woods, Dori C.; Guo, Lankai; Rueda, Bo R.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA O055 BP 172A EP 172A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721700358 ER PT J AU Chattergoon, NN Louey, S Giraud, GD Thornburg, KL AF Chattergoon, Natasha N. Louey, Samantha Giraud, George D. Thornburg, Kent L. TI Thyroid Hormone Deprivation Disrupts the IGF-I System in the Fetal Heart SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Chattergoon, Natasha N.; Louey, Samantha; Giraud, George D.; Thornburg, Kent L.] Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA. [Giraud, George D.] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F115 BP 205A EP 205A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701042 ER PT J AU Lannon, BM Cole, L Yeh, J AF Lannon, Benjamin M. Cole, Lawrence Yeh, John TI Familial Human Chorionic Gonadotropin Syndrome: A Case Report SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Lannon, Benjamin M.; Yeh, John] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Cole, Lawrence] Univ New Mexico, Albuquerque, NM 87131 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F286 BP 256A EP 256A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701213 ER PT J AU Imudia, AN White, YAR Woods, DC Tanaka, Y Tilly, JL AF Imudia, Anthony N. White, Yvonne A. R. Woods, Dori C. Tanaka, Yoshihiro Tilly, Jonathan L. TI Genetic Analysis of Mouse Embryonic Stem Cells (ESC), Primordial Germ Cells (PGC) and Postnatal Oogonial Stem Cells (OSC) Reveals a Progressive Germline Differentiation Profile SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Imudia, Anthony N.; White, Yvonne A. R.; Woods, Dori C.; Tanaka, Yoshihiro; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F298 BP 259A EP 260A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701225 ER PT J AU Lannon, BM Rhee, J Zimon, AE AF Lannon, Benjamin M. Rhee, Julie Zimon, Alison E. TI Characteristics of Couples Donating Cryopreserved Embryos for Human Embryonic Stem Cell Research SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Lannon, Benjamin M.; Rhee, Julie; Zimon, Alison E.] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Lannon, Benjamin M.; Zimon, Alison E.] Boston IVF, Waltham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F-301 BP 260A EP 260A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701228 ER PT J AU Satirapod, C Wang, N Niikura, Y Wright, DL Toth, TL Tilly, JL AF Satirapod, Chonthicha Wang, Ning Niikura, Yuichi Wright, Diane L. Toth, Thomas L. Tilly, Jonathan L. TI Human Seminal Fluid Contains a Factor That Enhances Postnatal Oogenesis in Adult Female Mice SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Satirapod, Chonthicha; Wang, Ning; Niikura, Yuichi; Wright, Diane L.; Toth, Thomas L.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F-304 BP 261A EP 262A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701231 ER PT J AU Wang, N Satirapod, C Tilly, JL AF Wang, Ning Satirapod, Chonthicha Tilly, Jonathan L. TI Suicide Gene-Based Targeted Cell Ablation Confirms a Critical Role for Oogonial Stem Cells (OSC) in Maintaining the Adult Ovarian Oocyte Pool SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Wang, Ning; Satirapod, Chonthicha; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F-305 BP 262A EP 262A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701232 ER PT J AU Woods, DC White, YAR Niikura, Y Tilly, JL AF Woods, Dori C. White, Yvonne A. R. Niikura, Yuichi Tilly, Jonathan L. TI Embryonic Stem Cell (ESC)-Derived Granulosa Cells Participate in Follicle Formation In Vitro and In Vivo. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Woods, Dori C.; White, Yvonne A. R.; Niikura, Yuichi; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA F-307 BP 262A EP 262A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701234 ER PT J AU Henry, DE Goldfarb, I Dumont, O Barth, W AF Henry, Dana E. Goldfarb, Ilona Dumont, Olivia Barth, William TI Inadvertent Hysterotomy Extension at Cesarean Delivery and Risk of Preterm Birth in the Next Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Henry, Dana E.; Goldfarb, Ilona; Dumont, Olivia; Barth, William] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA S043 BP 307A EP 307A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701385 ER PT J AU Bahado-Singh, RO Filetti, L Imudia, A Awonuga, A Kruger, M AF Bahado-Singh, Ray O. Filetti, Lusia Imudia, Anthony Awonuga, Awoniyi Kruger, Michael TI Late Onset Post Partum Preeclampsia: Are There Different Subtypes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Bahado-Singh, Ray O.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA S189 BP 349A EP 349A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701529 ER PT J AU Panda, B Panda, A Abrahams, VM Norwitz, ER Stanic-Kostic, A Shaw, AC AF Panda, Britta Panda, Alexander Abrahams, Vikki M. Norwitz, Errol R. Stanic-Kostic, Aleksandar Shaw, Albert C. TI Dendritic Cells in the Circulation of Women with Preeclampsia Demonstrate a Pro-Inflammatory Bias SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Panda, Britta; Stanic-Kostic, Aleksandar] Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. [Panda, Alexander; Abrahams, Vikki M.; Shaw, Albert C.] Yale Univ, New Haven, CT USA. [Norwitz, Errol R.] Tufts Univ, Tufts Med Ctr, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2011 VL 18 IS 3 SU S MA S217 BP 357A EP 357A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 778RE UT WOS:000291721701557 ER PT J AU Castelino, FV Goldberg, H Dellaripa, PF AF Castelino, Flavia V. Goldberg, Hilary Dellaripa, Paul F. TI The impact of rheumatological evaluation in the management of patients with interstitial lung disease SO RHEUMATOLOGY LA English DT Article DE Interstitial lung disease; CTD-related interstitial lung disease; Quality of care ID CONNECTIVE-TISSUE DISEASE; RHEUMATOID-ARTHRITIS; REVISED CRITERIA; CLASSIFICATION; PNEUMONIA; COMMUNITY; SMOKING AB Methods. Our multi-disciplinary ILD group evaluated 50 patients referred to our tertiary care practice over a 12-month period. Evaluation consisted of independent assessments by a pulmonologist and rheumatologist, including complete history and physical examination, review of laboratory data, as well as review of imaging and pathological specimens in conjunction with a radiologist and pathologist experienced in ILD. Therapy was initiated or changed in collaboration with the referring physicians. Results. Mean age was 65 years for patients with rheumatic or CTD-related ILD (CTD-ILD) and 70 years for those with idiopathic pulmonary fibrosis (IPF). The final diagnosis after evaluation in the clinic was 25 patients with CTD-ILD, 15 patients with IPF and 10 patients with other forms of lung disease. Of the patients with a final diagnosis of CTD-ILD, 28% were referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD-ILD. In total, the diagnosis was changed in 54% of patients who presented to the ILD clinic. Changes in therapy occurred in 80% of patients with CTD-ILD and in 27% of patients with IPF. Conclusion. A multi-disciplinary ILD clinic offers patients an innovative mode of health-care delivery that can enhance diagnosis, affect treatment regimens and improve quality of care. Rheumatologists play a significant role in the clinical care of these patients and should evaluate all patients with ILD. C1 [Castelino, Flavia V.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol, Boston, MA 02114 USA. [Goldberg, Hilary] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA 02115 USA. [Dellaripa, Paul F.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. RP Castelino, FV (reprint author), Massachusetts Gen Hosp, Dept Med, Div Rheumatol, 55 Fruit St,Bulfinch 165, Boston, MA 02114 USA. EM fcastelino@partners.org FU Genentech; Novartis Pharmaceuticals Corp.; Wyeth Pharmaceuticals; Gilead Sciences, Inc. FX Disclosure statement: P.F.D. has participated as a clinical investigator in a study supported by Genentech and a project with Gilead. A project with Gilead H. G. has been a site PI for multicenter clinical trials funded by Novartis Pharmaceuticals Corp., Wyeth Pharmaceuticals, Gilead Sciences, Inc. and Genentech. The other author has declared no conflicts of interest. NR 20 TC 20 Z9 20 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2011 VL 50 IS 3 BP 489 EP 493 DI 10.1093/rheumatology/keq233 PG 5 WC Rheumatology SC Rheumatology GA 726SE UT WOS:000287745600009 PM 20685802 ER PT J AU Baker-LePain, JC Nakamura, MC Shepherd, J von Scheven, E AF Baker-LePain, Julie C. Nakamura, Mary C. Shepherd, John von Scheven, Emily TI Assessment of bone remodelling in childhood-onset systemic lupus erythematosus SO RHEUMATOLOGY LA English DT Article DE Bone turnover; Systemic lupus erythematosus; Children; Cytokines; Interferon ID RESISTANT ACID-PHOSPHATASE; JUVENILE RHEUMATOID-ARTHRITIS; CHRONIC KIDNEY-DISEASE; MINERAL-DENSITY; IDIOPATHIC ARTHRITIS; KNEE OSTEOARTHRITIS; PREMENOPAUSAL WOMEN; NUTRITIONAL-STATUS; INTERFERON-BETA; GROWTH FAILURE AB Methods. Ninety subjects with SLE aged 8-22 years underwent yearly measurements of height, bone age, bone turnover markers, serum Type I IFNs, SLEDAI and BMD. Predictors of bone turnover were examined using serum osteocalcin as a marker of bone formation and both serum tartrate-resistant acid phosphatase (TRAP) and urine N-telopeptide (NTx) as markers of bone resorption. Results. Subjects demonstrated short stature, high BMI and bone age delay. A spine BMD Z-score of less than -2.0 was seen in 16.1% of subject visits. Serum osteocalcin was negatively correlated with glucocorticoid dose (Spearman rank correlation coefficient R = -0.34, P < 0.0001) but was not associated with SLEDAI after adjustment for confounders. Serum TRAP was negatively associated with SLEDAI, even after controlling for confounders (P = 0.04). Similar results were obtained for urine NTx. There was a negative association between TRAP and serum IFN-beta (P = 0.03). Conclusions. In this population of children and young adults with moderate lupus disease activity, glucocorticoid dose was a negative predictor of bone formation, whereas lupus disease activity was not. Interestingly, lupus disease activity was a negative predictor of bone resorption, suggesting that lupus disease activity is not the primary factor contributing to the bone deficits of childhood-onset SLE. The potential protective role of IFN-beta and the effects of SLE treatment on bone loss require further study. C1 [von Scheven, Emily] Univ Calif San Francisco, Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA. [Baker-LePain, Julie C.; Nakamura, Mary C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Nakamura, Mary C.] San Francisco VA Med Ctr, Dept Rheumatol, San Francisco, CA USA. [Shepherd, John] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP von Scheven, E (reprint author), Univ Calif San Francisco, Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA. EM evonsche@peds.ucsf.edu FU National Institutes of Health/National Center for Research Resources UCSF-Clinical and Translational Science Institute [UL1 RR024131]; NIH/NCRR [16319]; NIH [AR007304]; Department of Veterans' Affairs FX Funding: This publication was supported by National Institutes of Health/National Center for Research Resources UCSF-Clinical and Translational Science Institute Grant Number UL1 RR024131 and NIH/NCRR grant number 16319. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. J.C.B.-L. was supported by NIH Academic Rheumatology and Clinical Immunology Training Grant Number AR007304. M.C.N. was supported by the Department of Veterans' Affairs. NR 42 TC 10 Z9 10 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2011 VL 50 IS 3 BP 611 EP 619 DI 10.1093/rheumatology/keq307 PG 9 WC Rheumatology SC Rheumatology GA 726SE UT WOS:000287745600025 PM 21098573 ER PT J AU Kern, RS Gold, JM Dickinson, D Green, MF Nuechterlein, KH Baade, LE Keefe, RSE Mesholam-Gately, RI Seidman, LJ Lee, C Sugar, CA Marder, SR AF Kern, Robert S. Gold, James M. Dickinson, Dwight Green, Michael F. Nuechterlein, Keith H. Baade, Lyle E. Keefe, Richard S. E. Mesholam-Gately, Raquelle I. Seidman, Larry J. Lee, Cathy Sugar, Catherine A. Marder, Stephen R. TI The MCCB impairment profile for schizophrenia outpatients: Results from the MATRICS psychometric and standardization study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE MCCB; Cognition; Schizophrenia; Profile ID CONSENSUS COGNITIVE BATTERY; WORK PERFORMANCE; MEMORY; REHABILITATION; NEUROCOGNITION; IDENTIFICATION; METAANALYSIS; 1ST-EPISODE; PREDICTORS AB The MATRICS Psychometric and Standardization Study was conducted as a final stage in the development of the MATRICS Consensus Cognitive Battery (MCCB). The study included 176 persons with schizophrenia or schizoaffective disorder and 300 community residents. Data were analyzed to examine the cognitive profile of clinically stable schizophrenia patients on the MCCB. Secondarily, the data were analyzed to identify which combination of cognitive domains and corresponding cut-off scores best discriminated patients from community residents, and patients competitively employed vs. those not. Raw scores on the ten MCCB tests were entered into the MCCB scoring program which provided age- and gender-corrected T-scores on seven cognitive domains. To test for between-group differences, we conducted a 2 (group) x 7 (cognitive domain) MANOVA with follow-up independent t-tests on the individual domains. Classification and regression trees (CART) were used for the discrimination analyses. Examination of patient T-scores across the seven cognitive domains revealed a relatively compact profile with T-scores ranging from 33.4 for speed of processing to 39.3 for reasoning and problem-solving. Speed of processing and social cognition best distinguished individuals with schizophrenia from community residents: speed of processing along with visual leaming and attention/vigilance optimally distinguished patients competitively employed from those who were not. The cognitive profile findings provide a standard to which future studies can compare results from other schizophrenia samples and related disorders; the classification results point to specific areas and levels of cognitive impairment that may advance work rehabilitation efforts. Published by Elsevier B.V. C1 [Kern, Robert S.; Green, Michael F.; Nuechterlein, Keith H.; Sugar, Catherine A.; Marder, Stephen R.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Kern, Robert S.; Green, Michael F.; Marder, Stephen R.] VISN 22 Mental Illness Res, Dept Vet Affairs, Los Angeles, CA USA. [Kern, Robert S.; Green, Michael F.; Marder, Stephen R.] Ctr Clin, Los Angeles, CA USA. [Gold, James M.] Univ Maryland Baltimore, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD USA. [Dickinson, Dwight] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Baade, Lyle E.] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Keefe, Richard S. E.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Mesholam-Gately, Raquelle I.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat,Publ Psychiat Div, Beth Israel Deaconess Med Ctr,Massachusetts Menta, Boston, MA 02115 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Cathy; Sugar, Catherine A.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. RP Kern, RS (reprint author), VA Greater Los Angeles Healthcare Ctr, MIRECC 210 A,Bldg 210,Room 116,11301 Wilshire Blv, Los Angeles, CA 90073 USA. EM rkern@ucla.edu FU National Institute for Mental Health [N01MH22006] FX Funding for the MATRICS Initiative was provided through Contract N01MH22006 from the National Institute for Mental Health to the University of California, Los Angeles (Dr. Marder, PI; Dr. Green, Co-PI; Dr. Fenton, Project Officer). Funding for this study came from an Option (Dr. Green, PI; Dr. Nuechterlein, Co-PI) to the NIMH MATRICS Initiative. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 29 TC 65 Z9 68 U1 5 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2011 VL 126 IS 1-3 BP 124 EP 131 DI 10.1016/j.schres.2010.11.008 PG 8 WC Psychiatry SC Psychiatry GA 743NS UT WOS:000289025700018 PM 21159492 ER PT J AU Sousse, LE Yamamoto, Y Enkhbaatar, P Rehberg, SW Wells, SM Leonard, S Traber, MG Yu, YM Cox, RA Hawkins, HK Traber, LD Herndon, DN Traber, DL AF Sousse, Linda E. Yamamoto, Yusuke Enkhbaatar, Perenlei Rehberg, Sebastian W. Wells, Sandra M. Leonard, Scott Traber, Maret G. Yu, Yong-Ming Cox, Robert A. Hawkins, Hal K. Traber, Lillian D. Herndon, David N. Traber, Daniel L. TI ACUTE LUNG INJURY-INDUCED COLLAGEN DEPOSITION IS ASSOCIATED WITH ELEVATED ASYMMETRIC DIMETHYLARGININE AND ARGINASE ACTIVITY SO SHOCK LA English DT Article DE Fibrosis; NO synthase; oxidative stress; arginine metabolism ID SMOKE-INHALATION INJURY; NITRIC-OXIDE SYNTHASE; CIGARETTE-SMOKE; BURN INJURY; SHEEP; EXPRESSION; INHIBITOR; CELLS; DIMETHYLAMINOHYDROLASE; MALONDIALDEHYDE AB Evidence suggests that lung structure and function are partly maintained by a balance between the competing arginine-metabolizing enzymes arginase and nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. It is metabolized by dimethylarginine dimethylaminohydrolase 2 (DDAH-2), which is oxidant-sensitive. The mechanism that induces excess lung collagen deposition in burned patients has not yet been explored. Our objective was to investigate the role of ADMA and the arginase pathway in acute lung injury. An ovine model for burn and smoke inhalation injury was used to assess excess lung collagen deposition. Sheep were deeply anesthetized during the injury, mechanically ventilated, resuscitated with fluid, and killed after either 2 or 3 weeks. Lungs were assessed histologically and biochemically for collagen content, arginase activity, lipid peroxidation product and antioxidant concentration, and protein concentrations. Plasma was assessed for amino acid and nitrate/nitrite concentrations. Burn and inhalation injury resulted in significantly reduced pulmonary function and increased lung collagen deposition. These physiological changes were associated with significantly increased lung arginase activity, collagen synthesis precursor ornithine aminotransferase, and ornithine decarboxylase, which is associated with cell proliferation. Significant decreases in plasma nitrate/nitrite after injury were associated with increased lung ADMA concentrations and decreased DDAH-2 expression. The decreased DDAH-2 expression was associated with significantly increased lipid peroxidation product and decreased antioxidant content in the lung. These data support that excess lung collagen deposition and reduced pulmonary function in acute lung injury after burn and inhalation injury are mediated through the arginase pathway. C1 [Sousse, Linda E.; Yamamoto, Yusuke; Enkhbaatar, Perenlei; Rehberg, Sebastian W.; Cox, Robert A.; Hawkins, Hal K.; Traber, Lillian D.; Traber, Daniel L.] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. [Sousse, Linda E.; Yamamoto, Yusuke; Enkhbaatar, Perenlei; Rehberg, Sebastian W.; Cox, Robert A.; Hawkins, Hal K.; Traber, Lillian D.; Traber, Daniel L.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Wells, Sandra M.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Environm Agr & Occupat Hlth, Omaha, NE USA. [Leonard, Scott; Traber, Maret G.] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA. [Yu, Yong-Ming] MassGen Hosp Children, Burn Unit, Boston, MA USA. [Herndon, David N.] Shriners Hosp Children, Burn Unit, Galveston, TX 77550 USA. RP Traber, DL (reprint author), Univ Texas Med Branch, Dept Anesthesiol, 301 Univ Blvd,Route 1102, Galveston, TX 77555 USA. EM dltraber@utmb.edu OI Traber, Maret/0000-0002-2892-4024 FU National Institute of General Medical Science [GM66312, GM60668]; National Heart, Lung, and Blood Institute [R00HL088550]; Shrine Hospitals for Children (SHC) [8541, 8450] FX This work was supported by Grants GM66312 and GM60668 from the National Institute of General Medical Science, Grant R00HL088550 from the National Heart, Lung, and Blood Institute, and Grants 8541 and 8450 from the Shrine Hospitals for Children (SHC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the SHC. NR 35 TC 11 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD MAR PY 2011 VL 35 IS 3 BP 282 EP 288 DI 10.1097/SHK.0b013e3181fddd82 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 727DT UT WOS:000287778500010 PM 20938379 ER PT J AU Nehra, D Goldstein, AM AF Nehra, Deepika Goldstein, Allan M. TI Intestinal malrotation: Varied clinical presentation from infancy through adulthood SO SURGERY LA English DT Article ID MIDGUT MALROTATION; SURGICAL-MANAGEMENT; VOLVULUS; ROTATION; ANOMALIES; NONROTATION; OBSTRUCTION; MORBIDITY; AGE; CT AB Background. The purpose of this study was to determine the incidence and clinical presentation of intestinal malrotation from infancy through adulthood by examining the experience of a single institution caring for patients of all ages with this condition. Methods. We conducted a retrospective review on all patients diagnosed with intestinal malrotation at Massachusetts General Hospital between 1992 and 2009. Patient demographics, clinical history, diagnostic tests, operative procedures, and outcome variables were recorded. Patients were divided into 3 age groups: infants (< 1 year), children (1-18 years), and adults (18 years). Results. We identified 170 patients, of whom 31% were infants, 21% were children, and 48% were adults. Infants nearly always presented with emesis (93%), whereas adults most commonly presented with abdominal pain (87%), and less often with emesis (37%) or nausea (31%). The incidence of volvulus declined with age, from 37% to 22% to 12%, in each of the 3 age groups, respectively. Although infants were most often diagnosed within hours or days of symptom onset, 59% of children and 32% of adults experienced symptoms fir years before diagnosis. Upper gastrointestinal series was the most common imaging study performed in infants and children, but was replaced by abdominal computed tomography in adults. All infants and children underwent a Ladd's procedure, compared with only 61% of adults. The majority of patients experienced resolution of symptoms after operative intervention, although this decreased slightly with age. Conclusion. Intestinal malrotation can occur in patients of any age and, in contrast with traditional teaching, nearly half of these patients may present during adulthood. An increased awareness of this entity and an understanding of its varied presentation at different ages may reduce time to diagnosis and improve patient outcome. (Surgery 2011;149:386-93.) C1 [Nehra, Deepika] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Goldstein, Allan M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA 02114 USA. RP Goldstein, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Warren 1153, Boston, MA 02114 USA. EM agoldstein@partners.org NR 36 TC 35 Z9 40 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 MAR PY 2011 VL 149 IS 3 BP 386 EP 393 DI 10.1016/j.surg.2010.07.004 PG 8 WC Surgery SC Surgery GA 731MQ UT WOS:000288111500012 PM 20719352 ER PT J AU Viswanathan, J Haapasalo, A Bottcher, C Miettinen, R Kurkinen, KMA Lu, A Thomas, A Maynard, CJ Romano, D Hyman, BT Berezovska, O Bertram, L Soininen, H Dantuma, NP Tanzi, RE Hiltunen, M AF Viswanathan, Jayashree Haapasalo, Annakaisa Bottcher, Claudia Miettinen, Riitta Kurkinen, Kaisa M. A. Lu, Alice Thomas, Anne Maynard, Christa J. Romano, Donna Hyman, Bradley T. Berezovska, Oksana Bertram, Lars Soininen, Hilkka Dantuma, Nico P. Tanzi, Rudolph E. Hiltunen, Mikko TI Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation SO TRAFFIC LA English DT Article DE beta-amyloid precursor protein; high-molecular-weight forms; PEN-2; proteasomal degradation; transcript variant ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY; BETA-APP; PROTEASOME; UBIQUITINATION; IDENTIFICATION; DEGRADATION; ENDOPROTEOLYSIS; AGGREGATION; INTERACTS AB The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). PS-dependent gamma-secretase generates beta-amyloid (A beta) peptides, which excessively accumulate in AD brain. Here, we have characterized the effects of naturally occurring ubiquilin-1 transcript variants (TVs) on the levels and subcellular localization of PS1 and other gamma-secretase complex components and subsequent gamma-secretase function in human embryonic kidney 293, human neuroblastoma SH-SY5Y and mouse primary cortical cells. Full-length ubiquilin-1 TV1 and TV3 that lacks the proteasome-interaction domain increased full-length PS1 levels as well as induced accumulation of high-molecular-weight PS1 and aggresome formation. Accumulated PS1 colocalized with TV1 or TV3 in the aggresomes. Electron microscopy indicated that aggresomes containing TV1 or TV3 were targeted to autophagosomes. TV1- and TV3-expressing cells did not accumulate other unrelated proteasome substrates, suggesting that the increase in PS1 levels was not because of a general impairment of the ubiquitin-proteasome system. Furthermore, PS1 accumulation and aggresome formation coincided with alterations in A beta levels, particularly in cells overexpressing TV3. These effects were not related to altered gamma-secretase activity or PS1 binding to TV3. Collectively, our results indicate that specific ubiquilin-1 TVs can cause PS1 accumulation and aggresome formation, which may impact AD pathogenesis or susceptibility. C1 [Viswanathan, Jayashree; Haapasalo, Annakaisa; Miettinen, Riitta; Kurkinen, Kaisa M. A.; Soininen, Hilkka; Hiltunen, Mikko] Univ Eastern Finland, Dept Neurol, Inst Clin Med, Kuopio, Finland. [Viswanathan, Jayashree; Haapasalo, Annakaisa; Miettinen, Riitta; Kurkinen, Kaisa M. A.; Soininen, Hilkka; Hiltunen, Mikko] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Bottcher, Claudia; Maynard, Christa J.; Dantuma, Nico P.] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Miettinen, Riitta] CNServices Ltd, Kuopio, Finland. [Lu, Alice; Romano, Donna; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Lu, Alice; Romano, Donna; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA USA. [Thomas, Anne; Hyman, Bradley T.; Berezovska, Oksana] Harvard Univ, Massachusetts Alzheimer Dis Res Ctr, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Sch Med, Charlestown, MA USA. [Bertram, Lars] Max Planck Inst Mol Genet, Dept Vertebrate Genom, Berlin, Germany. RP Hiltunen, M (reprint author), Univ Eastern Finland, Dept Neurol, Inst Clin Med, Kuopio, Finland. EM mikko.hiltunen@uef.fi RI Bertram, Lars/K-3889-2015; OI Bertram, Lars/0000-0002-0108-124X; Dantuma, Nico/0000-0002-6090-4170; Chadchankar, Jayashree/0000-0002-0189-569X FU EC [MEST-CT-2005-019217]; Health Research Council of the Academy of Finland; EVO of Kuopio University Hospital [5772708]; Nordic Centre of Excellence in Neurodegeneration; Sigrid Juselius Foundation; Swedish Research Council; Wenner-Gren Foundation; NIH [AG15379]; Cure Alzheimer's Fund; NIA FX This study was supported by EC FP6, MEST-CT-2005-019217 (to J. V.), the Health Research Council of the Academy of Finland (to A. H., H. S. and M. H.), EVO grant 5772708 of Kuopio University Hospital (to H. S.), the Nordic Centre of Excellence in Neurodegeneration (to N. P. D., H. S. and M. H.), Sigrid Juselius Foundation (to M. H.), the Swedish Research Council (to N. P. D.), the Wenner-Gren Foundation (to C. B.), NIH AG15379 grant (to O. B.) and 'Cure Alzheimer's Fund' and NIA (to R. T.). The authors wish to thank Dr Stefan Lichtenthaler (Adolf-Butenandt-Institute, Ludwig-Maximilians-University) for the generous gift of the HEK293-AP-APP cells, Dr Samuel E. Gandy (Mount Sinai School of Medicine, New York, NY) for kindly providing the Ab14 antibody and Dr Garry Wong (A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland) for revising the language of the manuscript. NR 45 TC 36 Z9 42 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD MAR PY 2011 VL 12 IS 3 BP 330 EP 348 DI 10.1111/j.1600-0854.2010.01149.x PG 19 WC Cell Biology SC Cell Biology GA 719IS UT WOS:000287199000008 PM 21143716 ER PT J AU Glasgow, R Emmons, KM AF Glasgow, Russ Emmons, Karen M. TI The public health need for patient-reported measures and health behaviors in electronic health records: a policy statement of the Society of Behavioral Medicine SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article C1 [Glasgow, Russ] Kaiser Permanente Colorado, Denver, CO USA. [Emmons, Karen M.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Emmons, KM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,LW601, Boston, MA 02215 USA. EM karen_m_emmons@dfci.harvard.edu NR 6 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD MAR PY 2011 VL 1 IS 1 BP 108 EP 109 DI 10.1007/s13142-011-0017-3 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LG UT WOS:000209411900018 PM 24073037 ER PT J AU Bruner, DW Hanisch, LJ Reeve, BB Trotti, AM Schrag, D Sit, L Mendoza, TR Minasian, L O'Mara, A Denicoff, AM Rowland, JH Montello, M Geoghegan, C Abernethy, AP Clauser, SB Castro, K Mitchell, SA Burke, L Trentacosti, AM Basch, EM AF Bruner, Deborah Watkins Hanisch, Laura J. Reeve, Bryce B. Trotti, Andy M. Schrag, Deborah Sit, Laura Mendoza, Tito R. Minasian, Lori O'Mara, Ann Denicoff, Andrea M. Rowland, Julia H. Montello, Michael Geoghegan, Cindy Abernethy, Amy P. Clauser, Steven B. Castro, Kathleen Mitchell, Sandra A. Burke, Laurie Trentacosti, Ann Marie Basch, Ethan M. TI Stakeholder perspectives on implementing the National Cancer Institute's patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Patient-reported outcomes; Symptoms; adverse events; Oncology; Cancer; Clinical trials; Toxicity; safety; Tolerability; Comparative effectiveness research; Cooperative groups; National Cancer Institute AB The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the "PRO-CTCAE." The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI's cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self-reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials. C1 [Bruner, Deborah Watkins] Univ Penn, Abramson Canc Ctr, Sch Nursing, Philadelphia, PA 19104 USA. [Hanisch, Laura J.] Univ Penn, Abramson Canc Ctr, Canc Control & Outcomes Program, Philadelphia, PA 19104 USA. [Reeve, Bryce B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Lineberger Comprehens Canc Ctr, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Trotti, Andy M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Schrag, Deborah] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. [Sit, Laura; Basch, Ethan M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Hlth Outcomes Grp, New York, NY 10065 USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Minasian, Lori] NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [O'Mara, Ann] NCI, Palliat Care Res Community Oncol & Prevent Trial, Canc Prevent Div, Bethesda, MD 20892 USA. [Denicoff, Andrea M.] NCI, Clin Invest Branch, CTEP, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. [Montello, Michael] NCI, Clin Trials Technol, Bethesda, MD 20892 USA. [Geoghegan, Cindy] Breast Canc Network Strength, Chicago, IL 60603 USA. [Abernethy, Amy P.] Duke Univ, Med Ctr, Sch Med, Dept Med, Durham, NC 27710 USA. [Clauser, Steven B.; Castro, Kathleen; Mitchell, Sandra A.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Burke, Laurie; Trentacosti, Ann Marie] US FDA, Study Endpoints & Label Dev, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Basch, EM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Hlth Outcomes Grp, 307 E 63rd St,2nd Floor, New York, NY 10065 USA. EM basche@mskcc.org OI Abernethy, Amy/0000-0001-6930-8722 FU National Cancer Institute [HHSN261200800043C] FX This work was supported by the National Cancer Institute under contract HHSN261200800043C awarded to Dr. Ethan Basch, PI. NR 26 TC 16 Z9 17 U1 0 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD MAR PY 2011 VL 1 IS 1 BP 110 EP 122 DI 10.1007/s13142-011-0025-3 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LG UT WOS:000209411900019 PM 24073038 ER PT J AU Varghese, M Zhao, W Wang, J Cheng, A Qian, XJ Chaudhry, A Ho, L Pasinetti, GM AF Varghese, Merina Zhao, Wei Wang, Jun Cheng, Alice Qian, Xianjuan Chaudhry, Amna Ho, Lap Pasinetti, Giulio Maria TI MITOCHONDRIAL BIOENERGETICS IS DEFECTIVE IN PRESYMPTOMATIC TG2576 AD MICE SO TRANSLATIONAL NEUROSCIENCE LA English DT Article DE Alzheimer's disease; Amyloid; Dementia; Energy Metabolism; Memory; Mitochondria; Oxidative phosphorylation; Oxygen Consumption; Tg2576 ID DEHYDROGENASE COMPLEX ACTIVITY; ALZHEIMERS-DISEASE BRAIN; CYTOCHROME-C-OXIDASE; MOUSE MODEL; PYRUVATE-DEHYDROGENASE; SYNAPTIC MITOCHONDRIA; TRANSGENIC MICE; PROTEIN; MEMORY; ACCUMULATION AB Alzheimer's disease (AD) is an age-related dementia, with the pathological hallmarks of neuritic plaques and neurofibrillary tangles, brain atrophy and loss of synaptic terminals. Dysfunctional mitochondrial bioenergetics is implicated as a contributing factor to the cognitive decline observed in AD. We hypothesized that, in the presence of the AD neurotoxic peptide beta-amyloid, mitochondrial respiration is impaired early in synaptic terminals, which are vital to cognitive performance, preferentially in cognitive centers of the brain. We compared oxygen consumption in synaptosomal and perikaryal mitochondria prepared from the cerebral cortex and cerebellum of wild type (WT) and AD transgenic Tg2576 mice. Compared to WT mice, Tg2576 mice showed decreased mitochondrial respiration in the cerebral cortex specifically in synaptosomal fraction, while the perikaryal mitochondria were unaffected. Neither mitochondrial fraction was affected in the cerebellum of Tg2576 mice as compared to WT. The occurrence of a bioenergetic defect in synaptic terminals of mice over-expressing mutant beta-amyloid, in particular in an area of the brain important to cognition, points to an early role of mitochondrial defects in the onset of cognitive deficits in AD. C1 [Varghese, Merina; Zhao, Wei; Wang, Jun; Cheng, Alice; Qian, Xianjuan; Chaudhry, Amna; Ho, Lap; Pasinetti, Giulio Maria] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Varghese, Merina; Zhao, Wei; Wang, Jun; Cheng, Alice; Qian, Xianjuan; Ho, Lap; Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, Educ & Clin Ctr, Bronx, NY 10468 USA. RP Varghese, M (reprint author), Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu OI Varghese, Merina/0000-0002-1517-3903 FU National Institutes of Health (NIH) [AG02219]; Department of Veterans Affairs FX We are grateful to Dr David B. Hicks for technical assistance. This project was funded by grants from the National Institutes of Health (NIH AG02219 Project 2) and the Department of Veterans Affairs. NR 23 TC 8 Z9 8 U1 1 U2 4 PU VERSITA PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD MAR PY 2011 VL 2 IS 1 BP 1 EP 5 DI 10.2478/s13380-011-0011-8 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 873MD UT WOS:000298886500001 ER PT J AU Ning, MM Lo, EH AF Ning, MingMing Lo, Eng H. TI Opportunities and Challenges in Omics (vol 1, pg 233, 2010) SO TRANSLATIONAL STROKE RESEARCH LA English DT Correction C1 [Ning, MingMing; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Res Lab, Clin Prote Res Ctr, Boston, MA 02114 USA. [Ning, MingMing; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Clin Prote Res Ctr, Res Lab, Boston, MA 02114 USA. [Ning, MingMing; Lo, Eng H.] Harvard Univ, Sch Med, Boston, MA USA. RP Ning, MM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Res Lab, Clin Prote Res Ctr, Boston, MA 02114 USA. EM Ning@hms.harvard.edu; Lo@helix.mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD MAR PY 2011 VL 2 IS 1 BP 128 EP 128 DI 10.1007/s12975-010-0058-9 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 943YB UT WOS:000304162800016 PM 24323589 ER PT J AU Flynn, RL Zou, L AF Flynn, Rachel Litman Zou, Lee TI ATR: a master conductor of cellular responses to DNA replication stress SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID INTERSTRAND CROSS-LINK; S-PHASE CHECKPOINT; FANCONI-ANEMIA PATHWAY; CHROMATIN REMODELING COMPLEX; HOLLIDAY JUNCTION RESOLVASE; DAMAGE CHECKPOINT; STRANDED-DNA; MONOUBIQUITINATED FANCD2; SIGNALING PATHWAYS; POLYMERASE-ALPHA AB The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signaling pathways play crucial roles in detecting DNA damage, regulating DNA repair and coordinating DNA repair with other cellular processes. In vertebrates, the ATM- and Rad3-related (ATR) kinase plays a key role in the response to a broad spectrum of DNA damage and DNA replication stress. Here, we will discuss the recent findings on how ATR is activated by DNA damage and how it protects the genome against interference with DNA replication. C1 [Flynn, Rachel Litman; Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Zou, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. EM zou.lee@mgh.harvard.edu FU National Institutes of Health [GM076388]; American Cancer Society [0902501] FX L.Z. is supported by a National Institutes of Health grant (GM076388) and is an Ellison New Scholar on Aging. R.L.F. is supported by an American Cancer Society fellowship 0902501. We thank Dr. Bunsyo Shiotani for helpful comments and apologize to our colleagues whose work we could not cover owing to length constrains. NR 100 TC 106 Z9 109 U1 0 U2 16 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2011 VL 36 IS 3 BP 133 EP 140 DI 10.1016/j.tibs.2010.09.005 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 740WE UT WOS:000288824300002 PM 20947357 ER PT J AU Garcia-Garcia, F De la Herran-Arita, AK Juarez-Aguilar, E Regalado-Santiago, C Millan-Aldaco, D Blanco-Centurion, C Drucker-Colin, R AF Garcia-Garcia, Fabio De la Herran-Arita, Alberto K. Juarez-Aguilar, Enrique Regalado-Santiago, Citlalli Millan-Aldaco, Diana Blanco-Centurion, Carlos Drucker-Colin, Rene TI Growth hormone improves hippocampal adult cell survival and counteracts the inhibitory effect of prolonged sleep deprivation on cell proliferation SO BRAIN RESEARCH BULLETIN LA English DT Article DE BrdU; Cell proliferation; Neuroprotection; Neuronal survival; Growth hormone ID SLOW-WAVE SLEEP; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; DENTATE GYRUS; FACTOR-I; RAT HYPOTHALAMUS; DEFICIENT ADULTS; GENE-EXPRESSION; REM-SLEEP; NEUROGENESIS AB Sleep deprivation (SD) produces numerous deleterious changes in brain cells, including apoptosis. It has been demonstrated that growth hormone (GH) stimulates cell growth and counteracts apoptosis, although this anti-apoptotic effect has not been tested against SD. To determine the protective effect of GH administration on cell proliferation and survival in the dentate gyrus (DG) of the hippocampus after sleep deprivation: we injected Wistar adult rats with a low dose of recombinant human GH (rhGH 5 ng/kg) per seven days and then we gently sleep deprived the animals for 48 consecutive hours. 5-Bromodeoxiuridine (BrdU) was administered to assess cell proliferation after the GH treatment and NeuN was used as marker of cell fate. Our results indicate that GH produced a three fold increase in the number of BrdU positive cells within the DG [Control = 1044 +/- 106.38 cells, rhGH = 2952 +/- 99.84 cells, P < 0.011. In contrast, 48 h of SD significantly reduced cell proliferation but this effect was antagonized by the GH administration [SD = 540 +/- 18.3 cells, rhGH + SD = 1116 +/- 84.48 cells, P < 0.004]. Paradoxically, SD and GH administration increased cell survival separately but no significantly compared with control animals. However, cell survival was increased in animals treated with rhGH + SD compared to rats injected with saline solution [P < 0.04]. Within the survival cells, the percentage of neurons was higher in SD animals [95%] compared with saline group, while this percentage (NeuN positive cells) was increased in animals treated with rhGH + SD [120%] compared with rhGH [25%] alone. Our findings indicate that CH strongly promotes cell proliferation in the adult brain and also protects the hippocampal neuronal precursors against the deleterious effect of prolonged sleep loss. (C) 2011 Elsevier Inc. All rights reserved. C1 [Garcia-Garcia, Fabio; Juarez-Aguilar, Enrique; Regalado-Santiago, Citlalli] Univ Veracruzana, Dept Biomed, Inst Ciencias Salud, Xalapa 91190, Veracruz, Mexico. [De la Herran-Arita, Alberto K.; Millan-Aldaco, Diana; Drucker-Colin, Rene] Univ Nacl Autonoma Mexico, Dept Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico. [Blanco-Centurion, Carlos] Harvard Univ, Sch Med, Dept Neurol, Boston VA Healthcare Syst, Boston, MA 02132 USA. RP Garcia-Garcia, F (reprint author), Univ Veracruzana, Dept Biomed, Inst Ciencias Salud, Av Luis Castelazo Ayala S-N, Xalapa 91190, Veracruz, Mexico. EM fgarcia@uv.mx OI Garcia-Garcia, Fabio/0000-0002-3756-9845 FU PROMEP [UVER-PTC-118] FX This work was supported by a grant from PROMEP UVER-PTC-118. The authors wish to thank Marcela Palomero-Rivero for technical assistance. NR 65 TC 13 Z9 14 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB 28 PY 2011 VL 84 IS 3 BP 252 EP 257 DI 10.1016/j.brainresbull.2011.01.003 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 741SV UT WOS:000288885800009 PM 21256199 ER PT J AU Wang, TJ AF Wang, Thomas J. TI Usefulness of Novel Screening Tests for Cardiovascular Disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID CORONARY-HEART-DISEASE; RISK PREDICTION; BIOMARKERS; EVENTS C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. RP Wang, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org NR 13 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 28 PY 2011 VL 171 IS 4 BP 284 EP 285 DI 10.1001/archinternmed.2010.543 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 728FD UT WOS:000287858900002 PM 21357802 ER PT J AU Munshi, MN Segal, AR Suhl, E Staum, E Desrochers, L Sternthal, A Giusti, J McCartney, R Lee, Y Bonsignore, P Weinger, K AF Munshi, Medha N. Segal, Alissa R. Suhl, Emmy Staum, Elizabeth Desrochers, Laura Sternthal, Adrianne Giusti, Judy McCartney, Richard Lee, Yishan Bonsignore, Patricia Weinger, Katie TI Frequent Hypoglycemia Among Elderly Patients With Poor Glycemic Control SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID OLDER-ADULTS; ASSOCIATION; PERFORMANCE AB Background: Episodes of hypoglycemia are particularly dangerous in the older population. To reduce the risk of hypoglycemia, relaxation of the standard hemoglobin A(1c) (HbA(1c)) goals has been proposed for frail elderly patients. However, the risk of hypoglycemia in this population with higher HbA(1c) levels is unknown. Methods: Patients 69 years or older with HbA(1C) values of 8% or greater were evaluated with blinded continuous glucose monitoring for 3 days. Results: Forty adults (mean [SD] age, 75 [5] years; HbA1C value, 9.3% [1.3%]; diabetes duration, 22 [14] years; 28 patients [70%] with type 2 diabetes mellitus; and 37 [93%] using insulin) were evaluated. Twenty-six patients (65%) experienced 1 or more episodes of hypoglycemia (glucose level < 70 mg/dL). Among these, 12 (46%) experienced a glucose level below 50 mg/dL and 19 (73%), a level below 60 mg/dL. The average number of episodes was 4; average duration, 46 minutes. Eighteen patients (69%) had at least 1 nocturnal episode (10 PM to 6 AM). Of the total of 102 hypoglycemic episodes, 95 (93%) were unrecognized by finger-stick glucose measurements performed 4 times a day or by symptoms. Conclusions: Hypoglycemic episodes are common in older adults with poor glycemic control. Raising HbA(1C) goals may not be adequate to prevent hypoglycemia in this population. C1 [Munshi, Medha N.; Segal, Alissa R.; Staum, Elizabeth] Joslin Diabet Ctr, Sect Adult Diabet, Boston, MA 02215 USA. [Suhl, Emmy; Sternthal, Adrianne; Giusti, Judy; Lee, Yishan] Joslin Diabet Ctr, Sect Clin Behav & Outcome Res, Boston, MA 02215 USA. [Munshi, Medha N.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gerontol, Boston, MA 02215 USA. [Munshi, Medha N.; Weinger, Katie] Harvard Univ, Sch Med, Boston, MA USA. [Segal, Alissa R.] Massachusetts Coll Pharm & Hlth Sci, Dept Pharm Practice, Boston, MA USA. [Desrochers, Laura] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Bonsignore, Patricia] Valley Med Grp, Diabet Program, Amherst, MA USA. RP Munshi, MN (reprint author), Joslin Diabet Ctr, Sect Adult Diabet, 1 Joslin Pl, Boston, MA 02215 USA. EM medha.munshi@joslin.harvard.edu FU American Diabetes Association [1-07-CR-40]; Department of Defense Peer-Reviewed Medical Research Program of the Office of the Congressionally Directed Medical Research [W81XWH-07-1-0282]; Graetz Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [P30 NIDDK36836, R01 NIDDK060115] FX This study was supported in part by grant 1-07-CR-40 from a clinical research award from the American Diabetes Association (Dr Munshi), grant W81XWH-07-1-0282 from the Department of Defense Peer-Reviewed Medical Research Program of the Office of the Congressionally Directed Medical Research Programs (Dr Munshi), and by grants from the Graetz Foundation (Dr Munshi), and grants P30 NIDDK36836 (Joslin Diabetes Center) and R01 NIDDK060115 (Dr Weinger) from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 14 TC 53 Z9 55 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 28 PY 2011 VL 171 IS 4 BP 362 EP 364 DI 10.1001/archinternmed.2010.539 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 728FD UT WOS:000287858900019 PM 21357814 ER PT J AU Petnicki-Ocwieja, T DeFrancesco, AS Chung, E Darcy, CT Bronson, RT Kobayashi, KS Hu, LT AF Petnicki-Ocwieja, Tanja DeFrancesco, Alicia S. Chung, Erin Darcy, Courtney T. Bronson, Roderick T. Kobayashi, Koichi S. Hu, Linden T. TI Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance SO PLOS ONE LA English DT Article ID INNATE IMMUNE ACTIVATION; TOLL-LIKE RECEPTOR-2; NF-KAPPA-B; CROHNS-DISEASE; STREPTOCOCCUS-PNEUMONIAE; INFLAMMATORY RESPONSES; LEGIONELLA-PNEUMOPHILA; CYTOKINE INDUCTION; ADAPTIVE IMMUNITY; HOST-DEFENSE AB The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP), resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance. C1 [Petnicki-Ocwieja, Tanja; DeFrancesco, Alicia S.; Chung, Erin; Darcy, Courtney T.; Hu, Linden T.] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Petnicki-Ocwieja, T (reprint author), Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA USA. EM lhu@tuftsmedicalcenter.org RI Hu, Linden/L-6314-2016 OI Hu, Linden/0000-0003-1659-5558 FU [R01AI071107]; [R56AI80646]; [T32AI007329] FX This work was supported by R01AI071107 ( L. T. H.), R56AI80646 ( L. T. H.), and T32AI007329 (T.P.O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 15 Z9 15 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2011 VL 6 IS 2 AR e17414 DI 10.1371/journal.pone.0017414 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729EM UT WOS:000287931400071 PM 21387014 ER PT J AU Westover, MB Westover, KD Bianchi, MT AF Westover, M. Brandon Westover, Kenneth D. Bianchi, Matt T. TI Significance testing as perverse probabilistic reasoning SO BMC MEDICINE LA English DT Article ID GENERAL MEDICAL JOURNALS; P-VALUE FALLACY; BAYESIAN METHODS; DECISION-MAKING; GENETIC ASSOCIATIONS; CLINICAL-RESEARCH; HEART-FAILURE; STATISTICS; INFERENCE; TRIALS AB Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference. C1 [Westover, M. Brandon; Bianchi, Matt T.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Westover, Kenneth D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA. RP Westover, MB (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM mwestover@partners.org NR 137 TC 10 Z9 10 U1 4 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 28 PY 2011 VL 9 AR 20 DI 10.1186/1741-7015-9-20 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 763NF UT WOS:000290565300001 PM 21356064 ER PT J AU Zuleger, CL Macklin, MD Bostwick, BL Pei, QL Newton, MA Albertini, MR AF Zuleger, Cindy L. Macklin, Michael D. Bostwick, Bret L. Pei, Qinglin Newton, Michael A. Albertini, Mark R. TI In vivo 6-thioguanine-resistant T cells from melanoma patients have public TCR and share TCR beta amino acid sequences with melanoma-reactive T cells SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE T cell receptor; CDR3 sequencing; Tumor immunity; Hypoxanthine-guanine; phosphoribosyltransferase ID MYELIN BASIC-PROTEIN; PERIPHERAL-BLOOD; RECEPTOR REPERTOIRE; LYMPHOCYTE RECOGNITION; MULTIPLE-SCLEROSIS; MUTANT FREQUENCY; ANTIGEN RECEPTOR; SELF-ANTIGEN; ALPHA-CHAIN; INFLUENZA-A AB vivo hypoxanthine-guanine phosphoribosyltransferase (HPRT)-deficient T cells (MT) from melanoma patients are enriched for T cells with in vivo clonal amplifications that traffic between blood and tumor tissues. Melanoma is thus a model cancer to test the hypothesis that in vivo MT from cancer patients can be used as immunological probes for immunogenic tumor antigens. MT were obtained by 6-thioguanine (TG) selection of lymphocytes from peripheral blood and tumor tissues, and wild-type T cells (WT) were obtained analogously without TG selection. cDNA sequences of the T cell receptor beta chains (TRB) were used as unambiguous biomarkers of in vivo clonality and as indicators of T cell specificity. Public TRB were identified in MT from the blood and tumor of different melanoma patients. Such public TRB were not found in normal control MT or WT. As an indicator of T cell specificity for melanoma, the > 2600 MT and WT TRB, including the public TRB from melanoma patients, were compared to a literature-derived empirical database of > 1270 TRB from melanoma-reactive T cells. Various degrees of similarity, ranging from 100% conservation to 3-amino acid motifs (3-mer), were found between both melanoma patient MT and WT TRBs and the empirical database. The frequency of 3-mer and 4-mer TRB matching to the empirical database was significantly higher in MT compared with WT in the tumor (p = 0.0285 and p = 0.006, respectively). In summary, in vivo MT from melanoma patients contain public TRB as well as T cells with specificity for characterized melanoma antigens. We conclude that in vivo MT merit study as novel probes for uncharacterized immunogenic antigens in melanoma and other malignancies. Published by Elsevier B.V. C1 [Albertini, Mark R.] Univ Wisconsin, Dept Med, Carbone Canc Ctr, Madison, WI 53792 USA. [Pei, Qinglin; Newton, Michael A.] Univ Wisconsin, Dept Stat, Madison, WI 53792 USA. [Bostwick, Bret L.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Newton, Michael A.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53792 USA. [Albertini, Mark R.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Albertini, MR (reprint author), Univ Wisconsin, Dept Med, Carbone Canc Ctr, 600 Highland Ave,K6-530, Madison, WI 53792 USA. EM mralbert@wisc.edu FU National Cancer Institute [P30 CA014520]; Gretchen and Andrew Dawes Melanoma Research Fund; Ann's Hope Foundation; Steve Leuthold Family; Tim Eagle Memorial FX This material is based on work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Service; grant P30 CA014520 from the National Cancer Institute; the Gretchen and Andrew Dawes Melanoma Research Fund; Ann's Hope Foundation; the Jay Van Sloan Memorial from the Steve Leuthold Family; and the Tim Eagle Memorial. The funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. We also thank Drs. David Mahvi, Sharon Weber, and Tracey Weigel for identifying appropriate surgical specimens; Ms. Susi Nehls for assistance with manuscript preparation; and Dr. Richard Albertini for stimulating discussions. The authors have no financial or other conflicts of interests to disclose related to this publication. The contents do not represent the views of the Dept of Veterans Affairs or the United States Government. NR 56 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 28 PY 2011 VL 365 IS 1-2 BP 76 EP 86 DI 10.1016/j.jim.2010.12.007 PG 11 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 738DW UT WOS:000288620600008 PM 21182840 ER PT J AU Yeh, HD Smoot, E Schoenfeld, DA Markmann, JF AF Yeh, Heidi Smoot, Elizabeth Schoenfeld, David A. Markmann, James F. TI Geographic Inequity in Access to Livers for Transplantation SO TRANSPLANTATION LA English DT Article DE Liver transplantation; Allocation; Geographic variation; Organ demand; Listings per capita ID ORGAN ALLOCATION; MELD SCORE; SURVIVAL; MODEL; DISEASE; SYSTEM; IMPACT; RATES AB Background. Liver transplantation offers life-saving therapy for patients with decompensated liver disease or T2 hepatocellular carcinomas. In the United States, deceased donor livers are primarily allocated by Model for End-Stage Liver Disease (MELD) score within each of the country's more than 50 donation service areas (DSAs). Variation in DSA size, population, and organ availability have engendered concern that unequal access to deceased donor livers across DSAs contributes to geographic variability in outcome. Methods. To determine the extent to which DSA variability in organ availability correlated with combined waitlist and posttransplant mortality, we analyzed retrospectively national waitlist and posttransplant data for a 7-year period after implementation of the current MELD-based allocation system. Results. Marked variation among DSAs was evident in death rate (3.3-fold), transplant rate (20-fold), and mean transplant MELD (> 10 points). Death rate correlated with organ availability was assessed by transplant rate and transplant MELD. DSAs with low organ availability included the country's largest cities, had more new listings per capita, larger waitlists, more transplant centers per DSA, and a higher proportion of black and Asian patients. DSAs of organ shortage were also characterized by more frequent dual listing at another transplant center, more living donor liver transplants, and increased average length of the transplant admission. Conclusions. Geographic differences in deceased donor organ availability contribute to variation in overall death rate of liver transplant patients, shape the clinical practice of transplant, and influence the resources consumed per transplant. Geographic variation in organ access results primarily from rates of listing rather than donation. Our findings highlight the need to restructure organ distribution areas to achieve equal access to deceased donor livers for transplantation in the United States. C1 [Yeh, Heidi; Markmann, James F.] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. [Smoot, Elizabeth; Schoenfeld, David A.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Markmann, JF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Div, 5th Floor,White Bldg,55 Fruit St, Boston, MA 02114 USA. EM JMarkmann@partners.org FU NCATS NIH HHS [UL1 TR000170] NR 27 TC 68 Z9 68 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 27 PY 2011 VL 91 IS 4 BP 479 EP 486 DI 10.1097/TP.0b013e3182066275 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 718MR UT WOS:000287127600019 PM 21200366 ER PT J AU Guo, CG Alt, FW Giallourakis, C AF Guo, Chunguang Alt, Frederick W. Giallourakis, Cosmas TI PAIRing for Distal Igh Locus V(D)J Recombination SO IMMUNITY LA English DT Editorial Material ID HEAVY-CHAIN GENE; B-CELL; IMMUNOGLOBULIN; GENERATION; REPERTOIRE; SEGMENTS AB In this issue of Immunity Ebert et al. (2011) defined the lineage- and stage-specific Pax5-dependent cis-sequences termed PAIR elements in the distal region of the mouse heavy chain immunoglobulin locus (Igh). These sequences may have a role in long-range IgH V(D)J recombination. C1 [Guo, Chunguang; Alt, Frederick W.; Giallourakis, Cosmas] Harvard Univ, Immune Dis Inst, Howard Hughes Med Inst, Childrens Hosp,Dept Genet,Med Sch, Boston, MA 02115 USA. [Giallourakis, Cosmas] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Alt, FW (reprint author), Harvard Univ, Immune Dis Inst, Howard Hughes Med Inst, Childrens Hosp,Dept Genet,Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU NIAID NIH HHS [R01 AI020047] NR 10 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 25 PY 2011 VL 34 IS 2 BP 139 EP 141 DI 10.1016/j.immuni.2011.02.010 PG 3 WC Immunology SC Immunology GA 729YD UT WOS:000287989500002 PM 21349424 ER PT J AU Nagashima, K Shumway, SD Sathyanarayanan, S Chen, AH Dolinski, B Xu, YY Keilhack, H Thi, N Wiznerowicz, M Li, LX Lutterbach, BA Chi, A Paweletz, C Allison, T Yan, YW Munshi, SK Klippel, A Kraus, M Bobkova, EV Deshmukh, S Xu, ZW Mueller, U Szewczak, AA Pan, BS Richon, V Pollock, R Blume-Jensen, P Northrup, A Andersen, JN AF Nagashima, Kumiko Shumway, Stuart D. Sathyanarayanan, Sriram Chen, Albert H. Dolinski, Brian Xu, Youyuan Keilhack, Heike Thi Nguyen Wiznerowicz, Maciej Li, Lixia Lutterbach, Bart A. Chi, An Paweletz, Cloud Allison, Timothy Yan, Youwei Munshi, Sanjeev K. Klippel, Anke Kraus, Manfred Bobkova, Ekaterina V. Deshmukh, Sujal Xu, Zangwei Mueller, Uwe Szewczak, Alexander A. Pan, Bo-Sheng Richon, Victoria Pollock, Roy Blume-Jensen, Peter Northrup, Alan Andersen, Jannik N. TI Genetic and Pharmacological Inhibition of PDK1 in Cancer Cells CHARACTERIZATION OF A SELECTIVE ALLOSTERIC KINASE INHIBITOR SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMALL-MOLECULE INHIBITORS; HUMAN BREAST-CANCER; 3-PHOSPHOINOSITIDE-DEPENDENT KINASE-1; PHOSPHATIDYLINOSITOL 3-KINASE; STRUCTURAL MECHANISM; SIGNAL-TRANSDUCTION; TUMOR-SUPPRESSOR; TYROSINE KINASE; DRUG DISCOVERY; AGC KINASES AB Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems. C1 [Nagashima, Kumiko; Shumway, Stuart D.; Sathyanarayanan, Sriram; Chen, Albert H.; Dolinski, Brian; Xu, Youyuan; Keilhack, Heike; Thi Nguyen; Wiznerowicz, Maciej; Li, Lixia; Lutterbach, Bart A.; Chi, An; Paweletz, Cloud; Klippel, Anke; Kraus, Manfred; Bobkova, Ekaterina V.; Deshmukh, Sujal; Xu, Zangwei; Mueller, Uwe; Szewczak, Alexander A.; Pan, Bo-Sheng; Richon, Victoria; Pollock, Roy; Blume-Jensen, Peter; Northrup, Alan; Andersen, Jannik N.] Merck Res Labs, Boston, MA 02115 USA. [Allison, Timothy; Yan, Youwei; Munshi, Sanjeev K.] Merck & Co Inc, West Point, PA 19486 USA. RP Andersen, JN (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 44 Binney St, Boston, MA 02115 USA. EM jannik_andersen@dfci.harvard.edu NR 71 TC 37 Z9 38 U1 1 U2 8 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 FEB 25 PY 2011 VL 286 IS 8 BP 6433 EP 6448 DI 10.1074/jbc.M110.156463 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723AB UT WOS:000287476400054 PM 21118801 ER PT J AU Parchman, ML Scoglio, CM Schumm, P AF Parchman, Michael L. Scoglio, Caterina M. Schumm, Phillip TI Understanding the implementation of evidence-based care: A structural network approach SO IMPLEMENTATION SCIENCE LA English DT Article ID HEALTH-CARE; DISSEMINATION; INNOVATION; DIFFUSION; BEHAVIOR; SPREAD AB Background: Recent study of complex networks has yielded many new insights into phenomenon such as social networks, the internet, and sexually transmitted infections. The purpose of this analysis is to examine the properties of a network created by the 'co-care' of patients within one region of the Veterans Health Affairs. Methods: Data were obtained for all outpatient visits from 1 October 2006 to 30 September 2008 within one large Veterans Integrated Service Network. Types of physician within each clinic were nodes connected by shared patients, with a weighted link representing the number of shared patients between each connected pair. Network metrics calculated included edge weights, node degree, node strength, node coreness, and node betweenness. Log-log plots were used to examine the distribution of these metrics. Sizes of k core networks were also computed under multiple conditions of node removal. Results: There were 4,310,465 encounters by 266,710 shared patients between 722 provider types (nodes) across 41 stations or clinics resulting in 34,390 edges. The number of other nodes to which primary care provider nodes have a connection (172.7) is 42% greater than that of general surgeons and two and one-half times as high as cardiology. The log-log plot of the edge weight distribution appears to be linear in nature, revealing a 'scale-free' characteristic of the network, while the distributions of node degree and node strength are less so. The analysis of the k-core network sizes under increasing removal of primary care nodes shows that about 10 most connected primary care nodes play a critical role in keeping the k-core networks connected, because their removal disintegrates the highest k-core network. Conclusions: Delivery of healthcare in a large healthcare system such as that of the US Department of Veterans Affairs (VA) can be represented as a complex network. This network consists of highly connected provider nodes that serve as 'hubs' within the network, and demonstrates some 'scale-free' properties. By using currently available tools to explore its topology, we can explore how the underlying connectivity of such a system affects the behavior of providers, and perhaps leverage that understanding to improve quality and outcomes of care. C1 [Parchman, Michael L.] Univ Texas Hlth Sci Ctr San Antonio, Family & Community Med Dept, San Antonio, TX 78229 USA. [Parchman, Michael L.] S Texas Vet Healthcare Syst, VERDICT Hlth Serv Res Program 11C6, San Antonio, TX 78229 USA. [Scoglio, Caterina M.; Schumm, Phillip] Kansas State Univ, Elect & Comp Engn Dept, Manhattan, KS 66506 USA. RP Parchman, ML (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Family & Community Med Dept, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM parchman@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 FU National Academies Keck Futures Initiative (NAKFI) [CS15]; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service FX Funding for this study provided by the National Academies Keck Futures Initiative (NAKFI CS15) and the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 31 TC 10 Z9 10 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD FEB 24 PY 2011 VL 6 AR 14 DI 10.1186/1748-5908-6-14 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 734LJ UT WOS:000288335300001 PM 21349194 ER PT J AU Tsibris, AMN Shepard, JAO Zukerberg, LR AF Tsibris, Athe M. N. Shepard, Jo-Anne O. Zukerberg, Lawrence R. TI Case 6-2011: A 77-Year-Old Man with Dyspnea, Weakness, and Diaphoresis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN GRANULOCYTIC EHRLICHIOSIS; UNITED-STATES; ANAPLASMA-PHAGOCYTOPHILUM; SURVEILLANCE; INFECTION; FEVER; BLOOD C1 [Tsibris, Athe M. N.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tsibris, Athe M. N.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shepard, Jo-Anne O.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Tsibris, AMN (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. NR 24 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 24 PY 2011 VL 364 IS 8 BP 759 EP 767 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 725NP UT WOS:000287652500013 PM 21345106 ER PT J AU Benz, EJ AF Benz, Edward J., Jr. TI Newborn Screening for alpha-Thalassemia - Keeping Up with Globalization SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Benz, EJ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 7 Z9 7 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 FEB 24 PY 2011 VL 364 IS 8 BP 770 EP 771 DI 10.1056/NEJMe1013338 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 725NP UT WOS:000287652500015 PM 21345108 ER PT J AU Hornick, JL Shapiro, GI Antonescu, CR AF Hornick, Jason L. Shapiro, Geoffrey I. Antonescu, Cristina R. TI More on Crizotinib REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID INFLAMMATORY MYOFIBROBLASTIC TUMOR C1 [Hornick, Jason L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Hornick, JL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM geoffrey_shapiro@dfci.harvard.edu NR 5 TC 0 Z9 0 U1 0 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 FEB 24 PY 2011 VL 364 IS 8 BP 778 EP 779 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 725NP UT WOS:000287652500022 ER PT J AU Iafrate, AJ Kwak, E Clark, JW AF Iafrate, A. John Kwak, Eunice Clark, Jeffrey W. TI More on Crizotinib REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Iafrate, A. John; Kwak, Eunice; Clark, Jeffrey W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Iafrate, AJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ekwak@partners.org NR 1 TC 0 Z9 0 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 FEB 24 PY 2011 VL 364 IS 8 BP 778 EP 778 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 725NP UT WOS:000287652500021 ER PT J AU Kiessling, MK Oberholzer, PA Mondal, C Karpova, MB Zipser, MC Lin, WM Girardi, M MacConaill, LE Kehoe, SM Hatton, C French, LE Garraway, LA Polier, G Suss, D Klemke, CD Krammer, PH Gulow, K Dummer, R AF Kiessling, Michael K. Oberholzer, Patrick A. Mondal, Chandrani Karpova, Maria B. Zipser, Marie C. Lin, William M. Girardi, Michael MacConaill, Laura E. Kehoe, Sarah M. Hatton, Charlie French, Lars E. Garraway, Levi A. Polier, Gernot Suess, Dorothee Klemke, Claus-Detlev Krammer, Peter H. Guelow, Karsten Dummer, Reinhard TI High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade SO BLOOD LA English DT Article ID T-CELL LYMPHOMA; MYCOSIS-FUNGOIDES; SEZARY-SYNDROME; AZD6244 ARRY-142886; RAS MUTATIONS; LUNG-CANCER; KINASE; GENES; LEUKEMIA; DISEASE AB Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sezary syndrome, and 13 non-mycosis fungoides/Sezary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS(G13D) mutation; one Sezary syndrome and one CD30(+) CTCL harbored a NRAS(Q61K) amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRAS(Q61K) mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRASQ61K mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors. (Blood. 2011;117(8):2433-2440) C1 [Oberholzer, Patrick A.; Karpova, Maria B.; Zipser, Marie C.; French, Lars E.; Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Kiessling, Michael K.; Polier, Gernot; Suess, Dorothee; Krammer, Peter H.; Guelow, Karsten] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Oberholzer, Patrick A.; MacConaill, Laura E.; Hatton, Charlie; Garraway, Levi A.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Oberholzer, Patrick A.; Mondal, Chandrani; MacConaill, Laura E.; Kehoe, Sarah M.; Hatton, Charlie; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Oberholzer, Patrick A.; Mondal, Chandrani; MacConaill, Laura E.; Kehoe, Sarah M.; Hatton, Charlie; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Lin, William M.; Girardi, Michael] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Klemke, Claus-Detlev] Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol Venerol & Allergol, D-6800 Mannheim, Germany. RP Dummer, R (reprint author), Univ Zurich Hosp, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. EM k.guelow@dkfz.de; reinhard.dummer@usz.ch FU Novartis Foundation; Julius Muller Foundation; Gottfried and Julia Bangerter-Rhyner Foundation; Wilhelm Sander Foundation; Bayer Schering Pharma AG; Skin Cancer Foundation; Yale Cancer Center; American Skin Association; Yale School of Medicine Fellowship; Helmholtz Alliance Immunotherapy of Cancer [HA202] FX P.A.O. and L.A.G. were supported by the Novartis Foundation. M.B.K. was supported by the Julius Muller Foundation. M.C.Z. was supported by the Gottfried and Julia Bangerter-Rhyner Foundation. M.K.K. was supported by the Wilhelm Sander Foundation and Bayer Schering Pharma AG. W.M.L. and M.G. were supported by the Skin Cancer Foundation and the Yale Cancer Center Swebelius Fund. W.M.L. was also supported by the American Skin Association and the Yale School of Medicine Fellowship Program. K.G. and P.H.K. were supported by the Helmholtz Alliance Immunotherapy of Cancer (HA202). NR 50 TC 40 Z9 42 U1 0 U2 6 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 FEB 24 PY 2011 VL 117 IS 8 BP 2433 EP 2440 DI 10.1182/blood-2010-09-305128 PG 8 WC Hematology SC Hematology GA 726DK UT WOS:000287698800024 PM 21209378 ER PT J AU Engers, DW Field, JR Le, U Zhou, Y Bolinger, JD Zamorano, R Blobaum, AL Jones, CK Jadhav, S Weaver, CD Conn, PJ Lindsley, CW Niswender, CM Hopkins, CR AF Engers, Darren W. Field, Julie R. Le, Uyen Zhou, Ya Bolinger, Julie D. Zamorano, Rocio Blobaum, Anna L. Jones, Carrie K. Jadhav, Satyawan Weaver, C. David Conn, P. Jeffrey Lindsley, Craig W. Niswender, Colleen M. Hopkins, Corey R. TI Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-(4-Acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu(4)) with CNS Exposure in Rats SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PARKINSONS-DISEASE; MGLUR4; PHARMACOLOGY; MECHANISM; PAMS AB Herein we report the discovery, synthesis, and evaluation of a series of N-(4-acetamido)-phenylpico-linamides as positive allosteric modulators of mGlu(4). Compounds from the series show submicromolar potency at both human and rat mGlu(4). In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats. C1 [Engers, Darren W.; Field, Julie R.; Le, Uyen; Zhou, Ya; Bolinger, Julie D.; Zamorano, Rocio; Blobaum, Anna L.; Jones, Carrie K.; Jadhav, Satyawan; Weaver, C. David; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Engers, Darren W.; Zhou, Ya; Zamorano, Rocio; Blobaum, Anna L.; Jones, Carrie K.; Jadhav, Satyawan; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.] Vanderbilt Univ, Med Ctr, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. [Jones, Carrie K.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Lindsley, Craig W.] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. [Weaver, C. David; Conn, P. Jeffrey] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA. [Engers, Darren W.; Lindsley, Craig W.; Hopkins, Corey R.] Vanderbilt Specialized Chem Ctr Accelerated Probe, Nashville, TN 37232 USA. RP Niswender, CM (reprint author), Vanderbilt Univ, Med Ctr, Dept Pharmacol, 2213 Garland Ave, Nashville, TN 37232 USA. EM colleen.niswender@vanderbilt.edu; corey.r.hopkins@vanderbilt.edu RI Conn, Peter/D-7848-2012; Zhou, Ya/F-1220-2013 FU National Institute of Mental Health, National Institute of Neurological Disorders and Stroke; Michael J. Fox Foundation; Vanderbilt Department of Pharmacology; Vanderbilt Institute of Chemical Biology FX We thank Emily L. Days, Tasha Nalywajko, Cheryl A. Austin, and Michael Baxter Williams for their critical contributions to the HTS portion of the project. In addition, we thank Katrina Brewer, Ryan Morrison, and Matt Mulder for technical assistance with the PK assays and Chris Denicola, Nathan Kett, and Sichen Chang for the purification of compounds utilizing the mass-directed HPLC system. This work was supported by the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, the Michael J. Fox Foundation, the Vanderbilt Department of Pharmacology, and the Vanderbilt Institute of Chemical Biology. Vanderbilt is a member of the MLPCN and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (NIH/MLPCN; 5U54MH084659-02). NR 19 TC 22 Z9 22 U1 0 U2 2 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 FEB 24 PY 2011 VL 54 IS 4 BP 1106 EP 1110 DI 10.1021/jm101271s PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 721FE UT WOS:000287338200019 PM 21247167 ER PT J AU Lodato, S Rouaux, C Quast, KB Jantrachotechatchawan, C Studer, M Hensch, TK Arlotta, P AF Lodato, Simona Rouaux, Caroline Quast, Kathleen B. Jantrachotechatchawan, Chanati Studer, Michele Hensch, Takao K. Arlotta, Paola TI Excitatory Projection Neuron Subtypes Control the Distribution of Local Inhibitory Interneurons in the Cerebral Cortex SO NEURON LA English DT Article ID CORTICAL GABAERGIC INTERNEURONS; TANGENTIAL MIGRATION; IN-VIVO; IMMUNOREACTIVE NEURONS; GANGLIONIC EMINENCE; CELLULAR-PATTERNS; CORPUS-CALLOSUM; NERVOUS-SYSTEM; ADULT MICE; MOUSE AB In the mammalian cerebral cortex, the developmental events governing the integration of excitatory projection neurons and inhibitory interneurons into balanced local circuitry are poorly understood. We report that different subtypes of projection neurons uniquely and differentially determine the laminar distribution of cortical interneurons. We find that in Fezf2(-/-) cortex, the exclusive absence of subcerebral projection neurons and their replacement by callosal projection neurons cause distinctly abnormal lamination of interneurons and altered GABAergic inhibition. In addition, experimental generation of either corticofugal neurons or callosal neurons below the cortex is sufficient to recruit cortical interneurons to these ectopic locations. Strikingly, the identity of the projection neurons generated, rather than strictly their birthdate, determines the specific types of interneurons recruited. These data demonstrate that in the neocortex individual populations of projection neurons cell-extrinsically control the laminar fate of interneurons and the assembly of local inhibitory circuitry. C1 [Jantrachotechatchawan, Chanati; Arlotta, Paola] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Jantrachotechatchawan, Chanati; Arlotta, Paola] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Lodato, Simona; Rouaux, Caroline; Jantrachotechatchawan, Chanati; Arlotta, Paola] Harvard Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Lodato, Simona; Rouaux, Caroline; Jantrachotechatchawan, Chanati; Arlotta, Paola] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Quast, Kathleen B.; Hensch, Takao K.] Harvard Univ, Dept Mol & Cellular Biol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Studer, Michele] INSERM, U636, F-06108 Nice, France. [Studer, Michele] Univ Nice Sophia Antipolis, Lab Genet Dev Normal & Pathol, F-06108 Nice, France. [Lodato, Simona; Studer, Michele] European Sch Mol Med SEMM, Naples, Italy. RP Arlotta, P (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM paola_arlotta@hms.harvard.edu RI Studer, Michele/P-4580-2016; Lodato, Simona/A-3525-2017 OI Studer, Michele/0000-0001-7105-2957; Lodato, Simona/0000-0001-6498-2590 FU NIH [NS062849, 1DP1 OD 003699-01]; Harvard Stem Cell Institute; Ellison Medical Foundation; European School of Molecular Medicine; ALS Association FX We would like to thank Jeffrey Macklis and Bradley Molyneaux for reagents and insightful advice; Antonio Simeone, Antonio Baldini, and Tommaso Russo for serving on S.L.'s dissertation committee and for their comments; Oscar Mann for critical input during early stages of this study; Tracy Pearse-Young for sharing the APP shRNA construct and for help with electroporations in the rat; Roberto Rusconi for support with cell counting; Jeffrey Macklis, Verne Caviness, Eiman Azim, Giulio Srubek Tomassy, Feng Zhang, and Anne Goodwin for their careful reading of the manuscript and comments; Robert Hevner, Carlos Lois, John Rubenstein, Vassilis Pachnis, and Andre Goffinet for generous sharing of antibodies, cDNA clones, and expression vectors; Yuchio Yanagawa for sharing the GAD67::GFP mice; Alyssa Meleski, Amanda Merlino, and Zachary Trayes-Gibson for outstanding technical support; and Claudio Mare for schematic drawings. This work was partially supported by grants from the NIH (NS062849) and the Harvard Stem Cell Institute to P.A. and the NIH Director's Pioneer Award (1DP1 OD 003699-01) and Ellison Medical Foundation to T.K.H. S.L. was partially supported by a predoctoral fellowship from the European School of Molecular Medicine (S.E.M.M.) and C.R. was partially supported by a Milton-Safenowitz postdoctoral fellowship from the ALS Association. NR 67 TC 73 Z9 73 U1 3 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 24 PY 2011 VL 69 IS 4 BP 763 EP 779 DI 10.1016/j.neuron.2011.01.015 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 735KO UT WOS:000288413200017 PM 21338885 ER PT J AU Leykum, LK Palmer, R Lanham, H Jordan, M McDaniel, RR Noel, PH Parchman, M AF Leykum, Luci K. Palmer, Ray Lanham, Holly Jordan, Michelle McDaniel, Reuben R. Noel, Polly H. Parchman, Michael TI Reciprocal learning and chronic care model implementation in primary care: results from a new scale of learning in primary care SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID DECISION-SUPPORT-SYSTEM; CHRONIC ILLNESS CARE; CLINICAL-PRACTICE; HEALTH-CARE; MANAGEMENT; COMPLEXITY; ORGANIZATIONS; IMPROVEMENT; GUIDELINES; DELIVERY AB Background: Efforts to improve the care of patients with chronic disease in primary care settings have been mixed. Application of a complex adaptive systems framework suggests that this may be because implementation efforts often focus on education or decision support of individual providers, and not on the dynamic system as a whole. We believe that learning among clinic group members is a particularly important attribute of a primary care clinic that has not yet been well-studied in the health care literature, but may be related to the ability of primary care practices to improve the care they deliver. To better understand learning in primary care settings by developing a scale of learning in primary care clinics based on the literature related to learning across disciplines, and to examine the association between scale responses and chronic care model implementation as measured by the Assessment of Chronic Illness Care (ACIC) scale. Methods: Development of a scale of learning in primary care setting and administration of the learning and ACIC scales to primary care clinic members as part of the baseline assessment in the ABC Intervention Study. All clinic clinicians and staff in forty small primary care clinics in South Texas participated in the survey. Results: We developed a twenty-two item learning scale, and identified a five-item subscale measuring the construct of reciprocal learning (Cronbach alpha 0.79). Reciprocal learning was significantly associated with ACIC total and sub-scale scores, even after adjustment for clustering effects. Conclusions: Reciprocal learning appears to be an important attribute of learning in primary care clinics, and its presence relates to the degree of chronic care model implementation. Interventions to improve reciprocal learning among clinic members may lead to improved care of patients with chronic disease and may be relevant to improving overall clinic performance. C1 [Leykum, Luci K.; Palmer, Ray; Lanham, Holly; Noel, Polly H.; Parchman, Michael] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Leykum, Luci K.; Lanham, Holly; Noel, Polly H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Palmer, Ray; Parchman, Michael] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78229 USA. [Jordan, Michelle] Arizona State Univ, Mary Lou Fulton Teachers Coll, Phoenix, AZ USA. [Lanham, Holly; McDaniel, Reuben R.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. RP Leykum, LK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM Leykum@uthscsa.edu RI Jordan, Michelle/K-8757-2012; OI Parchman, Michael/0000-0001-7129-2889 FU National Institute of Health (NIDDK) [R18DK075692]; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service; South Texas Veterans Health Care System; IC2 Institute of the University of Texas at Austin FX The research reported here was supported by the National Institute of Health (NIDDK Grant R18DK075692) and the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service. Investigator salary support is provided through this funding, and through the South Texas Veterans Health Care System. Dr. McDaniel receives support from the IC2 Institute of the University of Texas at Austin. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 58 TC 12 Z9 12 U1 1 U2 10 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 FEB 23 PY 2011 VL 11 AR 44 DI 10.1186/1472-6963-11-44 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 730JU UT WOS:000288030400001 PM 21345225 ER PT J AU Hackett, TA Barkat, TR O'Brien, BMJ Hensch, TK Polley, DB AF Hackett, Troy A. Barkat, Tania Rinaldi O'Brien, Barbara M. J. Hensch, Takao K. Polley, Daniel B. TI Linking Topography to Tonotopy in the Mouse Auditory Thalamocortical Circuit SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL GENICULATE-BODY; RECEPTIVE-FIELD PLASTICITY; DORSAL COCHLEAR NUCLEUS; RESPONSE-SPECIFIC BANDS; HEARING-LOSS; IN-VITRO; FUNCTIONAL-ORGANIZATION; CORTICOFUGAL MODULATION; SYNAPTIC-TRANSMISSION; SPECTRAL INTEGRATION AB The mouse sensory neocortex is reported to lack several hallmark features of topographic organization such as ocular dominance and orientation columns in primary visual cortex or fine-scale tonotopy in primary auditory cortex (AI). Here, we re-examined the question of auditory functional topography by aligning ultra-dense receptive field maps from the auditory cortex and thalamus of the mouse in vivo with the neural circuitry contained in the auditory thalamocortical slice in vitro. We observed precisely organized tonotopic maps of best frequency (BF) in the middle layers of AI and the anterior auditory field as well as in the ventral and medial divisions of the medial geniculate body (MGBv and MGBm, respectively). Tracer injections into distinct zones of the BF map in AI retrogradely labeled topographically organized MGBv projections and weaker, mixed projections from MGBm. Stimulating MGBv along the tonotopic axis in the slice produced an orderly shift of voltage-sensitive dye (VSD) signals along the AI tonotopic axis, demonstrating topography in the mouse thalamocortical circuit that is preserved in the slice. However, compared with BF maps of neuronal spiking activity, the topographic order of subthreshold VSD maps was reduced in layer IV and even further degraded in layer II/III. Therefore, the precision of AI topography varies according to the source and layer of the mapping signal. Our findings further bridge the gap between in vivo and in vitro approaches for the detailed cellular study of auditory thalamocortical circuit organization and plasticity in the genetically tractable mouse model. C1 [Polley, Daniel B.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol,Eaton Peabody Lab, Boston, MA 02114 USA. [Hackett, Troy A.; O'Brien, Barbara M. J.] Vanderbilt Univ, Sch Med, Dept Hearing & Speech Sci, Vanderbilt Kennedy Ctr Res Human Dev, Nashville, TN 37232 USA. [Barkat, Tania Rinaldi; Hensch, Takao K.] Harvard Univ, Ctr Brain Sci, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Polley, DB (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol,Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM Daniel_polley@meei.harvard.edu OI Polley, Daniel/0000-0002-5120-2409 FU National Institutes of Health [DC009836, DC04318]; Core Research for Evolutional Science and Technology, Japan Science & Technology Agency; Human Frontiers Science Program FX This work was supported by National Institutes of Health Grants DC009836 (D. B. P.) and DC04318 (T. A. H.); Core Research for Evolutional Science and Technology, Japan Science & Technology Agency (T. K. H.); the Human Frontiers Science Program (T. K. H.); and the Harvard Society of Fellows (T. R. B.). We thank Michelle Young and Dr. Vivek Khatri for technical assistance and fruitful discussion. NR 93 TC 64 Z9 64 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 23 PY 2011 VL 31 IS 8 BP 2983 EP 2995 DI 10.1523/JNEUROSCI.5333-10.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 725TX UT WOS:000287670100027 PM 21414920 ER PT J AU Haun, JB Castro, CM Wang, R Peterson, VM Marinelli, BS Lee, H Weissleder, R AF Haun, Jered B. Castro, Cesar M. Wang, Rui Peterson, Vanessa M. Marinelli, Brett S. Lee, Hakho Weissleder, Ralph TI Micro-NMR for Rapid Molecular Analysis of Human Tumor Samples SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID BREAST-CANCER; LUNG-CANCER; NEOADJUVANT CHEMOTHERAPY; CLINICAL-TRIALS; CELL DETECTION; CORE BIOPSIES; IN-VIVO; NANOTECHNOLOGY; NANOPARTICLE; ONCOLOGY AB Although tumor cells obtained from human patients by image-guided intervention are a valuable source for diagnosing cancer, conventional means of analysis are limited. Here, we report the development of a quantitative micro-NMR (nuclear magnetic resonance) system for rapid, multiplexed analysis of human tumors. We implemented the technology in a clinical setting to analyze cells obtained by fine-needle aspirates from suspected lesions in 50 patients and validated the results in an independent cohort of another 20 patients. Single fine-needle aspirates yielded sufficient numbers of cells to enable quantification of multiple protein markers in all patients within 60 min. Moreover, using a four-protein signature, we report a 96% accuracy for establishing a cancer diagnosis, surpassing conventional clinical analyses by immunohistochemistry. Our results also show that protein expression patterns decay with time, underscoring the need for rapid sampling and diagnosis close to the patient bedside. We also observed a surprising degree of heterogeneity in protein expression both across the different patient samples and even within the same tumor, which has important implications for molecular diagnostics and therapeutic drug targeting. Our quantitative point-of-care micro-NMR technique shows potential for cancer diagnosis in the clinic. C1 [Haun, Jered B.; Castro, Cesar M.; Peterson, Vanessa M.; Marinelli, Brett S.; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Castro, Cesar M.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Wang, Rui] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Wang, Rui] Harvard Univ, Sch Med, Dept Biostat, Boston, MA 02115 USA. [Peterson, Vanessa M.] MIT, Cambridge, MA 02139 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU NCI NIH HHS [F32 CA144139-02, P50 CA127003, P50 CA127003-05, T32 CA079443, T32 CA079443-10, U54 CA119349, U54 CA119349-05, F32 CA144139]; NHLBI NIH HHS [U01 HL080731, U01 HL080731-05, UO1 HL080731]; NIBIB NIH HHS [R01 EB004626, R01 EB004626-07, R01 EB010011, R01 EB010011-03] NR 54 TC 87 Z9 88 U1 1 U2 38 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 23 PY 2011 VL 3 IS 71 AR 71ra16 DI 10.1126/scitranslmed.3002048 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795JZ UT WOS:000292971800003 PM 21346169 ER PT J AU Bourdette, D Yadav, V AF Bourdette, Dennis Yadav, Vijayshree TI The radiologically isolated syndrome revisited When is it presymptomatic multiple sclerosis? SO NEUROLOGY LA English DT Editorial Material ID DIAGNOSTIC-CRITERIA C1 [Bourdette, Dennis; Yadav, Vijayshree] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Bourdette, Dennis] Portland VA Med Ctr, VA Multiple Sclerosis Ctr Excellence W, Portland, OR USA. RP Bourdette, D (reprint author), Oregon Hlth & Sci Univ, Dept Neurol L226, Portland, OR 97239 USA. EM bourdett@ohsu.edu NR 11 TC 6 Z9 8 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 FEB 22 PY 2011 VL 76 IS 8 BP 680 EP 681 DI 10.1212/WNL.0b013e31820e7769 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 724KH UT WOS:000287574500005 PM 21270414 ER PT J AU Moskowitz, MA Waeber, C AF Moskowitz, Michael A. Waeber, Christian TI Remote Ischemic Preconditioning Making the Brain More Tolerant, Safely and Inexpensively SO CIRCULATION LA English DT Editorial Material DE Editorials; acute stroke; brain; cerebral ischemia; postconditioning ID RANDOMIZED CONTROLLED-TRIAL; CEREBRAL-ISCHEMIA; INJURY; MECHANISMS; SURGERY; STROKE; RATS C1 [Moskowitz, Michael A.; Waeber, Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA USA. RP Moskowitz, MA (reprint author), Massachusetts Gen Hosp, CNY149-6403,149 13th St, Charlestown, MA 02129 USA. EM moskowitz@helix.mgh.harvard.edu RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 NR 21 TC 9 Z9 9 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 22 PY 2011 VL 123 IS 7 BP 709 EP 711 DI 10.1161/CIRCULATIONAHA.110.009688 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 724PF UT WOS:000287588000008 PM 21300956 ER PT J AU Wang, TY White, JA Tricoci, P Giugliano, RP Zeymer, U Harrington, RA Montalescot, G James, SK Van de Werf, F Armstrong, PW Braunwald, E Califf, RM Newby, LK AF Wang, Tracy Y. White, Jennifer A. Tricoci, Pierluigi Giugliano, Robert P. Zeymer, Uwe Harrington, Robert A. Montalescot, Gilles James, Stefan K. Van de Werf, Frans Armstrong, Paul W. Braunwald, Eugene Califf, Robert M. Newby, L. Kristin TI Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial SO CIRCULATION LA English DT Article DE platelets; anticoagulants; eptifibatide; clopidogrel; acute coronary syndrome ID WAVE MYOCARDIAL-INFARCTION; UNSTABLE ANGINA; PLATELET INHIBITION; INTERNATIONAL PERSPECTIVE; CARDIAC-CATHETERIZATION; STENT IMPLANTATION; GLOBAL REGISTRY; INTERVENTION; REACTIVITY; OUTCOMES AB Background-In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use. Methods and Results-In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P = 0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P = 0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata. Conclusions-Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials. C1 [Wang, Tracy Y.; White, Jennifer A.; Tricoci, Pierluigi; Harrington, Robert A.; Newby, L. Kristin] Duke Clin Res Inst, Durham, NC 27705 USA. [Giugliano, Robert P.; Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Zeymer, Uwe] Herzzentrum Ludwigshafen, Ludwigshafen, Germany. [Montalescot, Gilles] Hop La Pitie Salpetriere, Inst Cardiol, Paris, France. [James, Stefan K.] Univ Uppsala Hosp, Uppsala, Sweden. [Van de Werf, Frans] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Van de Werf, Frans] Leuven Coordinating Ctr, Louvain, Belgium. [Armstrong, Paul W.] Univ Alberta, Edmonton, AB, Canada. [Califf, Robert M.] Duke Translat Med Inst, Durham, NC USA. RP Wang, TY (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM tracy.wang@duke.edu FU Schering-Plough Inc; Merck Pharmaceuticals; Bristol-Myers; Squibb/Sanofi; Schering-Plough; Medicines Company; Heartscape; Canyon Pharmaceuticals; Eli Lilly/Daiichi-Sankyo Alliance; Merck & Co Inc through the Duke Clinical Research Institute; Daiichi-Sankyo; Schering-Plough (now Merck); Bristol-Myers Squibb; Boston Scientific; Centocor; Cordis; Eli-Lilly; Federation Franccaise de Cardiologie; Fondation de France; Guerbet Medical; INSERM; ITC Edison; Medtronic; Pfizer; Sanofi-Aventis Group; Societe Franccaise de Cardiologie; Accumetrics; Bayer; Boehringer-Ingelheim; Eisai; Menarini; MSD; Novartis; Portola; Sanofi-Aventis; Roche; Merck; Boehringer Ingelheim (Canada) Ltd; Sanofi-Aventis Canada; Schering-Plough Research Institute; Scios Inc/Ortho-Biotech; GlaxoSmithKline; Portola Pharmaceutical Inc; Uppsala Clinical Research Center; Merck Company Inc; Merck Co Inc FX The EARLY ACS trial and this work were funded by research grants from Schering-Plough Inc and Merck Pharmaceuticals.; Dr Wang has received research grants from Bristol-Myers Squibb/Sanofi Partnership, Schering-Plough, The Medicines Company, Heartscape, Canyon Pharmaceuticals, and Eli Lilly/Daiichi-Sankyo Alliance. Dr Tricoci has received research grants from Merck & Co Inc through the Duke Clinical Research Institute and is on the advisory board for Merck & Co Inc. Dr Giugliano has received research grant support from Daiichi-Sankyo and Schering-Plough, honoraria from Schering-Plough, Bristol-Myers Squib, and Sanofi-Aventis and is on the advisory board for Schering-Plough and Merck & Co Inc. Dr Zeymer has received research grants from Schering-Plough (now Merck). Dr Harrington has received research funding from and consults with Schering-Plough (now Merck). A complete listing of Dr Harrington's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. Dr Montalescot has received research grants (to his institution) from Bristol-Myers Squibb, Boston Scientific, Centocor, Cordis, Eli-Lilly, Federation Franccaise de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, Sanofi-Aventis Group, and Societe Franccaise de Cardiologie and consulting or lecture fees from Accumetrics, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli-Lilly, Menarini, MSD, Novartis, Portola, Sanofi-Aventis Group, Schering-Plough, and The Medicines Company. Dr James has received research grants and speaker fees from AstraZeneca, Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, and Schering-Plough. Dr Van de Werf has received research grants from Schering-Plough (now Merck) and Roche and advisory board and speaker's fees from Schering-Plough, Merck, and Roche. Dr Armstrong has provided consulting or other services that generate personal income to Sanofi-Aventis, Bristol-Myers Squibb Canada, Merck Frosst Canada Ltd, Abbott Laboratories, GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, Regado Biosciences, and F. Hoffmann-La Roche Ltd and has received research grants or contracts from Boehringer Ingelheim (Canada) Ltd, Sanofi-Aventis Canada, Eli Lilly, Schering-Plough Research Institute, Scios Inc/Ortho-Biotech, GlaxoSmithKline, Portola Pharmaceutical Inc, Uppsala Clinical Research Center and AstraZeneca, and Merck & Company Inc that partially support his university salary and/or research projects. Dr Braunwald is chair of the TIMI Study Group at the Brigham and Women's Hospital, which receives (or has received within the past 24 months) grant support for the TIMI Study Group from the following pharmaceutical companies (all >$10 000): Eli Lilly, Merck & Co Inc, Schering-Plough Research Institute, and Daiichi-Sankyo. Dr Braunwald has also participated occasionally (maximum 2 to 3 times/y) in symposia/advisory board meetings/consultancies for the following companies, for which he receives an honorarium (always >$10 000) and reimbursement of travel-related expenses: Daiichi-Sankyo, Eli Lilly, Merck & Co Inc, and Schering-Plough. Dr Califf has received research funding from and consulted for Schering-Plough (now Merck; all consulting funds donated to not-for-profit organizations). A complete listing of Dr Califf's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. Dr Newby has received research grants from Schering-Plough and Merck & Co Inc through the Duke Clinical Research Institute and consulting honoraria from Schering-Plough. A complete listing of Dr. Newby's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp.; J White reports no conflicts. NR 32 TC 17 Z9 18 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 FEB 22 PY 2011 VL 123 IS 7 BP 722 EP 730 DI 10.1161/CIRCULATIONAHA.110.958041 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 724PF UT WOS:000287588000011 PM 21300952 ER PT J AU Fonarow, GC Smith, EE Saver, JL Reeves, MJ Bhatt, DL Grau-Sepulveda, MV Olson, DM Hernandez, AF Peterson, ED Schwamm, LH AF Fonarow, Gregg C. Smith, Eric E. Saver, Jeffrey L. Reeves, Mathew J. Bhatt, Deepak L. Grau-Sepulveda, Maria V. Olson, DaiWai M. Hernandez, Adrian F. Peterson, Eric D. Schwamm, Lee H. TI Timeliness of Tissue-Type Plasminogen Activator Therapy in Acute Ischemic Stroke Patient Characteristics, Hospital Factors, and Outcomes Associated With Door-to-Needle Times Within 60 Minutes SO CIRCULATION LA English DT Article DE hospital performance; mortality; registries; stroke; thrombolytics ID RT-PA STROKE; INTRAVENOUS THROMBOLYSIS; POOLED ANALYSIS; CARE; GUIDELINES; ALTEPLASE; NINDS; RECOMMENDATIONS; ESTABLISHMENT; EXPERIENCE AB Background-The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time dependent, and guidelines recommend an arrival to treatment initiation (door-to-needle) time of <= 60 minutes. Methods and Results-Data from acute ischemic stroke patients treated with tPA within 3 hours of symptom onset in 1082 hospitals participating in the Get With the Guidelines-Stroke Program from April 1, 2003, to September 30, 2009 were studied to determine frequency, patient and hospital characteristics, and temporal trends in patients treated with door-to-needle times <= 60 minutes. Among 25 504 ischemic stroke patients treated with tPA, door-to-needle time was <= 60 minutes in only 6790 (26.6%). Patient factors most strongly associated with door-to-needle time <= 60 minutes were younger age, male gender, white race, or no prior stroke. Hospital factors associated with <= 60 minute door-to-needle time included greater annual volumes of tPA-treated stroke patients. The proportion of patients with door-to-needle times <= 60 minutes varied widely by hospital (0% to 79.2%) and increased from 19.5% in 2003 to 29.1% in 2009 (P < 0.0001). Despite similar stroke severity, in-hospital mortality was lower (adjusted odds ratio, 0.78; 95% confidence interval, 0.69 to 0.90; P < 0.0003) and symptomatic intracranial hemorrhage was less frequent (4.7% versus 5.6%; P < 0.0017) for patients with door-to-needle times <= 60 minutes compared with patients with door-to-needle times <= 60 minutes. Conclusions-Fewer than one-third of patients treated with intravenous tPA had door-to-needle times <= 60 minutes, with only modest improvement over the past 6.5 years. These findings support the need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke. (Circulation. 2011; 123: 750-758.) C1 [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Div Cardiol VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Grau-Sepulveda, Maria V.; Olson, DaiWai M.; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Ctr, Durham, NC USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room 47-123 CHS, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Hernandez, Adrian F./A-7818-2016; OI Saver, Jeffrey/0000-0001-9141-2251; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616; Smith, Eric/0000-0003-3956-1668 FU Bristol-Myers; Squib/Sanofi Pharmaceutical; AHA Pharmaceutical Roundtable [0675060N]; Boeringher-Ingelheim; Merck; National Institutes of Health; NIH (NINDS) [R01 NS062028]; Canadian Stroke Network; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; Michigan Stroke Registry; AstraZeneca; Bristol-Myers Squibb; Eisai; Sanofi Aventis; Medicines Co.; Johnson Johnson; Lilly; Merck-Schering Plough FX The GWTG-Stroke program is provided by the AHA/ASA. The GWTG-Stroke program is currently supported in part by a charitable contribution from Bristol-Myers Squib/Sanofi Pharmaceutical Partnership and the AHA Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim and Merck. The industry sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.; Dr Fonarow receives research support from the National Institutes of Health; served as a consultant to Pfizer, Merck, Schering Plough, Bristol Myers Squibb, and Sanofi-Aventis; received honoraria from Pfizer, Merck, Schering Plough, Bristol Myers Squibb, and Sanofi-Aventis; and is an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Fonarow 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. Dr Smith serves as a member of the GWTG Science Subcommittee; receives research support from the NIH (NINDS R01 NS062028), Canadian Stroke Network, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Canada; and has served on an advisory board for Genentech. Dr Saver serves as a member of the GWTG Science Subcommittee and as a scientific consultant regarding trial design and conduct to CoAxia, Concentric Medical, Talacris, Ferrer, Photothera, Brainsgate, Sygnis, and Ev3; received lecture honoraria from Ferrer; and is an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Reeves receives salary support from the Michigan Stroke Registry and serves as a member of the AHA's GWTG Quality Improvement Subcommittee. Dr Bhatt receives research support from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi Aventis, and The Medicines Co. Dr Grau-Sepulveda is a member of the Duke Clinical Research Institute, which serves as the AHA GWTG data coordinating center. Drs Olson and Hernandez are members of the Duke Clinical Research Institute, which serves as the AHA GWTG Data Coordinating Center. Dr Hernandez is a recipient of an AHA Pharmaceutical Roundtable grant (0675060N); has received a research grant from Johnson & Johnson; and has received honorarium from AstraZeneca and Amgen. Dr Peterson has received research grants from Lilly, Johnson & Johnson, and Bristol-Myers Squibb, Sanofi-Aventis, and Merck-Schering Plough partnership. Dr Peterson serves as principal investigator of the Data Analytic Center for AHAs GWTG. Dr Schwamm serves as chair of the AHA GWTG Steering Committee; serves as a consultant to the Research Triangle Institute and to the Massachusetts Department of Public Health; and serves on the Steering Committee for Lundbeck's DIAS4 clinical trial. NR 23 TC 224 Z9 241 U1 3 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 22 PY 2011 VL 123 IS 7 BP 750 EP U184 DI 10.1161/CIRCULATIONAHA.110.974675 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 724PF UT WOS:000287588000014 PM 21311083 ER PT J AU Tamietto, M de Gelder, B AF Tamietto, Marco de Gelder, Beatrice TI Sentinels in the visual system SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Editorial Material C1 [Tamietto, Marco; de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [de Gelder, Beatrice] Harvard Univ, Sch Med, Boston, MA USA. RP de Gelder, B (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. EM degelder@nmr.mgh.harvard.edu OI Tamietto, Marco/0000-0002-8815-8499 NR 15 TC 1 Z9 1 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD FEB 22 PY 2011 VL 5 AR 6 DI 10.3389/fnbeh.2011.00006 PG 2 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V29VN UT WOS:000208776000001 PM 21373367 ER PT J AU Dell'Italia, LJ AF Dell'Italia, Louis J. TI The Forgotten Left Ventricle in Right Ventricular Pressure Overload SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE atrophy; pulmonary hypertension; right ventricular failure ID CONTRACTILE FUNCTION; HYPERTENSION; HEARTS C1 [Dell'Italia, Louis J.] Univ Alabama, Dept Med, Div Cardiovasc Dis, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Dell'Italia, LJ (reprint author), UAB, Ctr Heart Failure Res, Div Cardiol, 434 BMR2,1530 3rd Ave S, Birmingham, AL 35294 USA. EM loudell@uab.edu NR 7 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 22 PY 2011 VL 57 IS 8 BP 929 EP 930 DI 10.1016/j.jacc.2010.08.647 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 725NB UT WOS:000287650900008 PM 21329839 ER PT J AU Fifer, KM Qadir, S Subramanian, S Vijayakumar, J Figueroa, AL Quynh, AT Hoffman, U Brady, TJ Tawakol, A AF Fifer, Kenneth M. Qadir, Sadia Subramanian, Sharath Vijayakumar, Jayanthi Figueroa, Amparo L. Quynh A. Truong Hoffman, Udo Brady, Thomas J. Tawakol, Ahmed TI Positron Emission Tomography Measurement of Periodontal F-18-Fluorodeoxyglucose Uptake Is Associated With Histologically Determined Carotid Plaque Inflammation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atherosclerosis; carotid; inflammation; periodontal; PET ID CORONARY-HEART-DISEASE; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; SYSTEMIC INFLAMMATION; ATHEROMATOUS PLAQUES; COMPUTED-TOMOGRAPHY; VASCULAR-DISEASE; FDG-PET; ATHEROSCLEROSIS; PATHOGENS AB Objectives This study aimed to test the hypothesis that metabolic activity within periodontal tissue (a possible surrogate for periodontal inflammation) predicts inflammation in a remote atherosclerotic vessel, utilizing F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging. Background Several lines of evidence establish periodontal disease as an important risk factor for atherosclerosis. FDG-PET imaging is an established method for measuring metabolic activity in human tissues and blood vessels. Methods One hundred twelve patients underwent FDG-PET imaging 92 +/- 5 min after FDG administration (13 to 25 mCi). Periodontal FDG uptake was measured by obtaining standardized uptake values from the periodontal tissue of each patient, and the ratio of periodontal to background (blood) activity was determined (TBR). Standardized uptake value measurements were obtained in the carotid and aorta as well as in a venous structure. Localization of periodontal, carotid, and aortic activity was facilitated by PET coregistration with computed tomography or magnetic resonance imaging. A subset of 16 patients underwent carotid endarterectomy within 1 month of PET imaging, during which atherosclerotic plaques were removed and subsequently stained with anti-CD68 antibodies to quantify macrophage infiltration. Periodontal FDG uptake was compared with carotid plaque macrophage infiltration. Results Periodontal FDG uptake (TBR) is associated with carotid TBR (R = 0.64, p < 0.0001), as well as aortic TBR (R = 0.38; p = 0.029). Moreover, a strong relationship was observed between periodontal TBR and histologically assessed inflammation within excised carotid artery plaques (R = 0.81, p < 0.001). Conclusions FDG-PET measurements of metabolic activity within periodontal tissue correlate with macrophage infiltration within carotid plaques. These findings provide direct evidence for an association between periodontal disease and atherosclerotic inflammation. (J Am Coll Cardiol 2011;57:971-6) (C) 2011 by the American College of Cardiology Foundation C1 [Fifer, Kenneth M.; Quynh A. Truong; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, Boston, MA 02114 USA. [Fifer, Kenneth M.; Qadir, Sadia; Subramanian, Sharath; Vijayakumar, Jayanthi; Figueroa, Amparo L.; Quynh A. Truong; Hoffman, Udo; Brady, Thomas J.; Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Qadir, Sadia; Subramanian, Sharath; Vijayakumar, Jayanthi; Figueroa, Amparo L.; Quynh A. Truong; Hoffman, Udo; Brady, Thomas J.; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Imaging, Boston, MA 02114 USA. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM atawakol@partners.org NR 49 TC 26 Z9 27 U1 2 U2 5 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 FEB 22 PY 2011 VL 57 IS 8 BP 971 EP 976 DI 10.1016/j.jacc.2010.09.056 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 725NB UT WOS:000287650900013 PM 21329844 ER PT J AU Zhou, XH Wong, LL Karakoti, AS Seal, S McGinnis, JF AF Zhou, Xiaohong Wong, Lily L. Karakoti, Ajay S. Seal, Sudipta McGinnis, James F. TI Nanoceria Inhibit the Development and Promote the Regression of Pathologic Retinal Neovascularization in the Vldlr Knockout Mouse SO PLOS ONE LA English DT Article ID DENSITY LIPOPROTEIN RECEPTOR; ENDOTHELIAL GROWTH-FACTOR; OXIDATIVE STRESS; ANGIOMATOUS PROLIFERATION; RETINITIS-PIGMENTOSA; NADPH OXIDASE; SUBRETINAL NEOVASCULARIZATION; PHOTORECEPTOR DEGENERATION; MACULAR DEGENERATION; MODEL AB Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share oxidative stress as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR. C1 [Zhou, Xiaohong; Wong, Lily L.; Karakoti, Ajay S.; Seal, Sudipta; McGinnis, James F.] Univ Oklahoma, Coll Med, Dept Ophthalmol, Dean McGee Eye Inst, Oklahoma City, OK 73190 USA. [Karakoti, Ajay S.; Seal, Sudipta] Univ Cent Florida, Adv Mat Proc Anal Ctr, Mech Mat Aerosp Engn Nanosci & Technol Ctr, Orlando, FL 32816 USA. [McGinnis, James F.] Oklahoma Ctr Neurosci, Dept Ophthalmol & Cell Biol, Oklahoma City, OK USA. RP Zhou, XH (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab, Boston, MA 02115 USA. EM lily-wong@ouhsc.edu; james-mcginnis@ouhsc.edu RI Wong, Lily/D-7737-2011 OI Wong, Lily/0000-0003-0569-3398 FU NIH [P30-EY12190, COBRE-P20 RR017703, R21EY018306, R01EY018724]; FFB [C-NP-0707-0404-UOK08]; NSF [CBET-0708172]; OCAST [HR06-075]; Presbyterian Health Foundation; Research to Prevent Blindness; RPB FX This work was supported by grants from: NIH: P30-EY12190, COBRE-P20 RR017703, R21EY018306, R01EY018724; FFB (http://www.blindness.org/): C-NP-0707-0404-UOK08; NSF: CBET-0708172; OCAST(http://www.ok.gov/ocast/Programs/Oklahoma_Health_Research_(OHR)/in dex.html): HR06-075, and unrestricted funds from Presbyterian Health Foundation (http://www.phfokc.com/research.htm) and Research to Prevent Blindness (http://www.rpbusa.org/rpb/) (RPB). JFM is a recipient of an RPB Senior Scientific Investigator Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 56 Z9 56 U1 5 U2 24 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 FEB 22 PY 2011 VL 6 IS 2 AR e16733 DI 10.1371/journal.pone.0016733 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 725PA UT WOS:000287656600014 PM 21364932 ER PT J AU Kveraga, K Ghuman, AS Kassam, KS Aminoff, EA Hamalainen, MS Chaumon, M Bar, M AF Kveraga, Kestutis Ghuman, Avniel Singh Kassam, Karim S. Aminoff, Elissa A. Haemaelaeinen, Matti S. Chaumon, Maximilien Bar, Moshe TI Early onset of neural synchronization in the contextual associations network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phase locking; oscillations; beta; visual cognition ID PARAHIPPOCAMPAL PLACE AREA; MEDIAL TEMPORAL-LOBES; VISUAL OBJECT RECOGNITION; TOP-DOWN FACILITATION; RETROSPLENIAL CORTEX; MEMORY RETRIEVAL; SCENE PERCEPTION; PHASE SYNCHRONIZATION; ORBITOFRONTAL CORTEX; CORTICAL NETWORKS AB Objects are more easily recognized in their typical context. However, is contextual information activated early enough to facilitate the perception of individual objects, or is contextual facilitation caused by postperceptual mechanisms? To elucidate this issue, we first need to study the temporal dynamics and neural interactions associated with contextual processing. Studies have shown that the contextual network consists of the parahippocampal, retrosplenial, and medial prefrontal cortices. We used functional MRI, magnetoencephalography, and phase synchrony analyses to compare the neural response to stimuli with strong or weak contextual associations. The context network was activated in functional MRI and preferentially synchronized in magnetoencephalography (MEG) for stimuli with strong contextual associations. Phase synchrony increased early (150-250 ms) only when it involved the parahippocampal cortex, whereas retrosplenial-medial prefrontal cortices synchrony was enhanced later (300-400 ms). These results describe the neural dynamics of context processing and suggest that context is activated early during object perception. C1 [Kveraga, Kestutis; Haemaelaeinen, Matti S.; Chaumon, Maximilien; Bar, Moshe] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Kveraga, Kestutis; Haemaelaeinen, Matti S.; Bar, Moshe] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Ghuman, Avniel Singh] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kassam, Karim S.] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. [Aminoff, Elissa A.] Univ Calif Santa Barbara, Dept Psychol, Santa Barbara, CA 93106 USA. [Chaumon, Maximilien] Boston Coll, Dept Psychol, Chestnut Hill, MA 02459 USA. [Bar, Moshe] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Kveraga, K (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM kestas@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; OI Aminoff, Elissa/0000-0002-6455-8930; Ghuman, Avniel/0000-0003-1746-4656 FU National Institute of Mental Health [K01-MH084011]; National Institutes of Health [NS50615, EY019477]; National Science Foundation [0842947] FX This research was supported by National Institute of Mental Health Grant K01-MH084011 (to K.K.), National Institutes of Health Grants NS50615 and EY019477 (to M.B.), and National Science Foundation Grant 0842947 (to M.B.). NR 84 TC 49 Z9 55 U1 5 U2 21 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 FEB 22 PY 2011 VL 108 IS 8 BP 3389 EP 3394 DI 10.1073/pnas.1013760108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 724ML UT WOS:000287580400059 PM 21300869 ER PT J AU Shamis, Y Hewitt, KJ Carlson, MW Margvelashvilli, M Dong, SM Kuo, CK Daheron, L Egles, C Garlick, JA AF Shamis, Yulia Hewitt, Kyle J. Carlson, Mark W. Margvelashvilli, Mariam Dong, Shumin Kuo, Catherine K. Daheron, Laurence Egles, Christophe Garlick, Jonathan A. TI Fibroblasts derived from human embryonic stem cells direct development and repair of 3D human skin equivalents SO STEM CELL RESEARCH & THERAPY LA English DT Article ID KERATINOCYTES IN-VITRO; STROMAL CELLS; GROWTH; DIFFERENTIATION; CULTURE; REEPITHILIALIZATION; REGENERATION; PHENOTYPE; FEEDERS; SUPPORT AB Introduction: Pluripotent, human stem cells hold tremendous promise as a source of progenitor and terminally differentiated cells for application in future regenerative therapies. However, such therapies will be dependent upon the development of novel approaches that can best assess tissue outcomes of pluripotent stem cell-derived cells and will be essential to better predict their safety and stability following in vivo transplantation. Methods: In this study we used engineered, human skin equivalents (HSEs) as a platform to characterize fibroblasts that have been derived from human embryonic stem (hES) cell. We characterized the phenotype and the secretion profile of two distinct hES-derived cell lines with properties of mesenchymal cells (EDK and H9-MSC) and compared their biological potential upon induction of differentiation to bone and fat and following their incorporation into the stromal compartment of engineered, HSEs. Results: While both EDK and H9-MSC cell lines exhibited similar morphology and mesenchymal cell marker expression, they demonstrated distinct functional properties when incorporated into the stromal compartment of HSEs. EDK cells displayed characteristics of dermal fibroblasts that could support epithelial tissue development and enable re-epithelialization of wounds generated using a 3D tissue model of cutaneous wound healing, which was linked to elevated production of hepatocyte growth factor (HGF). Lentiviral shRNA-mediated knockdown of HGF resulted in a dramatic decrease of HGF secretion from EDK cells that led to a marked reduction in their ability to promote keratinocyte proliferation and re-epithelialization of cutaneous wounds. In contrast, H9-MSCs demonstrated features of mesenchymal stem cells (MSC) but not those of dermal fibroblasts, as they underwent multilineage differentiation in monolayer culture, but were unable to support epithelial tissue development and repair and produced significantly lower levels of HGF. Conclusions: Our findings demonstrate that hES-derived cells could be directed to specified and alternative mesenchymal cell fates whose function could be distinguished in engineered HSEs. Characterization of hES-derived mesenchymal cells in 3D, engineered HSEs demonstrates the utility of this tissue platform to predict the functional properties of hES-derived fibroblasts before their therapeutic transplantation. C1 [Shamis, Yulia; Hewitt, Kyle J.; Garlick, Jonathan A.] Tufts Univ, Sackler Sch Grad Biomed Sci, Sch Med, Program Cell Mol & Dev Biol, Boston, MA 02111 USA. [Carlson, Mark W.; Margvelashvilli, Mariam; Dong, Shumin; Egles, Christophe; Garlick, Jonathan A.] Tufts Univ, Sch Dent Med, Dept Oral & Maxillofacial Pathol, Boston, MA 02111 USA. [Kuo, Catherine K.] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. [Daheron, Laurence] Massachusetts Gen Hosp, Ctr Regenerat Med & Technol, Boston, MA 02114 USA. RP Garlick, JA (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Sch Med, Program Cell Mol & Dev Biol, 136 Harrison Ave, Boston, MA 02111 USA. EM Jonathan.Garlick@tufts.edu OI EGLES, Christophe/0000-0003-0982-7752 FU National Institute for Dental Research (NIDCR) [DE017413] FX We thank Dr. Addy Alt-Holland, Cathy X. Zhao, and Adam G. Sowalsky for their contributions during the progress of this work and Judith Edwards for assistance in the preparation of the manuscript. This work was supported by grant #DE017413 to JAG from National Institute for Dental Research (NIDCR). NR 37 TC 20 Z9 21 U1 0 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD FEB 21 PY 2011 VL 2 AR 10 DI 10.1186/scrt51 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 794HL UT WOS:000292886000001 PM 21338517 ER PT J AU Moteabbed, M Espana, S Paganetti, H AF Moteabbed, M. Espana, S. Paganetti, H. TI Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-BEAM; IRRADIATION; DELIVERY; SYSTEM; DISTRIBUTIONS; FEASIBILITY; SIMULATIONS; DESIGN; CAMERA AB The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non-invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as C-11, O-15, N-13, P-30 and K-38 were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity. C1 [Moteabbed, M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Moteabbed, M (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM mmoteabbed@partners.org RI Espana, Samuel/E-9240-2010 OI Espana, Samuel/0000-0001-9092-4597 FU NIH/NCI [P01 CA-21239]; Massachusetts General Hospital, 'Proton Therapy Research and Treatment Center' [C06 CA059267] FX The project was supported by NIH/NCI P01 CA-21239 'Proton Therapy Research' and by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, 'Proton Therapy Research and Treatment Center'. NR 29 TC 64 Z9 64 U1 2 U2 19 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 FEB 21 PY 2011 VL 56 IS 4 BP 1063 EP 1082 DI 10.1088/0031-9155/56/4/012 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 714HX UT WOS:000286800800012 PM 21263174 ER PT J AU Wen, PY van den Bent, MJ Macdonald, DR Tsien, C Vogelbaum, MA Chang, SM AF Wen, Patrick Y. van den Bent, Martin J. Macdonald, David R. Tsien, Christina Vogelbaum, Michael A. Chang, Susan M. TI Baseline Preadjuvant Magnetic Resonance Imaging for Response Assessment and for Planning Radiotherapy in Glioblastoma Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID HIGH-GRADE GLIOMAS C1 [Wen, Patrick Y.] Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Boston, MA 02115 USA. [van den Bent, Martin J.] Erasmus Univ Hosp Rotterdam, Daniel den Hoed Canc Ctr, Neurooncol Unit, Rotterdam, Netherlands. [Macdonald, David R.] Univ Western Ontario, London Reg Canc Program, London, ON, Canada. [Tsien, Christina] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Vogelbaum, Michael A.] Cleveland Clin, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44106 USA. [Chang, Susan M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Wen, PY (reprint author), Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2011 VL 29 IS 6 BP E149 EP E149 DI 10.1200/JCO.2010.33.1215 PG 1 WC Oncology SC Oncology GA 722OP UT WOS:000287444000011 ER PT J AU Oberoi, D Matthews, LD Cairns, IH Emrich, D Lobzin, V Lonsdale, CJ Morgan, EH Prabu, T Vedantham, H Wayth, RB Williams, A Williams, C White, SM Allen, G Arcus, W Barnes, D Benkevitch, L Bernardi, G Bowman, JD Briggs, FH Bunton, JD Burns, S Cappallo, RC Clark, MA Corey, BE Dawson, M DeBoer, D De Gans, A deSouza, L Derome, M Edgar, RG Elton, T Goeke, R Gopalakrishna, MR Greenhill, LJ Hazelton, B Herne, D Hewitt, JN Kamini, PA Kaplan, DL Kasper, JC Kennedy, R Kincaid, BB Kocz, J Koeing, R Kowald, E Lynch, MJ Madhavi, S McWhirter, SR Mitchell, DA Morales, MF Ng, A Ord, SM Pathikulangara, J Rogers, AEE Roshi, A Salah, JE Sault, RJ Schinckel, A Shankar, NU Srivani, KS Stevens, J Subrahmanyan, R Thakkar, D Tingay, SJ Tuthill, J Vaccarella, A Waterson, M Webster, RL Whitney, AR AF Oberoi, Divya Matthews, Lynn D. Cairns, Iver H. Emrich, David Lobzin, Vasili Lonsdale, Colin J. Morgan, Edward H. Prabu, T. Vedantham, Harish Wayth, Randall B. Williams, Andrew Williams, Christopher White, Stephen M. Allen, G. Arcus, Wayne Barnes, David Benkevitch, Leonid Bernardi, Gianni Bowman, Judd D. Briggs, Frank H. Bunton, John D. Burns, Steve Cappallo, Roger C. Clark, M. A. Corey, Brian E. Dawson, M. DeBoer, David De Gans, A. deSouza, Ludi Derome, Mark Edgar, R. G. Elton, T. Goeke, Robert Gopalakrishna, M. R. Greenhill, Lincoln J. Hazelton, Bryna Herne, David Hewitt, Jacqueline N. Kamini, P. A. Kaplan, David L. Kasper, Justin C. Kennedy, Rachel Kincaid, Barton B. Kocz, Jonathan Koeing, R. Kowald, Errol Lynch, Mervyn J. Madhavi, S. McWhirter, Stephen R. Mitchell, Daniel A. Morales, Miguel F. Ng, A. Ord, Stephen M. Pathikulangara, Joseph Rogers, Alan E. E. Roshi, Anish Salah, Joseph E. Sault, Robert J. Schinckel, Antony Shankar, N. Udaya Srivani, K. S. Stevens, Jamie Subrahmanyan, Ravi Thakkar, D. Tingay, Steven J. Tuthill, J. Vaccarella, Annino Waterson, Mark Webster, Rachel L. Whitney, Alan R. TI FIRST SPECTROSCOPIC IMAGING OBSERVATIONS OF THE SUN AT LOW RADIO FREQUENCIES WITH THE MURCHISON WIDEFIELD ARRAY PROTOTYPE SO ASTROPHYSICAL JOURNAL LETTERS LA English DT Article DE instrumentation: interferometers; radiation mechanisms: non-thermal; Sun: corona; Sun: radio radiation ID SOLAR CORONA; IMAGES; FLARE; MHZ AB We present the first spectroscopic images of solar radio transients from the prototype for the Murchison Widefield Array, observed on 2010 March 27. Our observations span the instantaneous frequency band 170.9-201.6 MHz. Though our observing period is characterized as a period of "low" to "medium" activity, one broadband emission feature and numerous short-lived, narrowband, non-thermal emission features are evident. Our data represent a significant advance in low radio frequency solar imaging, enabling us to follow the spatial, spectral, and temporal evolution of events simultaneously and in unprecedented detail. The rich variety of features seen here reaffirms the coronal diagnostic capability of low radio frequency emission and provides an early glimpse of the nature of radio observations that will become available as the next generation of low-frequency radio interferometers come online over the next few years. C1 [Oberoi, Divya; Matthews, Lynn D.; Lonsdale, Colin J.; Benkevitch, Leonid; Cappallo, Roger C.; Corey, Brian E.; Derome, Mark; Kennedy, Rachel; Kincaid, Barton B.; McWhirter, Stephen R.; Rogers, Alan E. E.; Salah, Joseph E.; Whitney, Alan R.] MIT, Haystack Observ, Westford, MA 01886 USA. [Cairns, Iver H.; Lobzin, Vasili; Thakkar, D.] Univ Sydney, Sch Phys, Sydney, NSW 2006, Australia. [Emrich, David; Wayth, Randall B.; Arcus, Wayne; Herne, David; Lynch, Mervyn J.; Tingay, Steven J.; Waterson, Mark] Curtin Univ, Curtin Inst Radio Astron, Perth, WA, Australia. [Morgan, Edward H.; Williams, Christopher; Goeke, Robert; Hewitt, Jacqueline N.] MIT, Kavli Inst Astrophys & Space Res, Cambridge, MA 02139 USA. [Prabu, T.; Vedantham, Harish; Gopalakrishna, M. R.; Kamini, P. A.; Madhavi, S.; Roshi, Anish; Shankar, N. Udaya; Srivani, K. S.; Subrahmanyan, Ravi] Raman Res Inst, Bangalore 560080, Karnataka, India. [Williams, Andrew] Univ Western Australia, Perth Observ, Perth, WA 6009, Australia. [White, Stephen M.] USAF, Res Lab, Kirtland, NM USA. [Allen, G.; Bunton, John D.; DeBoer, David; deSouza, Ludi; Elton, T.; Ng, A.; Pathikulangara, Joseph; Schinckel, Antony; Stevens, Jamie; Tuthill, J.] CSIRO Astron & Space Sci, Epping, NSW, Australia. [Barnes, David] Swinburne Univ Technol, Ctr Astrophys & Supercomp, Melbourne, Vic, Australia. [Bernardi, Gianni; Greenhill, Lincoln J.; Kasper, Justin C.; Mitchell, Daniel A.; Ord, Stephen M.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA. [Bowman, Judd D.] Arizona State Univ, Sch Earth & Space Explorat, Tempe, AZ USA. [Briggs, Frank H.; Dawson, M.; De Gans, A.; Kocz, Jonathan; Kowald, Errol; Vaccarella, Annino; Waterson, Mark] Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT, Australia. [Burns, Steve] Burns Ind Inc, Nashua, NH USA. [Clark, M. A.; Edgar, R. G.] Harvard Univ, Fac Arts & Sci, Cambridge, MA 02138 USA. [DeBoer, David; Kennedy, Rachel] Univ Calif Berkeley, Berkeley Astron Dept, Berkeley, CA 94720 USA. [Edgar, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hazelton, Bryna; Morales, Miguel F.] Univ Washington, Dept Phys, Seattle, WA 98195 USA. [Kaplan, David L.] Univ Wisconsin, Dept Phys, Milwaukee, WI USA. [Roshi, Anish] Natl Radio Astron Observ, Green Bank, WV USA. [Sault, Robert J.; Webster, Rachel L.] Univ Melbourne, Sch Phys, Melbourne, Vic, Australia. RP Oberoi, D (reprint author), MIT, Haystack Observ, Westford, MA 01886 USA. RI Bunton, John/A-4944-2008; Astronomy & Astrophysics Group, Raman Res Institute/D-4046-2012; M, Manjunath/N-4000-2014; Kasper, Justin/D-1152-2010; Wayth, Randall/B-2444-2013; Tingay, Steven/B-5271-2013; Emrich, David/B-7002-2013; Waterson, Mark/B-7352-2013; Ord, Stephen/C-6138-2013; Subrahmanyan, Ravi/D-4889-2012; Williams, Andrew/K-2931-2013; Udayashankar , N/D-4901-2012 OI Cairns, Iver/0000-0001-6978-9765; M, Manjunath/0000-0001-8710-0730; Kocz, Jonathon/0000-0003-0249-7586; Kasper, Justin/0000-0002-7077-930X; Wayth, Randall/0000-0002-6995-4131; Emrich, David/0000-0002-4058-1837; Waterson, Mark/0000-0002-0192-2686; Williams, Andrew/0000-0001-9080-0105; FU Commonwealth Government of Australia; Western Australian State government; U.S. National Science Foundation [AST-0457585, PHY-0835713]; Australian Research Council [LE0775621, LE0882938]; U.S. Air Force Office of Scientific Research [FA9550-0510247]; National Collaborative Infrastructure Strategy; Australian federal government via Astronomy Australia Limited; Smithsonian Astrophysical Observatory; MIT School of Science; Raman Research Institute; Australian National University; iVEC; Initiative in Innovative Computing; NVIDIA; International Centre for Radio Astronomy Research, a Joint Venture of Curtin University FX This work uses data obtained from the Murchison Radioastronomy Observatory (MRO), jointly funded by the Commonwealth Government of Australia and Western Australian State government. The MRO is managed by the CSIRO, who also provides operational support to the MWA. We acknowledge the Wajarri Yamatji people as the traditional owners of the Observatory site. Support came from the U.S. National Science Foundation (grants AST-0457585 and PHY-0835713), the Australian Research Council (grants LE0775621 and LE0882938), the U.S. Air Force Office of Scientific Research (grant FA9550-0510247), the National Collaborative Infrastructure Strategy, funded by the Australian federal government via Astronomy Australia Limited, the Smithsonian Astrophysical Observatory, the MIT School of Science, the Raman Research Institute, The Australian National University, iVEC, the Initiative in Innovative Computing and NVIDIA sponsored Center for Excellence at Harvard, and the International Centre for Radio Astronomy Research, a Joint Venture of Curtin University, and The University of Western Australia funded by the Western Australian State government. NR 17 TC 15 Z9 15 U1 1 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 2041-8205 J9 ASTROPHYS J LETT JI Astrophys. J. Lett. PD FEB 20 PY 2011 VL 728 IS 2 AR L27 DI 10.1088/2041-8205/728/2/L27 PG 7 WC Astronomy & Astrophysics SC Astronomy & Astrophysics GA 715YI UT WOS:000286931200003 ER PT J AU Ciaranello, AL Lockman, S Freedberg, KA Hughes, M Chu, J Currier, J Wood, R Holmes, CB Pillay, S Conradie, F McIntyre, J Losina, E Walensky, RP AF Ciaranello, Andrea L. Lockman, Shahin Freedberg, Kenneth A. Hughes, Michael Chu, Jennifer Currier, Judith Wood, Robin Holmes, Charles B. Pillay, Sandy Conradie, Francesca McIntyre, James Losina, Elena Walensky, Rochelle P. CA CEPAC Int OCTANE Investigators TI First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial SO AIDS LA English DT Article DE antiretroviral therapy; cost-effectiveness; HIV; mother-to-child transmission; single-dose nevirapine ID RESOURCE-LIMITED SETTINGS; HIV-INFECTED ADULTS; COTE-DIVOIRE; WOMEN; RITONAVIR; OUTCOMES; LOPINAVIR/RITONAVIR; TRANSMISSION; INTRAPARTUM; ZIDOVUDINE AB Background: The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine. Methods: We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/mu l); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US$), and incremental cost-effectiveness ratios. Results: With no ART, projected life expectancy was 1.6 years and per-person cost was $2980. First-line nevirapine increased life expectancy (15.2 years) and cost ($13 990; cost-effectiveness ratio: $810/year of life saved versus no ART). First-line lopinavir/ritonavir further increased life expectancy to 16.3 years and cost to $15 630 (cost-effectiveness ratio: $1520/year of life saved versus first-line nevirapine). First-line lopinavir/ritonavir cost-effectiveness was sensitive to prevalence of nevirapine-resistant virus at ART initiation, time from single-dose nevirapine exposure to ART initiation (6-12, 12-24, or > 24 months), second-line ART efficacies, and outcomes after 24 weeks on ART. Conclusions: First-line lopinavir/ritonavir-based ART is very cost-effective in single-dose nevirapine-exposed, South African women similar to OCTANE participants. Lopinavir/ritonavir should be initiated in women with known nevirapine resistance or single-dose nevirapine exposure less than 12 months prior, or in whom such information is unknown. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Ciaranello, Andrea L.; Lockman, Shahin; Walensky, Rochelle P.] Harvard Univ, Div Infect Dis, Massachusetts Gen Hosp, Sch Publ Hlth, Boston, MA 02114 USA. [Ciaranello, Andrea L.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Univ, Div Infect Dis, Sch Publ Hlth, Boston, MA 02114 USA. [Lockman, Shahin] Harvard Univ, Div Immunol & Infect Dis, Sch Publ Hlth, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Chu, Jennifer; Losina, Elena; Walensky, Rochelle P.] Harvard Univ, Div Gen Med, Sch Publ Hlth, Boston, MA 02114 USA. [Freedberg, Kenneth A.] Harvard Univ, Brigham & Womens Hosp, Sch Publ Hlth, Ctr AIDS Res, Boston, MA 02114 USA. [Hughes, Michael] Harvard Univ, Ctr Biostat AIDS Res, Sch Publ Hlth, Boston, MA 02114 USA. [Currier, Judith] Univ Calif Los Angeles, Div Infect Dis, Los Angeles, CA USA. [Wood, Robin] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Holmes, Charles B.] Off Global AIDS Coordinator, Washington, DC USA. [Pillay, Sandy] Nelson Mandela Sch Med, Infect Dis Unit, Durban, South Africa. [Conradie, Francesca] Univ Witwatersrand, Johannesburg, South Africa. [McIntyre, James] Anova Hlth Inst, Johannesburg, South Africa. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Orthoped Surg, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Ciaranello, AL (reprint author), Harvard Univ, Div Infect Dis, Massachusetts Gen Hosp, Sch Publ Hlth, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM aciaranello@partners.org RI Anglaret, Xavier/F-7333-2013; OI Walensky, Rochelle P./0000-0002-8795-379X; Lipsitch, Marc/0000-0003-1504-9213 FU National Institute of Allergy and Infectious Disease [K01 AI078754, K24 AI56933, K24 AI062476, R01 AI058736, R01 HD044391, P30 AI 60354, R01 AI 69453]; Adult AIDS Clinical Trials Group [U01 AI068636, U01 AI069424]; Statistical and Data Management Center for the AIDS Clinical Trials Group [U01 AI68634]; Comprehensive International Program for Research on AIDS in South Africa [U19 AI53217]; Elizabeth Glaser Pediatric AIDS Foundation; NIAID [U01 AI06836, AI68634]; General Clinical Research Centers (GCRC) of the National Center for Research Resources; Boehringer Ingelheim; Glaxo SmithKline FX Funding for this work was provided by the National Institute of Allergy and Infectious Disease [K01 AI078754 (A.L.C.), K24 AI56933 (J. Currier), K24 AI062476 (K.A.F.), R01 AI058736 (K.A.F., R.P.W., A.L.C., R.W., J. Chu, E.L.), R01 HD044391 (S.L.), P30 AI 60354 (A.L.C.), R01 AI 69453 (J.M.)]; the Adult AIDS Clinical Trials Group [U01 AI068636 (A.L.C., K.A.F., R.P.W.), U01 AI069424 (J. Currier), Statistical and Data Management Center for the AIDS Clinical Trials Group (U01 AI68634 (M.D.H.)]; the Comprehensive International Program for Research on AIDS in South Africa [U19 AI53217 (R.W..)]; and the Elizabeth Glaser Pediatric AIDS Foundation (A.L.C., K.A.F., J. Chu, R.P.W.).; The OCTANE trial is registered on ClinicalTrials.gov (NCT 00089505) and supported by NIAID (U01 AI06836, AI68634) and the General Clinical Research Centers (GCRC) of the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAID or the National Institutes of Health.; Michael Hughes is a paid member of Data and Safety Monitoring Boards for the following manufacturers of antiretroviral therapy: Boehringer Ingelheim, Pfizer, Tibotec. James McIn-tyre has received speaker's honoraria from Abbott Pharmaceuticals, and research funding, travel grants and speaker's honoraria from Boehringer Ingelheim and Glaxo SmithKline. All other authors have no conflicts of interest to disclose. NR 50 TC 18 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 20 PY 2011 VL 25 IS 4 BP 479 EP 492 DI 10.1097/QAD.0b013e3283428cbe PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 716LN UT WOS:000286970300010 PM 21293199 ER PT J AU Choueiri, TK Mayer, EL Je, YJ Rosenberg, JE Nguyen, PL Azzi, GR Bellmunt, J Burstein, HJ Schutz, FAB AF Choueiri, Toni K. Mayer, Erica L. Je, Youjin Rosenberg, Jonathan E. Nguyen, Paul L. Azzi, Georges R. Bellmunt, Joaquim Burstein, Harold J. Schutz, Fabio A. B. TI Congestive Heart Failure Risk in Patients With Breast Cancer Treated With Bevacizumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INHIBITOR SUNITINIB; PHASE-III; METAANALYSIS; CARDIOTOXICITY; HYPERTENSION; CHEMOTHERAPY; DOCETAXEL; BIAS AB Purpose Bevacizumab is a treatment option in patients with metastatic breast cancer. Congestive heart failure (CHF) has been reported, although the overall incidence and relative risk (RR) of this complication remains unclear. We performed an up-to-date, comprehensive meta-analysis to determine the risk of serious CHF in patients with breast cancer receiving bevacizumab. Methods The databases of Medline were searched for articles from 1966 to March 2010. Abstracts presented at the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium meetings were also searched for relevant clinical trials. Eligible studies include randomized trials with bevacizumab in patients with breast cancer. Adequate reporting of safety profile data was required for inclusion. Statistical analyses were conducted to calculate the summary incidence, RR, and 95% CIs by using random-effects models. Results A total of 3,784 patients were included. Overall incidence results for high-grade CHF in bevacizumab- and placebo-treated patients were 1.6% (95% CI, 1.0% to 2.6%) and 0.4% (95% CI, 0.2% to 1.0%), respectively. The RR of CHF in bevacizumab-treated patients was 4.74 (95% CI, 1.66 to 11.18; P = .001) compared with placebo-treated ones. In subgroup analyses, there were no significant differences in CHF incidence or risk between patients treated with low-dose (2.5 mg/kg) versus high-dose (5 mg/kg) bevacizumab or among patients treated with different chemotherapy regimens. No evidence of publication bias was observed. Conclusion This is the first comprehensive report to show that bevacizumab is associated with an increased risk of significant heart failure in patients with breast cancer. J Clin Oncol 29: 632-638. (C) 2011 by American Society of Clinical Oncology C1 [Schutz, Fabio A. B.] Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Hosp Mar, Inst Municipal Invest Med, Barcelona, Spain. RP Schutz, FAB (reprint author), Dana Farber Canc Inst, 44 Binney St Dana 1230, Boston, MA 02115 USA. EM FabioA_Schutz@dfci.harvard.edu FU Jonathan E. Rosenberg; GlaxoSmithKline; sanofi-aventis; Novartis FX Research Funding: Jonathan E. Rosenberg, GlaxoSmithKline, sanofi-aventis, Novartis NR 30 TC 129 Z9 135 U1 1 U2 3 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 FEB 20 PY 2011 VL 29 IS 6 BP 632 EP 638 DI 10.1200/JCO.2010.31.9129 PG 7 WC Oncology SC Oncology GA 722OP UT WOS:000287444000019 PM 21205755 ER PT J AU Ruan, J Martin, P Furman, RR Lee, SM Cheung, K Vose, JM LaCasce, A Morrison, J Elstrom, R Ely, S Chadburn, A Cesarman, E Coleman, M Leonard, JP AF Ruan, Jia Martin, Peter Furman, Richard R. Lee, Shing M. Cheung, Ken Vose, Julie M. LaCasce, Ann Morrison, Julia Elstrom, Rebecca Ely, Scott Chadburn, Amy Cesarman, Ethel Coleman, Morton Leonard, John P. TI Bortezomib Plus CHOP-Rituximab for Previously Untreated Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROTEASOME INHIBITOR BORTEZOMIB; PROSPECTIVE RANDOMIZED-TRIAL; PROGRESSION-FREE SURVIVAL; EUROPEAN MCL NETWORK; PHASE-II; CLINICAL-TRIALS; ELDERLY-PATIENTS; MOLECULAR SUBTYPES; R-CHOP AB Purpose The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Patients and Methods Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m(2) (n = 4), 1.0 mg/m(2) (n = 9), or 1.3 mg/m(2) (n = 63) on days 1 and 4 for six cycles. Results Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. Conclusion Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies. C1 [Leonard, John P.] Weill Cornell Med Coll, Ctr Lymphoma & Myeloma, New York, NY 10065 USA. New York Presbyterian Hosp, New York, NY USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. Univ Nebraska, Med Ctr, Omaha, NE USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Leonard, JP (reprint author), Weill Cornell Med Coll, Ctr Lymphoma & Myeloma, 525 E 68th St,Starr 340, New York, NY 10065 USA. EM jpleonar@med.cornell.edu FU Millennium Pharmaceuticals; Lymphoma Research Foundation; Lymphoma Foundation; American Society of Clinical Oncology Career Development Award; Genentech; Millennium FX Supported in part by Millennium Pharmaceuticals, grants from the Lymphoma Research Foundation (J.P.L.) and the Lymphoma Foundation (J.P.L.), and an American Society of Clinical Oncology Career Development Award (J.R.).; Research Funding: Richard R. Furman, Genentech, Millennium; Julie M. Vose, Genentech, Millennium; John P. Leonard, Genentech, Millennium NR 46 TC 142 Z9 148 U1 0 U2 8 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 FEB 20 PY 2011 VL 29 IS 6 BP 690 EP 697 DI 10.1200/JCO.2010.31.1142 PG 8 WC Oncology SC Oncology GA 722OP UT WOS:000287444000027 PM 21189393 ER PT J AU Petrocca, F Lieberman, J AF Petrocca, Fabio Lieberman, Judy TI Promise and Challenge of RNA Interference-Based Therapy for Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; DOUBLE-STRANDED-RNA; CELL-CYCLE ARREST; DOWN-REGULATION; IN-VIVO; CAENORHABDITIS-ELEGANS; MIR-34A CONTRIBUTES; NONHUMAN-PRIMATES; OVARIAN-CANCER; TUMOR-GROWTH AB Cancer therapeutics still fall far short of our goals for treating patients with locally advanced or metastatic disease. Until recently, almost all cancer drugs were crude cytotoxic agents that discriminate poorly between cancer cells and normally dividing cells. The development of targeted biologics that recognize tumor cell surface antigens and of specific inhibitors of pathways dysregulated in cancer cells or normal cellular pathways on which a cancer cell differentially depends has provided hope for converting our increasing understanding of cellular transformation into intelligently designed anticancer therapeutics. However, new drug development is painfully slow, and the pipeline of new therapeutics is thin. The discovery of RNA interference (RNAi), a ubiquitous cellular pathway of gene regulation that is dysregulated in cancer cells, provides an exciting opportunity for relatively rapid and revolutionary approaches to cancer drug design. Small RNAs that harness the RNAi machinery may become the next new class of drugs for treating a variety of diseases. Although it has only been 9 years since RNAi was shown to work in mammalian cells, about a dozen phase I to III clinical studies have already been initiated, including four for cancer. So far there has been no unexpected toxicity and suggestions of benefit in one phase II study. However, the obstacles for RNAi-based cancer therapeutics are substantial. This article will discuss how the endogenous RNAi machinery might be harnessed for cancer therapeutics, why academic researchers and biotech and pharmaceutical companies are so excited, and what the obstacles are and how they might be overcome. C1 Childrens Hosp Boston, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lieberman, J (reprint author), 200 Longwood Ave,WAB 255, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu RI Lieberman, Judy/A-2717-2015 FU Department of Defense [W81XWH-09-1-0058]; GlaxoSmithKline-Immune Disease Institute FX Supported by Department of Defense Breast Cancer Research Program Grant No. W81XWH-09-1-0058 (J.L.) and fellowship (F.P.) and by a GlaxoSmithKline-Immune Disease Institute Alliance research grant (J.L.). NR 81 TC 66 Z9 71 U1 0 U2 19 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 FEB 20 PY 2011 VL 29 IS 6 BP 747 EP 754 DI 10.1200/JCO.2009.27.6287 PG 8 WC Oncology SC Oncology GA 722OP UT WOS:000287444000035 PM 21079135 ER PT J AU Nalls, MA Plagnol, V Hernandez, DG Sharma, M Sheerin, UM Saad, M Simon-Sanchez, J Schulte, C Lesage, S Sveinbjornsdottir, S Arepalli, S Barker, R Ben-Shlomo, Y Berendse, HW Berg, D Bhatia, K de Bie, RMA Biffi, A Bloem, B Bochdanovits, Z Bonin, M Bras, JM Brockmann, K Brooks, J Burn, DJ Charlesworth, G Chen, HL Chinnery, PF Chong, S Clarke, CE Cookson, MR Cooper, JM Corvol, JC Counsell, C Damier, P Dartigues, JF Deloukas, P Deuschl, G Dexter, DT van Dijk, KD Dillman, A Durif, F Durr, A Edkins, S Evans, JR Foltynie, T Gao, JJ Gardner, M Gibbs, JR Goate, A Gray, E Guerreiro, R Gustafsson, O Harris, C van Hilten, JJ Hofman, A Hollenbeck, A Holton, J Hu, M Huang, XM Huber, H Hudson, G Hunt, SE Huttenlocher, J Illig, T Jonsson, PV Lambert, JC Langford, C Lees, A Lichtner, P Limousin, P Lopez, G Lorenz, D McNeill, A Moorby, C Moore, M Morris, HR Morrison, KE Mudanohwo, E O'Sullivan, SS Pearson, J Perlmutter, JS Petursson, H Pollak, P Post, B Potter, S Ravina, B Revesz, T Riess, O Rivadeneira, F Rizzu, P Ryten, M Sawcer, S Schapira, A Scheffer, H Shaw, K Shoulson, I Sidransky, E Smith, C Spencer, CCA Stefansson, H Stockton, JD Strange, A Talbot, K Tanner, CM Tashakkori-Ghanbaria, A Tison, F Trabzuni, D Traynor, BJ Uitterlinden, AG Velseboer, D Vidailhet, M Walker, R van de Warrenburg, B Wickremaratchi, M Williams, N Williams-Gray, CH Winder-Rhodes, S Stefansson, K Martinez, M Hardy, J Heutink, P Brice, A Gasser, T Singleton, AB Wood, NW AF Nalls, Michael A. Plagnol, Vincent Hernandez, Dena G. Sharma, Manu Sheerin, Una-Marie Saad, Mohamad Simon-Sanchez, Javier Schulte, Claudia Lesage, Suzanne Sveinbjornsdottir, Sigurlaug Arepalli, Sampath Barker, Roger Ben-Shlomo, Yoav Berendse, Henk W. Berg, Daniela Bhatia, Kailash de Bie, Rob M. A. Biffi, Alessandro Bloem, Bas Bochdanovits, Zoltan Bonin, Michael Bras, Jose M. Brockmann, Kathrin Brooks, Janet Burn, David J. Charlesworth, Gavin Chen, Honglei Chinnery, Patrick F. Chong, Sean Clarke, Carl E. Cookson, Mark R. Cooper, J. Mark Corvol, Jean Christophe Counsell, Carl Damier, Philippe Dartigues, Jean-Francois Deloukas, Panos Deuschl, Guenther Dexter, David T. van Dijk, Karin D. Dillman, Allissa Durif, Frank Duerr, Alexandra Edkins, Sarah Evans, Jonathan R. Foltynie, Thomas Gao, Jianjun Gardner, Michelle Gibbs, J. Raphael Goate, Alison Gray, Emma Guerreiro, Rita Gustafsson, Omar Harris, Clare van Hilten, Jacobus J. Hofman, Albert Hollenbeck, Albert Holton, Janice Hu, Michele Huang, Xuemei Huber, Heiko Hudson, Gavin Hunt, Sarah E. Huttenlocher, Johanna Illig, Thomas Jonsson, Palmi V. Lambert, Jean-Charles Langford, Cordelia Lees, Andrew Lichtner, Peter Limousin, Patricia Lopez, Grisel Lorenz, Delia McNeill, Alisdair Moorby, Catriona Moore, Matthew Morris, Huw R. Morrison, Karen E. Mudanohwo, Ese O'Sullivan, Sean S. Pearson, Justin Perlmutter, Joel S. Petursson, Hjoervar Pollak, Pierre Post, Bart Potter, Simon Ravina, Bernard Revesz, Tamas Riess, Olaf Rivadeneira, Fernando Rizzu, Patrizia Ryten, Mina Sawcer, Stephen Schapira, Anthony Scheffer, Hans Shaw, Karen Shoulson, Ira Sidransky, Ellen Smith, Colin Spencer, Chris C. A. Stefansson, Hreinn Stockton, Joanna D. Strange, Amy Talbot, Kevin Tanner, Carlie M. Tashakkori-Ghanbaria, Avazeh Tison, Francois Trabzuni, Daniah Traynor, Bryan J. Uitterlinden, Andre G. Velseboer, Daan Vidailhet, Marie Walker, Robert van de Warrenburg, Bart Wickremaratchi, Mirdhu Williams, Nigel Williams-Gray, Caroline H. Winder-Rhodes, Sophie Stefansson, Kari Martinez, Maria Hardy, John Heutink, Peter Brice, Alexis Gasser, Thomas Singleton, Andrew B. Wood, Nicholas W. CA Int Parkinson Dis Genomics Consort Wellcome Trust Case-Control Consor TI Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies SO LANCET LA English DT Article ID SYNAPTOTAGMIN-XI; COMMON; LOCI; SUSCEPTIBILITY; MUTATIONS; SUGGESTS; REGION; STK39; SNCA AB Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. C1 [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20837 USA. [Plagnol, Vincent; Wood, Nicholas W.] UCL Genet Inst, London, England. [Hernandez, Dena G.; Sheerin, Una-Marie; Bhatia, Kailash; Bras, Jose M.; Charlesworth, Gavin; Gardner, Michelle; Gibbs, J. Raphael; Guerreiro, Rita; Ryten, Mina; Trabzuni, Daniah; Hardy, John; Wood, Nicholas W.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Sharma, Manu] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Sharma, Manu] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Saad, Mohamad] CPTP, INSERM, U563, Toulouse, France. [Saad, Mohamad; Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Simon-Sanchez, Javier; Bochdanovits, Zoltan; Rizzu, Patrizia; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Lesage, Suzanne; Corvol, Jean Christophe; Duerr, Alexandra] INSERM, UMR S975, Paris, France. [Lesage, Suzanne] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, Paris, France. [Lesage, Suzanne; Corvol, Jean Christophe; Duerr, Alexandra] CNRS, Paris, France. [Sveinbjornsdottir, Sigurlaug] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland. [Sveinbjornsdottir, Sigurlaug] MEHT Broomfield Hosp, Dept Neurol, Chelmsford, Essex, England. [Sveinbjornsdottir, Sigurlaug] Univ London, Queen Mary Coll, London, England. [Barker, Roger] Univ Cambridge, Addenbrookes Hosp, Dept Neurol, Cambridge CB2 2QQ, England. [Ben-Shlomo, Yoav] Univ Bristol, Dept Social Med, Bristol BS8 1TH, Avon, England. [Berendse, Henk W.; van Dijk, Karin D.] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Berendse, Henk W.; van Dijk, Karin D.] Vrije Univ Amsterdam Med Ctr, Alzheimers Ctr, Amsterdam, Netherlands. [de Bie, Rob M. A.; Velseboer, Daan] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Biffi, Alessandro] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Biffi, Alessandro] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bloem, Bas; Post, Bart; van de Warrenburg, Bart] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 ED Nijmegen, Netherlands. [Bonin, Michael; Petursson, Hjoervar; Riess, Olaf] Univ Tubingen, Inst Human Genet, Dept Med Genet, Tubingen, Germany. [Burn, David J.] Newcastle Univ, Clin Ageing Res Unit, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Chen, Honglei] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Chinnery, Patrick F.; Hudson, Gavin] Newcastle Univ, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Clarke, Carl E.; Moorby, Catriona; Morrison, Karen E.] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Clarke, Carl E.] Sandwell & W Birmingham Hosp NHS Trust, City Hosp, Dept Neurol, Birmingham, W Midlands, England. [Cooper, J. Mark; McNeill, Alisdair; Schapira, Anthony] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Corvol, Jean Christophe] Hop La Pitie Salpetriere, INSERM, CIC 9503, Paris, France. [Counsell, Carl] Univ Aberdeen, Div Appl Hlth Sci, Populat Hlth Sect, Aberdeen, Scotland. [Damier, Philippe] CHU Nantes, CIC0004, Serv Neurol, F-44035 Nantes 01, France. [Dartigues, Jean-Francois] Univ Victor Segalen, INSERM, U897, Bordeaux, France. [Deloukas, Panos; Edkins, Sarah; Gray, Emma; Hunt, Sarah E.; Potter, Simon; Tashakkori-Ghanbaria, Avazeh] Wellcome Trust Sanger Inst, Cambridge, England. [Deuschl, Guenther] Univ Kiel, Univ Klinikum Schleswig Holstein, Neurol Klin, Kiel, Germany. [Dexter, David T.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Parkinsons Dis Res Grp, London, England. [Durif, Frank] Hop Gabriel Montpied, Serv Neurol, Clermont Ferrand, France. [Duerr, Alexandra] Hop La Pitie Salpetriere, AP HP, Paris, France. [Evans, Jonathan R.; Langford, Cordelia] Cambridge Ctr Brain Repair, Cambridge, England. [Gustafsson, Omar] Oslo Univ Hosp, deCODE Genet, N-0407 Oslo, Norway. [Gustafsson, Omar] Oslo Univ Hosp, Dept Psychiat, N-0407 Oslo, Norway. [van Hilten, Jacobus J.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Hollenbeck, Albert] AARP, Washington, DC USA. [Holton, Janice] UCL Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England. [Hu, Michele] John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Bioengn, Hershey, PA 17033 USA. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Jonsson, Palmi V.] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Lambert, Jean-Charles] INSERM, U744, F-59045 Lille, France. [Lambert, Jean-Charles] Univ Lille Nord, Inst Pasteur Lille, Lille, France. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Limousin, Patricia] Inst Neurol, Sobell Dept, Unit Funct Neurosurg, London WC1N 3BG, England. [Lopez, Grisel] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD USA. [Morris, Huw R.] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Morrison, Karen E.] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Dept Neurosci, Birmingham, W Midlands, England. [Mudanohwo, Ese] UCL Inst Neurol, Neurogenet Unit, London, England. [Perlmutter, Joel S.] Washington Univ, Dept Neurol Radiol & Neurobiol, St Louis, MO 63130 USA. [Pollak, Pierre] CHU Grenoble, Serv Neurol, F-38043 Grenoble, France. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Sawcer, Stephen] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Scheffer, Hans] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Shoulson, Ira] Univ Rochester, Dept Neurol, Rochester, NY USA. [Smith, Colin; Walker, Robert] Univ Edinburgh, Dept Pathol, Edinburgh, Midlothian, Scotland. [Spencer, Chris C. A.; Strange, Amy] Wellcome Trust Ctr Human Genet, Oxford, England. [Talbot, Kevin] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Tanner, Carlie M.] Parkinsons Inst & Clin Ctr, Dept Clin Res, Sunnyvale, CA USA. [Tison, Francois] Hop Haut Leveque, Serv Neurol, Pessac, France. [Vidailhet, Marie] Univ Paris 06, INSERM, UMR S975, CNRS,UMR 7225, F-75252 Paris 05, France. [Wickremaratchi, Mirdhu] Cardiff Univ, Dept Neurol, Cardiff, S Glam, Wales. [Williams-Gray, Caroline H.] Addenbrookes Hosp, Dept Neurol, Cambridge, England. [Winder-Rhodes, Sophie] Univ Cambridge, Dept Psychiat, Cambridge CB2 1TN, England. [Winder-Rhodes, Sophie] Univ Cambridge, MRC, Cambridge CB2 1TN, England. [Winder-Rhodes, Sophie] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 1TN, England. [Martinez, Maria] INSERM, U563, F-75654 Paris 13, France. [Brice, Alexis] Univ Paris 06, Pitie Salpetriere Hosp, AP HP, CNRS,UMR 7225,INSERM,UMR S975, F-75252 Paris 05, France. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, 35 Convent Dr, Bethesda, MD 20837 USA. EM singleta@mail.nih.gov RI Morris, Huw/B-8527-2008; Bloem, Bastiaan/E-3812-2010; Charlesworth, Gavin/B-5895-2011; Singleton, Andrew/C-3010-2009; turton, miranda/F-4682-2011; Holton, Janice/F-6831-2011; Talbot, Kevin /F-7361-2011; Guerreiro, Rita/A-1327-2011; Plagnol, Vincent/A-5667-2011; mcneill, alisdair/B-1267-2012; O'Sullivan, Sean/C-9333-2012; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; Scheffer, Hans/E-4644-2012; Traynor, Bryan/G-5690-2010; Deloukas, Panos/B-2922-2013; Bras, Jose/A-1428-2011; Cooper, J Mark/D-5826-2013; Deuschl, Gunther/A-7986-2010; lambert, jean-charles/F-8787-2013; Wood, Nicholas/C-2505-2009; LICEND, CEMND/F-1296-2015; Bloem, B.R./H-8013-2014; Trabzuni, Daniah/C-4034-2012; Rivadeneira, Fernando/O-5385-2015; van de Warrenburg, Bart/D-1935-2010; Lambert, jean-charles/A-9553-2014; Martinez, Maria/B-3111-2013; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010; Hudson, Gavin/E-7117-2017; OI Morris, Huw/0000-0002-5473-3774; Holton, Janice/0000-0002-3882-5249; O'Sullivan, Sean/0000-0002-0583-7956; Scheffer, Hans/0000-0002-2986-0915; Deloukas, Panos/0000-0001-9251-070X; Cooper, J Mark/0000-0002-3007-3054; Wood, Nicholas/0000-0002-9500-3348; Trabzuni, Daniah/0000-0003-4826-9570; Rivadeneira, Fernando/0000-0001-9435-9441; Lambert, jean-charles/0000-0003-0829-7817; Bhatia, Kailash/0000-0001-8185-286X; Chen, Honglei/0000-0003-3446-7779; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259; Walker, Robert/0000-0001-7383-7846; Bras, Jose/0000-0001-8186-0333; Schulte, Claudia/0000-0003-4006-1265; Plagnol, Vincent/0000-0002-5597-9215; Stefansson, Hreinn/0000-0002-9331-6666 FU deCODE; Eisai; Merck-Serono; Cephalon; Novartis; National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences; National Human Genome Research Institute of the National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986]; US Department of Defense [W81XWH-09-2-0128]; National Institutes of Health [NS057105, RA024992]; American Parkinson disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; section of medical genomics; Prinses Beatrix Fonds; Forschungszentrum fur Umwelt und Gesundheit; German National Genome Network (German Ministry for Education and Research) [01GS08134]; German Federal Ministry of Education and Research [NGFN 01GR0468]; Helmholtz Alliance Mental Health in an Ageing Society [HA-215]; Helmholtz Association; French National Agency of Research [ANR-08-MNP-012]; Landspitali University Hospital; Icelandic Research Council; European Community [PIAP-GA-2008-230596]; Wellcome Trust [083948/Z/07/Z]; Medical Research Council; Wellcome Trust disease centre [WT089698/Z/09/Z]; Parkinson's UK [8047, J-0804]; Medical Research Council [G0700943]; Department of Health's National Institute for Health Research Biomedical Research Centres; Wellcome Trust/Medical Research Council [WT089698]; Parkinson's Disease Consortium (UKPDC) FX KSt has received grants from deCODE. JH has received consulting fees or honoraria from Eisai and his institute has received consulting fees or honoraria from Merck-Serono. TG has received consultancy fees from Cephalon and Merck-Serono; grants from Novartis; payments for lectures including service on speakers' bureaus from Boehringer Ingelheim, Merck-Serono, UCB, and Valeant; and holds patents NGFN2 and KASPP. MAN, VP, DGH, MSh, U-MS, MSa, JS-S, CS, SL, SS, KS, MM, PH, ABr, ABS, and NWW declare that they have no conflicts of interest.; This work was supported by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, and National Human Genome Research Institute of the National Institutes of Health, Department of Health and Human Services (project numbers Z01-AG000949-02 and Z01-ES101986). This work was also supported by the US Department of Defense (award number W81XWH-09-2-0128); National Institutes of Health (grants NS057105 and RA024992); American Parkinson disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum fur Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGENplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also sponsored by the Landspitali University Hospital Research Fund (grant to SSv); Icelandic Research Council (grant to SSv); and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to HP and JHu). We used the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA, and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank The French Parkinson's Disease Genetics Study Group: Y Agid, M Anheim, A-M Bonnet, M Borg, A Brice, E Broussolle, J-C Corvol, P Damier, A Destee, A Darr, F Durif, S Klebe, E Lohmann, M Martinez, P Pollak, O Rascol, F Tison, C Tranchant, M Venn, F Viallet, and M Vidailhet. We also thank the members of the French 3C Consortium: Annick Alperovitch, Claudine Berr, Christophe Tzourio, and Philippe Amouyel for allowing us souse part of the 3C cohort; and D Zelenika for support in generating the genome-wide molecular data. We used genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson's disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). UK population control data was made available through WTCCC1. This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to NW, J Ha, and ASc). This study was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). We thank Jeffrey Barrett for assistance with the design of the ImmunoChip.; DNA extration work that was done in the UK was undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson's Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. NR 35 TC 382 Z9 384 U1 10 U2 78 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD FEB 19 PY 2011 VL 377 IS 9766 BP 641 EP 649 DI 10.1016/S0140-6736(10)62345-8 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 727DB UT WOS:000287776600033 ER PT J AU Banz, VM Paul, K de Moya, M Zimmermann, H Candinas, D Exadaktylos, AK AF Banz, Vanessa M. Paul, Katrin de Moya, Marc Zimmermann, Heinz Candinas, Daniel Exadaktylos, Aristomenis K. TI Ignoring non-specific abdominal pain in emergency department patients may be related to decreased quality of life SO SWISS MEDICAL WEEKLY LA English DT Article DE abdominal pain; prospective survey; emergency medicine; pain ID LOW-BACK-PAIN; ABNORMAL ILLNESS BEHAVIOR; MAJOR DEPRESSION; SYMPTOMS; POPULATION; HEALTH; SOMATIZATION; PREVALENCE; DISORDERS; ANXIETY AB QUESTIONS UNDER STUDY: Patients suffering from chronic pain have a high prevalence of depression, resulting in a significant impact on overall quality of life. Our aim was to investigate how long term acute non-specific abdominal pain (NSAP) affected overall physical and mental well-being in patients admitted to our emergency department (ED). METHODS: All patients discharged from the ED with NSAP between 06/2007 and 06/2008 were included for follow up. Current health and well-being was evaluated using the SF-36 (R) health questionnaire. Ordinal linear regression models were chosen to separately assess variables influencing SF-36 (R) outcome, with adjustment for age and gender. Results were expressed as differences of means with corresponding 95% confidence intervals and p-values. RESULTS: Of the 200 patients included (57% female, mean age 33 years), 53 (26.5%) still suffered from NSAP after a 12.5-month mean follow up. Patients with persistent NSAP suffered more from chronic pain (26.4%) or known psychiatric illnesses (15.1%) than unaffected patients (p < 0.001 and p = 0.028). Mental (MCS) and physical component scores (PCS) were significantly worse in patients suffering from persistent NSAP, even when adjusted for confounding factors including chronic pain syndromes, pre-existing psychiatric illnesses, other concomitant comorbidities and previous abdominal surgery (p < 0.001 for both scores). Other risk factors included chronic pain syndromes, pre-existing psychiatric illnesses, other concomitant comorbidities and previous abdominal surgery. CONCLUSIONS: NSAP persistence may be associated with a decreased quality of life. Emphasis should be put on providing early counselling and support, with the aim of minimising the long term detrimental side effects of NSAP. C1 [Banz, Vanessa M.; Candinas, Daniel] Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland. [Banz, Vanessa M.; Paul, Katrin; Zimmermann, Heinz; Candinas, Daniel; Exadaktylos, Aristomenis K.] Univ Bern, CH-3010 Bern, Switzerland. [Paul, Katrin; Zimmermann, Heinz; Exadaktylos, Aristomenis K.] Univ Hosp Bern, Inselspital, Dept Emergency Med, CH-3010 Bern, Switzerland. [de Moya, Marc] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Trauma Emergency Surg Surg Crit Care, Boston, MA USA. RP Banz, VM (reprint author), Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland. EM vanessa.banz@insel.ch NR 27 TC 3 Z9 3 U1 3 U2 4 PU E M H SWISS MEDICAL PUBLISHERS LTD PI MUTTENZ PA FARNSBURGERSTR 8, CH-4132 MUTTENZ, SWITZERLAND SN 1424-7860 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD FEB 18 PY 2011 VL 141 AR w13167 DI 10.4414/smw.2011.13167 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 756EF UT WOS:000289993800003 PM 21337174 ER PT J AU Jiang, H Shukla, A Wang, XL Chen, WY Bernstein, BE Roeder, RG AF Jiang, Hao Shukla, Abhijit Wang, Xiaoling Chen, Wei-yi Bernstein, Bradley E. Roeder, Robert G. TI Role for Dpy-30 in ES Cell-Fate Specification by Regulation of H3K4 Methylation within Bivalent Domains SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; ELEGANS DOSAGE COMPENSATION; HISTONE H3; DEVELOPMENTAL REGULATORS; CHROMATIN SIGNATURES; GROUP PROTEINS; POLYCOMB; PLURIPOTENT; DIFFERENTIATION; TRITHORAX AB Histone H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in embryonic stem cells (ESCs). However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of the SET1/MLL histone methyltransferase complexes, modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4 trimethylation (H3K4me3) throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and in H3K4 methylation at key developmental loci. Our results strongly indicate an essential functional role for Dpy-30 and SET1/MLL complex-mediated H3K4 methylation, as a component of the bivalent mark, at developmental genes during the ESC fate transitions. C1 [Jiang, Hao; Wang, Xiaoling; Chen, Wei-yi; Roeder, Robert G.] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. [Shukla, Abhijit; Bernstein, Bradley E.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Shukla, Abhijit; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shukla, Abhijit; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Roeder, RG (reprint author), Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. EM roeder@mail.rockefeller.edu RI Wang, Xiaoling/D-4208-2013 FU Tri-Institutional Starr Stem Cell Scholars fellowship; NIH [DK071900]; Starr Cancer Consortium [I2-A88]; Leukemia and Lymphoma Society [7132-08] FX We are grateful to Yali Dou for baculoviruses encoding RbBP5, WDR5 and Ash2L, Cristina Hughes (David Allis lab), and Eric McIntush (Bethyl Laboratories) for Dpy-30 antibody, Joanna Wysocka for WDR5 antibody, Aaron Goldberg (David Allis lab) for LIF, Shannon Lauberth and Zhanyun Tang for providing supporting data, Zheng-Yuan Fu for technical assistance, Esther Rheinbay, Jing Wang and Xiaojian Sun for data analyses, and Bing Ren (UCSD) and Xiangdong Lu for insightful discussions of the project. H.J. and W.-Y.C. are Leukemia and Lymphoma Society Fellows. X. W. is a recipient of a Tri-Institutional Starr Stem Cell Scholars fellowship. This work was supported by NIH (DK071900), Starr Cancer Consortium (I2-A88), and Leukemia and Lymphoma Society (7132-08) grants to R.G.R. NR 44 TC 140 Z9 150 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 18 PY 2011 VL 144 IS 4 BP 513 EP 525 DI 10.1016/j.cell.2011.01.020 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 722ZC UT WOS:000287473100007 PM 21335234 ER PT J AU Pellegrini, M Calzascia, T Toe, JG Preston, SP Lin, AE Elford, AR Shahinian, A Lang, PA Lang, KS Morre, M Assouline, B Lahl, K Sparwasser, T Tedder, TF Paik, JH DePinho, RA Basta, S Ohashi, PS Mak, TW AF Pellegrini, Marc Calzascia, Thomas Toe, Jesse G. Preston, Simon P. Lin, Amy E. Elford, Alisha R. Shahinian, Arda Lang, Philipp A. Lang, Karl S. Morre, Michel Assouline, Brigitte Lahl, Katharina Sparwasser, Tim Tedder, Thomas F. Paik, Ji-hye DePinho, Ronald A. Basta, Sameh Ohashi, Pamela S. Mak, Tak W. TI IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology SO CELL LA English DT Article ID CD4(+) T-CELLS; IN-VIVO; LYMPHOID-TISSUE; HOST-DEFENSE; INTERLEUKIN-22; ACTIVATION; EXPANSION; INFLAMMATION; PERSISTENCE; HEPATOCYTES AB Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 down-regulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases. C1 [Pellegrini, Marc; Calzascia, Thomas; Lin, Amy E.; Elford, Alisha R.; Shahinian, Arda; Lang, Philipp A.; Lang, Karl S.; Ohashi, Pamela S.; Mak, Tak W.] Univ Hlth Network, Dept Med Biophys, Campbell Family Canc Res Inst, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. [Pellegrini, Marc; Calzascia, Thomas; Lin, Amy E.; Elford, Alisha R.; Shahinian, Arda; Lang, Philipp A.; Lang, Karl S.; Ohashi, Pamela S.; Mak, Tak W.] Univ Hlth Network, Dept Immunol, Campbell Family Canc Res Inst, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. [Pellegrini, Marc; Toe, Jesse G.; Preston, Simon P.] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia. [Pellegrini, Marc] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3050, Australia. [Morre, Michel; Assouline, Brigitte] Cytheris Inc, F-92130 Issy Les Moulineaux, France. [Lahl, Katharina] Stanford Univ, Lab Immunol & Vasc Biol, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Sparwasser, Tim] Ctr Expt & Clin Infect Res, Inst Infect Immunol, TWINCORE, D-30625 Hannover, Germany. [Tedder, Thomas F.] Duke Univ, Dept Immunol, Med Ctr, Durham, NC 27708 USA. [Paik, Ji-hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med Oncol,Dept Med,Dana Farber Canc Inst, Boston, MA 02115 USA. [Paik, Ji-hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Dana Farber Canc Inst, Boston, MA 02115 USA. [Basta, Sameh] Queens Univ, Dept Microbiol & Immunol, Kingston, ON K7L 396, Canada. RP Ohashi, PS (reprint author), Univ Hlth Network, Dept Med Biophys, Campbell Family Canc Res Inst, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. EM pohashi@uhnres.utoronto.ca RI Pellegrini, Marc/F-7670-2014; Lang, Karl/R-2505-2016 FU Canadian Institute for Health Research [CIHR-MOP-106529]; Terry Fox Cancer Foundation National Cancer Institute of Canada; Boninchi Foundation (Geneva, Switzerland); National Cancer Institute of Canada; Irvington Institute with the Cancer Research Institute (New York, NY); Australian National Health and Medical Research Council; Natural Sciences and Engineering Research Council of Canada; Ontario Ministry of Health and Long Term Care (OMOHLTC) FX Dr. Mandana Nikpour assisted with statistical analyses. Marina Zaitseva contributed to the analysis of thymic emigrants; Alain Lamarre, Paul Jolicoeur, and Michel Nussenzweig provided reagents and mice. This work was supported by a Canadian Institute for Health Research grant to T. W. M. and P.S.O. (CIHR-MOP-106529) and a Terry Fox Cancer Foundation National Cancer Institute of Canada grant to T. W. M. T. C. was supported by the Boninchi Foundation (Geneva, Switzerland) and The Terry Fox Foundation through an award from the National Cancer Institute of Canada. M. P. was supported through an Irvington Institute Fellowship with the Cancer Research Institute (New York, NY) and an Australian National Health and Medical Research Council Fellowship. S. B receives support from the Natural Sciences and Engineering Research Council of Canada. P.S.O. holds a Canada Research Chair in autoimmunity and tumor immunity. This research was also funded, in part, by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC. NR 48 TC 143 Z9 147 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 18 PY 2011 VL 144 IS 4 BP 601 EP 613 DI 10.1016/j.cell.2011.01.011 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 722ZC UT WOS:000287473100014 PM 21295337 ER PT J AU Fung, H Demple, B AF Fung, Hua Demple, Bruce TI Distinct Roles of Ape1 Protein in the Repair of DNA Damage Induced by Ionizing Radiation or Bleomycin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; DOUBLE-STRAND-BREAK; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN CELL-EXTRACTS; SINGLE-STRAND; ABASIC SITES; IN-VITRO; SACCHAROMYCES-CEREVISIAE; CLUSTERED DAMAGE; CANCER AB Ionizing radiation (IR) and bleomycin (BLM) are used to treat various types of cancers. Both agents generate cytotoxic double strand breaks (DSB) and abasic (apurinic/apyrimidinic (AP)) sites in DNA. The human AP endonuclease Ape1 acts on abasic or 3'-blocking DNA lesions such as those generated by IR or BLM. We examined the effect of siRNA-mediated Ape1 suppression on DNA repair and cellular resistance to IR or BLM in human B-lymphoblastoid TK6 cells and HCT116 colon tumor cells. Partial Ape1 deficiency (similar to 30% of normal levels) sensitized cells more dramatically to BLM than to IR cytotoxicity. In both cases, expression of the unrelated yeast AP endonuclease, Apn1, largely restored resistance. Ape1 deficiency increased DNA AP site accumulation due to IR treatment but reduced the number of DSB. In contrast, for BLM, there were more DSB under Ape1 deficiency, with little change in the accumulation of AP sites. Although the role of Ape1 in generating DSB was greater for IR, the enzyme facilitated removal of AP sites, which may mitigate the cytotoxic effects of IR. In contrast, BLM generates scattered AP sites, and the DSB have 3'-phosphoglycolate termini that require Ape1 processing. These DSB persist under Ape1 deficiency. Apoptosis induced by BLM (but not by IR) under Ape1 deficiency was partially p53-dependent, more dramatically in TK6 than HCT116 cells. Thus, Ape1 suppression or inhibition may be a more efficacious adjuvant for BLM than for IR cancer therapy, particularly for tumors with a functional p53 pathway. C1 [Demple, Bruce] SUNY Stony Brook, Dept Pharmacol Sci, Sch Med, Stony Brook, NY 11794 USA. [Fung, Hua] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Demple, B (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Sch Med, Stony Brook, NY 11794 USA. EM bruce@pharm.stonybrook.edu FU National Institutes of Health [R01 GM040000] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 GM040000 (to B. D.). NR 60 TC 39 Z9 39 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2011 VL 286 IS 7 BP 4968 EP 4977 DI 10.1074/jbc.M110.146498 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 719SY UT WOS:000287230600005 PM 21081487 ER PT J AU Riese, MJ Grewal, J Das, J Zou, T Patil, V Chakraborty, AK Koretzky, GA AF Riese, Matthew J. Grewal, Jashanpreet Das, Jayajit Zou, Tao Patil, Vineet Chakraborty, Arup K. Koretzky, Gary A. TI Decreased Diacylglycerol Metabolism Enhances ERK Activation and Augments CD8(+) T Cell Functional Responses SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CBL-B; KINASE-ZETA; HOMEOSTATIC PROLIFERATION; RAS ACTIVATION; IN-VIVO; POSITIVE SELECTION; ANTIGEN; PROTEIN; ALPHA; NAIVE AB Modulation of T cell receptor signal transduction in CD8(+) T cells represents a novel strategy toward enhancing the immune response to tumor. Recently, levels of guanine exchange factors, RasGRP and SOS, within T cells have been shown to represent a key determinant in the regulation of the analog to the digital activation threshold of Ras. One important for regulating activation levels of RasGRP is diacylglycerol (DAG), and its levels are influenced by diacylglycerol kinase-zeta (DGK zeta), which metabolizes DAG into phosphatidic acid, terminating DAG-mediated Ras signaling. We sought to determine whether DGK zeta-deficient CD8(+) T cells demonstrated enhanced in vitro responses in a manner predicted by the current model of Ras activation and to evaluate whether targeting this threshold confers enhanced CD8(+) T cell responsiveness to tumor. We observed that DGK zeta-deficient CD8(+) T cells conform to most predictions of the current model of how RasGRP levels influence Ras activation. But our results differ in that the EC50 value of stimulation is not altered for any T cell receptor stimulus, a finding that suggests a further degree of complexity to how DGK zeta deficiency affects signals important for Ras and ERK activation. Additionally, we found that DGK zeta-deficient CD8(+) T cells demonstrate enhanced responsiveness in a subcutaneous lymphoma model, implicating the analog to a digital conversion threshold as a novel target for potential therapeutic manipulation. C1 [Koretzky, Gary A.] Univ Penn, Dept Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Riese, Matthew J.] Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Koretzky, Gary A.] Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Das, Jayajit] Nationwide Childrens Hosp, Battelle Ctr Math Med, Columbus, OH 43205 USA. [Das, Jayajit] Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. [Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Koretzky, Gary A.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA 02129 USA. RP Koretzky, GA (reprint author), 413 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM koretzky@mail.med.upenn.edu RI Das, Jayajit/E-2951-2011 FU National Institutes of Health FX This work was supported, in whole or in part, by a National Institutes of Health grant. NR 46 TC 24 Z9 24 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 FEB 18 PY 2011 VL 286 IS 7 BP 5254 EP 5265 DI 10.1074/jbc.M110.171884 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 719SY UT WOS:000287230600034 PM 21138839 ER PT J AU Lee, KH Liu, YJ Biswas, A Ogawa, C Kobayashi, KS AF Lee, Kyoung-Hee Liu, Yuen-Joyce Biswas, Amlan Ogawa, Chikako Kobayashi, Koichi S. TI A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; BLAU-SYNDROME; BACTERIAL PEPTIDOGLYCAN; REGULATORY ROLES; CARD15 MUTATIONS; CROHNS-DISEASE; CUTTING EDGE; MURINE MODEL; STRANDED-RNA AB Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR- or NLR-induced activation of p38 and JNK, phosphorylation/degradation of I kappa B, and subsequent nuclear translocation of NF-kappa B subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders. C1 [Lee, Kyoung-Hee; Liu, Yuen-Joyce; Biswas, Amlan; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Lee, Kyoung-Hee; Biswas, Amlan; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ogawa, Chikako] Eisai Res Inst, Andover, MA 01810 USA. RP Kobayashi, KS (reprint author), 1420A,44 Binney St, Boston, MA 02115 USA. EM Koichi_Kobayashi@dfci.harvard.edu FU Eisai Research Institute under Dana-Farber Cancer Institute [2696, CRF 734]; Cancer Research Institute; Claudia Adams Barr Award FX This work was supported by the Eisai Research Institute under the Sponsored Research Agreement (Dana-Farber Cancer Institute Agreement Number Reference 2696/Eisai Research Institute CRF 734).; A recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award. NR 59 TC 7 Z9 7 U1 0 U2 1 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 FEB 18 PY 2011 VL 286 IS 7 BP 5727 EP 5735 DI 10.1074/jbc.M110.108001 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 719SY UT WOS:000287230600081 PM 21138842 ER PT J AU Nagaike, T Logan, C Hotta, I Rozenblatt-Rosen, O Meyerson, M Manley, JL AF Nagaike, Takashi Logan, Charlotte Hotta, Ikuko Rozenblatt-Rosen, Orit Meyerson, Matthew Manley, James L. TI Transcriptional Activators Enhance Polyadenylation of mRNA Precursors SO MOLECULAR CELL LA English DT Article ID POLYMERASE-II ELONGATION; 3' UNTRANSLATED REGIONS; B-CELL DIFFERENTIATION; PAF1 COMPLEX; TUMOR-SUPPRESSOR; SACCHAROMYCES-CEREVISIAE; IN-VIVO; GENE-EXPRESSION; HISTONE H3; PROTEIN AB Polyadenylation of mRNA precursors is frequently coupled to transcription by RNA polymerase II. Although this coupling is known to involve interactions with the C-terminal domain of the RNA polymerase II largest subunit, the possible role of other factors is not known. Here we show that a prototypical transcriptional activator, GAL4-VP16, stimulates transcription-coupled polyadenylation in vitro. In the absence of GAL4-VP16, specifically initiated transcripts accumulated but little polyadenylation was observed, while in its presence polyadenylation was strongly enhanced. We further show that this stimulation requires the transcription elongation-associated PAF complex (PAF1c), as PAF1c depletion blocked GAL4-VP16-stimulated polyadenylation. Furthermore, knockdown of PAF subunits by siRNA resulted in decreased 3' cleavage, and nuclear export, of mRNA in vivo. Finally, we show that GAL4-VP16 interacts directly with PAF1c and recruits it to DNA templates. Our results indicate that a transcription activator can stimulate transcription-coupled 3' processing and does so via interaction with PAF1c. C1 [Nagaike, Takashi; Logan, Charlotte; Hotta, Ikuko; Manley, James L.] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Rozenblatt-Rosen, Orit; Meyerson, Matthew] Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Rozenblatt-Rosen, Orit; Meyerson, Matthew] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Manley, JL (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. EM jlm2@columbia.edu RI Meyerson, Matthew/E-7123-2012 FU National Institutes of Health [R01 GM28983] FX We thank Nishta Rao for preparing HeLa nuclear extract. We are grateful to Dr. Jerry Workman and Dr. Russ Carstens for providing 5SG5E4 plasmid and pIRES-puro3 plasmid, respectively. We also thank Dr. Bin Tian for communicating results prior to publication. This study was supported by National Institutes of Health grant R01 GM28983 to J.L.M. NR 56 TC 53 Z9 57 U1 0 U2 4 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 FEB 18 PY 2011 VL 41 IS 4 BP 409 EP 418 DI 10.1016/j.molcel.2011.01.022 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 727BW UT WOS:000287773300006 PM 21329879 ER PT J AU Rodgers, JT Vogel, RO Puigserver, P AF Rodgers, Joseph T. Vogel, Rutger O. Puigserver, Pere TI Clk2 and B56 beta Mediate Insulin-Regulated Assembly of the PP2A Phosphatase Holoenzyme Complex on Akt SO MOLECULAR CELL LA English DT Article ID PROTEIN-KINASE-B; PHOSPHORYLATION; ACTIVATION; SUBUNIT; AKT/PKB; SENSITIVITY; INHIBITION; METABOLISM; RESISTANCE; ATTENUATE AB Akt mediates important cellular decisions involved in growth, survival, and metabolism. The mechanisms by which Akt is phosphorylated and activated in response to growth factors or insulin have been extensively studied, but the molecular regulatory components and dynamics of Akt attenuation are poorly understood. Here we show that a downstream target of insulin-induced Akt activation, Clk2, triggers Akt dephosphorylation through the PP2A phosphatase complex. Clk2 phosphorylates the PP2A regulatory subunit B56 beta (PPP2R5B, B'beta), which is a critical regulatory step in the assembly of the PP2A holoenzyme complex on Akt leading to dephosphorylation of both S473 and T308 Akt sites. Since Akt plays a pivotal role in cellular signaling, these results have important implications for our understanding of Akt regulation in many biological processes. C1 [Rodgers, Joseph T.; Vogel, Rutger O.; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rodgers, Joseph T.; Vogel, Rutger O.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu FU Ellison Medical Foundation; American Diabetes Association; U.S. Department of Defense; National Institutes of Health (NIH) [RO1, DK069966]; American Heart Association; Energy4All Foundation FX We would like to thank Christine Chin for technical assistance, Francisca Vazquez and Zachary Gerhart-Hines for careful reviewing of this manuscript, and Bruce Spiegelman and all members of the Puigserver lab for discussions relating to this project. A special thanks to David Virshup for supplying 856 plasmids and antibodies. These studies were supported in part by an Ellison Medical Foundation New Scholar Award, American Diabetes Association, U.S. Department of Defense, and National Institutes of Health (NIH) RO1, DK069966 (to P.P.); an American Heart Association Predoctoral fellowship (to J.T.R.); and the Energy4All Foundation (to fly.). J.T.R. and R.V. performed experiments and analyzed data, and J.T.R. and P.P. designed experiments, analyzed data, and wrote the manuscript. NR 30 TC 32 Z9 37 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 18 PY 2011 VL 41 IS 4 BP 471 EP 479 DI 10.1016/j.molcel.2011.02.007 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 727BW UT WOS:000287773300011 PM 21329884 ER PT J AU Fu, J Ghali, BW Lozynsky, AJ Oral, E Muratoglu, OK AF Fu, Jun Ghali, Bassem W. Lozynsky, Andrew J. Oral, Ebru Muratoglu, Orhun K. TI Wear resistant UHMWPE with high toughness by high temperature melting and subsequent radiation cross-linking SO POLYMER LA English DT Article DE High temperature melting; Radiation cross-linking; Low wear ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; ALPHA-TOCOPHEROL; IRRADIATED UHMWPE; UNITED-STATES; VITAMIN-E; OXIDATION; COMPONENTS; CRYSTALS AB The goal of this study was to create wear resistant ultra high molecular weight polyethylene (UHMWPE) with improved strength and toughness. It was previously demonstrated that high temperature melting (HIM) of UHMWPE at 280-320 degrees C improved its toughness without detrimentally affecting its wear resistance. We hypothesized that radiation cross-linking after high temperature melting could further improve the wear resistance of UHMWPE, and the loss in toughness by radiation cross-linking could be compensated by the improved toughness achieved by the high temperature melting prior to irradiation. In this work, we demonstrated that irradiation after HTM generated UHMWPE with improved toughness compared to the irradiated UHMWPEs without HIM, partly due to the low cross-link density of irradiated HIM UHMWPE. At a given cross-link density, irradiated HTM UHMWPEs showed higher wear resistance than irradiated UHMWPE. Therefore, successive HTM and radiation cross-linking strategy is promising to create UHMWPE materials with low wear and improved mechanical properties for total joint implants. (C) 2011 Published by Elsevier Ltd. C1 [Fu, Jun; Ghali, Bassem W.; Lozynsky, Andrew J.; Oral, Ebru; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Fu, Jun; Oral, Ebru; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. RP Oral, E (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St, Boston, MA 02114 USA. EM eoral@partners.org RI Fu, Jun/C-1648-2012 OI Fu, Jun/0000-0002-8723-1439 NR 26 TC 10 Z9 14 U1 0 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0032-3861 J9 POLYMER JI Polymer PD FEB 17 PY 2011 VL 52 IS 4 BP 1155 EP 1162 DI 10.1016/j.polymer.2011.01.017 PG 8 WC Polymer Science SC Polymer Science GA 722WV UT WOS:000287466900031 ER PT J AU Kaufman, DS Zietman, AL Dahl, DM Harisinghani, MG Wu, CL AF Kaufman, Donald S. Zietman, Anthony L. Dahl, Douglas M. Harisinghani, Mukesh G. Wu, Chin-Lee TI Case 5-2011: A 65-Year-Old Man with Hematuria after Treatment for Prostate Cancer ANATOMICAL DIAGNOSIS SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ADENOCARCINOMA; BRACHYTHERAPY; RADIOTHERAPY; OUTCOMES C1 [Kaufman, Donald S.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Dahl, Douglas M.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kaufman, Donald S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Zietman, Anthony L.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Dahl, Douglas M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Harisinghani, Mukesh G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Kaufman, DS (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. NR 11 TC 1 Z9 1 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 17 PY 2011 VL 364 IS 7 BP 667 EP 675 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 722BW UT WOS:000287406000014 PM 21323545 ER PT J AU Cao, Y Staropoli, JF Biswas, S Espinola, JA MacDonald, ME Lee, JM Cotman, SL AF Cao, Yi Staropoli, John F. Biswas, Sunita Espinola, Janice A. MacDonald, Marcy E. Lee, Jong-Min Cotman, Susan L. TI Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells SO PLOS ONE LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; LINK BATTEN-DISEASE; TRANSMEMBRANE PROTEIN; LYSOSOMAL STORAGE; CLN3 PROTEIN; PATHWAY; MOUSE; EXPRESSION; TRAFFICKING; DEFICIENCY AB Variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), caused by CLN6 mutation, and juvenile neuronal ceroid lipofuscinosis (JNCL), caused by CLN3 mutation, share clinical and pathological features, including lysosomal accumulation of mitochondrial ATP synthase subunit c, but the unrelated CLN6 and CLN3 genes may initiate disease via similar or distinct cellular processes. To gain insight into the NCL pathways, we established murine wild-type and CbCln6(nclf/nclf) cerebellar cells and compared them to wild-type and CbCln3(Delta ex7/8/Delta ex7/8) cerebellar cells. CbCln6(nclf/nclf) cells and CbCln3(Delta ex7/8/Delta ex7/8) cells both displayed abnormally elongated mitochondria and reduced cellular ATP levels and, as cells aged to confluence, exhibited accumulation of subunit c protein in Lamp 1-positive organelles. However, at sub-confluence, endoplasmic reticulum PDI immunostain was decreased only in CbCln6(nclf/nclf) cells, while fluid-phase endocytosis and LysoTracker (R) labeled vesicles were decreased in both CbCln6(nclf/nclf) and CbCln3(Delta ex7/8/Delta ex7/8) cells, though only the latter cells exhibited abnormal vesicle subcellular distribution. Furthermore, unbiased gene expression analyses revealed only partial overlap in the cerebellar cell genes and pathways that were altered by the Cln3(Delta ex7/8) and Cln6(nclf) mutations. Thus, these data support the hypothesis that CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival. C1 [Cao, Yi; Staropoli, John F.; Biswas, Sunita; Espinola, Janice A.; MacDonald, Marcy E.; Lee, Jong-Min; Cotman, Susan L.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. RP Cao, Y (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. EM cotman@helix.mgh.harvard.edu FU Batten Disease Support and Research Association; National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS33648]; National Tay-Sachs and Allied Diseases Association; Massachusetts Alzheimer's Disease Research Center; Harvard NeuroDiscovery Center; Dubai-Harvard Foundation for Medical Research FX This study was funded by the Batten Disease Support and Research Association (www.bdsra.org; Postdoctoral Fellowships to Y.C. and S.B., Grant to S.L.C.), by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (www.ninds.nih.gov; NS33648, to M.E.M.), the National Tay-Sachs and Allied Diseases Association (www.ntsad.org; to S.L.C.), the Massachusetts Alzheimer's Disease Research Center and Harvard NeuroDiscovery Center Pilot Study Grants Program (madrc.mgh.harvard.edu; to S.L.C.) and the Dubai-Harvard Foundation for Medical Research (www.dhfmr.hms.harvard.edu; to S.L.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 24 Z9 24 U1 0 U2 2 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 FEB 17 PY 2011 VL 6 IS 2 AR e17118 DI 10.1371/journal.pone.0017118 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723BX UT WOS:000287482300030 PM 21359198 ER PT J AU Sarantopoulos, S Stevenson, KE Kim, HT Washel, WS Bhuiya, NS Cutler, CS Alyea, EP Ho, VT Soiffer, RJ Antin, JH Ritz, J AF Sarantopoulos, Stefanie Stevenson, Kristen E. Kim, Haesook T. Washel, Whitney S. Bhuiya, Nazmim S. Cutler, Corey S. Alyea, Edwin P. Ho, Vincent T. Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome TI Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease SO BLOOD LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; LIVED PLASMA-CELLS; RHEUMATOID-ARTHRITIS; LYMPHOCYTE STIMULATOR; TISSUE AUTOANTIGENS; DEPLETION THERAPY; ACTIVATING FACTOR; PERIPHERAL-BLOOD; IMMUNE-SYSTEM AB Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/ improved group, BAFF/B-cell ratios and CD27(+) B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD(+) B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-R(Lo)CD20(Lo) cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance. (Blood. 2011;117(7):2275-2283) C1 [Sarantopoulos, Stefanie] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Stevenson, Kristen E.; Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Washel, Whitney S.; Bhuiya, Nazmim S.; Cutler, Corey S.; Alyea, Edwin P.; Ho, Vincent T.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Washel, Whitney S.; Bhuiya, Nazmim S.; Cutler, Corey S.; Alyea, Edwin P.; Ho, Vincent T.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ritz, Jerome] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Ritz, Jerome] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. RP Sarantopoulos, S (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295, Chapel Hill, NC 27599 USA. EM stefanie_sarantopoulos@med.unc.edu OI Ritz, Jerome/0000-0001-5526-4669 FU National Marrow Donor Program; Jock and Bunny Adams Research and Education Endowment; Ted and Eileen Pasquarello Research Fund; National Institutes of Health [AI29530, CA142106, K12CA087723] FX This work was supported by the National Marrow Donor Program Amy Strelzer Manasevit Award, the Jock and Bunny Adams Research and Education Endowment, the Ted and Eileen Pasquarello Research Fund, and the National Institutes of Health (grants AI29530, CA142106, and K12CA087723). NR 49 TC 55 Z9 58 U1 3 U2 6 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 FEB 17 PY 2011 VL 117 IS 7 BP 2275 EP 2283 DI 10.1182/blood-2010-10-307819 PG 9 WC Hematology SC Hematology GA 722OB UT WOS:000287440900030 PM 21097674 ER PT J AU Sahin, E Colla, S Liesa, M Moslehi, J Muller, FL Guo, MR Cooper, M Kotton, D Fabian, AJ Walkey, C Maser, RS Tonon, G Foerster, F Xiong, R Wang, YA Shukla, SA Jaskelioff, M Martin, ES Heffernan, TP Protopopov, A Ivanova, E Mahoney, JE Kost-Alimova, M Perry, SR Bronson, R Liao, RL Mulligan, R Shirihai, OS Chin, L DePinho, RA AF Sahin, Erguen Colla, Simona Liesa, Marc Moslehi, Javid Mueller, Florian L. Guo, Mira Cooper, Marcus Kotton, Darrell Fabian, Attila J. Walkey, Carl Maser, Richard S. Tonon, Giovanni Foerster, Friedrich Xiong, Robert Wang, Y. Alan Shukla, Sachet A. Jaskelioff, Mariela Martin, Eric S. Heffernan, Timothy P. Protopopov, Alexei Ivanova, Elena Mahoney, John E. Kost-Alimova, Maria Perry, Samuel R. Bronson, Roderick Liao, Ronglih Mulligan, Richard Shirihai, Orian S. Chin, Lynda DePinho, Ronald A. TI Telomere dysfunction induces metabolic and mitochondrial compromise SO NATURE LA English DT Article ID HEART-FAILURE; STEM-CELLS; HEPATOCELLULAR-CARCINOMA; P53; MICE; DAMAGE; LEADS; COACTIVATORS; PGC-1-ALPHA; BIOGENESIS AB Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1 alpha and PGC-1 beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1a expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1 alpha and PGC-1 beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction. C1 [Sahin, Erguen; Colla, Simona; Mueller, Florian L.; Maser, Richard S.; Tonon, Giovanni; Foerster, Friedrich; Xiong, Robert; Wang, Y. Alan; Shukla, Sachet A.; Jaskelioff, Mariela; Martin, Eric S.; Heffernan, Timothy P.; Protopopov, Alexei; Ivanova, Elena; Mahoney, John E.; Kost-Alimova, Maria; Perry, Samuel R.; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Sahin, Erguen; Colla, Simona; Moslehi, Javid; Mueller, Florian L.; Maser, Richard S.; Tonon, Giovanni; Foerster, Friedrich; Jaskelioff, Mariela; Martin, Eric S.; Chin, Lynda; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Liesa, Marc; Kotton, Darrell; Shirihai, Orian S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Moslehi, Javid; Liao, Ronglih; DePinho, Ronald A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Guo, Mira] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Cooper, Marcus] Univ Massachusetts, Div Cardiovasc Med, Worcester, MA 01605 USA. [Fabian, Attila J.; Mulligan, Richard; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Walkey, Carl] Univ Melbourne, St Vincents Hosp, St Vincents Inst, Victoria 3065, Australia. [Walkey, Carl] Univ Melbourne, St Vincents Hosp, Dept Med, Victoria 3065, Australia. [Bronson, Roderick] Harvard Univ, Sch Med, Rodent Histopathol Lab, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu RI Maser, Richard/B-2970-2012; OI Liesa Roig, Marc/0000-0002-5909-8570; Kotton, Darrell/0000-0002-9604-8476; Walkley, Carl/0000-0002-4784-9031; Colla, Simona/0000-0001-6583-8910 FU Deutsche Forschungsgemeinschaft; NIH National Cancer Institute; Robert A. and Renee E. Belfer Foundation; Ellison Foundation; American Cancer Society; Fundacion Ramon Areces FX We thank C. Bianchi, J. Moriarty, K. Marmon and E. Thompson for excellent mouse husbandry and care. We are grateful to B. Spiegelman, P. Puigserver, J. E. Dominy and J. L. Estall for providing Ad-PGC-1 alpha and Ad-GFP virus and helpful comments on the manuscript. We thank G. I. Evan for the p53-ER construct. We appreciate input, critical comments and helpful discussions from many DePinho/Chin lab members, in particular A.-J. Chen, C. Khoo, R. Carrasco, A. Kimmelman, S. Quayle, D. Liu and R. Wiedemeyer. We acknowledge the services of the Mouse Metabolism Cores at Yale (NIH/NIDDK U24 DK-59635) and at Baylor College of Medicine (BCM) and the BCM Diabetes & Endocrinology Research Center (DERC) grant (P30 DK079638). E.S. was supported by the Deutsche Forschungsgemeinschaft and this work and R.A.D. are supported by R01 and U01 grants from the NIH National Cancer Institute and the Robert A. and Renee E. Belfer Foundation. R.A.D. was supported by an Ellison Foundation for Medical Research Senior Scholar and an American Cancer Society Research Professor award. M.L. is a recipient of a postdoctoral fellowship from Fundacion Ramon Areces. NR 45 TC 430 Z9 437 U1 15 U2 110 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 17 PY 2011 VL 470 IS 7334 BP 359 EP 365 DI 10.1038/nature09787 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 722CS UT WOS:000287409100034 PM 21307849 ER PT J AU Bookman, EB Langehorne, AA Eckfeldt, JH Glass, KC Jarvik, GP Klag, M Koski, G Motulsky, A Wilfond, B Manolio, TA Fabsitz, RR Luepker, RV AF Bookman, Ebony B. Langehorne, Aleisha A. Eckfeldt, John H. Glass, Kathleen C. Jarvik, Gail P. Klag, Michael Koski, Greg Motulsky, Arno Wilfond, Benjamin Manolio, Teri A. Fabsitz, Richard R. Luepker, Russell V. TI Comment on "Multidimensional Results Reporting to Participants in Genomic Studies: Getting It Right" SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Letter ID WORKING GROUP C1 [Bookman, Ebony B.; Manolio, Teri A.; Fabsitz, Richard R.] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Langehorne, Aleisha A.] NHLBI, Biomed Res Training Program Underrepresented, Bethesda, MD 20892 USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Glass, Kathleen C.] McGill Univ, Dept Human Genet & Pediat, Montreal, PQ H3G 1Y6, Canada. [Klag, Michael] Johns Hopkins Univ, Dept Internal Med, Baltimore, MD 21205 USA. [Koski, Greg] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Jarvik, Gail P.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA. [Motulsky, Arno] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wilfond, Benjamin] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Luepker, Russell V.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. RP Bookman, EB (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. EM ebony.bookman@nih.gov RI Jarvik, Gail/N-6476-2014 OI Jarvik, Gail/0000-0002-6710-8708 NR 3 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 16 PY 2011 VL 3 IS 70 AR 70le1 DI 10.1126/scitranslmed.3001516 PG 1 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795JW UT WOS:000292971500005 PM 21325615 ER PT J AU Gollub, RL Kong, J AF Gollub, Randy L. Kong, Jian TI For Placebo Effects in Medicine, Seeing Is Believing SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID INDUCED EXPECTATIONS; CONTROLLED-TRIALS; HUMAN BRAIN; PAIN; MECHANISMS; ACUPUNCTURE; ANALGESIA; FMRI; DISSOCIATION; ANTICIPATION AB The gold standard for determining the efficacy of biomedical therapies is the detection of a significant difference between the therapeutic effects of an active pharmacological agent or procedure and a matched inert placebo in a randomized controlled trial. Detecting this difference has become a challenge for medicine, especially for outcomes that are based on patient self-rated scales. Yet factors that contribute to placebo responses have received scant attention. In this issue of Science Translational Medicine, Bingel et al. report on an example of how noninvasive whole-brain imaging contributes to our understanding of brain-based placebo effects. Here we highlight ways in which neuroimaging is catalyzing a revolution in society's perspective of placebo effects by providing a compelling visualization of how brain activities that reflect a person's thoughts, feelings, and past experiences can enhance or antagonize his or her response to a medical treatment. C1 [Gollub, Randy L.; Kong, Jian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Gollub, RL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. EM rgollub@partners.org OI Gollub, Randy L./0000-0002-9434-4044 NR 35 TC 6 Z9 7 U1 0 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 16 PY 2011 VL 3 IS 70 AR 70ps5 DI 10.1126/scitranslmed.3002120 PG 5 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795JW UT WOS:000292971500002 PM 21325616 ER PT J AU Cooke, CR Joo, MJ Anderson, SM Lee, TA Udris, EM Johnson, E Au, DH AF Cooke, Colin R. Joo, Min J. Anderson, Stephen M. Lee, Todd A. Udris, Edmunds M. Johnson, Eric Au, David H. TI The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Chronic Obstructive Pulmonary Disease; Statistical Models; Epidemiology; Veterans; Sensitivity and Specificity; Logistic Models ID ARTIFICIAL NEURAL-NETWORKS; INHALED CORTICOSTEROIDS; LOGISTIC-REGRESSION; ADMINISTRATIVE DATABASES; MEDICAID POPULATION; AIRWAY-OBSTRUCTION; COPD; MORTALITY; BURDEN; DIAGNOSIS AB Background: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. Methods: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC < 0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. Results: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of >= 1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: >= 6 albuterol MDI, >= 3 ipratropium MDI, >= 1 outpatient ICD-9 code, >= 1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). Conclusion: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD. C1 [Cooke, Colin R.] Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Cooke, Colin R.] Univ Michigan, Robert Wood Johnson Fdn Clin Scholars Program, Ann Arbor, MI 48109 USA. [Joo, Min J.; Lee, Todd A.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Joo, Min J.] Univ Illinois, Sect Pulm Crit Care Sleep & Allergy, Chicago, IL USA. [Anderson, Stephen M.; Udris, Edmunds M.; Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Lee, Todd A.] Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL USA. [Lee, Todd A.] Univ Illinois, Coll Pharm, Ctr Pharmacoecon Res, Chicago, IL USA. [Johnson, Eric] Grp Hlth Res Inst, Seattle, WA USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. RP Cooke, CR (reprint author), Univ Michigan, Div Pulm & Crit Care Med, 6312 Med Sci Bldg 1,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM cookecr@umich.edu; joo@uic.edu; stephen.anderson@va.gov; todd.lee@va.gov; Ed.Udris@va.gov; johnson.ex@ghc.org; dau@u.washington.edu OI Cooke, Colin/0000-0001-9713-5371 FU Department of Veterans Affairs, Health Services Research and Development (DHA); American Lung Association [CI-51755-N]; American Thoracic Society; Robert Wood Johnson Foundation; University of Michigan COPE FX This study was supported by the Department of Veterans Affairs, Health Services Research and Development (DHA), American Lung Association (CI-51755-N) awarded to DHA, the American Thoracic Society Fellow Career Development Award (CRC), and the Robert Wood Johnson Foundation Clinical Scholar's Program (CRC). The funding bodies had no role in study design analysis, interpretation and writing of the manuscript, and in the decision to submit the manuscript for publication. The authors would also like to acknowledge the referees for their thoughtful contributions to the manuscript.; This article was made available as Open Access with the support of the University of Michigan COPE Fund, http://lib.umich.edu/cope NR 46 TC 40 Z9 40 U1 0 U2 2 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 FEB 16 PY 2011 VL 11 AR 37 DI 10.1186/1472-6963-11-37 PG 25 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 730JS UT WOS:000288030200001 PM 21324188 ER PT J AU Wang, LX Million, M Rivier, J Rivier, C Craft, N Stenzel-Poore, MP Tache, Y AF Wang, Lixin Million, Mulugeta Rivier, Jean Rivier, Catherine Craft, Noah Stenzel-Poore, Mary P. Tache, Yvette TI CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-Expressing Mice SO PLOS ONE LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; HAIR-GROWTH; TRANSGENIC MICE; DIFFERENTIAL EXPRESSION; CUTANEOUS EXPRESSION; STRESS-RESPONSE; MOUSE MODELS; HPA AXIS; SKIN; UROCORTIN AB Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 mu g/mouse) injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, astressin(2)-B had moderate effect on pigmentation, but not on hair regrowth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress. C1 [Wang, Lixin; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Div Digest Dis,Dept Med,CURE, Los Angeles, CA 90095 USA. [Wang, Lixin; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. [Rivier, Jean; Rivier, Catherine] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, San Diego, CA 92138 USA. [Craft, Noah] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Div Dermatol,Dept Med,Los Angeles Biomed Res Inst, Torrance, CA USA. [Craft, Noah] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Div Infect Dis,Dept Med,Los Angeles Biomed Res In, Torrance, CA USA. [Stenzel-Poore, Mary P.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. RP Wang, LX (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Div Digest Dis,Dept Med,CURE, Los Angeles, CA 90095 USA. EM milllionmulugeta@mednet.ucla.edu FU Department of Veterans Affairs; NIH [R01 DK-57238, R21 DK-068155, RO1 DK-078676, R01 DK-33061, P50 DK-64539, DK PO1-26741] FX This work was supported by the Research Career Scientist Award, Department of Veterans Affairs (Y. Tache); and the following NIH grants: R01 DK-57238 (Y. Tache); R21 DK-068155 and RO1 DK-078676 (M. Million); R01 DK-33061 (Y. Tache, M. Million); P50 DK-64539 (Y. Tache, M. Million); DK PO1-26741 (J. Rivier). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 8 Z9 8 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 16 PY 2011 VL 6 IS 2 AR e16377 DI 10.1371/journal.pone.0016377 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721YC UT WOS:000287392700017 PM 21359208 ER PT J AU Bello, AK Thadhani, R Hemmelgarn, B Klarenbach, S Gill, J Chan, C Zimmerman, D Holmes, D Cembrowski, G Opgenorth, D Sibrian, R Karkhaneh, M Tiv, S Wiebe, N Tonelli, M AF Bello, Aminu K. Thadhani, Ravi Hemmelgarn, Brenda Klarenbach, Scott Gill, John Chan, Christopher Zimmerman, Deborah Holmes, Daniel Cembrowski, George Opgenorth, Dawn Sibrian, Rafael Karkhaneh, Mohammad Tiv, Sophanny Wiebe, Natasha Tonelli, Marcello TI Design and implementation of the canadian kidney disease cohort study (CKDCS): A prospective observational study of incident hemodialysis patients SO BMC NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; PERITONEAL-DIALYSIS; ADMINISTRATIVE DATA; PRACTICE PATTERNS; CLINICAL-RESEARCH; UNITED-STATES; HEALTH; OUTCOMES; CLASSIFICATION AB Background: Many nephrology observational studies use renal registries, which have well known limitations. The Canadian Kidney Disease Cohort Study (CKDCS) is a large prospective observational study of patients commencing hemodialysis in five Canadian centers. This study focuses on delineating potentially reversible determinants of adverse outcomes that occur in patients receiving dialysis for end-stage renal disease (ESRD). Methods/Design: The CKDCS collects information on risk factors and outcomes, and stores specimens (blood, dialysate, hair and fingernails) at baseline and in long-term follow-up. Such specimens will permit measurements of biochemical markers, proteomic and genetic parameters (proteins and DNA) not measured in routine care. To avoid selection bias, all consenting incident hemodialysis patients at participating centers are enrolled, the large sample size (target of 1500 patients), large number of exposures, and high event rates will permit the exploration of multiple potential research questions. Preliminary Results: Data on the baseline characteristics from the first 1074 subjects showed that the average age of patients was 62 (range; 50-73) years. The leading cause of ESRD was diabetic nephropathy (41.9%), and the majority of the patients were white (80.0%). Only 18.7% of the subjects received dialysis in a satellite unit, and over 80% lived within a 50 km radius of the nearest nephrologist's practice. Discussion: The prospective design, detailed clinical information, and stored biological specimens provide a wealth of information with potential to greatly enhance our understanding of risk factors for adverse outcomes in dialysis patients. The scientific value of the stored patient tissue will grow as new genetic and biochemical markers are discovered in the future. C1 [Bello, Aminu K.; Klarenbach, Scott; Opgenorth, Dawn; Sibrian, Rafael; Karkhaneh, Mohammad; Tiv, Sophanny; Wiebe, Natasha; Tonelli, Marcello] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hemmelgarn, Brenda] Univ Calgary, Dept Med, Calgary, AB, Canada. [Gill, John] Univ British Columbia, Div Nephrol, Vancouver, BC, Canada. [Chan, Christopher] Univ Toronto, Univ Hlth Network, Div Nephrol, Toronto, ON, Canada. [Zimmerman, Deborah] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Holmes, Daniel] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Cembrowski, George] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. RP Tonelli, M (reprint author), Univ Alberta, Dept Med, Edmonton, AB, Canada. EM mtonelli@ualberta.ca RI Hemmelgarn, Brenda/I-6894-2012; Bello, Aminu/D-2213-2013; Klarenbach, Scott/E-7731-2013; Tonelli, Marcello/B-3028-2009 OI Klarenbach, Scott/0000-0002-8611-1056; FU Canadian Institutes of Health Research (CIHR); Abbott Laboratories; Alberta Heritage Foundation for Medical Research; Northern Alberta Renal Program FX The CKDCS is being funded by the Canadian Institutes of Health Research (CIHR), Abbott Laboratories, Alberta Heritage Foundation for Medical Research, and the Northern Alberta Renal Program. NR 33 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 16 PY 2011 VL 12 AR 10 DI 10.1186/1471-2369-12-10 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 946MT UT WOS:000304356700002 PM 21324196 ER PT J AU Joynt, KE Orav, EJ Jha, AK AF Joynt, Karen E. Orav, E. John Jha, Ashish K. TI Thirty-Day Readmission Rates for Medicare Beneficiaries by Race and Site of Care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-CARE; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; CONGESTIVE-HEART-FAILURE; SAFETY-NET HOSPITALS; DUTY HOUR REFORM; BLACK PATIENTS; TRANSITIONS INTERVENTION; ADMINISTRATIVE DATA; RACIAL DISPARITIES AB Context Understanding whether and why there are racial disparities in readmissions has implications for efforts to reduce readmissions. Objective To determine whether black patients have higher odds of readmission than white patients and whether these disparities are related to where black patients receive care. Design Using national Medicare data, we examined 30-day readmissions after hospitalization for acute myocardial infarction (MI), congestive heart failure (CHF), and pneumonia. We categorized hospitals in the top decile of proportion of black patients as minority-serving. We determined the odds of readmission for black patients compared with white patients at minority-serving vs non-minority-serving hospitals. Setting and Participants Medicare Provider Analysis Review files of more than 3.1 million Medicare fee-for-service recipients who were discharged from US hospitals in 2006-2008. Main Outcome Measure Risk-adjusted odds of 30-day readmission. Results Overall, black patients had higher readmission rates than white patients (24.8% vs 22.6%, odds ratio [OR], 1.13; 95% confidence interval [CI], 1.11-1.14; P<.001); patients from minority-serving hospitals had higher readmission rates than those from non-minority-serving hospitals (25.5% vs 22.0%, OR, 1.23; 95% CI, 1.20-1.27; P<.001). Among patients with acute MI and using white patients from non-minority-serving hospitals as the reference group (readmission rate 20.9%), black patients from minority-serving hospitals had the highest readmission rate (26.4%; OR, 1.35; 95% CI, 1.28-1.42), while white patients from minority-serving hospitals had a 24.6% readmission rate (OR, 1.23; 95% CI, 1.18-1.29) and black patients from non-minority-serving hospitals had a 23.3% readmission rate (OR, 1.20; 95% CI, 1.16-1.23; P<.001 for each); patterns were similar for CHF and pneumonia. The results were unchanged after adjusting for hospital characteristics including markers of caring for poor patients. Conclusion Among elderly Medicare recipients, black patients were more likely to be readmitted after hospitalization for 3 common conditions, a gap that was related to both race and to the site where care was received. JAMA. 2011;305(7):675-681 www.jama.com C1 [Joynt, Karen E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Joynt, KE (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM kjoynt@partners.org FU National Institutes of Health, Brigham and Women's Hospital, Division of Cardiovascular Medicine [T32HL007604-24] FX Dr Joynt was supported by National Institutes of Health Training Grant T32HL007604-24, Brigham and Women's Hospital, Division of Cardiovascular Medicine. NR 45 TC 274 Z9 274 U1 4 U2 27 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 FEB 16 PY 2011 VL 305 IS 7 BP 675 EP 681 DI 10.1001/jama.2011.123 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 721NH UT WOS:000287361100018 PM 21325183 ER PT J AU Irving, S Moore, DR Liberman, MC Sumner, CJ AF Irving, Samuel Moore, David R. Liberman, M. Charles Sumner, Christian J. TI Olivocochlear Efferent Control in Sound Localization and Experience-Dependent Learning SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AUDITORY SPACE; ELECTRICAL-STIMULATION; HEARING IMPAIRMENT; BINAURAL HEARING; OPTIC TECTUM; PLASTICITY; FERRETS; NOISE; INNERVATION; MODULATION AB Efferent auditory pathways have been implicated in sound localization and its plasticity. We examined the role of the olivocochlear system (OC) in horizontal sound localization by the ferret and in localization learning following unilateral earplugging. Under anesthesia, adult ferrets underwent olivocochlear bundle section at the floor of the fourth ventricle, either at the midline or laterally (left). Lesioned and control animals were trained to localize 1 s and 40 ms amplitude-roved broadband noise stimuli from one of 12 loudspeakers. Neither type of lesion affected normal localization accuracy. All ferrets then received a left earplug and were tested and trained over 10 d. The plug profoundly disrupted localization. Ferrets in the control and lateral lesion groups improved significantly during subsequent training on the 1 s stimulus. No improvement (learning) occurred in the midline lesion group. Markedly poorer performance and failure to learn was observed with the 40 ms stimulus in all groups. Plug removal resulted in a rapid resumption of normal localization in all animals. Insertion of a subsequent plug in the right ear produced similar results to left earplugging. Learning in the lateral lesion group was independent of the side of the lesion relative to the earplug. Lesions in all reported cases were verified histologically. The results suggest the OC system is not needed for accurate localization, but that it is involved in relearning localization during unilateral conductive hearing loss. C1 [Irving, Samuel; Moore, David R.; Sumner, Christian J.] Inst Hearing Res, MRC, Nottingham NG7 2RD, England. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Liberman, M. Charles] Harvard Univ, Dept Otol & Laryngol, Sch Med, Boston, MA 02114 USA. RP Sumner, CJ (reprint author), Inst Hearing Res, MRC, Univ Pk, Nottingham NG7 2RD, England. EM chris@ihr.mrc.ac.uk FU Medical Research Council; National Institute on Deafness and Other Communication Disorders [R01 DC 0188, P30 05209] FX Research was supported by the Medical Research Council and by the National Institute on Deafness and Other Communication Disorders (Grants R01 DC 0188 and P30 05209 to M.C.L.). NR 33 TC 32 Z9 32 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 16 PY 2011 VL 31 IS 7 BP 2493 EP 2501 DI 10.1523/JNEUROSCI.2679-10.2011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 721XZ UT WOS:000287392400018 PM 21325517 ER PT J AU Kalia, LV Kalia, SK Chau, H Lozano, AM Hyman, BT McLean, PJ AF Kalia, Lorraine V. Kalia, Suneil K. Chau, Hien Lozano, Andres M. Hyman, Bradley T. McLean, Pamela J. TI Ubiquitinylation of alpha-Synuclein by Carboxyl Terminus Hsp70-Interacting Protein (CHIP) Is Regulated by Bcl-2-Associated Athanogene 5 (BAG5) SO PLOS ONE LA English DT Article ID HEAT-SHOCK PROTEINS; DEPENDENT E3 LIGASE; PARKINSONS-DISEASE; LEWY BODIES; MOLECULAR CHAPERONES; NUCLEOTIDE EXCHANGE; COCHAPERONE BAG2; QUALITY-CONTROL; CELL-DEATH; DEGRADATION AB Parkinson's disease (PD) is a common neurodegenerative condition in which abnormalities in protein homeostasis, or proteostasis, may lead to accumulation of the protein alpha-synuclein (alpha-syn). Mutations within or multiplications of the gene encoding alpha-syn are known to cause genetic forms of PD and polymorphisms in the gene are recently established risk factors for idiopathic PD. alpha-syn is a major component of Lewy bodies, the intracellular proteinaceous inclusions which are pathological hallmarks of most forms of PD. Recent evidence demonstrates that alpha-syn can self associate into soluble oligomeric species and implicates these alpha-syn oligomers in cell death. We have previously shown that carboxyl terminus of Hsp70-interacting protein (CHIP), a co-chaperone molecule with E3 ubiquitin ligase activity, may reduce the levels of toxic alpha-syn oligomers. Here we demonstrate that alpha-syn is ubiquitinylated by CHIP both in vitro and in cells. We find that the products from ubiquitinylation by CHIP include both monoubiquitinylated and polyubiquitinylated forms of alpha-syn. We also demonstrate that CHIP and alpha-syn exist within a protein complex with the co-chaperone bcl-2-associated athanogene 5 (BAG5) in brain. The interaction of CHIP with BAG5 is mediated by Hsp70 which binds to the tetratricopeptide repeat domain of CHIP and the BAG domains of BAG5. The Hsp70-mediated association of BAG5 with CHIP results in inhibition of CHIP E3 ubiquitin ligase activity and subsequently reduces alpha-syn ubiquitinylation. Furthermore, we use a luciferase-based protein-fragment complementation assay of alpha-syn oligomerization to investigate regulation of alpha-syn oligomers by CHIP in living cells. We demonstrate that BAG5 mitigates the ability of CHIP to reduce alpha-syn oligomerization and that non-ubiquitinylated alpha-syn has an increased propensity for oligomerization. Thus, our results identify CHIP as an E3 ubiquitin ligase of alpha-syn and suggest a novel function for BAG5 as a modulator of CHIP E3 ubiquitin ligase activity with implications for CHIP-mediated regulation of alpha-syn oligomerization. C1 [Kalia, Lorraine V.; Kalia, Suneil K.; Hyman, Bradley T.; McLean, Pamela J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Kalia, Lorraine V.] Univ Toronto, Div Neurol, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Kalia, Suneil K.; Lozano, Andres M.] Univ Toronto, Div Neurosurg, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. [Kalia, Lorraine V.; Kalia, Suneil K.; Chau, Hien; Lozano, Andres M.] Univ Toronto, Div Brain Imaging & Behav Syst Neurosci, Toronto Western Res Inst, Univ Hlth Network, Toronto, ON, Canada. RP Kalia, LV (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. EM lorraine.kalia@utoronto.ca FU NIH/NINDS [NS 063963]; Michael J. Fox Foundation FX This work was supported by NIH/NINDS grant NS 063963 and research grants from the Michael J. Fox Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 52 Z9 55 U1 2 U2 21 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 FEB 16 PY 2011 VL 6 IS 2 AR e14695 DI 10.1371/journal.pone.0014695 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721YC UT WOS:000287392700008 PM 21358815 ER PT J AU Traugott, KA Maxwell, PR Green, K Frei, C Lewis, JS AF Traugott, Kristi A. Maxwell, Pamela R. Green, Kay Frei, Christopher Lewis, James S., II TI Effects of therapeutic drug monitoring criteria in a computerized prescriber-order-entry system on the appropriateness of vancomycin level orders SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Antibiotics; Blood levels; Computers; Dosage; Medication orders; Prescribing; Protocols; Rational therapy; Vancomycin AB Purpose. The effects of therapeutic drug monitoring (TDM) criteria in a computerized prescriber-order-entry (CPOE) system on the appropriateness of orders for vancomycin levels were evaluated. Methods. Vancomycin TDM criteria were developed and implemented in a CPOE system. These criteria were displayed via a pop-up alert message when vancomycin levels were ordered and included directions for appropriate timing and justification for routine monitoring. Data for two groups of adult inpatients who had vancomycin levels ordered before and after criteria implementation were compared. Medical records were retrospectively reviewed for these patients to collect information regarding patient demographics, vancomycin dosage and indication, concurrent antibiotics and nephrotoxic agents during vancomycin therapy, length of stay, duration of vancomycin therapy, and number of vancomycin levels drawn, The primary outcome was the percent change in appropriate vancomycin levels ordered after criteria implementation. Results. A total of 200 patients were analyzed, 100 in each group. The percentage of appropriate orders for vancomycin levels significantly increased after criteria implementation (from 58% to 68%, p = 0.02). The greatest effect on appropriateness occurred with the first level ordered (52% versus 70% in the preimplementation and postimplementation groups, respectively; p = 0.01). The majority of inappropriate levels were due to improper timing of sample collections, accounting for 55% of the inappropriate levels evaluated. Conclusion. A significant increase in the number of appropriately ordered and drawn serum vancomycin levels occurred after implementation of TDM criteria in the hospital's CPOE system. The majority of orders that were deemed inappropriate were due to improper timing of laboratory collection. C1 [Traugott, Kristi A.] Ochsner Hlth Syst, New Orleans, LA 70121 USA. [Traugott, Kristi A.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Frei, Christopher] Univ Texas Austin, Coll Pharm, Pharmacotherapy Div, Austin, TX 78712 USA. [Frei, Christopher] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. [Frei, Christopher] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. RP Traugott, KA (reprint author), Ochsner Hlth Syst, 1514 Jefferson Highway, New Orleans, LA 70121 USA. EM ktraugott@ochsner.org NR 18 TC 13 Z9 13 U1 1 U2 5 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 15 PY 2011 VL 68 IS 4 BP 347 EP 352 DI 10.2146/ajhp090661 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858CC UT WOS:000297772500012 PM 21289330 ER PT J AU Astor, TL AF Astor, Todd L. TI RNA Interference, RSV, and Lung Transplantation A Promising Future for siRNA Therapeutics SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID RESPIRATORY SYNCYTIAL VIRUS; DENDRITIC CELLS; RIBAVIRIN; POTENT; INDUCTION; INFECTION C1 Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. RP Astor, TL (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. NR 21 TC 6 Z9 7 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2011 VL 183 IS 4 BP 427 EP 428 DI 10.1164/rccm.201009-1488ED PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 724IE UT WOS:000287568500004 PM 21325081 ER PT J AU Rodriguez, AE Vigo, CF Delacasa, A Mieres, J Fernandez-Pereira, C Bernardi, V Bettinoti, M Rodriguez-Granillo, AM Rodriguez-Granillo, G Santaera, O Curotto, V Rubilar, B Tronge, J Palacios, IF Antoniucci, D AF Rodriguez, Alfredo E. Vigo, Cesar F. Delacasa, Alejandro Mieres, Juan Fernandez-Pereira, Carlos Bernardi, Victor Bettinoti, Marcelo Rodriguez-Granillo, Alfredo M. Rodriguez-Granillo, Gaston Santaera, Omar Curotto, Valeria Rubilar, Bibiana Tronge, Jorge Palacios, Igor F. Antoniucci, David CA EUCATAX Investigators TI Efficacy and Safety of a Double-Coated Paclitaxel-Eluting Coronary Stent: The EUCATAX Trial SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE percutaneous coronary intervention (PCI); restenosis (RSTN); acute coronary syndrome (ACS); drug delivery (DDEL); quantitative coronary angiography (QCA) ID BARE-METAL STENTS; RANDOMIZED CONTROLLED-TRIAL; FOLLOW-UP; ARTERY LESIONS; POLYMER; LONG; IMPLANTATION; REGISTRY; REVASCULARIZATION; THROMBOSIS AB Objectives: The aim of this study was the comparison of a new double-coated paclitaxel-eluting coronary stent with bare-metal stent (BMS) in patients undergoing percutaneous coronary intervention. Background: Stent coating with biodegradable polymers as a platform for elution of drugs has the potential for complete elution of drugs and for decreasing the risk of late complications. Methods: Multicenter randomized trial comparing a paclitaxel-eluting stent (PES) coated with a biodegradable polymer and glycocalyx with the equivalent BMS. We randomly assigned 422 patients with de novo coronary lesions to PES (211 patients) or to BMS (211 patients). Primary end point was target vessel failure (TVF) defined as cardiac death, myocardial infarction, and target vessel revascularization. Clinical secondary end points were target vessel revascularization, target lesion revascularization, stent thrombosis (ST), and major adverse cardiovascular events (MACE). Angiographic secondary end points were late loss and binary restenosis. Results: At 1 year of follow-up, TVF rate was 9.5% in the PES group and 17.1% in the BMS group (P = 0.02), and MACE rate was 10% in PES and 19% in BMS arm (P = 0.009). All other secondary end points were reached but ST. ST rate was low and similar in both study arms. Conclusions: The study shows that patients treated with PES with dual coating technology had significantly lower incidence of TVF and MACE than those treated with BMS design; however, longer follow-up should be necessary to assess true advantages of this technology compared with the previous one. (C) 2010 Wiley-Liss, Inc. C1 [Rodriguez, Alfredo E.; Mieres, Juan; Fernandez-Pereira, Carlos; Curotto, Valeria; Rubilar, Bibiana] Sanatorio Otamendi, Cardiac Unit, Buenos Aires, DF, Argentina. [Vigo, Cesar F.] Sanatorio Del Salvador, Intervent Cardiol, Cordoba, Argentina. [Delacasa, Alejandro] Sanatorio Belgrano, Intervent Cardiol, Buenos Aires, DF, Argentina. [Mieres, Juan] Sanatorio Los Lomas, Intervent Cardiol, Buenos Aires, DF, Argentina. [Fernandez-Pereira, Carlos; Tronge, Jorge] Clin IMA, Intervent Cardiol & Cardiol Dept, Buenos Aires, DF, Argentina. [Bernardi, Victor] Clin Sol, Buenos Aires, DF, Argentina. [Bettinoti, Marcelo] Sanatorio Guemes Hosp Privado, Intervent Cardiol, Buenos Aires, DF, Argentina. [Rodriguez, Alfredo E.; Rodriguez-Granillo, Alfredo M.; Rodriguez-Granillo, Gaston] CECI, Buenos Aires, DF, Argentina. [Palacios, Igor F.] Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. [Antoniucci, David] Careggi Hosp, Div Cardiovasc, Florence, Italy. RP Rodriguez, AE (reprint author), Callao 1441 4B C1024AAA, Buenos Aires, DF, Argentina. EM rodriguezalfredo.e@gmail.com FU Eucatech AG, Reinhelfeden, Germany FX Grant sponsor: Eucatech AG, Reinhelfeden, Germany. NR 23 TC 6 Z9 6 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD FEB 15 PY 2011 VL 77 IS 3 BP 335 EP 342 DI 10.1002/ccd.22769 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 725QD UT WOS:000287659800003 PM 20824769 ER PT J AU Lacadie, SA Zon, LI AF Lacadie, Scott A. Zon, Leonard I. TI The ERGonomics of hematopoietic stem cell self-renewal SO GENES & DEVELOPMENT LA English DT Article DE ERG; ETS family transcription factors; Gata2; hematopoietic development; hematopoietic stem cells; Runx1; self-renewal ID TRANSCRIPTION FACTOR GATA-2; AORTIC ENDOTHELIUM; PRIMITIVE HEMATOPOIESIS; PROGENITOR CELLS; PROSTATE-CANCER; FACTOR ERG; DIFFERENTIATION; TRANSITION; ONCOGENE; SCREEN AB Stem cells make more of themselves by self-renewing cell divisions. In the February 1, 2011, issue of Genes & Development, Taoudi and colleagues (pp. 251-262) show an essential role for the ETS transcription factor ERG in the self-renewal of embryonic hematopoietic stem cells. A model is presented in which the redundant functions of GATA2 and RUNX1 in self-renewal are under direct control of ERG. C1 [Zon, Leonard I.] Harvard Univ, Harvard Stem Cell Inst,Childrens Hosp, Howard Hughes Med Inst,Dana Farber Canc Inst, Stem Cell Program,Div Hematol Oncol,Sch Med, Boston, MA 02115 USA. RP Zon, LI (reprint author), Harvard Univ, Harvard Stem Cell Inst,Childrens Hosp, Howard Hughes Med Inst,Dana Farber Canc Inst, Stem Cell Program,Div Hematol Oncol,Sch Med, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu NR 45 TC 3 Z9 3 U1 0 U2 1 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 FEB 15 PY 2011 VL 25 IS 4 BP 289 EP 293 DI 10.1101/gad.2031511 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 721OT UT WOS:000287365000001 PM 21325129 ER PT J AU Diop-Frimpong, B Chauhan, VP Krane, S Boucher, Y Jain, RK AF Diop-Frimpong, Benjamin Chauhan, Vikash P. Krane, Stephen Boucher, Yves Jain, Rakesh K. TI Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug delivery; matrix modifier; thrombospondin-1; transforming growth factor beta; transport ID GROWTH-FACTOR-BETA; CONVERTING-ENZYME-INHIBITORS; INTERSTITIAL FLUID PRESSURE; TYPE-1 RECEPTOR BLOCKADE; MOUSE MODEL; PANCREATIC-CANCER; RENAL INJURY; SOLID TUMORS; BLOOD-FLOW; ANGIOTENSIN AB The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan-a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity-can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. C1 [Diop-Frimpong, Benjamin; Chauhan, Vikash P.; Boucher, Yves; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Diop-Frimpong, Benjamin; Chauhan, Vikash P.; Krane, Stephen; Boucher, Yves; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Diop-Frimpong, Benjamin] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Diop-Frimpong, Benjamin; Chauhan, Vikash P.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Krane, Stephen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Boucher, Y (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM yves@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu RI Chauhan, Vikash/H-8172-2013 OI Chauhan, Vikash/0000-0001-9126-2302 FU Dyax; AstraZeneca; Medimmune; AstraZeneca/Medimmune; Astellas-Fibrogen; Regeneron; Genzyme; Morphosys; Noxxon Pharma; US National Cancer Institute [P01CA80124, R01CA85140, R01CA98706]; Department of Defense [W91ZSQ7342N607, W81XWH-10-1-0016] FX R.K.J. received commercial research grants from Dyax, AstraZeneca, and Medimmune; consultant fees from AstraZeneca/Medimmune, Dyax, Astellas-Fibrogen, Regeneron, Genzyme, Morphosys, and Noxxon Pharma; and a speaker honorarium from Genzyme. R.K.J. owns stock in SynDevRx. No reagents or funding from these companies was used in these studies. There is no significant financial or other competing interest in the work.; We acknowledge Drs. N. Kirkpatrick, D. Lacorre, and R. Guang for help in planning experiments, Dr. T. Stylianopoulos for help with manuscript preparation, and Dr. L. Fisher (National Institute of Dental Research) for kindly providing the LF-67 antibody. We thank Eve Smith and Sylvie Roberge for their technical assistance. This work was supported by US National Cancer Institute grants to R.K.J. (P01CA80124 and R01CA85140) and Y.B. (R01CA98706) and a Department of Defense Breast Cancer research fellowship to B.D.-F. (W91ZSQ7342N607) and innovator award to R.K.J. (W81XWH-10-1-0016). NR 54 TC 143 Z9 145 U1 5 U2 49 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 FEB 15 PY 2011 VL 108 IS 7 BP 2909 EP 2914 DI 10.1073/pnas.1018892108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721TB UT WOS:000287377000054 PM 21282607 ER PT J AU Chui, KKH Wenger, JB Cohen, SA Naumova, EN AF Chui, Kenneth K. H. Wenger, Julia B. Cohen, Steven A. Naumova, Elena N. TI Visual Analytics for Epidemiologists: Understanding the Interactions Between Age, Time, and Disease with Multi-Panel Graphs SO PLOS ONE LA English DT Article ID INFECTIOUS-DISEASES; PUBLIC-HEALTH; UNITED-STATES; SEASONALITY; SURVEILLANCE; MORTALITY; INFLUENZA; TEMPERATURE; POPULATION; PNEUMONIA AB Background: Visual analytics, a technique aiding data analysis and decision making, is a novel tool that allows for a better understanding of the context of complex systems. Public health professionals can greatly benefit from this technique since context is integral in disease monitoring and biosurveillance. We propose a graphical tool that can reveal the distribution of an outcome by time and age simultaneously. Methodology/Principal Findings: We introduce and demonstrate multi-panel (MP) graphs applied in four different settings: U.S. national influenza-associated and salmonellosis-associated hospitalizations among the older adult population (>= 65 years old), 1991-2004; confirmed salmonellosis cases reported to the Massachusetts Department of Public Health for the general population, 2004-2005; and asthma-associated hospital visits for children aged 0-18 at Milwaukee Children's Hospital of Wisconsin, 1997-2006. We illustrate trends and anomalies that otherwise would be obscured by traditional visualization techniques such as case pyramids and time-series plots. Conclusion/Significance: MP graphs can weave together two vital dynamics-temporality and demographics-that play important roles in the distribution and spread of diseases, making these graphs a powerful tool for public health and disease biosurveillance efforts. C1 [Chui, Kenneth K. H.; Cohen, Steven A.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Wenger, Julia B.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Naumova, Elena N.] Tufts Univ, Sch Engn, Dept Civil & Environm Engn, Medford, MA 02155 USA. RP Chui, KKH (reprint author), Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. EM kenneth.chui@tufts.edu RI Naumova, Elena/C-5954-2011; OI Naumova, Elena/0000-0002-9562-4734 FU National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) [U19 AI062627, N01 AI-50032] FX The research was supported by National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) grants U19 AI062627 and N01 AI-50032. The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 9 Z9 9 U1 1 U2 7 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 FEB 15 PY 2011 VL 6 IS 2 AR e14683 DI 10.1371/journal.pone.0014683 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721QH UT WOS:000287369200002 PM 21347221 ER PT J AU Arif, SA Mitchell, MM AF Arif, Sally A. Mitchell, Melissa M. TI Iloperidone: A new drug for the treatment of schizophrenia SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Absorption; Antipsychotic agents; Dosage; Drugs; availability; Iloperidone; Mechanism of action; Pharmacogenetics; Pharmacokinetics; Schizophrenia; Toxicity ID ANTIPSYCHOTIC ILOPERIDONE; SAFETY PROFILE; RATING-SCALE; EFFICACY; AGENTS; TOLERABILITY; METABOLITES; DISORDERS; RECEPTORS; BINDING AB Purpose. The pharmacology, pharmacokinetics, pharmacogenomics, clinical efficacy, and safety and tolerability profile of iloperidone for the treatment of schizophrenia are reviewed. Summary. Iloperidone is an atypical antipsychotic that recently received marketing approval from the Food and Drug Administration for the acute treatment of schizophrenia. Iloperidone is a pure antagonist and the first antipsychotic to have pharmacogenomic studies indicate predictive response based on six identified polymorphisms. Pharmacokinetic studies have determined that iloperidone is well absorbed orally, with a bioavailability of 96%. Phase II and III clinical trials have shown iloperidone to improve symptoms of schizophrenia, based on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale, and Clinical Global Impressions Severity scores (p < 0.05). Iloperidone has established tolerability at recommended dosages of up to 24 mg daily; however, the dosage must be slowly increased over seven days, and twice-daily administration is required to avoid orthostatic hypotension. The most common adverse effects associated with iloperidone were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain. Safety studies have also found that iloperidone increases the risk of Q-Tc interval prolongation, similar to that seen with ziprasidone. Minimal changes in glucose and lipid abnormalities were seen in short-term (4- and 6-week) and long-term (52-week) studies, indicating a low chance of metabolic disturbance with iloperidone. Conclusion. Iloperidone may be a viable and safe option for the treatment of schizophrenia in adult patients, especially for patients who cannot tolerate other antipsychotic agents. However, iloperidone lacks a clear benefit over other antipsychotic agents. C1 [Arif, Sally A.] Midwestern Univ, Chicago Coll Pharm, Downers Grove, IL 60515 USA. [Arif, Sally A.; Mitchell, Melissa M.] Long Isl Univ, Arnold & Marie Schwartz Coll Pharm & Hlth Sci, Brooklyn, NY USA. [Arif, Sally A.] James J Peters Vet Affairs Med Ctr, Dept Pharm, Bronx, NY USA. [Mitchell, Melissa M.] Riverside Cty Reg Med Ctr, Moreno Valley, CA USA. [Mitchell, Melissa M.] St Vincents Hosp, Dept Pharm, New York, NY USA. RP Arif, SA (reprint author), Midwestern Univ, Chicago Coll Pharm, 555 31st St, Downers Grove, IL 60515 USA. EM sarif@midwestern.edu NR 41 TC 14 Z9 15 U1 0 U2 7 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 15 PY 2011 VL 68 IS 4 BP 301 EP 308 DI 10.2146/ajhp100079 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858CC UT WOS:000297772500006 PM 21289324 ER PT J AU Gajic, O Dabbagh, O Park, PK Adesanya, A Chang, SY Hou, P Anderson, H Hoth, JJ Mikkelsen, ME Gentile, NT Gong, MN Talmor, D Bajwa, E Watkins, TR Festic, E Yilmaz, M Iscimen, R Kaufman, DA Esper, AM Sadikot, R Douglas, I Sevransky, J Malinchoc, M AF Gajic, Ognien Dabbagh, Ousama Park, Pauline K. Adesanya, Adebola Chang, Steven Y. Hou, Peter Anderson, Harry, III Hoth, J. Jason Mikkelsen, Mark E. Gentile, Nina T. Gong, Michelle N. Talmor, Daniel Bajwa, Ednan Watkins, Timothy R. Festic, Emir Yilmaz, Murat Iscimen, Remzi Kaufman, David A. Esper, Annette M. Sadikot, Ruxana Douglas, Ivor Sevransky, Jonathan Malinchoc, Michael CA US Critical Illness Injury Trials TI Early Identification of Patients at Risk of Acute Lung Injury Evaluation of Lung Injury Prediction Score in a Multicenter Cohort Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE respiratory distress syndrome; adult; prevention; prediction model; acute respiratory failure ID RESPIRATORY-DISTRESS-SYNDROME; COMMUNITY-ACQUIRED PNEUMONIA; MAJOR NONCARDIAC SURGERY; INTENSIVE-CARE-UNIT; CLINICAL PREDICTORS; VENTILATOR SETTINGS; ACUTE-PANCREATITIS; RELEVANT OUTCOMES; CONTROLLED-TRIAL; SEVERITY SCORES AB Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk All developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80(95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772). C1 [Gajic, Ognien; Malinchoc, Michael] Mayo Clin, Rochester, MN 55905 USA. [Dabbagh, Ousama] Univ Missouri, Columbia, MO USA. [Park, Pauline K.] Univ Michigan, Ann Arbor, MI 48109 USA. [Adesanya, Adebola] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Chang, Steven Y.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Hou, Peter] Brigham & Womens Hosp, Boston, MA 02115 USA. [Anderson, Harry, III] Wright State Univ, Boonshoft Sch Med, Dayton, OH 45435 USA. [Anderson, Harry, III] Miami Valley Hosp, Dayton, OH USA. [Hoth, J. Jason] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Mikkelsen, Mark E.] Univ Penn, Philadelphia, PA 19104 USA. [Gentile, Nina T.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Gong, Michelle N.] Mt Sinai Sch Med, New York, NY USA. [Talmor, Daniel] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bajwa, Ednan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Watkins, Timothy R.] Univ Washington, Harborview, WA USA. [Festic, Emir] Mayo Clin, Jacksonville, FL 32224 USA. [Yilmaz, Murat] Akdeniz Univ, Antalyia, Turkey. [Iscimen, Remzi] Uludag Univ, Bursa, Turkey. [Kaufman, David A.] Bridgeport Hosp, New Haven, CT USA. [Esper, Annette M.] Emory Univ, Atlanta, GA 30322 USA. [Sadikot, Ruxana] Univ Illinois, Chicago, IL USA. [Douglas, Ivor] Univ Colorado, Denver, CO 80202 USA. [Sevransky, Jonathan] Johns Hopkins Univ, Baltimore, MD USA. RP Gajic, O (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM gajic.ognjen@mayo.edu OI Douglas, Ivor/0000-0002-4541-1431 FU National Institute of Health [HL78743-01A1, 1 KL2 RR024151]; Mayo Clinic Critical Care Research Committee; Sanofi-Aventis; Bristol Myer Squib/Pfizer; University Of Missouri; Vital Therapies; Maquet, Inc.; Eli Lilly; Artisan Pharma; Walker; Allen; Grice; Ammons; NIH; American Lung Association; American College of Surgeons; Vapotherm in industry FX The study was supported in part by grants from the National Institute of Health: HL78743-01A1 and 1 KL2 RR024151 (O.G.) and the Mayo Clinic Critical Care Research Committee.; Author Disclosure: O.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. O.D. received $1,001-85,000 from Sanofi-Aventis in lecture fees and $10,001-$50,000 from Bristol Myer Squib/Pfizer in industry-sponsored grants paid to the University Of Missouri. P.K.P. received up to $1,000 from Bayer for serving as a consultant and $10,001-$50,000 from Vital Therapies for serving as a co-investigator in industry-sponsored grants. A.A. received up to $1,000 from Maquet, Inc. in consultancy fees. S.Y.C. received $50,001-$100,000 from Eli Lilly as both the PI and the National Coordinator for a clinical trial and $10,001 $50,000 from Artisan Pharma as the PI for a study that has just closed in industry-sponsored grants. P.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.J.H. received $1,001-$5,000 from Walker, Allen, Grice, Ammons, and Foy LLP for serving as an expert witness and more than $100,001 from the NIH, $50,001-$100,000 from the American Lung Association, and more than $100,001 from the American College of Surgeons in sponsored grants;. M.E.M. received $50,001-8100,000 from the NIH as a T32 cardiopulmonary grant funding during M.E.M.'s fellowship;. N.T.G. received $10,001-850,000 from Vapotherm in industry-sponsored grants for a research studyand more than $100,001 fro the NIH in sponsored grants,. M.N.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.T. received $1,001 $5,000 from Elcam Medical for serving as a member of a scientific advisory board until 2009. E.B. received more than $100,001 from the NIH in sponsored grants as a K23 grant,. T.R.W. received more than $100,001 from the NIH in sponsored grants as a 1K23GM086729 (career development award);. E.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.A.K. received $10,001 $50,000 from the Port Authority of NY and NJ, up to $1,000 from Goldberg Segalla LLP, $1,001 $5,000 from Burton Schulte Weekley McLaughlin & Beytin for serving as an expert witness, and $1,001-$5,000 from UpToDate in royalties. A.M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.D. received $10,001-$50,000 from Eli Lilly for serving on a scientific advisory board (study steering committee), more than $100,001 from the NIH as a research grant for lung injury and ARDS research, and $10,001-$50,000 from the Canadian CC Trials Group as a research grant for lung injury and ARDS research;. J.S. received $1,001-$5,000 from Idaho Technology in consultancy fees, more than $100,001 from the NIH in sponsored grants, and $5,001-$10,000 from Critical Care Medicine as a journal section editor. M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 53 TC 173 Z9 184 U1 2 U2 10 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2011 VL 183 IS 4 BP 462 EP 470 DI 10.1164/rccm.201004-0549OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 724IE UT WOS:000287568500010 PM 20802164 ER PT J AU Levine, S Biswas, C Dierov, J Barsotti, R Shrager, JB Taitan, N Sonnad, S Kucharchzuk, JC Kaiser, LR Singhal, S Budak, MT AF Levine, Sanford Biswas, Chhanda Dierov, Jamil Barsotti, Robert Shrager, Joseph B. Taitan Nguyen Sonnad, Seema Kucharchzuk, John C. Kaiser, Larry R. Singhal, Sunil Budak, Murat T. TI Increased Proteolysis, Myosin Depletion, and Atrophic AKT-FOXO Signaling in Human Diaphragm Disuse SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE AKT; FOXO; ubiquitination; proteasome; myosin heavy chains ID SKELETAL-MUSCLE ATROPHY; MECHANICAL VENTILATION; OXIDATIVE STRESS; PROTEIN-DEGRADATION; DYSFUNCTION; PATHWAYS; PHOSPHORYLATION; ACTIVATION; PROTEASOME; CACHEXIA AB Rationale: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy. Objectives: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse. Methods: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours. Measurements and Main Results: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 265 proteasome, and decreased levels of MyHCs and a-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates. Conclusions: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse. C1 [Levine, Sanford; Biswas, Chhanda; Dierov, Jamil; Shrager, Joseph B.; Taitan Nguyen; Sonnad, Seema; Kucharchzuk, John C.; Kaiser, Larry R.; Singhal, Sunil; Budak, Murat T.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Levine, Sanford; Biswas, Chhanda; Barsotti, Robert; Shrager, Joseph B.; Budak, Murat T.] Univ Penn, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Levine, Sanford] Gift Life Donor Program, Philadelphia, PA USA. [Levine, Sanford; Biswas, Chhanda; Dierov, Jamil; Shrager, Joseph B.; Taitan Nguyen; Singhal, Sunil; Budak, Murat T.] Dept Vet Affairs Med Ctr, Surg Serv, Philadelphia, PA 19104 USA. [Levine, Sanford; Biswas, Chhanda; Dierov, Jamil; Shrager, Joseph B.; Taitan Nguyen; Singhal, Sunil; Budak, Murat T.] Dept Vet Affairs Med Ctr, Med Res Serv, Philadelphia, PA 19104 USA. [Barsotti, Robert] Philadelphia Coll Osteopath Med, Philadelphia, PA USA. [Shrager, Joseph B.] Palo Alto Vet Affairs Med Ctr, Palo Alto, CA USA. [Shrager, Joseph B.] Stanford Univ, Dept Cardiothorac Surg, Palo Alto, CA 94304 USA. [Kaiser, Larry R.] Univ Texas Hlth Sci Ctr Houston, Off President, Houston, TX USA. RP Levine, S (reprint author), 1495 Wesleys Run, Gladwyne, PA 19035 USA. EM sdlevine@mail.med.upenn.edu RI Budak, Murat/I-8358-2013 OI Budak, Murat/0000-0002-5059-9651 FU NHLBI [R01-HL-078834]; Ventalis, Inc.; GlaxoSmithKline; Imedex; aparoscopic Institute of Gynecologic Oncology; Hall; Hieatt; Connelly; NIH FX Supported by NHLBI grant R01-HL-078834 (S.L.).; S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.B.S. was employed by Projects in Knowledge for development of an online lung cancer course, received $1,001-$5,000 from Ventalis, Inc. in consultancy fees as own founders stock, $1,001 $5,000 from GlaxoSmithKline for serving on the MAGRIT study advisory board, 51,001-55,000 from Imedex and $1,001 $5,000 from Laparoscopic Institute of Gynecologic Oncology in lecture fees, $1,001 $5,000 from Hall, Hieatt, and Connelly, LLP for serving as an expert witness on legal case reviews, 510,001-550,000 from the NIH in sponsored grants as a coinvestigator on R01, and more than $100,001 from the Merit Review Board in sponsored grants for serving as a PI on a Merit Review Grant. T.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.R.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.T.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 40 TC 63 Z9 65 U1 1 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2011 VL 183 IS 4 BP 483 EP 490 DI 10.1164/200910-1487OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 724IE UT WOS:000287568500012 PM 20833824 ER PT J AU Kelley, AS Ettner, SL Morrison, RS Du, QL Wenger, NS Sarkisian, CA AF Kelley, Amy S. Ettner, Susan L. Morrison, R. Sean Du, Qingling Wenger, Neil S. Sarkisian, Catherine A. TI Determinants of Medical Expenditures in the Last 6 Months of Life SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID QUALITY-OF-CARE; REGIONAL-VARIATIONS; PATIENT PREFERENCES; TREATMENT INTENSITY; END; DISABILITY; CANCER; DEATH; AGE; HOSPITALIZATION AB Background: End-of-life medical expenditures exceed costs of care during other years, vary across regions, and are likely to be unsustainable. Identifying determinants of expenditure variation may reveal opportunities for reducing costs. Objective: To identify patient-level determinants of Medicare expenditures at the end of life and to determine the contributions of these factors to expenditure variation while accounting for regional characteristics. It was hypothesized that race or ethnicity, social support, and functional status are independently associated with treatment intensity and controlling for regional characteristics, and that individual characteristics account for a substantial proportion of expenditure variation. Design: Using data from the Health and Retirement Study, Medicare claims, and The Dartmouth Atlas of Health Care, relationships were modeled between expenditures and patient and regional characteristics. Setting: United States, 2000 to 2006. Participants: 2394 Health and Retirement Study decedents aged 65.5 years or older. Measurements: Medicare expenditures in the last 6 months of life were estimated in a series of 2-level multivariable regression models that included patient, regional, and patient and regional characteristics. Results: Decline in function (rate ratio [RR], 1.64 [95% CI, 1.46 to 1.83]); Hispanic ethnicity (RR, 1.50 [CI, 1.22 to 1.85]); black race (RR, 1.43 [CI, 1.25 to 1.64]); and certain chronic diseases, including diabetes (RR, 1.16 [CI, 1.06 to 1.27]), were associated with higher expenditures. Nearby family (RR, 0.90 [CI, 0.82 to 0.98]) and dementia (RR, 0.78 CI, 0.71 to 0.87]) were associated with lower expenditures, and advance care planning had no association. Regional characteristics, including end-of-life practice patterns (RR, 1.09 [CI, 1.06 to 1.14]) and hospital beds per capita (RR, 1.01 [CI, 1.00 to 1.02]), were associated with higher expenditures. Patient characteristics explained 10% of overall variance and retained statistically significant relationships with expenditures after regional characteristics were controlled for. Limitation: The study limitations include the decedent sample, proxy informants, and a large proportion of unexplained variation. Conclusion: Patient characteristics, such as functional decline, race or ethnicity, chronic disease, and nearby family, are important determinants of expenditures at the end of life, independent of regional characteristics. C1 [Kelley, Amy S.] Mt Sinai Sch Med, Dept Geriatr & Palliat Med, New York, NY 10029 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. James J Peters Vet Affairs Med Ctr, Bronx, NY USA. Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, Los Angeles, CA USA. RP Kelley, AS (reprint author), Mt Sinai Sch Med, Dept Geriatr & Palliat Med, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. EM amy.kelley@mssm.edu FU Brookdale Foundation; National Institute on Aging [K24 AG022345]; National Palliative Care Research Center; Veterans Affairs Greater Los Angeles Healthcare System Geriatric Research Education Clinical Center FX Grant Support: By the Brookdale Foundation. Dr. Kelley is a Brookdale Leadership in Aging Fellow. Dr. Morrison is the recipient of a MidCareer Investigator Award in Patient-Oriented Research (K24 AG022345) from the National Institute on Aging and is supported by the National Palliative Care Research Center. Dr. Sarkisian is supported by the Veterans Affairs Greater Los Angeles Healthcare System Geriatric Research Education Clinical Center. NR 49 TC 63 Z9 63 U1 4 U2 23 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 15 PY 2011 VL 154 IS 4 BP 235 EP W78 DI 10.7326/0003-4819-154-4-201102150-00004 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 720VF UT WOS:000287310000015 PM 21320939 ER PT J AU Qaseem, A Humphrey, LL Chou, R Snow, V Shekelle, P AF Qaseem, Amir Humphrey, Linda L. Chou, Roger Snow, Vincenza Shekelle, Paul CA Amer Coll Phys TI Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CRITICALLY-ILL PATIENTS; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; GLUCOSE-INSULIN; CARDIAC-SURGERY; ISCHEMIC-STROKE; OLDER PATIENTS; HYPERGLYCEMIA; HYPOGLYCEMIA AB Description: The American College of Physicians (ACP) developed this guideline to present the evidence for the link between the use of intensive insulin therapy to achieve different glycemic targets and health outcomes in hospitalized patients with or without diabetes mellitus. Methods: Published literature on this topic was identified by using MEDLINE and the Cochrane Library. Additional articles were obtained from systematic reviews and the reference lists of pertinent studies, reviews, and editorials, as well as by consulting experts; unpublished studies on ClinicalTrials.gov were also identified. The literature search included studies published from 1950 through March 2009. Searches were limited to English-language publications. The primary outcomes of interest were short-term mortality and hypoglycemia. This guideline grades the evidence and recommendations by using the ACP clinical practice guidelines grading system. Recommendation 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non-surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence). Recommendation 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence). Recommendation 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence). C1 [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. Pfizer, Collegeville, PA USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Qaseem, A (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. EM aqaseem@acponline.org FU ACP operating budget; Agency for Healthcare Research and Quality FX Financial support for the development of this guideline comes exclusively from the ACP operating budget.; Any financial and nonfinancial conflicts of interest of the group members were declared, discussed, and resolved. Dr. Vincenza Snow was an employee of the American College of Physicians at the time of the writing of this guideline. Dr. Snow: Employment: American College of Physicians, Pfizer. Dr. Shekelle: Grants/grants pending (money to institution): Agency for Healthcare Research and Quality; Royalties: UpToDate. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-272 5. NR 59 TC 131 Z9 145 U1 3 U2 14 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 15 PY 2011 VL 154 IS 4 BP 260 EP W81 DI 10.7326/0003-4819-154-4-201102150-00007 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 720VF UT WOS:000287310000018 PM 21320941 ER PT J AU Kansagara, D Fu, RW Freeman, M Wolf, F Helfand, M AF Kansagara, Devan Fu, Rongwei Freeman, Michele Wolf, Fawn Helfand, Mark TI Intensive Insulin Therapy in Hospitalized Patients: A Systematic Review SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID CRITICALLY-ILL PATIENTS; BLOOD-GLUCOSE CONTROL; TIGHT GLYCEMIC CONTROL; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; PREDICTIVE CONTROL ALGORITHM; CLINICAL-PRACTICE GUIDELINES; DEPENDENT DIABETES-MELLITUS; CARDIAC SURGICAL-PROCEDURES; STERNAL WOUND-INFECTION AB Background: The benefits and harms of intensive insulin therapy (IIT) titrated to strict glycemic targets in hospitalized patients remain uncertain. Purpose: To evaluate the benefits and harms of IIT in hospitalized patients. Data Sources: MEDLINE and Cochrane Database of Systematic Reviews from 1950 to January 2010, reference lists, experts, and unpublished sources. Study Selection: English-language randomized, controlled trials comparing protocols titrated to strict or less strict glycemic targets. Data Extraction: Two reviewers independently abstracted data from each study on sample, setting, glycemic control interventions, glycemic targets, mean glucose levels achieved, and outcomes. Results were grouped by patient population or setting. A random-effects model was used to combine trial data on short-term mortality (<= 28 days), long-term mortality (90 or 180 days), infection, length of stay, and hypoglycemia. The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate the overall body of evidence for each outcome. Data Synthesis: In a meta-analysis of 21 trials in intensive care unit, perioperative care, myocardial infarction, and stroke or brain injury settings, IIT did not affect short-term mortality (relative risk, 1.00 [95% CI, 0.94 to 1.07]). No consistent evidence showed that IIT reduced long-term mortality, infection rates, length of stay, or the need for renal replacement therapy. No evidence of benefit from IIT was reported in any hospital setting, although the best evidence for lack of benefit was in intensive care unit settings. Data combined from 10 trials showed that IIT was associated with a high risk for severe hypoglycemia (relative risk, 6.00 [CI, 4.06 to 8.87]; P < 0.001). Risk for IIT-associated hypoglycemia was increased in all hospital settings. Limitations: Methodological shortcomings and inconsistencies limit the data in perioperative care, myocardial infarction, and stroke or brain injury settings. Differences in insulin protocols and patient and hospital characteristics may affect generalizability across treatment settings. Conclusion: No consistent evidence demonstrates that IIT targeted to strict glycemic control compared with less strict glycemic control improves health outcomes in hospitalized patients. Furthermore, IIT is associated with an increased risk for severe hypoglycemia. C1 [Kansagara, Devan] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Portland Diabet & Endocrinol Ctr, Portland, OR 97239 USA. RP Kansagara, D (reprint author), Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, 3710 SW US Vet Hosp Rd,Mailcode R&D 71, Portland, OR 97239 USA. EM kansagar@ohsu.edu FU Department of Veterans Affairs, Veterans Health Administration [ESP 05-225, 01-0206]; American College of Physicians FX Financial Support: By the Department of Veterans Affairs, Veterans Health Administration (VHA Project ESP 05-225, VA #01-0206). The American College of Physicians provided funding for the preparation of this manuscript. NR 143 TC 86 Z9 94 U1 4 U2 14 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 15 PY 2011 VL 154 IS 4 BP 268 EP W89 DI 10.7326/0003-4819-154-4-201102150-00008 PG 23 WC Medicine, General & Internal SC General & Internal Medicine GA 720VF UT WOS:000287310000019 PM 21320942 ER PT J AU Hallahan, B Newell, J Soares, JC Brambilla, P Strakowski, SM Fleck, DE Kieseppa, T Altshuler, LL Fornito, A Malhi, GS McIntosh, AM Yurgelun-Todd, DA Labar, KS Sharma, V MacQueen, GM Murray, RM McDonald, C AF Hallahan, Brian Newell, John Soares, Jair C. Brambilla, Paolo Strakowski, Stephen M. Fleck, David E. Kieseppa, Tuula Altshuler, Lori L. Fornito, Alex Malhi, Gin S. McIntosh, Andrew M. Yurgelun-Todd, Deborah A. Labar, Kevin S. Sharma, Verinder MacQueen, Glenda M. Murray, Robin M. McDonald, Colm TI Structural Magnetic Resonance Imaging in Bipolar Disorder: An International Collaborative MegaAnalysis of Individual Adult Patient Data SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 8th International Conference on Bipolar Disorder CY JUN 25-27, 2009 CL Pittsburgh, PA SP NIMH DE Amygdala; bipolar disorder; hippocampus; lateral ventricles; lithium; mega-analysis ID SUBGENUAL PREFRONTAL CORTEX; TEMPORAL-LOBE STRUCTURES; BRAIN GRAY-MATTER; HIPPOCAMPAL VOLUME; MOOD DISORDERS; WHITE-MATTER; LITHIUM TREATMENT; BASAL GANGLIA; HEALTHY-INDIVIDUALS; NEUROTROPHIC FACTOR AB Background: There is substantial inconsistency in results of brain structural magnetic resonance imaging studies in adult bipolar disorder. This is likely consequent upon limited statistical power of studies together with their clinical and methodological heterogeneity. The current study was undertaken to perform an international collaborative mega-analysis of regional volumetric measurements of individual patient and healthy subject data, to optimize statistical power, detect case-control differences, assess the association of psychotropic medication usage with brain structural variation, and detect other possible sources of heterogeneity. Methods: Eleven international research groups contributed published and unpublished data on 321 individuals with bipolar disorder land 442 healthy subjects. We used linear mixed effects regression models to evaluate differences in brain structure between patient groups. Results: Individuals with bipolar disorder had increased right lateral ventricular, left temporal lobe, and right putamen volumes. Bipolar patients taking lithium displayed significantly increased hippocampal and amygdala volume compared with patients not treated with lithium and healthy comparison subjects. Cerebral volume reduction was significantly associated with illness duration in bipolar individuals. Conclusions: The application of mega-analysis to bipolar disorder imaging identified lithium use and illness duration as substantial and consistent sources of heterogeneity, with lithium use associated with regionally specific increased brain volume. C1 [Hallahan, Brian; McDonald, Colm] Natl Univ Ireland Galway, Dept Psychiat, Inst Clin Sci, Galway, Ireland. Natl Univ Ireland Galway, Hlth Res Board, Clin Res Facil, Galway, Ireland. [Newell, John] Natl Univ Ireland Galway, Sch Math Stat & Appl Math, Galway, Ireland. [Brambilla, Paolo] Univ N Carolina, Sch Med, Dept Psychiat, Ctr Excellence Res & Treatment Bipolar Disorders, Chapel Hill, NC USA. [Brambilla, Paolo] Univ Udine, DPMSC, Sect Psychiat, I-33100 Udine, Italy. IRCCS E Medea, Inst Sci, Udine, Italy. [Strakowski, Stephen M.; Fleck, David E.] Univ Cincinnati, Coll Med, Div Bipolar Disorder Res, Cincinnati, OH USA. [Strakowski, Stephen M.; Fleck, David E.] Univ Cincinnati, Coll Med, Ctr Imaging Res, Cincinnati, OH USA. [Kieseppa, Tuula] Univ Helsinki, Cent Hosp, Natl Inst Hlth & Welf, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. Univ Helsinki, Dept Psychiat, Cent Hosp, Helsinki, Finland. [Altshuler, Lori L.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Psychiat, W Los Angeles Healthcare Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Fornito, Alex] Univ Cambridge, Addenbrookes Hosp, Brain Mapping Unit, Dept Psychiat, Cambridge CB2 2QQ, England. Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Natl Neurosci Facil, Melbourne, Vic 3010, Australia. [Malhi, Gin S.] Univ Sydney, Discipline Psychol Med, Sydney, NSW 2006, Australia. [McIntosh, Andrew M.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Yurgelun-Todd, Deborah A.] Univ Utah, Dept Psychiat, Utahs Sch Med, Cognit Imaging Lab,Brain Inst, Salt Lake City, UT USA. [Labar, Kevin S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Labar, Kevin S.] Duke Univ, Med Ctr, Ctr Cognit Neurosci, Durham, NC USA. [Sharma, Verinder] Univ Western Ontario, Dept Psychiat, Reg Mental Hlth Care London, London, ON N6A 3K7, Canada. [MacQueen, Glenda M.] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Murray, Robin M.; McDonald, Colm] Inst Psychiat, Div Psychol Med, London, England. [Soares, Jair C.] Univ Texas Hlth Sci Ctr, Ctr Excellence Mood Disorders, Houston, TX USA. Harris Cty Psychiat Ctr, Houston, TX USA. RP Hallahan, B (reprint author), Natl Univ Ireland, Dept Psychiat, Inst Clin Sci, Galway, Ireland. EM brian.hallahan@nuigalway.ie RI McIntosh, Andrew/B-9379-2008; McDonald, Colm/C-1430-2009; Murray, Robin/F-8658-2012; Alex, Fornito/N-8214-2013; OI McIntosh, Andrew/0000-0002-0198-4588; Murray, Robin/0000-0003-0829-0519; Alex, Fornito/0000-0001-9134-480X; Newell, John/0000-0001-7685-6655; Hallahan, Brian/0000-0003-0518-9757 NR 72 TC 123 Z9 125 U1 1 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2011 VL 69 IS 4 BP 326 EP 335 DI 10.1016/j.biopsych.2010.08.029 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 718JV UT WOS:000287118300006 PM 21030008 ER PT J AU Hutton, J Walker, LG Gilbert, FJ Evans, DG Eeles, R Kwan-Lim, GE Thompson, D Pointon, LJ Sharp, DM Leach, MO AF Hutton, J. Walker, L. G. Gilbert, F. J. Evans, D. G. Eeles, R. Kwan-Lim, G. E. Thompson, D. Pointon, L. J. Sharp, D. M. Leach, M. O. CA High Risk Study TI Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study SO BRITISH JOURNAL OF CANCER LA English DT Article DE MARIBS; psychology; MRI; anxiety; breast cancer ID HIGH FAMILIAL RISK; BREAST-CANCER; NATIONAL MULTICENTER; HOSPITAL ANXIETY; DEPRESSION SCALE; GENETIC RISK; WOMEN; MRI; HISTORY; PERFORMANCE AB BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM). METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans). RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P = 0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P = 0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P = 0.006) and total MRI-related distress (P = 0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P < 0.0005). These effects were most marked for the first year of screening, although they were also statistically significant in subsequent years. CONCLUSION: Given the proven benefits of MRI in screening for breast cancer in this population, these data point to the urgent need to provide timely information and support to women undergoing MRI. British Journal of Cancer (2011) 104, 578-586. doi:10.1038/bjc.2011.1 www.bjcancer.com (C) 2011 Cancer Research UK C1 [Hutton, J.] N Lanarkshire Council, Motherwell ML1 1JE, Lanark, Scotland. [Walker, L. G.; Sharp, D. M.] Univ Hull, Postgrad Med Inst, Inst Rehabil, Kingston Upon Hull HU3 2PG, Yorks, England. [Walker, L. G.; Sharp, D. M.] Hull York Med Sch, Kingston Upon Hull HU3 2PG, Yorks, England. [Gilbert, F. J.] Univ Aberdeen, Aberdeen Biomed Imaging Ctr, Aberdeen AB25 2ZD, Scotland. [Evans, D. G.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester M13 9WL, Lancs, England. [Eeles, R.; Kwan-Lim, G. E.; Leach, M. O.] Canc Res UK Clin Magnet Resonance Res Grp, Inst Canc Res, Sutton SM2 5PT, Surrey, England. [Eeles, R.; Kwan-Lim, G. E.; Leach, M. O.] Royal Marsden NHS Fdn Trust, Sutton SM2 5PT, Surrey, England. [Thompson, D.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge CB1 8RN, England. [Pointon, L. J.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. RP Hutton, J (reprint author), N Lanarkshire Council, 73-77 Merry St, Motherwell ML1 1JE, Lanark, Scotland. EM huttonJe@northlan.gov.uk RI leach, martin/C-2248-2008; OI leach, martin/0000-0002-0756-5368; Eeles, Rosalind/0000-0002-3698-6241; Evans, Gareth/0000-0002-8482-5784 FU UK Medical Research Council [G960413]; NHS funding as an NIHR Biomedical Research Centre; CRUK; EPSRC Cancer Imaging Centre; MRC; Department of Health (England) [C1060/A10334]; NIHR FX The study is a UK-wide collaboration of 22 genetics centres, and their associated MRI and Mammography Departments. We acknowledge the vital contributions of clinical colleagues, radiographers, nurses, clerical staff, physicists, and engineers. A special thank you is extended to the women and their surgeons and oncologists who referred them, without whom the study would not have been possible. The national study is supported by a grant from the UK Medical Research Council (G960413). The cost of the MRI studies is paid for by subvention funding for research from the UK National Health Service. The protocol is based, in part, on developments supported by Cancer Research UK and the Yorkshire Cancer Research Campaign. Contributions towards training and education have been made by Schering Healthcare (Burgess Hill, UK) and Oracle Education (Bracknell, UK). We thank Myriad Genetics (Saltlake, UT, USA) for doing the anonymous genetic testing and Paula Smith for doing the risk calculations for the Genetic Eligibility Panel. The Institute of Cancer Research (ICR) receives NHS funding as an NIHR Biomedical Research Centre. The ICR Imaging Centre receives support from the CRUK and EPSRC Cancer Imaging Centre funding in association with the MRC and Department of Health (England) grant C1060/A10334. DGE is supported by an NIHR grant to the Biomedical Research Centre, Manchester. NR 29 TC 9 Z9 9 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 15 PY 2011 VL 104 IS 4 BP 578 EP 586 DI 10.1038/bjc.2011.1 PG 9 WC Oncology SC Oncology GA 728ZY UT WOS:000287915600006 PM 21326245 ER PT J AU Ellisen, LW AF Ellisen, Leif W. TI PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles SO CANCER CELL LA English DT Editorial Material ID POLY(ADP-RIBOSE) POLYMERASE; TUMORS C1 [Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ellisen, Leif W.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu FU NCI NIH HHS [P30 CA006516-44S2, P30 CA006516] NR 10 TC 26 Z9 29 U1 1 U2 3 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 FEB 15 PY 2011 VL 19 IS 2 BP 165 EP 167 DI 10.1016/j.ccr.2011.01.047 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 727BE UT WOS:000287771500005 PM 21316599 ER PT J AU Frank, NY Schatton, T Kim, S Zhan, QA Wilson, BJ Ma, J Saab, KR Osherov, V Widlund, HR Gasser, M Waaga-Gasser, AM Kupper, TS Murphy, GF Frank, MH AF Frank, Natasha Y. Schatton, Tobias Kim, Soo Zhan, Qian Wilson, Brian J. Ma, Jie Saab, Karim R. Osherov, Veronika Widlund, Hans R. Gasser, Martin Waaga-Gasser, Ana-Maria Kupper, Thomas S. Murphy, George F. Frank, Markus H. TI VEGFR-1 Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Growth SO CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; VASCULOGENIC MIMICRY; IN-VIVO; ANGIOGENESIS; RECEPTOR; CHEMORESISTANCE; IDENTIFICATION; ABCB5; CD133 AB \ Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5(+) melanoma subpopulations have been shown to over-express the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31(-) vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5(+) MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5(+) tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5(+) subpopulations that constitutively expressed VEGFR-1 but not in ABCB5(-) bulk populations that were predominantly VEGFR-1(-). In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5(+) VM morphology and inhibited ABCB5(+) VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. Cancer Res; 71(4); 1474-85. (c) 2011 AACR. C1 [Frank, Natasha Y.; Schatton, Tobias; Kim, Soo; Wilson, Brian J.; Ma, Jie; Saab, Karim R.; Osherov, Veronika; Frank, Markus H.] Childrens Hosp Boston, Transplantat Res Ctr, Boston, MA 02115 USA. [Frank, Natasha Y.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Frank, Natasha Y.] Boston VA Healthcare Syst, Dept Med, Boston, MA USA. [Schatton, Tobias; Wilson, Brian J.; Ma, Jie; Saab, Karim R.; Widlund, Hans R.; Kupper, Thomas S.; Frank, Markus H.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Zhan, Qian; Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Gasser, Martin; Waaga-Gasser, Ana-Maria] Univ Wurzburg, Dept Surg, Wurzburg, Germany. RP Frank, MH (reprint author), Childrens Hosp Boston, Transplantat Res Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM gmurphy@rics.bwh.harvard.edu; mfrank@rics.bwh.harvard.edu RI Frank, Markus/O-1625-2014 OI Frank, Markus/0000-0002-1312-0488 FU NIH/NCI [1RO1CA113796, 1R01CA138231, 2P50CA093683-06A20006]; NIH/NINDS [KO8NS051349] FX This work was supported by funds provided by the NIH/NCI (grants 1RO1CA113796 and 1R01CA138231 to M.H. Frank and grant 2P50CA093683-06A20006 to T.S. Kupper, M.H. Frank, and G.F. Murphy) and the NIH/NINDS (grant KO8NS051349 to N.Y. Frank). NR 46 TC 65 Z9 73 U1 2 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2011 VL 71 IS 4 BP 1474 EP 1485 DI 10.1158/0008-5472.CAN-10-1660 PG 12 WC Oncology SC Oncology GA 721KP UT WOS:000287352600029 PM 21212411 ER PT J AU Clair, DG Hopkins, LN Mehta, M Kasirajan, K Schermerhorn, M Schonholz, C Kwolek, CJ Eskandari, MK Powell, RJ Ansel, GM AF Clair, Daniel G. Hopkins, L. Nelson Mehta, Manish Kasirajan, Karthikeshwar Schermerhorn, Marc Schoenholz, Claudio Kwolek, Christopher J. Eskandari, Mark K. Powell, Richard J. Ansel, Gary M. CA EMPiRe Clinical Study TI Neuroprotection During Carotid Artery Stenting Using the GORE Flow Reversal System: 30-Day Outcomes in the EMPiRE Clinical Study SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE angioplasty; carotid arteries; embolism; stents; stroke ID SURGICAL-RISK PATIENTS; CEREBRAL PROTECTION DEVICES; EMBOLIC PROTECTION; DISTAL PROTECTION; ENDOVASCULAR TREATMENT; FILTERWIRE EX/EZ; CAPTURE REGISTRY; RANDOMIZED-TRIAL; BEACH TRIAL; ANGIOPLASTY AB Background: Each of the embolic protection devices used in carotid artery stenting (CAS) has advantages and disadvantages. The prospective, multicenter, single-arm EMPiRE Clinical Study investigated a proximally placed device (GORE Flow Reversal System) that provides distal neuroprotection during CAS by reversing blood flow in the internal carotid artery, thereby directing emboli away from the brain. Methods: The study evaluated 30-day outcomes in 245 pivotal high-surgical-risk patients (mean age, 70 years; 32% symptomatic; 16% >= 80-years old) with carotid stenosis who underwent CAS using the flow reversal system. The primary endpoint was a major adverse event (MAE; stroke, death, myocardial infarction, or transient ischemic attack) within 30 days of CAS. The MAE rate was compared with an objective performance criterion (OPC) derived from CAS studies that included embolic protection. Results: The MAE rate was 4.5% (11 patients; P = 0.002 compared with the OPC). The stroke and death rate was 2.9%. No patient had a major ischemic stroke. Six patients (2.4%) had intolerance to flow reversal. The death and stroke rates in the symptomatic, asymptomatic, and octogenarian subgroups were 2.6, 3, and 2.6%, respectively, meeting American Heart Association guidelines for carotid endarterectomy. Conclusion: The stroke and death rate in this study was among the lowest in CAS trials. The results indicate that the flow reversal system is safe and effective when used for neuroprotection during CAS and that it provides benefits in a broad patient population. (C) 2010 Wiley-Liss, Inc. C1 [Clair, Daniel G.] Cleveland Clin, Lerner Coll Med, Dept Vasc Surg, Inst Heart & Vasc, Cleveland, OH 44135 USA. [Hopkins, L. Nelson] SUNY Buffalo, Buffalo, NY 14260 USA. [Hopkins, L. Nelson] Toshiba Stroke Ctr, Buffalo, NY USA. [Mehta, Manish] Albany Vasc Grp, Albany, NY USA. [Kasirajan, Karthikeshwar] Emory Univ Hosp, Atlanta, GA 30322 USA. [Schermerhorn, Marc] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Schoenholz, Claudio] Med Univ S Carolina, Charleston, SC 29425 USA. [Kwolek, Christopher J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Eskandari, Mark K.] NW Mem Hosp, Chicago, IL 60611 USA. [Powell, Richard J.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Ansel, Gary M.] Riverside Methodist Hosp, Columbus, OH 43214 USA. RP Clair, DG (reprint author), Cleveland Clin, Lerner Coll Med, Dept Vasc Surg, Inst Heart & Vasc, 9500 Euclid Ave,H32, Cleveland, OH 44135 USA. EM CLAIRD@ccf.org NR 51 TC 63 Z9 64 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD FEB 15 PY 2011 VL 77 IS 3 BP 420 EP 429 DI 10.1002/ccd.22789 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 725QD UT WOS:000287659800017 PM 20853365 ER PT J AU Neal, JW Shaw, AT AF Neal, Joel W. Shaw, Alice T. TI One Allele's Loss Is Another's Gain: Alterations of NKX2-8 in Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material AB Large-scale genetic changes such as loss or gain of chromosomes are important drivers of solid tumor carcinogenesis. Recent technological advances in genomic profiling have allowed quantitative detection of gene copy numbers, leading to identification of the 14q13.3 gene locus as functionally important in non-small cell lung cancers. Clin Cancer Res; 17(4); 638-9. (C) 2010 AACR. C1 [Shaw, Alice T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Ctr Thorac Canc, Boston, MA 02114 USA. [Neal, Joel W.] Stanford Canc Ctr, Stanford, CA USA. RP Shaw, AT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Ctr Thorac Canc, Profess Off Bldg 222, Boston, MA 02114 USA. EM ashaw1@partners.org FU Novartis; AztraZeneca FX A. Shaw, commercial research grant, Novartis, AztraZeneca; consultant, Pfizer, Millennium. NR 9 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2011 VL 17 IS 4 BP 638 EP 639 DI 10.1158/1078-0432.CCR-10-3081 PG 2 WC Oncology SC Oncology GA 728ZM UT WOS:000287913200002 PM 21163872 ER PT J AU Diamond, JR Bastos, BR Hansen, RJ Gustafson, DL Eckhardt, SG Kwak, EL Pandya, SS Fletcher, GC Pitts, TM Kulikowski, GN Morrow, M Arnott, J Bray, MR Sidor, C Messersmith, W Shapiro, GI AF Diamond, Jennifer R. Bastos, Bruno R. Hansen, Ryan J. Gustafson, Daniel L. Eckhardt, S. Gail Kwak, Eunice L. Pandya, Shuchi S. Fletcher, Graham C. Pitts, Todd M. Kulikowski, Gillian N. Morrow, Mark Arnott, Jamie Bray, Mark R. Sidor, Carolyn Messersmith, Wells Shapiro, Geoffrey I. TI Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of ENMD-2076, a Novel Angiogenic and Aurora Kinase Inhibitor, in Patients with Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; ANTITUMOR-ACTIVITY; COLORECTAL-CANCER; BEVACIZUMAB; SUNITINIB; TARGETS; HYPERTENSION; SORAFENIB AB Purpose: ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity. Experimental Design: Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m(2) were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors. Results: A total of 67 patients (46 F, 21M; ages 30-76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m(2) were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m(2), and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m(2) was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (T(max) 3-7.8 hours), a t(1/2) of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses. Conclusions: ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m(2) administered orally once daily with continuous dosing. Clin Cancer Res; 17(4); 849-60. (C) 2010 AACR. C1 [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Diamond, Jennifer R.; Eckhardt, S. Gail; Pitts, Todd M.; Kulikowski, Gillian N.; Morrow, Mark; Messersmith, Wells] Univ Colorado Denver, Aurora, CO USA. [Hansen, Ryan J.; Gustafson, Daniel L.] Colorado State Univ, Anim Canc Ctr, Ft Collins, CO 80523 USA. [Kwak, Eunice L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pandya, Shuchi S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fletcher, Graham C.; Arnott, Jamie; Bray, Mark R.; Sidor, Carolyn] EntreMed Inc, Toronto, ON, Canada. [Arnott, Jamie; Bray, Mark R.; Sidor, Carolyn] EntreMed Inc, Durham, NC USA. RP Shapiro, GI (reprint author), Dana Farber Canc Inst, Early Drug Dev Ctr, 44 Binney St, Boston, MA 02115 USA. EM geoffrey_shapiro@dfci.harvard.edu FU EntreMed, Inc. [NCT00658671]; Colorado State University FX Supported by EntreMed, Inc. (NCT00658671), including a Sponsored Research Agreement with Colorado State University for performance of pharmacokinetics. NR 37 TC 31 Z9 31 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2011 VL 17 IS 4 BP 849 EP 860 DI 10.1158/1078-0432.CCR-10-2144 PG 12 WC Oncology SC Oncology GA 728ZM UT WOS:000287913200024 PM 21131552 ER PT J AU Quek, R Wang, QA Morgan, JA Shapiro, GI Butrynski, JE Ramaiya, N Huftalen, T Jederlinic, N Manola, J Wagner, AJ Demetri, GD George, S AF Quek, Richard Wang, Qian Morgan, Jeffrey A. Shapiro, Geoffrey I. Butrynski, James E. Ramaiya, Nikhil Huftalen, Tarsha Jederlinic, Nicole Manola, Judith Wagner, Andrew J. Demetri, George D. George, Suzanne TI Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODY CP-751,871; GROWTH-FACTOR RECEPTOR; MAMMALIAN TARGET; PATHWAY; FIBROBLASTS; ACTIVATION; SUNITINIB; CARCINOMA; CANCER; CELLS AB Purpose: Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG2 anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated. Experimental Design: Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1. Results: NoDLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab. Conclusions: Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation. Clin Cancer Res; 17(4); 871-9. (C) 2010 AACR. C1 [Quek, Richard; Morgan, Jeffrey A.; Butrynski, James E.; Huftalen, Tarsha; Jederlinic, Nicole; Wagner, Andrew J.; George, Suzanne] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Wang, Qian; Manola, Judith] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Ramaiya, Nikhil] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Demetri, George D.] Dana Farber Canc Inst, Ludwig Ctr, Boston, MA 02115 USA. RP George, S (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. EM suzanne_george@dfci.harvard.edu FU Novartis; Pfizer; Genentech; Arqule; Exelixis; Ariad FX SG has received research funding from, and have served in a consultant or advisory role for Novartis and Pfizer. AJW has received research funding from Genentech, Prolexys, Arqule, and Exelixis, and have served in a consultant or advisory role for Genentech. GDD has received research funding from Novartis, Pfizer, and Ariad; served in a consultant or advisory role for Novartis, Pfizer, Ariad, Amgen, and Genentech; received honoraria from Novartis, Pfizer; and has provided expert testimony for Novartis, Pfizer, and Ariad. All other authors declared no conflicts of interest.; Research drugs and pharmacokinetic assay support were provided by Novartis and Pfizer. NR 34 TC 88 Z9 91 U1 1 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 FEB 15 PY 2011 VL 17 IS 4 BP 871 EP 879 DI 10.1158/1078-0432.CCR-10-2621 PG 9 WC Oncology SC Oncology GA 728ZM UT WOS:000287913200026 PM 21177764 ER PT J AU Zhu, AX Duda, DG Ancukiewicz, M di Tomaso, E Clark, JW Miksad, R Fuchs, CS Ryan, DP Jain, RK AF Zhu, Andrew X. Duda, Dan G. Ancukiewicz, Marek di Tomaso, Emmanuelle Clark, Jeffrey W. Miksad, Rebecca Fuchs, Charles S. Ryan, David P. Jain, Rakesh K. TI Exploratory Analysis of Early Toxicity of Sunitinib in Advanced Hepatocellular Carcinoma Patients: Kinetics and Potential Biomarker Value SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; SKIN TOXICITY; GROWTH-FACTOR; BEVACIZUMAB; SORAFENIB; BLOOD; TUMOR; INHIBITORS; CANCER; VEGF AB Purpose: Sunitinib-a multitargeted tyrosine kinase inhibitor-can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study. Experimental Design: Toxicity was evaluated every two weeks during the first cycle of therapy. Biomarker changes from baseline were tested after adjusting for multiple comparisons. Correlation between toxicities and overall survival (OS) or time-to-tumor progression (TTP) was evaluated in a Cox model using log-transformed levels or change in biomarkers, after stratifying by stage and adjusting for baseline level. Results: Myeloid and lymphoid blood cell counts decreased by 20% to 50% after sunitinib treatment (P < 0.05 for all). The extent of the early decrease in neutrophils and monocytes, and the development of nonhematologic toxicities (i.e., skin toxicities), were significantly associated with both OS and TTP (P < 0.05). Changes in circulating cells significantly associated with specific changes in plasma biomarkers (i.e., changes in platelets with changes in VEGF-C and soluble-VEGFR3; changes in neutrophils with changes in IL-8, TNF-alpha, and soluble-VEGFR2). Conclusions: The adverse effects of sunitinib, particularly on the hematopoietic system, may be rapid and appear directly related to its activity in HCC. This exploratory study suggests that early hematopoietic toxicities may potentially predict outcome in advanced HCC after sunitinib treatment. Clin Cancer Res; 17(4); 918-27. (C) 2010 AACR. C1 [Zhu, Andrew X.; Clark, Jeffrey W.; Ryan, David P.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Duda, Dan G.; Ancukiewicz, Marek; di Tomaso, Emmanuelle; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Duda, Dan G.; Ancukiewicz, Marek; di Tomaso, Emmanuelle; Miksad, Rebecca; Fuchs, Charles S.; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA USA. [Miksad, Rebecca] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Zhu, AX (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, 55 Fruit St,LH-POB,Room 232, Boston, MA 02114 USA. EM azhu@partners.org OI Miksad, Rebecca/0000-0003-3194-5122 FU Pfizer; National Institutes of Health [P01CA80124, R01CA115767]; Federal Share/NCI Proton Beam Program Income; Harvard Clinical and Translational Science Center [M01-RR-01066] FX A.X. Zhu: consultant/advisory board, Genentech, Bayer Pharmaceuticals, Pfizer. E. di Tomaso: current employment, Novartis. C. S. Fuchs: consultant/advisory board, Bristol-Myers Squibb, Merck, Roche, Amgen, Genentech, Alynylam, Imclone Systems, Genomic Health; commercial research grant, Pfizer. D. P. Ryan: honorarium, Genentech. R. K. Jain: commercial research grant, Dyax, AstraZeneca, and MedImmune; consultant/advisory board, AstraZeneca, Dyax, Astellas-Fibrogen, Regeneron, SynDevRx, Genzyme, Morphosys, and Noxxon Pharma; speaker honorarium, Genzyme; stock ownership, SynDevRx. D. G. Duda, J. W. Clark, R. Miksad, and M. Ancukiewicz reported no potential conflicts of interest.; This study was supported by Pfizer (A. X. Zhu) and correlative studies were supported in part by National Institutes of Health Grants P01CA80124, R01CA115767, and Federal Share/NCI Proton Beam Program Income (R. K. Jain) and by Grant M01-RR-01066, Harvard Clinical and Translational Science Center. NR 36 TC 15 Z9 18 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 FEB 15 PY 2011 VL 17 IS 4 BP 918 EP 927 DI 10.1158/1078-0432.CCR-10-0515 PG 10 WC Oncology SC Oncology GA 728ZM UT WOS:000287913200031 PM 20843836 ER PT J AU Kenny, EE Kim, M Gusev, A Lowe, JK Salit, J Smith, JG Kovvali, S Kang, HM Newton-Cheh, C Daly, MJ Stoffel, M Altshuler, DM Friedman, JM Eskin, E Breslow, JL Pe'er, I AF Kenny, Eimear E. Kim, Minseung Gusev, Alexander Lowe, Jennifer K. Salit, Jacqueline Smith, J. Gustav Kovvali, Sirisha Kang, Hyun Min Newton-Cheh, Christopher Daly, Mark J. Stoffel, Markus Altshuler, David M. Friedman, Jeffrey M. Eskin, Eleazar Breslow, Jan L. Pe'er, Itsik TI Increased power of mixed models facilitates association mapping of 10 loci for metabolic traits in an isolated population SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; QUANTITATIVE TRAITS; FOUNDER POPULATION; COMPLEX TRAITS; WHOLE-GENOME; LINKAGE DISEQUILIBRIUM; VARIANCE-COMPONENTS AB The potential benefits of using population isolates in genetic mapping, such as reduced genetic, phenotypic and environmental heterogeneity, are offset by the challenges posed by the large amounts of direct and cryptic relatedness in these populations confounding basic assumptions of independence. Wehave evaluated four representative specialized methods for association testing in the presence of relatedness; (i) within-family (ii) within-and between-family and (iii) mixed-models methods, using simulated traits for 2906 subjects with known genome-wide genotype data from an extremely isolated population, the Island of Kosrae, Federated States of Micronesia. We report that mixed models optimally extract association information from such samples, demonstrating 88% power to rank the true variant as among the top 10 genome-wide with 56% achieving genome-wide significance, a > 80% improvement over the other methods, and demonstrate that population isolates have similar power to non-isolate populations for observing variants of known effects. We then used the mixed-model method to reanalyze data for 17 published phenotypes relating to metabolic traits and electrocardiographic measures, along with another 8 previously unreported. We replicate nine genome-wide significant associations with known loci of plasma cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, thyroid stimulating hormone, homocysteine, C-reactive protein and uric acid, with only one detected in the previous analysis of the same traits. Further, we leveraged shared identity-by-descent genetic segments in the region of the uric acid locus to fine-map the signal, refining the known locus by a factor of 4. Finally, we report a novel associations for height (rs17629022, P < 2.1 x 10(-8)). C1 [Kenny, Eimear E.; Kim, Minseung; Gusev, Alexander; Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Kenny, Eimear E.; Salit, Jacqueline; Friedman, Jeffrey M.; Breslow, Jan L.] Rockefeller Univ, New York, NY 10065 USA. [Lowe, Jennifer K.; Kovvali, Sirisha; Daly, Mark J.; Altshuler, David M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Lowe, Jennifer K.; Daly, Mark J.; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Smith, J. Gustav; Newton-Cheh, Christopher; Altshuler, David M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kang, Hyun Min] Univ Michigan, Bioinformat Grad Program, Ann Arbor, MI 48109 USA. [Stoffel, Markus] Swiss Fed Inst Technol, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90024 USA. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90024 USA. RP Pe'er, I (reprint author), Columbia Univ, Dept Comp Sci, 450 Comp Sci Bldg,500 W 120th St,Mailcode 0401, New York, NY 10027 USA. EM itsik@cs.columbia.edu RI Altshuler, David/A-4476-2009; Breslow, Jan/B-7544-2008; Eskin, Eleazar/J-9187-2012 OI Altshuler, David/0000-0002-7250-4107; Eskin, Eleazar/0000-0003-1149-4758 FU Starr Foundation; Howard Hughes Medical Institute; National Heart, Lung and Blood Institute [080025]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund Career Award; Women & Science fellowship; National Science Foundation [CAREER 0845677, EMT 0829882] FX This work was supported by grants from the Starr Foundation and Howard Hughes Medical Institute for all measurement of metabolic traits and genotypes. Measurements of electrocardiographic traits in Kosrae were supported by a K23 from the National Heart, Lung and Blood Institute (grant number 080025), a Doris Duke Charitable Foundation Clinical Scientist Development Award and a Burroughs Wellcome Fund Career Award for Medical Scientists to CNC. Support from a Women & Science fellowship was provided to EEK. Support from the National Science Foundation (grant numbers CAREER 0845677, EMT 0829882) was provided to IP. NR 69 TC 12 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2011 VL 20 IS 4 BP 827 EP 839 DI 10.1093/hmg/ddq510 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 709VL UT WOS:000286469400017 PM 21118897 ER PT J AU Eccleston, J Yan, C Yuan, K Alt, FW Selsing, E AF Eccleston, Jennifer Yan, Catherine Yuan, Karen Alt, Frederick W. Selsing, Erik TI Mismatch Repair Proteins MSH2, MLH1, and EXO1 Are Important for Class-Switch Recombination Events Occurring in B Cells That Lack Nonhomologous End Joining SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTIDINE DEAMINASE AID; SINGLE-STRANDED-DNA; SOMATIC HYPERMUTATION; ANTIBODY DIVERSIFICATION; LIGASE-IV; MICE; MECHANISM; TRANSLOCATIONS; DEFICIENCY; ABSENCE AB In the absence of core nonhomologous end-joining (NHEJ) factors, Ab gene class-switch recombination (CSR) uses an alternative end-joining (A-EJ) pathway to recombine switch (S) region DNA breaks. Previous reports showing decreased S-junction microhomologies in MSH2-deficient mice and an exonuclease 1 (EXO1) role in yeast microhomology-mediated end joining suggest that mismatch repair (MMR) proteins might influence A-EJ-mediated CSR. We have directly investigated whether MMR proteins collectively or differentially influence the A-EJ mechanism of CSR by analyzing CSR in mice deficient in both XRCC4 and individual MMR proteins. We find CSR is reduced and that Igh locus chromosome breaks are reduced in the MMR/XRCC4 double-deficient B cells compared with B cells deficient in XRCC4 alone, suggesting MMR proteins function upstream of double-strand break formation to influence CSR efficiency in these cells. Our results show that MLH1, EXO1, and MSH2 are all important for efficient A-EJ-mediated CSR, and we propose that MMR proteins convert DNA nicks and point mutations into dsDNA breaks for both C-NHEJ and A-EJ pathways of CSR. We also find Mlh1-XRCC4(-) B cells have an increased frequency of direct S junctions, suggesting that MLH1 proteins may have additional functions that influence A-EJ-mediated CSR. The Journal of Immunology, 2011, 186: 2336-2343. C1 [Eccleston, Jennifer; Yuan, Karen; Selsing, Erik] Tufts Univ, Sch Med, Dept Pathol, Program Immunol, Boston, MA 02111 USA. [Yan, Catherine] Beth Israel Deaconess Med Ctr, Dept Pathol, Div Expt Pathol, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Selsing, E (reprint author), Tufts Univ, Sch Med, Dept Pathol, Program Immunol, 150 Harrison Ave, Boston, MA 02111 USA. EM erik.selsing@tufts.edu FU National Institutes of Health [AI24465, AI077595]; Eshe Foundation FX This work was supported by National Institutes of Health Grants AI24465 (to E.S.) and AI077595 (to F.W.A.) and by the Eshe Foundation. NR 45 TC 15 Z9 15 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2011 VL 186 IS 4 BP 2336 EP 2343 DI 10.4049/jimmunol.1003104 PG 8 WC Immunology SC Immunology GA 715KF UT WOS:000286882700054 PM 21242524 ER PT J AU Triant, VA Grinspoon, SK AF Triant, Virginia A. Grinspoon, Steven K. TI Immune Dysregulation and Vascular Risk in HIV-Infected Patients: Implications for Clinical Care SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID T-CELL COUNT; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS; EVENTS; IMMUNODEFICIENCY; INTERRUPTION; MEN C1 [Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nut Metab, Boston, MA 02114 USA. [Triant, Virginia A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nut Metab, 55 Fruit St,Longfellow 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIAID NIH HHS [K01 AI073109]; NIDDK NIH HHS [K24 DK064545] NR 22 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2011 VL 203 IS 4 BP 439 EP 441 DI 10.1093/infdis/jiq084 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 709VE UT WOS:000286468700002 PM 21220778 ER PT J AU Manzano-Fernandez, S Januzzi, JL Boronat-Garcia, M Bonaque-Gonzalez, JC Truong, QA Pastor-Perez, FJ Munoz-Esparza, C Pastor, P Albaladejo-Oton, MD Casas, T Valdes, M Pascual-Figal, DA AF Manzano-Fernandez, Sergio Januzzi, James L., Jr. Boronat-Garcia, Miguel Carlos Bonaque-Gonzalez, Juan Truong, Quynh A. Pastor-Perez, Francisco J. Munoz-Esparza, Carmen Pastor, Patricia Albaladejo-Oton, Maria D. Casas, Teresa Valdes, Mariano Pascual-Figal, Domingo A. TI beta-Trace Protein and Cystatin C as Predictors of Long-Term Outcomes in Patients With Acute Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute heart failure; beta-trace protein; cystatin C; prognosis ID PROSTAGLANDIN-D-SYNTHASE; GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION; INDEPENDENT PREDICTOR; NATRIURETIC PEPTIDE; RISK STRATIFICATION; SERUM CONCENTRATION; PROGNOSTIC VALUE; ELDERLY PERSONS; GAMMA-TRACE AB Objectives The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). Background beta-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. Methods A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. Results Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l [range 0.80 to 1.49 mg/l] vs. 0.88 mg/l [range 0.68 to 1.17 mg/l], p = 0.003) and cystatin C (1.29 mg/l [range 1.00 to 1.71 mg/l] vs. 1.03 mg/l [range 0.86 to 1.43 mg/l], p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m(2), elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. Conclusions Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication. (J Am Coll Cardiol 2011; 57: 849-58) (C) 2011 by the American College of Cardiology Foundation C1 [Januzzi, James L., Jr.; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Manzano-Fernandez, Sergio; Carlos Bonaque-Gonzalez, Juan; Pastor-Perez, Francisco J.; Munoz-Esparza, Carmen; Valdes, Mariano; Pascual-Figal, Domingo A.] Univ Hosp Virgen de la Arrixaca, Dept Cardiol, Murcia, Spain. [Boronat-Garcia, Miguel; Albaladejo-Oton, Maria D.; Casas, Teresa] Univ Hosp Virgen de la Arrixaca, Dept Biochem, Murcia, Spain. [Pastor, Patricia] Univ Hosp Virgen de la Arrixaca, Dept Gen Surg, Murcia, Spain. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,32 Fruit St, Boston, MA 02114 USA. EM JJanuzzi@partners.org RI Pascual Figal, Domingo /B-3794-2008 OI Pascual Figal, Domingo /0000-0002-4993-9540 FU Roche Diagnostics; Siemens; Critical Diagnostics FX Dr. Januzzi, Jr, has received grant support from Roche Diagnostics, Siemens, and Critical Diagnostics; has served as a consultant to Roche Diagnostics and Critical Diagnostics; and has received speaking fees from Roche Diagnostics and Siemens. Dr. Pascual-Figal has received grant support from Roche Diagnostics. All other authors have reported that they have no relationships to disclose. NR 46 TC 39 Z9 42 U1 0 U2 3 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 FEB 15 PY 2011 VL 57 IS 7 BP 849 EP 858 DI 10.1016/j.jacc.2010.08.644 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 718MK UT WOS:000287126700014 PM 21310322 ER PT J AU Tinaz, S Courtney, MG Stern, CE AF Tinaz, Sule Courtney, Maureen G. Stern, Chantal E. TI Focal Cortical and Subcortical Atrophy in Early Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE MRI; orbitofrontal cortex; emotional dysregulation; cognition ID HUMAN CEREBRAL-CORTEX; SURFACE-BASED ANALYSIS; HUNTINGTONS-DISEASE; ALZHEIMERS-DISEASE; COORDINATE SYSTEM; DEMENTIA; BRAIN; SEGMENTATION AB Neurodegeneration in clinically manifest Parkinson's disease affects the substantia nigra pars compacta, and gradually spreads to the limbic cortices and the neocortex. We used MRI imaging coupled with automated surface reconstruction and segmentation methods to examine cortical thickness and subcortical volumes in nondemented, early-stage Parkinson's disease patients compared to matched healthy control participants. These methods, which have been previously used to document cortical thickness changes in patients with Alzheimer's disease and Huntington's disease but not Parkinson's disease, use MR signal intensity information and the geometric constraints of the cortical and subcortical structures for an accurate tissue classification. Parkinson's disease patients were matched to the control group in psychomotor processing speed and executive functioning, but showed higher anxiety state scores. Our results demonstrated focal cortical thinning in the Parkinson's disease group in the orbitofrontal cortex, ventrolateral prefrontal cortex, and occipito-parietal areas. Subcortically, striatal volume loss was noted. These results demonstrate that both cortical and subcortical structural changes occur at relatively early stages of the disease, and are discussed in terms of the emotional dysregulation that occurs early on in patients with Parkinson's disease. (C) 2010 Movement Disorder Society C1 [Tinaz, Sule; Courtney, Maureen G.; Stern, Chantal E.] Boston Univ, Ctr Memory & Brain, Boston, MA 02215 USA. [Stern, Chantal E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Tinaz, S (reprint author), Boston Univ, Ctr Memory & Brain, 2 Cummington St,Room 109, Boston, MA 02215 USA. EM aysesule.tinaz@nih.gov FU NIMH [R21 MH066213]; Athinoula A. Martinos Center for Biomedical Imaging [NCRR P41 RR14075] FX The study was supported by NIMH award R21 MH066213, and the Athinoula A. Martinos Center for Biomedical Imaging award (NCRR P41 RR14075). NR 39 TC 47 Z9 47 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB 15 PY 2011 VL 26 IS 3 BP 436 EP 441 DI 10.1002/23453 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 748UU UT WOS:000289418900010 PM 21462259 ER PT J AU Kimberly, WT Sheth, KN AF Kimberly, W. Taylor Sheth, Kevin N. TI Approach to Severe Hemispheric Stroke SO NEUROLOGY LA English DT Article ID MIDDLE CEREBRAL-ARTERY; ISCHEMIC-STROKE; INFARCTION; PREDICTORS; CRANIECTOMY; MANAGEMENT C1 [Kimberly, W. Taylor] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Sheth, Kevin N.] Univ Maryland, Med Ctr, Dept Neurol, Div Neurocrit Care & Stroke, Baltimore, MD 21201 USA. RP Sheth, KN (reprint author), 110 S Paca St,3rd Floor, Baltimore, MD 21201 USA. EM ksheth@som.umaryland.edu FU Harvard-MIT Clinical Investigator Training Program; American Academy of Neurology Foundation; Brainscope FX Dr. Kimberly has received research support from the Harvard-MIT Clinical Investigator Training Program and the American Academy of Neurology Foundation (Clinical Research Fellowship). Dr. Sheth serves on the editorial boards of Frontiers in Hospitalist Neurology and Neurology Today; receives publishing royalties for Blueprints Clinical Cases in Neurology (Lippincott Williams & Wilkins, 2006); and has received research support from Brainscope and the American Academy of Neurology Foundation (Clinical Research Fellowship). NR 15 TC 11 Z9 12 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 FEB 15 PY 2011 VL 76 IS 7 SU 2 BP S50 EP S56 DI 10.1212/WNL.0b013e31820c35f4 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 721NT UT WOS:000287362300009 PM 21321352 ER PT J AU Gesta, S Bezy, O Mori, MA Macotela, Y Lee, KY Kahn, CR AF Gesta, Stephane Bezy, Olivier Mori, Marcelo A. Macotela, Yazmin Lee, Kevin Y. Kahn, C. Ronald TI Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE thiazolidinedione; bioenergetics profile; Oil Red O ID VISCERAL ADIPOSE-TISSUE; BODY-FAT DISTRIBUTION; IN-VIVO; OBESITY; METABOLISM; GLUCOSE; ORIGIN; CELLS; IDENTIFICATION; ADIPOGENESIS AB Increased intraabdominal (visceral) fat is associated with a high risk of diabetes and metabolic syndrome. We have previously shown that the mesodermal developmental transcription factor Tbx15 is highly differentially expressed between visceral and subcutaneous (s.c.) fat in both humans and rodents, and in humans visceral fat Tbx15 expression is decreased in obesity. Here we show that, in mice, Tbx15 is 260-fold more highly expressed in s.c. preadipocytes than in epididymal preadipocytes. Overexpression of Tbx15 in 3T3-L1 preadipocytes impairs adipocyte differentiation and decreases triglyceride content. This defect in differentiation can be corrected by stimulating cells with the PPAR. agonist rosiglitazone (Rosi). However, triglyceride accumulation remains decreased by similar to 50%, due to a decrease in basal lipogenic rate and increase in basal lipolytic rate. 3T3-L1 preadipocytes overexpressing Tbx15 also have a 15% reduction in mitochondrial mass and a 28% reduction in basal mitochondrial respiration (P = 0.004) and ATP turnover (P = 0.02), and a 45% (P = 0.003) reduction in mitochondrial respiratory capacity. Thus, differential expression of Tbx15 between fat depots plays an important role in the interdepot differences in adipocyte differentiation, triglyceride accumulation, and mitochondrial function that may contribute to the risk of diabetes and metabolic disease. C1 [Gesta, Stephane; Bezy, Olivier; Mori, Marcelo A.; Macotela, Yazmin; Lee, Kevin Y.; Kahn, C. Ronald] Harvard Univ, Sch Med, Dept Integrat Physiol & Metab, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Dept Integrat Physiol & Metab, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health [DK82659, DK60837]; Diabetes and Endocrinology Research Center [DK36836]; Eli Lilly foundation; Loveman foundation FX This work was supported in part by National Institutes of Health Grants DK82659 and DK60837, Diabetes and Endocrinology Research Center Grant DK36836, the Mary K. Iacocca Professorship, and grants from the Eli Lilly and Loveman foundations. NR 43 TC 31 Z9 31 U1 1 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 FEB 15 PY 2011 VL 108 IS 7 BP 2771 EP 2776 DI 10.1073/pnas.1019704108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721TB UT WOS:000287377000031 PM 21282637 ER PT J AU Green, MR Monti, S Dalla-Favera, R Pasqualucci, L Walsh, NC Schmidt-Supprian, M Kutok, JL Rodig, SJ Neuberg, DS Rajewsky, K Golub, TR Alt, FW Shipp, MA Manis, JP AF Green, Michael R. Monti, Stefano Dalla-Favera, Riccardo Pasqualucci, Laura Walsh, Nicole C. Schmidt-Supprian, Marc Kutok, Jeffery L. Rodig, Scott J. Neuberg, Donna S. Rajewsky, Klaus Golub, Todd R. Alt, Frederick W. Shipp, Margaret A. Manis, John P. TI Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTORS; GENE-EXPRESSION; BCL-2 EXPRESSION; BINDING; APOPTOSIS; LINEAGE; MECHANISM; LYMPHOMAS; NETWORKS; PROTEINS AB We utilized gene expression profiling of a comprehensive panel of purified developmentally defined normal murine B cells to identify unique transcriptional signatures for each subset. To elucidate transcription factor activities that function in a stage-specific fashion, we used gene sets that share transcription factor targets and found that germinal center B cells had a robust enrichment of up-regulated and down-regulated signatures compared with the other B-cell subsets. Notably, we found Yy1 and its targets to be central regulators of the germinal center B (GCB)-specific transcriptional program with binding of Yy1 to select signature genes in GCB cells, and translation of the Yy1 signatures to human GCB cells. We then tested whether our newly generated, stage-specific transcriptional signatures could be used to link murine lymphoma models to stages of normal B-cell development. Although each of the molecularly defined murine lymphoma models conserved certain stage-specific features of normal B-cell development, there was a significant alteration of the normal differentiation signature following malignant transformation. These findings offer important tools and insights for elucidating differences between normal and malignant B cells. C1 [Green, Michael R.; Rajewsky, Klaus; Alt, Frederick W.; Shipp, Margaret A.; Manis, John P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Green, Michael R.; Neuberg, Donna S.; Golub, Todd R.; Shipp, Margaret A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Monti, Stefano; Golub, Todd R.] Broad Inst, Cambridge, MA 02142 USA. [Dalla-Favera, Riccardo; Pasqualucci, Laura] Columbia Univ, New York, NY 10032 USA. [Walsh, Nicole C.; Golub, Todd R.; Alt, Frederick W.; Manis, John P.] Childrens Hosp, Boston, MA 02115 USA. [Schmidt-Supprian, Marc; Rajewsky, Klaus; Alt, Frederick W.] Immune Dis Inst, Boston, MA 02115 USA. [Kutok, Jeffery L.; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Golub, Todd R.; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; margaret_shipp@dfci.harvard.edu; john.manis@childrens.harvard.edu RI Schmidt-Supprian, Marc/F-5893-2011; Green, Michael/F-3482-2013; OI Schmidt-Supprian, Marc/0000-0002-8543-6166; Green, Michael/0000-0001-6309-9472; Monti, Stefano/0000-0002-9376-0660 FU National Institutes of Health [CA92625] FX We thank Drs. Carlo Croce, Fritz Melchers, Max Cooper, and Barry Sleckman for critical review of this manuscript. This work was supported by National Institutes of Health Grant CA92625. F. W. A. and T. G. are Investigators of The Howard Hughes Medical Institute. NR 42 TC 22 Z9 23 U1 1 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 FEB 15 PY 2011 VL 108 IS 7 BP 2873 EP 2878 DI 10.1073/pnas.1019537108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721TB UT WOS:000287377000048 PM 21282644 ER PT J AU Ahmad, R Rajabi, H Kosugi, M Joshi, MD Alam, M Vasir, B Kawano, T Kharbanda, S Kufe, D AF Ahmad, Rehan Rajabi, Hasan Kosugi, Michio Joshi, Maya Datt Alam, Maroof Vasir, Baldev Kawano, Takeshi Kharbanda, Surender Kufe, Donald TI MUC1-C Oncoprotein Promotes STAT3 Activation in an Autoinductive Regulatory Loop SO SCIENCE SIGNALING LA English DT Article ID NF-KAPPA-B; GROWTH-FACTOR RECEPTOR; SIGNAL TRANSDUCER; UNPHOSPHORYLATED STAT3; RESPONSIVE ELEMENT; CARCINOMA-CELLS; BREAST-CANCER; JAK-STAT; TRANSCRIPTION-3; PROTEIN AB Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130-Janus-activated kinase 1 (JAK1)-STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1-mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival. C1 [Ahmad, Rehan; Rajabi, Hasan; Kosugi, Michio; Joshi, Maya Datt; Alam, Maroof; Vasir, Baldev; Kawano, Takeshi; Kharbanda, Surender; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA42802, CA100707] FX Funding: This work was supported by grants CA97098, CA42802, and CA100707 awarded by the National Cancer Institute. NR 50 TC 39 Z9 41 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD FEB 15 PY 2011 VL 4 IS 160 AR ra9 DI 10.1126/scisignal.2001426 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 721KF UT WOS:000287351300001 PM 21325207 ER PT J AU Carlson, CM Kirby, KA Casadei, MA Partin, MR Kistler, CE Walter, LC AF Carlson, Charlotte M. Kirby, Katharine A. Casadei, Michele A. Partin, Melissa R. Kistler, Christine E. Walter, Louise C. TI Lack of Follow-up After Fecal Occult Blood Testing in Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PRIMARY-CARE PHYSICIANS; COMPLETE DIAGNOSTIC EVALUATION; COLORECTAL-CANCER; COMORBIDITY INDEX; ELDERLY-PATIENTS; COLON EVALUATION; NATIONAL-SURVEY; HEALTH-CARE; PATIENT; VETERANS AB Background: It is unclear whether lack of follow-up after screening fecal occult blood testing (FOBT) in older adults is due to screening patients whose comorbidity or preferences do not permit follow-up vs failure to complete follow-up in healthy patients. Methods: A prospective cohort study of 2410 patients 70 years or older screened with FOBT was conducted at 4 Veteran Affairs (VA) medical centers from January 1 to December 31, 2001. The main outcome measure was receipt of follow-up within 1 year of FOBT based on national VA and Medicare data. For patients with positive FOBT results, age and Charlson comorbidity scores were evaluated as potential predictors of receiving a complete colon evaluation (colonoscopy or sigmoidoscopy plus barium enema), and medical records were reviewed to determine reasons for lack of follow-up. Results: A total of 212 patients (9%) had positive FOBT results; 42% received a complete colon evaluation within 1 year. Age and comorbidity were not associated with receipt of a complete follow-up, which was similar among patients 70 to 74 years old with a Charlson score of 0 compared with patients 80 years or older with a Charlson score of 1 or higher (48% vs 41%; P=.28). The VA site, number of positive FOBT cards, and number of VA outpatient visits were predictors. Of 122 patients who did not receive a complete follow-up within 1 year, 38% had documentation that comorbidity or preferences did not permit follow-up, and over the next 5 years 76% never received a complete follow-up. Conclusions: While follow-up after positive FOBT results was low regardless of age or comorbidity, screening patients in whom complete evaluation would not be pursued substantially contributes to lack of follow-up. Efforts to improve follow-up should address the full chain of decision making, including decisions to screen and decisions to follow up. C1 [Carlson, Charlotte M.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Kirby, Katharine A.; Casadei, Michele A.; Kistler, Christine E.; Walter, Louise C.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Partin, Melissa R.] Univ Minnesota, Ctr Chron Dis Outcomes Res, Minneapolis VA Med Ctr, Minneapolis, MN 55455 USA. [Partin, Melissa R.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. RP Walter, LC (reprint author), VA Med Ctr 181G, Div Geriatr, 4150 Clement St, San Francisco, CA 94121 USA. EM Louise.Walter@ucsf.edu FU VA Health Services Research and Development [IIR-04-427]; National Cancer Institute [1R01CA134425]; Center for Chronic Disease Outcomes Research [HFP 98-001]; [AG000212-16] FX Dr Walter is supported by a VA Health Services Research and Development grant IIR-04-427 and by grant 1R01CA134425 from the National Cancer Institute and is a Robert Wood Johnson Physician Faculty Scholar. Dr Kistler is supported by a T-32 Training Grant AG000212-16. Dr Partin is supported by the Center for Chronic Disease Outcomes Research, VA Health Services Research and Development grant HFP 98-001. NR 37 TC 18 Z9 18 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 14 PY 2011 VL 171 IS 3 BP 249 EP 256 DI 10.1001/archinternmed.2010.372 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 721CI UT WOS:000287328700012 PM 20937917 ER PT J AU Milane, L Duan, ZF Amiji, M AF Milane, Lara Duan, Zhenfeng Amiji, Mansoor TI Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning SO CANCER CELL INTERNATIONAL LA English DT Article ID DRUG-RESISTANCE; CANCER-CELLS; INDUCIBLE FACTOR-1; AEROBIC GLYCOLYSIS; THERAPY; WARBURG; METASTASIS; INHIBITORS; OXYGEN; GENES AB Background: The development of multi-drug resistant (MDR) cancer is a significant challenge in the clinical treatment of recurrent disease. Hypoxia is an environmental selection pressure that contributes to the development of MDR. Many cancer cells, including MDR cells, resort to glycolysis for energy acquisition. This study aimed to explore the relationship between hypoxia, glycolysis, and MDR in a panel of human breast and ovarian cancer cells. A second aim of this study was to develop an orthotopic animal model of MDR breast cancer. Methods: Nucleic and basal protein was extracted from a panel of human breast and ovarian cancer cells; MDR cells and cells pre-exposed to either normoxic or hypoxic conditions. Western blotting was used to assess the expression of MDR markers, hypoxia inducible factors, and glycolytic proteins. Tumor xenografts were established in the mammary fat pad of nu/nu mice using human breast cancer cells that were pre-exposed to either hypoxic or normoxic conditions. Immunohistochemistry was used to assess the MDR character of excised tumors. Results: Hypoxia induces MDR and glycolysis in vitro, but the cellular response is cell-line specific and duration dependent. Using hypoxic, triple-negative breast cancer cells to establish 100 mm(3) tumor xenografts in nude mice is a relevant model for MDR breast cancer. Conclusion: Hypoxic pre-conditiong and xenografting may be used to develop a multitude of orthotopic models for MDR cancer aiding in the study and treatment of the disease. C1 [Milane, Lara; Amiji, Mansoor] Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, Boston, MA 02115 USA. [Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. RP Amiji, M (reprint author), Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, 360 Huntington Ave, Boston, MA 02115 USA. EM m.amiji@neu.edu RI Amiji, Mansoor/A-4365-2014 OI Amiji, Mansoor/0000-0001-6170-881X FU National Cancer Institute, National Institutes of Health [R01 CA 119617, R01 CA 119617S1, R21 CA- 135594] FX This study was supported by the National Cancer Institute, National Institutes of Health through grants R01 CA 119617 and R01 CA 119617S1 (ARRA Supplement), and R21 CA- 135594. Husain Attarwala is kindly thanked for assistance with the animal model development and in vivo studies. NR 55 TC 33 Z9 36 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2867 J9 CANCER CELL INT JI Cancer Cell Int. PD FEB 14 PY 2011 VL 11 AR 3 DI 10.1186/1475-2867-11-3 PG 16 WC Oncology SC Oncology GA 728CR UT WOS:000287852200001 PM 21320311 ER PT J AU Leritz, EC Salat, DH Williams, VJ Schnyer, DM Rudolph, JL Lipsitz, L Fischl, B McGlinchey, RE Milberg, WP AF Leritz, Elizabeth C. Salat, David H. Williams, Victoria J. Schnyer, David M. Rudolph, James L. Lipsitz, Lewis Fischl, Bruce McGlinchey, Regina E. Milberg, William P. TI Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults SO NEUROIMAGE LA English DT Article DE Aging; Cerebrovascular health; Cerebrovascular risk; Cortical thickness; Brain structure ID WHITE-MATTER LESIONS; MEDIAL TEMPORAL-LOBE; MILD COGNITIVE IMPAIRMENT; MAGNETIC-RESONANCE IMAGES; SYSTOLIC BLOOD-PRESSURE; SURFACE-BASED ANALYSIS; 6-YEAR FOLLOW-UP; ALZHEIMERS-DISEASE; CORTICAL SURFACE; RISK-FACTORS AB We examined how wide ranges in levels of risk factors for cerebrovascular disease are associated with thickness of the human cerebral cortex in 115 individuals ages 43-83 with no cerebrovascular or neurologic history. Cerebrovascular risk factors included blood pressure, cholesterol, body mass index, creatinine, and diabetes-related factors. Variables were submitted into a principal components analysis that confirmed four orthogonal factors (blood pressure, cholesterol, cholesterol/metabolic and glucose). T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness. Increasing blood pressure factor scores were associated with numerous regions of reduced thickness. Increasing glucose scores were modestly associated with areas of regionally decreased thickness. Increasing cholesterol scores, in contrast, were associated with thicker cortex across the whole brain. All findings were primarily independent of age. These results provide evidence that normal and moderately abnormal levels of parameters used to assess cerebrovascular health may impact brain structure, even in the absence of cerebrovascular disease. Our data have important implications for the clinical management of vascular health, as well as for what is currently conceptualized as "normal aging" as they suggest that subclinical levels of risk may impact cortical gray matter before a disease process is evident. (C) 2010 Elsevier Inc. All rights reserved. C1 [Leritz, Elizabeth C.; Salat, David H.; Williams, Victoria J.; Rudolph, James L.; McGlinchey, Regina E.; Milberg, William P.] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Leritz, Elizabeth C.; Williams, Victoria J.; Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Leritz, Elizabeth C.; Salat, David H.; Lipsitz, Lewis; McGlinchey, Regina E.; Milberg, William P.] Harvard Univ, Sch Med, Boston, MA USA. [Leritz, Elizabeth C.; Salat, David H.; Williams, Victoria J.; Fischl, Bruce] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Fischl, Bruce] MIT, CSAIL HST, Cambridge, MA 02139 USA. [Lipsitz, Lewis] Beth Israel Deaconess Med Ctr, Gerontol Div, Hebrew Senior Life Inst Aging Res, Boston, MA 02215 USA. [Schnyer, David M.] Univ Texas Austin, Austin, TX 78712 USA. RP Leritz, EC (reprint author), 150 S Huntington Ave,GRECC 182 JP, Boston, MA 02130 USA. EM bleritz@nmr.mgh.harvard.edu RI McGlinchey, Regina/R-1971-2016; OI Kennedy, Kristen/0000-0001-5373-9026 FU National Institute of Neurologic Disorders and Stroke [K23NS062148, K23NS06214802S1, R01NS052585]; National Institute of Nursing Research [R01NR010827]; National Institute on Aging [P60AG08812, P01AG004390, K01AG24898, AG02238]; Medical Research Service VA; National Institutes of Health through the Roadmap for Medical Research [P41-RR14075, BIRN002, U24 RR021382, R01EB006758, U54 EB005149] FX This work was supported by the National Institute of Neurologic Disorders and Stroke (grant numbers K23NS062148, K23NS06214802S1 and R01NS052585); the National Institute of Nursing Research (grant number R01NR010827), the National Institute on Aging (grant numbers P60AG08812, P01AG004390, K01AG24898 and AG02238); and by Medical Research Service VA Merit Review Awards to William Milberg and Regina McGlinchey. Further support was provided in part by the National Center for Research Resources (grant number P41-RR14075), and the NCRR BIRN Morphometric Project (grant numbers BIRN002 and U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (grant number R01EB006758), as well as the Mental Illness and Neuroscience Discovery (MIND) Institute, and is part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the Roadmap for Medical Research (grant number U54 EB005149). Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation. The authors would like to thank Marge Ahlquist for her assistance with BP collection and phlebotomy on all participants. NR 72 TC 49 Z9 49 U1 1 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 FEB 14 PY 2011 VL 54 IS 4 BP 2659 EP 2671 DI 10.1016/j.neuroimage.2010.10.050 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 710FH UT WOS:000286495800012 PM 21035552 ER PT J AU Chan, AM Halgren, E Marinkovic, K Cash, SS AF Chan, Alexander M. Halgren, Eric Marinkovic, Ksenija Cash, Sydney S. TI Decoding word and category-specific spatiotemporal representations from MEG and EEG SO NEUROIMAGE LA English DT Article DE Language; Semantic category; Machine learning; Decoding; MEG; EEG ID CONCEPTUAL KNOWLEDGE; BRAIN POTENTIALS; DISTRIBUTED ACCOUNT; NEURAL BASIS; LANGUAGE; DYNAMICS; MAGNETOENCEPHALOGRAPHY; ELECTROENCEPHALOGRAM; ORGANIZATION; RECOGNITION AB The organization and localization of lexico-semantic information in the brain has been debated for many years. Specifically, lesion and imaging studies have attempted to map the brain areas representing living versus nonliving objects, however, results remain variable. This may be due, in part, to the fact that the univariate statistical mapping analyses used to detect these brain areas are typically insensitive to subtle, but widespread, effects. Decoding techniques, on the other hand, allow for a powerful multivariate analysis of multichannel neural data. In this study, we utilize machine-learning algorithms to first demonstrate that semantic category, as well as individual words, can be decoded from EEG and MEG recordings of subjects performing a language task. Mean accuracies of 76% (chance = 50%) and 83% (chance = 20%) were obtained for the decoding of living vs. nonliving category or individual words respectively. Furthermore, we utilize this decoding analysis to demonstrate that the representations of words and semantic category are highly distributed both spatially and temporally. In particular, bilateral anterior temporal, bilateral inferior frontal, and left inferior temporal-occipital sensors are most important for discrimination. Successful intersubject and intermodality decoding shows that semantic representations between stimulus modalities and individuals are reasonably consistent. These results suggest that both word and category-specific information are present in extracranially recorded neural activity and that these representations may be more distributed, both spatially and temporally, than previous studies suggest. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chan, Alexander M.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chan, Alexander M.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Halgren, Eric; Marinkovic, Ksenija] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. RP Chan, AM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Thier 423,55 Fruit St, Boston, MA 02114 USA. EM amchan@mit.edu FU NDSEG Fellowship; Frank H. Buck Scholarship; Rappaport Fellowship; NIH [NS18741] FX This work was supported by an NDSEG Fellowship and a Frank H. Buck Scholarship to AMC and a Rappaport Fellowship to SSC. Overall support was provided by NIH grant NS18741. We thank J.M. Baker, A.R. Dykstra, C.J. Keller, F.E. McAllister, H. McAllister, N. Dehghani, J. Cormier, L.R. Hochberg, R. Zepeda, J. Donoghue, C. Sherman, C. Raclin, I. Sukhotinsky, S.S. Hou, and G.C. Sing for their helpful comments. NR 54 TC 45 Z9 45 U1 2 U2 12 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 FEB 14 PY 2011 VL 54 IS 4 BP 3028 EP 3039 DI 10.1016/j.neuroimage.2010.10.073 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 710FH UT WOS:000286495800044 PM 21040796 ER PT J AU Tao, H Manak, JR Sowers, L Mei, X Kiyonari, H Abe, T Dandaleh, NS Yang, TA Wu, S Chen, S Fox, MH Gurnett, C Montine, T Bird, T Shaffer, LG Rosenfeld, JA McConne, J Madan-Khetarpal, S Berry-Kravis, E Griesbach, H Saneto, RP Scott, MP Antic, D Reed, J Boland, R Ehaideb, SN El-Shanti, H Mahajan, VB Ferguson, PJ Axelrod, JD Lehesjoki, AE Fritzsch, B Slusarski, DC Wemmie, J Ueno, N Bassuk, AG AF Tao, Hirotaka Manak, J. Robert Sowers, Levi Mei, Xue Kiyonari, Hiroshi Abe, Takaya Dandaleh, Nader S. Yang, Tian Wu, Shu Chen, Shan Fox, Mark H. Gurnett, Christina Montine, Thomas Bird, Thomas Shaffer, Lisa G. Rosenfeld, Jill A. McConne, Juliann Madan-Khetarpal, Suneeta Berry-Kravis, Elizabeth Griesbach, Hilary Saneto, Russell P. Scott, Matthew P. Antic, Dragana Reed, Jordan Boland, Riley Ehaideb, Salleh N. El-Shanti, Hatem Mahajan, Vinit B. Ferguson, Polly J. Axelrod, Jeffrey D. Lehesjoki, Anna-Elina Fritzsch, Bernd Slusarski, Diane C. Wemmie, John Ueno, Naoto Bassuk, Alexander G. TI Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROGRESSIVE MYOCLONUS EPILEPSY; PLANAR CELL POLARITY; DROSOPHILA-MELANOGASTER; NEURON MIGRATION; MOUSE PRICKLE1; GENE; ZEBRAFISH; GASTRULATION; MOVEMENTS; CHANNEL AB Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution. C1 [Tao, Hirotaka; Ueno, Naoto] Natl Inst Basic Biol, Div Morphogenesis, Okazaki, Aichi 4448585, Japan. [Manak, J. Robert; Mei, Xue; Yang, Tian; Reed, Jordan; Boland, Riley; Ehaideb, Salleh N.; Fritzsch, Bernd; Slusarski, Diane C.] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA. [Sowers, Levi; Wu, Shu; Chen, Shan; Fox, Mark H.; El-Shanti, Hatem; Ferguson, Polly J.; Bassuk, Alexander G.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Kiyonari, Hiroshi; Abe, Takaya] RIKEN Ctr Dev Biol, Lab Anim Resources & Genet Engn, Chuo Ku, Kobe, Hyogo 650047, Japan. [Dandaleh, Nader S.] Univ Iowa, Dept Neurosurg, Carver Coll Med, Iowa City, IA 52242 USA. [Gurnett, Christina] Washington Univ, Dept Neurol, St Louis, MO 63310 USA. [Montine, Thomas] Univ Washington, Dept Pathol, Seattle, WA 98104 USA. [Bird, Thomas] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98104 USA. [Shaffer, Lisa G.; Rosenfeld, Jill A.] Signature Genom Labs, Spokane, WA 99202 USA. [McConne, Juliann; Madan-Khetarpal, Suneeta] Childrens Hosp Pittsburgh UPMC, Pittsburgh, PA 15224 USA. [Berry-Kravis, Elizabeth] Rush Presbyterian St Lukes Med Ctr, Dept Pediat, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Presbyterian St Lukes Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Saneto, Russell P.] Seattle Childrens Hosp, Div Pediat Neurol, Seattle, WA 98105 USA. [Scott, Matthew P.; Antic, Dragana] Stanford Univ, Sch Med, Dept Dev Biol, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Scott, Matthew P.; Antic, Dragana] Stanford Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Scott, Matthew P.; Antic, Dragana] Stanford Univ, Sch Med, Dept Bioengn, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Antic, Dragana; Axelrod, Jeffrey D.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [El-Shanti, Hatem] Shafallah Med Genet Ctr, Doha 33123, Qatar. [Mahajan, Vinit B.] Univ Iowa, Dept Ophthalmol & Visual Sci, Carver Coll Med, Iowa City, IA 52242 USA. [Lehesjoki, Anna-Elina] Univ Helsinki, Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland. [Lehesjoki, Anna-Elina] Univ Helsinki, Ctr Neurosci, FIN-00014 Helsinki, Finland. [Wemmie, John] Univ Iowa, Dept Psychiat, Ia City, IA 52242 USA. [Wemmie, John] Univ Iowa, Dept Neurosurg, Neurosci Program, Roy J & Lucille A Carver Coll Med, Ia City, IA 52242 USA. [Wemmie, John] Dept Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Ueno, Naoto] Grad Univ Adv Studies SOKENDAI, Dept Basic Biol, Sch Life Sci, Okazaki, Aichi 4448585, Japan. RP Ueno, N (reprint author), Natl Inst Basic Biol, Div Morphogenesis, 38 Nishigonaka, Okazaki, Aichi 4448585, Japan. EM nueno@nibb.ac.jp; alexander-bassuk@uiowa.edu RI Kiyonari, Hiroshi/N-7936-2015; EL-SHANTI, HATEM/Q-4932-2016; OI EL-SHANTI, HATEM/0000-0001-6230-8316; Fritzsch, Bernd/0000-0002-4882-8398 FU National Institutes of Health [R01 NS064159, 3R01NS064159-02S1, R01 GM059823, RO1 CA112369, P50 AG05136, 1R21NS058309-01A1]; VA; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health grants R01 NS064159 and 3R01NS064159-02S1 (to A.G.B.), R01 GM059823 (to J.D.A.), RO1 CA112369 (to D.C.S.), and P50 AG05136 (to T.M.), by 1R21NS058309-01A1 (to J.W.), by a VA Merit Review Award (to J.W.), and by a grant from the Howard Hughes Medical Institute (to M.S.). We thank Jeff Murray, Jeff Neul, Val Sheffield, Bev Davidson, Zoha Kibar, Heather Mefford, and Sam Berkovic for their thoughtful reviews. We thank Jeff Murray for access to the CEPH-HGD samples and Taqman assay. L.G.S. and J.A.R. are employed by Signature Genomics Laboratories. NR 57 TC 46 Z9 50 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 11 PY 2011 VL 88 IS 2 BP 138 EP 149 DI 10.1016/j.ajhg.2010.12.012 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 725YZ UT WOS:000287684100002 PM 21276947 ER PT J AU Jang, C Choi, JK Kim, E Park, ES Wasco, W Buxbaum, JD Kim, YS Choi, EK AF Jang, Changhwan Choi, Jin-Kyu Kim, EunYoung Park, Eun-Su Wasco, Wilma Buxbaum, Joseph D. Kim, Yong-Sun Choi, Eun-Kyoung TI Calsenilin is degraded by the ubiquitin-proteasome pathway SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Calsenilin; Proteasome; Ubiquitin ID CAPACITATIVE CALCIUM-ENTRY; ALZHEIMERS-DISEASE; ENDOPLASMIC-RETICULUM; MEDIATED DEGRADATION; PROTEIN-DEGRADATION; POTASSIUM CHANNELS; PRESENILIN; CALSENILIN/DREAM/KCHIP3; MODULATION; EXPRESSION AB Calsenilin, a neuronal calcium binding protein that has been shown to have multiple functions in the cell, interacts with presenilin 1 (PS1) and presenilin 2 (PS2), represses gene transcription and binds to A-type voltage-gated potassium channels. In addition, increased levels of calsenilin are observed in the brains of Alzheimer's disease and epilepsy patients. The present study was designed to investigate the molecular mechanism of calsenilin degradation pathways in cultured cells. Here, we demonstrate that inhibition of the ubiquitin-proteasomal pathway (UPP) but not lysosomal pathway markedly increased the expression levels of calsenilin. Immunofluorescence analysis revealed that following proteasomal inhibition calsenilin accumulated in the endoplasmic reticulum (ER) and Golgi, while lysosomal inhibition had no effect on calsenilin localization. In addition, we found the change of subcellular localization of PS1 from diffuse pattern to punctuate staining pattern in the ER and perinuclear region in the presence of calsenilin. These findings suggest that calsenilin degradation is primarily mediated by the UPP and that impairment in the UPP may contribute to the involvement of calsenilin in disease-associated neurodegeneration. (C) 2011 Elsevier Inc. All rights reserved. C1 [Choi, Eun-Kyoung] Hallym Univ, Ilsong Inst Life Sci, Lab Cellular Aging & Neurodegenerat, Anyang 431060, Gyeonggi Do, South Korea. [Jang, Changhwan; Kim, Yong-Sun] Hallym Univ, Coll Med, Dept Microbiol, Chunchon, South Korea. [Wasco, Wilma] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat & Neurobiol, Lab Mol Neuropsychiat, New York, NY 10029 USA. RP Choi, EK (reprint author), Hallym Univ, Ilsong Inst Life Sci, Lab Cellular Aging & Neurodegenerat, 1605-4 Gwanyang Dong, Anyang 431060, Gyeonggi Do, South Korea. EM ekchoi@hallym.ac.kr OI Buxbaum, Joseph/0000-0001-8898-8313 FU Ministry of Education, Science and Technology [2010-0001262]; Korean Government (MOEHRD) [KRF-2006-331-E00287] FX We thank Drs. J.H. Boo and H.S. Hong for helpful discussions and Dr. W. Xia for providing WT PSI cDNA. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0001262) and the Korea Research Foundation grant funded by Korean Government (MOEHRD, Basic Research Promotion Fund) [KRF-2006-331-E00287]. NR 36 TC 4 Z9 4 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 11 PY 2011 VL 405 IS 2 BP 180 EP 185 DI 10.1016/j.bbrc.2010.12.137 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 725EH UT WOS:000287627500006 PM 21216226 ER PT J AU Nichols, FC Yao, XD Bajrami, B Downes, J Finegold, SM Knee, E Gallagher, JJ Housley, WJ Clark, RB AF Nichols, Frank C. Yao, Xudong Bajrami, Bekim Downes, Julia Finegold, Sydney M. Knee, Erica Gallagher, James J. Housley, William J. Clark, Robert B. TI Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues SO PLOS ONE LA English DT Article ID PORPHYROMONAS-GINGIVALIS LIPIDS; SYSTEMIC INNATE IMMUNITY; RHEUMATOID-ARTHRITIS; MICROBIOTA; PERIODONTITIS; ASSOCIATION; DISEASE AB Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease. C1 [Nichols, Frank C.; Knee, Erica] Univ Connecticut, Sch Dent Med, Dept Oral Hlth & Diagnost Sci, Farmington, CT 06032 USA. [Yao, Xudong; Bajrami, Bekim] Univ Connecticut, Dept Chem, Storrs, CT USA. [Downes, Julia; Finegold, Sydney M.] VA Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Gallagher, James J.] Univ Connecticut, Sch Med, Dept Surg, Farmington, CT 06032 USA. [Gallagher, James J.] Connecticut Vasc Inst, Hartford, CT USA. [Housley, William J.; Clark, Robert B.] Univ Connecticut, Sch Med, Dept Immunol, Farmington, CT 06032 USA. [Housley, William J.; Clark, Robert B.] Univ Connecticut, Sch Med, Dept Med, Farmington, CT 06032 USA. RP Nichols, FC (reprint author), Univ Connecticut, Sch Dent Med, Dept Oral Hlth & Diagnost Sci, Farmington, CT 06032 USA. EM nichols@nso.uchc FU National Multiple Sclerosis Society [RG4070-A-6] FX This work was supported by a grant from the National Multiple Sclerosis Society (RG4070-A-6). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 10 Z9 11 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 11 PY 2011 VL 6 IS 2 AR e16771 DI 10.1371/journal.pone.0016771 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721OO UT WOS:000287364500005 PM 21347306 ER PT J AU El Saleeby, CM Grottkau, BE Friedmann, AM Westra, SJ Sohani, AR AF El Saleeby, Chadi M. Grottkau, Brian E. Friedmann, Alison M. Westra, Sjirk J. Sohani, Aliyah R. TI Case 4-2011: A 4-Year-Old Boy with Back Pain and Hypercalcemia B lymphoblastic leukemia, not otherwise specified SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ORTHOPEDIC MANIFESTATIONS; PEDIATRIC-PATIENTS; BONE PAIN; CHILDREN; MANAGEMENT; ARTHRITIS; LYMPHOMA; CRLF2 C1 [El Saleeby, Chadi M.] Massachusetts Gen Hosp, Dept Pediat, Div Pediat Hosp Med & Infect Dis, Boston, MA 02114 USA. [Grottkau, Brian E.] Massachusetts Gen Hosp, Dept Pediat, Div Pediat Orthoped Surg, Boston, MA 02114 USA. [Friedmann, Alison M.] Massachusetts Gen Hosp, Dept Pediat, Div Pediat Oncol, Boston, MA 02114 USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [El Saleeby, Chadi M.; Friedmann, Alison M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Grottkau, Brian E.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Westra, Sjirk J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP El Saleeby, CM (reprint author), Massachusetts Gen Hosp, Dept Pediat, Div Pediat Hosp Med & Infect Dis, Boston, MA 02114 USA. FU Harvard Medical School Office of Continuing Education FX This case was presented at the postgraduate course Primary Care Pediatrics, sponsored by the Harvard Medical School Office of Continuing Education. NR 35 TC 4 Z9 4 U1 0 U2 5 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 FEB 10 PY 2011 VL 364 IS 6 BP 552 EP 562 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 718QH UT WOS:000287139900012 PM 21306242 ER PT J AU Giralt, SA Horowitz, M Weisdorf, D Cutler, C AF Giralt, Sergio A. Horowitz, Mary Weisdorf, Daniel Cutler, Corey TI Review of Stem-Cell Transplantation for Myelodysplastic Syndromes in Older Patients in the Context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Emanating From the Centers for Medicare and Medicaid Services SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; DAILY INTRAVENOUS BUSULFAN; PROGNOSTIC SCORING SYSTEM; IDENTICAL SIBLING DONOR; HIGH-RISK; CONDITIONING REGIMEN; PREDICTING SURVIVAL; CLINICAL-OUTCOMES; UNRELATED DONORS AB Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem-cell disorders that result in varying degrees of cytopenia and risk of transformation into acute leukemia. Allogeneic stem-cell transplantation (SCT) is the only known cure for this disease. The treatment is routinely used for younger patients, but only a minority of patients older than the age of 60 undergo this procedure. The overall MDS incidence is 3.3 per 100,000, but the incidence in patients older than age 70 is between 15 and 50 per 100,000. The median age at presentation is 76 years. Medicare-age patients 65 or older represent 80% of the total population receiving an MDS diagnosis. In the United States, one of the obstacles to SCT for older patients with MDS has been lack of third party reimbursement. On August 4, 2010, the Centers for Medicare and Medicaid Services released their Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome. This memo states: "Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below ... . " In this review, we will summarize what is known regarding the role of allogeneic SCT in older patients as well as other elements that should be included within clinical trials that can provide the evidence necessary to demonstrate that allogeneic SCT should be a covered benefit for Medicare beneficiaries. J Clin Oncol 29:566-572. (C) 2011 by American Society of Clinical Oncology C1 [Giralt, Sergio A.] Mem Sloan Kettering Canc Ctr, Adult Bone Marrow Transplant Program, New York, NY 10065 USA. Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. Univ Minnesota, Minneapolis, MN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Giralt, SA (reprint author), Mem Sloan Kettering Canc Ctr, Adult Bone Marrow Transplant Program, 1275 York Ave,Box 235, New York, NY 10065 USA. EM giralts@mskcc.org FU NHLBI NIH HHS [U10 HL069315] NR 70 TC 12 Z9 13 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2011 VL 29 IS 5 BP 566 EP 572 DI 10.1200/JCO.2010.32.1919 PG 7 WC Oncology SC Oncology GA 717XX UT WOS:000287082900022 PM 21220586 ER PT J AU Ross, DS AF Ross, Douglas S. TI Radioiodine Therapy for Hyperthyroidism. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MULTINODULAR TOXIC GOITER; DOSE I-131 THERAPY; GRAVES-DISEASE; RADIOACTIVE IODINE; ANTITHYROID DRUGS; THYROID-NODULES; FOLLOW-UP; CANCER INCIDENCE; OPHTHALMOPATHY; LONG AB A 37-year-old woman presented with palpitations, tremulousness, shortness of breath, and a 9-kg (20-lb) weight loss, and received a diagnosis of Graves' hyperthyroidism. At the time of diagnosis, she had mild proptosis, no diplopia, and no signs of eye inflammation. Her thyroid gland was two times the normal size and non-nodular. Her initial serum triiodothyronine (T(3)) concentration was 655 ng per deciliter (9.2 nmol per liter), and her free thyroxine (T(4)) concentration was 5.7 ng per deciliter (73 pmol per liter). She was treated with methimazole for a year, and her thyroid tests became normal. She discontinued the methimazole 10 weeks before the current presentation with recurrent palpitations and tremulousness. Her serum T(3) concentration is 345 ng per deciliter (5.4 nmol per liter), and her free T(4) concentration is 2.8 ng per deciliter (36.0 pmol per liter). The patient does not smoke. She has a 3-year-old daughter and wishes to become pregnant again. Her endocrinologist recommends radioiodine ablation of her thyroid. C1 Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. RP Ross, DS (reprint author), Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. NR 49 TC 42 Z9 54 U1 1 U2 18 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 10 PY 2011 VL 364 IS 6 BP 542 EP 550 DI 10.1056/NEJMct1007101 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 718QH UT WOS:000287139900008 PM 21306240 ER PT J AU Ng, S Fanta, C Okam, M Bhatt, AS AF Ng, Samuel Fanta, Christopher Okam, Maureen Bhatt, Ami S. TI NK-Cell and B-Cell Deficiency with a Thymic Mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Ng, Samuel; Fanta, Christopher; Okam, Maureen] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bhatt, Ami S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ng, S (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM asbhatt@partners.org NR 5 TC 4 Z9 4 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 10 PY 2011 VL 364 IS 6 BP 586 EP 588 DI 10.1056/NEJMc1012485 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 718QH UT WOS:000287139900041 PM 21306273 ER PT J AU Li, Q Haigis, KM McDaniel, A Harding-Theobald, E Kogan, SC Akagi, K Wong, JCY Braun, BS Wolff, L Jacks, T Shannon, K AF Li, Qing Haigis, Kevin M. McDaniel, Andrew Harding-Theobald, Emily Kogan, Scott C. Akagi, Keiko Wong, Jasmine C. Y. Braun, Benjamin S. Wolff, Linda Jacks, Tyler Shannon, Kevin TI Hematopoiesis and leukemogenesis in mice expressing oncogenic Nras(G12D) from the endogenous locus SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; K-RAS ONCOGENE; SOMATIC ACTIVATION; N-RAS; MYELOPROLIFERATIVE DISORDER; ERYTHROID-DIFFERENTIATION; CONDITIONAL EXPRESSION; SIGNAL-TRANSDUCTION; HYPERACTIVE RAS; HUMAN CANCER AB NRAS is frequently mutated in hematologic malignancies. We generated Mx1-Cre, Lox-STOP-Lox (LSL)-Nras(G12D) mice to comprehensively analyze the phenotypic, cellular, and biochemical consequences of endogenous oncogenic Nras expression in hematopoietic cells. Here we show that Mx1-Cre, LSL-Nras(G12D) mice develop an indolent myeloproliferative disorder but ultimately die of a diverse spectrum of hematologic cancers. Expressing mutant Nras in hematopoietic tissues alters the distribution of hematopoietic stem and progenitor cell populations, and Nras mutant progenitors show distinct responses to cytokine growth factors. Injecting Mx1-Cre, LSL-Nras(G12D) mice with the MOL4070LTR retrovirus causes acute myeloid leukemia that faithfully recapitulates many aspects of human NRAS-associated leukemias, including cooperation with deregulated Evi1 expression. The disease phenotype in Mx1-Cre, LSL-Nras(G12D) mice is attenuated compared with Mx1-Cre, LSL-Kras(G12D) mice, which die of aggressive myeloproliferative disorder by 4 months of age. We found that endogenous Kras(G12D) expression results in markedly elevated Ras protein expression and Ras-GTP levels in Mac1(+) cells, whereas Mx1-Cre, LSL-Nras(G12D) mice show much lower Ras protein and Ras-GTP levels. Together, these studies establish a robust and tractable system for interrogating the differential properties of oncogenic Ras proteins in primary cells, for identifying candidate cooperating genes, and for testing novel therapeutic strategies. (Blood. 2011; 117(6): 2022-2032) C1 [McDaniel, Andrew; Harding-Theobald, Emily; Wong, Jasmine C. Y.; Braun, Benjamin S.; Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Li, Qing] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94158 USA. [Kogan, Scott C.; Shannon, Kevin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol, Columbus, OH 43210 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol, Columbus, OH 43210 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Dept Med Genet, Columbus, OH 43210 USA. [Wolff, Linda] NCI, Cellular Oncol Lab, Frederick, MD 21701 USA. [Jacks, Tyler] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Shannon, K (reprint author), Univ Calif San Francisco, Dept Pediat, Helen Diller Family Canc Res Bldg,1450 3rd St,Rm, San Francisco, CA 94158 USA. EM shannonk@peds.ucsf.edu FU National Institutes of Health [U01 CA84221, R37 CA72614, K01 CA118425, K08 CA134649, K08 CA119105, T32 CA129583]; Leukemia & Lymphoma Society; Jeffrey and Karen Peterson Family Foundation; Frank A. Campini Foundation; National Cancer Institute Center for Cancer Research FX This work was supported by the National Institutes of Health (grants U01 CA84221, R37 CA72614, K01 CA118425, K08 CA134649, K08 CA119105, and T32 CA129583), the Leukemia & Lymphoma Society, the Jeffrey and Karen Peterson Family Foundation, and the Frank A. Campini Foundation. T.J. is an Investigator of the Howard Hughes Medical Institute. S.C.K. is a Leukemia & Lymphoma Society Scholar. The Intramural Research Program of the National Cancer Institute Center for Cancer Research supports research in the laboratory of L.W. NR 46 TC 56 Z9 57 U1 0 U2 3 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 FEB 10 PY 2011 VL 117 IS 6 BP 2022 EP 2032 DI 10.1182/blood-2010-04-280750 PG 11 WC Hematology SC Hematology GA 719HA UT WOS:000287192300039 PM 21163920 ER PT J AU Bejar, R Levine, R Ebert, BL AF Bejar, Rafael Levine, Ross Ebert, Benjamin L. TI Unraveling the Molecular Pathophysiology of Myelodysplastic Syndromes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; THERAPY-RELATED MYELODYSPLASIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; FAMILIAL PLATELET DISORDER; METHYLTRANSFERASE GENE EZH2; AML1/RUNX1 POINT MUTATIONS; CHROMOSOME 5Q DELETION; THROMBOCYTOSIS RARS-T; UNIPARENTAL DISOMY; C-CBL AB Somatically acquired genetic abnormalities lead to the salient features that define myelodysplastic syndromes (MDS): clonal hematopoiesis, aberrant differentiation, peripheral cytopenias, and risk of progression to acute myeloid leukemia. Although specific karyotypic abnormalities have been linked to MDS for decades, more recent findings have demonstrated the importance of mutations within individual genes, focal alterations that are not apparent by standard cytogenetics, and aberrant epigenetic regulation of gene expression. The spectrum of genetic abnormalities in MDS implicates a wide range of molecular mechanisms in the pathogenesis of these disorders, including activation of tyrosine kinase signaling, genomic instability, impaired differentiation, altered ribosome function, and changes in the bone marrow microenvironment. Specific alterations present in individual patients with MDS may explain much of the heterogeneity in clinical phenotype associated with this disease and can predict prognosis and response to therapy. Elucidation of the full complement of genetic causes of MDS promises profound insight into the biology of the disease, improved classification and prognostic scoring schemes, and the potential for novel targeted therapies with molecular predictors of response. J Clin Oncol 29:504-515. (c) 2011 by American Society of Clinical Oncology C1 [Ebert, Benjamin L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Stem Cell Inst, Cambridge, MA USA. Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10021 USA. RP Ebert, BL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Karp Res Bldg,CHRB 05-211,1 Blackfan Cir, Boston, MA 02115 USA. EM bebert@partners.org FU GlaxoSmithKline FX Benjamin L. Ebert, GlaxoSmithKline NR 139 TC 150 Z9 156 U1 0 U2 12 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 FEB 10 PY 2011 VL 29 IS 5 BP 504 EP 515 DI 10.1200/JCO.2010.31.1175 PG 12 WC Oncology SC Oncology GA 717XX UT WOS:000287082900016 PM 21220588 ER PT J AU Uemura, K Farner, KC Nasser-Ghodsi, N Jones, P Berezovska, O AF Uemura, Kengo Farner, Katherine C. Nasser-Ghodsi, Navine Jones, Phill Berezovska, Oksana TI Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation SO MOLECULAR NEURODEGENERATION LA English DT Article ID AMYLOID PRECURSOR PROTEIN; FAMILIAL ALZHEIMERS-DISEASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GAMMA-SECRETASE ACTIVITY; A-BETA; STRUCTURAL-CHANGES; PRESENILIN; MUTATIONS; MECHANISM; TARGET AB Background: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the A beta(42/40) ratio without increasing total A beta production. In the present study, we analyzed the impact of FAD mutations and g-secretase modulators (GSMs) that alter the A beta(42/40) ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/gamma-secretase cleavage site on APP. Results: By using a Forster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that A beta(42/40) ratio-modulating factors which target either APP substrate or PS1/gamma-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation. Conclusions: Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically. C1 [Farner, Katherine C.; Nasser-Ghodsi, Navine; Jones, Phill; Berezovska, Oksana] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Alzheimer Res Unit, Charlestown, MA 02129 USA. [Uemura, Kengo] Kyoto Univ, Grad Sch Med, Kyoto 6068501, Japan. RP Berezovska, O (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Alzheimer Res Unit, Charlestown, MA 02129 USA. EM oberezovska@partners.org FU [AG026593]; [AG15379] FX We are grateful to Dr. Bradley T. Hyman for helpful discussions, to Ms. Mary Banks for technical assistance, to Drs. Koo (UCSD) and DeStrooper (VIB, Belgium) for PS1/2 dko and APP/APLP2 dko MEF cells, respectively; and to Dr. Wolfe (BWH, Boston) for HP. This work was supported by AG026593 and AG15379 (OB). NR 46 TC 11 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD FEB 10 PY 2011 VL 6 AR 15 DI 10.1186/1750-1326-6-15 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 729EO UT WOS:000287931600001 PM 21310068 ER PT J AU Berger, MF Lawrence, MS Demichelis, F Drier, Y Cibulskis, K Sivachenko, AY Sboner, A Esgueva, R Pflueger, D Sougnez, C Onofrio, R Carter, SL Park, K Habegger, L Ambrogio, L Fennell, T Parkin, M Saksena, G Voet, D Ramos, AH Pugh, TJ Wilkinson, J Fisher, S Winckler, W Mahan, S Ardlie, K Baldwin, J Simons, JW Kitabayashi, N MacDonald, TY Kantoff, PW Chin, L Gabriel, SB Gerstein, MB Golub, TR Meyerson, M Tewari, A Lander, ES Getz, G Rubin, MA Garraway, LA AF Berger, Michael F. Lawrence, Michael S. Demichelis, Francesca Drier, Yotam Cibulskis, Kristian Sivachenko, Andrey Y. Sboner, Andrea Esgueva, Raquel Pflueger, Dorothee Sougnez, Carrie Onofrio, Robert Carter, Scott L. Park, Kyung Habegger, Lukas Ambrogio, Lauren Fennell, Timothy Parkin, Melissa Saksena, Gordon Voet, Douglas Ramos, Alex H. Pugh, Trevor J. Wilkinson, Jane Fisher, Sheila Winckler, Wendy Mahan, Scott Ardlie, Kristin Baldwin, Jennifer Simons, Jonathan W. Kitabayashi, Naoki MacDonald, Theresa Y. Kantoff, Philip W. Chin, Lynda Gabriel, Stacey B. Gerstein, Mark B. Golub, Todd R. Meyerson, Matthew Tewari, Ashutosh Lander, Eric S. Getz, Gad Rubin, Mark A. Garraway, Levi A. TI The genomic complexity of primary human prostate cancer SO NATURE LA English DT Article ID MYELOID-LEUKEMIA GENOME; GENE FUSIONS; ANDROGEN RECEPTOR; TUMOR-SUPPRESSOR; HUMAN BREAST; PTEN; PROGRESSION; REARRANGEMENTS; MUTATION; PATHWAY AB Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms. C1 [Demichelis, Francesca; Esgueva, Raquel; Pflueger, Dorothee; Park, Kyung; Kitabayashi, Naoki; MacDonald, Theresa Y.; Rubin, Mark A.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Berger, Michael F.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey Y.; Sougnez, Carrie; Onofrio, Robert; Carter, Scott L.; Ambrogio, Lauren; Fennell, Timothy; Parkin, Melissa; Saksena, Gordon; Voet, Douglas; Ramos, Alex H.; Pugh, Trevor J.; Wilkinson, Jane; Fisher, Sheila; Winckler, Wendy; Mahan, Scott; Ardlie, Kristin; Baldwin, Jennifer; Chin, Lynda; Gabriel, Stacey B.; Golub, Todd R.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Garraway, Levi A.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Berger, Michael F.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey Y.; Sougnez, Carrie; Onofrio, Robert; Carter, Scott L.; Ambrogio, Lauren; Fennell, Timothy; Parkin, Melissa; Saksena, Gordon; Voet, Douglas; Ramos, Alex H.; Pugh, Trevor J.; Wilkinson, Jane; Fisher, Sheila; Winckler, Wendy; Mahan, Scott; Ardlie, Kristin; Baldwin, Jennifer; Chin, Lynda; Gabriel, Stacey B.; Golub, Todd R.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Garraway, Levi A.] MIT, Cambridge, MA 02142 USA. [Demichelis, Francesca] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA. [Drier, Yotam] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Sboner, Andrea; Gerstein, Mark B.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Sboner, Andrea; Habegger, Lukas; Gerstein, Mark B.] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Ramos, Alex H.; Pugh, Trevor J.; Kantoff, Philip W.; Chin, Lynda; Meyerson, Matthew; Lander, Eric S.; Garraway, Levi A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Pugh, Trevor J.; Kantoff, Philip W.; Chin, Lynda; Meyerson, Matthew; Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Simons, Jonathan W.] Prostate Canc Fdn, Santa Monica, CA 90401 USA. [Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Golub, Todd R.; Meyerson, Matthew; Garraway, Levi A.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Tewari, Ashutosh] Weill Cornell Med Coll, Inst Prostate Canc, Dept Urol, New York, NY 10065 USA. [Tewari, Ashutosh] Weill Cornell Med Coll, Lefrak Ctr Robot Surg, New York, NY 10065 USA. [Tewari, Ashutosh] New York Presbyterian Hosp, New York, NY 10065 USA. [Lander, Eric S.] 9 Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. RP Rubin, MA (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. EM rubinma@med.cornell.edu; levi_garraway@dfci.harvard.edu RI Sboner, Andrea/C-6487-2008; Meyerson, Matthew/E-7123-2012; Drier, Yotam/K-5208-2012; OI Sboner, Andrea/0000-0001-6915-3070; Drier, Yotam/0000-0003-1725-2995; Rubin, Mark/0000-0002-8321-9950; Demichelis, Francesca/0000-0002-8266-8631 FU Prostate Cancer Foundation/Movember; Howard Hughes Medical Institute; National Human Genome Research Institute; Kohlberg Foundation; National Cancer Institute (NCI); NCI Early Detection Research Network; National Institutes of Health; Department of Defense; Dana-Farber/Harvard Cancer Center [2 P50 CA090381-11]; Starr Cancer Consortium FX We thank R. Leung and all members of the Broad Institute Sequencing Platform. This work was supported by the Prostate Cancer Foundation/Movember (T. R. G., M. A. R., L. A. G.), the Howard Hughes Medical Institute (T. R. G.), the National Human Genome Research Institute (S. B. G., E. S. L.), the Kohlberg Foundation (P. W. K., L. A. G.), the National Cancer Institute (NCI; F. D., M. A. R., M. M.), the NCI Early Detection Research Network (M. A. R.), the National Institutes of Health (L. A. G.), the Department of Defense (F. D.), the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE grant 2 P50 CA090381-11 (P. W. K.), and the Starr Cancer Consortium (M. F. B., F. D., M. A. R., L.A.G.). NR 50 TC 601 Z9 614 U1 7 U2 57 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 10 PY 2011 VL 470 IS 7333 BP 214 EP 220 DI 10.1038/nature09744 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 718RQ UT WOS:000287144200035 PM 21307934 ER PT J AU Ding, ZH Wu, CJ Chu, GC Xiao, YH Ho, D Zhang, JF Perry, SR Labrot, ES Wu, XQ Lis, R Hoshida, Y Hiller, D Hu, BL Jiang, S Zheng, HW Stegh, AH Scott, KL Signoretti, S Bardeesy, N Wang, YA Hill, DE Golub, TR Stampfer, MJ Wong, WH Loda, M Mucci, L Chin, L DePinho, RA AF Ding, Zhihu Wu, Chang-Jiun Chu, Gerald C. Xiao, Yonghong Ho, Dennis Zhang, Jingfang Perry, Samuel R. Labrot, Emma S. Wu, Xiaoqiu Lis, Rosina Hoshida, Yujin Hiller, David Hu, Baoli Jiang, Shan Zheng, Hongwu Stegh, Alexander H. Scott, Kenneth L. Signoretti, Sabina Bardeesy, Nabeel Wang, Y. Alan Hill, David E. Golub, Todd R. Stampfer, Meir J. Wong, Wing H. Loda, Massimo Mucci, Lorelei Chin, Lynda DePinho, Ronald A. TI SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression SO NATURE LA English DT Article ID PHYSICIANS HEALTH; TGF-BETA; EXPRESSION; PTEN; SMAD4; DIFFERENTIATION; TRANSCRIPTION; INACTIVATION; OSTEOPONTIN; APOPTOSIS AB Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression(1). Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGF beta/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans. C1 [Ding, Zhihu; Wu, Chang-Jiun; Chu, Gerald C.; Xiao, Yonghong; Ho, Dennis; Perry, Samuel R.; Labrot, Emma S.; Hu, Baoli; Jiang, Shan; Zheng, Hongwu; Stegh, Alexander H.; Scott, Kenneth L.; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Ding, Zhihu; Wu, Chang-Jiun; Chu, Gerald C.; Xiao, Yonghong; Ho, Dennis; Perry, Samuel R.; Labrot, Emma S.; Wu, Xiaoqiu; Lis, Rosina; Hu, Baoli; Jiang, Shan; Zheng, Hongwu; Stegh, Alexander H.; Scott, Kenneth L.; Wang, Y. Alan; Loda, Massimo; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ding, Zhihu; Wu, Chang-Jiun; Ho, Dennis; Zheng, Hongwu; Stegh, Alexander H.; Scott, Kenneth L.; Hill, David E.; Chin, Lynda; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ding, Zhihu; Wu, Chang-Jiun; Ho, Dennis; Zheng, Hongwu; Stegh, Alexander H.; Scott, Kenneth L.; Chin, Lynda; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Chu, Gerald C.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Zhang, Jingfang] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. [Wu, Xiaoqiu; Lis, Rosina; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Hoshida, Yujin; Golub, Todd R.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Hoshida, Yujin; Golub, Todd R.] Harvard Univ, Cambridge, MA 02142 USA. [Hiller, David; Wong, Wing H.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Signoretti, Sabina] Dana Farber Harvard Canc Ctr, Renal Canc Program, Boston, MA 02115 USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Hill, David E.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Hill, David E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Chin, Lynda] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Stampfer, Meir J.; Mucci, Lorelei] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Stampfer, Meir J.; Mucci, Lorelei] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu; ron_depinho@dfci.harvard.edu RI Hill, David/B-6617-2011; OI Zheng, Hongwu/0000-0002-5823-4913 FU Damon Runyon Cancer Research Foundation; National Science Foundation; Helen Hay Whitney Foundation; Multiple Myeloma Research Foundation; Belfer Institute for Applied Cancer Science (NCI) [U01-CA84313]; DF/HCC SPORE in Prostate Cancer [P50 CA090381-08]; National Cancer Institute [RO1CA131945, P50 CA90381, RO1 5R01CA136578, R01CA141298]; Linda and Arthur Gelb Center for Translational Research; Prostate Cancer Foundation FX The authors are grateful to the late W. Gerald for providing the primary gene expression data and clinical outcome files13. We thank S. Zhou for excellent mouse husbandry and care, B. Xiong and G. Tonon for bioinformatic assistance, and S. Jia, J. M. Stommel, J. Paik, M. Kim and A. C. Kimmelman for helpful discussion. We thank M. Vidal, the Ellison Foundation and DFCI ISR for support of ORF cloning efforts, R. Maser for MSCV-puro-v5 gateway vector, W. Hahn for shRNA constructs. We thank the DF/HCC Specialized Histopathology Core and the DF/HCC Tissue Microarray and Imaging core for the TMA IHC staining; the DFCI/BWH Center for Molecular Oncologic Pathology (CMOP) for the quantification of the IHC. Z.D was supported by the Damon Runyon Cancer Research Foundation. D. H. was supported by a graduate fellowship from the National Science Foundation. H.Z. was supported by the Helen Hay Whitney Foundation. Y.A.W. was supported by the Multiple Myeloma Research Foundation. This work is supported by the Belfer Institute for Applied Cancer Science, NCI U01-CA84313 (L. C. and R. A. D.), DF/HCC SPORE in Prostate Cancer P50 CA090381-08 (Z.D.), the National Cancer Institute (M. L. RO1CA131945 and P50 CA90381, L. M. RO1 5R01CA136578, M. S. R01CA141298), and the Linda and Arthur Gelb Center for Translational Research (M. L.). R. A. D. was supported by an American Cancer Society Research Professorship and L. M. was supported by the Prostate Cancer Foundation. NR 33 TC 220 Z9 228 U1 3 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 10 PY 2011 VL 470 IS 7333 BP 269 EP + DI 10.1038/nature09677 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 718RQ UT WOS:000287144200046 PM 21289624 ER PT J AU Oberaigner, W Buchberger, W Frede, T Daniaux, M Knapp, R Marth, C Siebert, U AF Oberaigner, Willi Buchberger, Wolfgang Frede, Thomas Daniaux, Martin Knapp, Rudolf Marth, Christian Siebert, Uwe TI Introduction of organised mammography screening in tyrol: results of a one-year pilot phase SO BMC PUBLIC HEALTH LA English DT Article ID BREAST-CANCER MORTALITY; SERVICES TASK-FORCE; FINLAND; US; REDUCTION; AUSTRIA; PROGRAM; TRENDS AB Background: Efficiency and efficacy of organised mammography screening programs have been proven in large randomised trials. But every local implementation of mammography screening has to check whether the well established quality standards are met. Therefore it was the aim of this study to analyse the most common quality indices after introducing organised mammography screening in Tyrol, Austria, in a smooth transition from the existing system of opportunistic screening. Methods: In June 2007, the system of opportunistic mammography screening in Tyrol was changed to an organised system by introducing a personal invitation system, a training program, a quality assurance program and by setting up a screening database. All procedures are noted in a written protocol. Most EU recommendations for organised mammography screening were followed, except double reading. All women living in Tyrol and covered by social insurance are now invited for a mammography, in age group 40-59 annually and in age group 60-69 biannually. Screening mammography is offered mainly by radiologists in private practice. We report on the results of the first year of piloting organised mammography screening in two counties in Tyrol. Results: 56,432 women were invited. Estimated participation rate was 34.5% at one year of follow-up (and 55.5% at the second year of follow-up); 3.4% of screened women were recalled for further assessment or intermediate screening within six months. Per 1000 mammograms nine biopsies were performed and four breast cancer cases detected (N = 68). Of invasive breast cancer cases 34.4% were <= 10 mm in size and 65.6% were node-negative. In total, six interval cancer cases were detected during one year of follow-up; this is 19% of the background incidence rate. Conclusions: In the Tyrolean breast cancer screening program, a smooth transition from a spontaneous to an organised mammography screening system was achieved in a short time and with minimal additional resources. One year after introduction of the screening program, most of the quality indicators recommended by the European guidelines had been reached. However, it will be necessary to introduce double reading, to change the rule for BI-RADS 3, and to concentrate on actions toward improving the participation rate. C1 [Oberaigner, Willi] Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. [Oberaigner, Willi; Buchberger, Wolfgang; Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Inst Publ Hlth Med Decis Making & Hlth Technol As, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Hall In Tirol, Austria. [Oberaigner, Willi; Siebert, Uwe] ONCOTYROL Ctr Personalized Canc Med, Innsbruck, Austria. [Buchberger, Wolfgang] TILAK, Innsbruck, Austria. [Frede, Thomas; Daniaux, Martin] Innsbruck Med Univ, Dept Radiol, Innsbruck, Austria. [Knapp, Rudolf] Kufstein Cty Hosp, Dept Radiol, Kufstein, Austria. [Marth, Christian] Innsbruck Med Univ, Dept Obstet & Gynecol, Innsbruck, Austria. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Inst Technol Assessment, Sch Med, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Oberaigner, W (reprint author), Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. EM willi.oberaigner@tilak.at FU ONCOTYROL Center for Personal Cancer Medicine; Federal Ministry for Transport Innovation and Technology (BMVIT); Federal Ministry of Economics and Labour (BMWA); Tyrolean Future Foundation (TZS); UMIT - University for Health Sciences; Medical Informatics and Technology; Innsbruck Medical University; Tyrolean Health Insurance Fund; Tyrolean Health Company FX This work was supported by the ONCOTYROL Center for Personal Cancer Medicine. ONCOTYROL is a COMET Center funded by the Federal Ministry for Transport Innovation and Technology (BMVIT) and the Federal Ministry of Economics and Labour (BMWA), the Tyrolean Future Foundation (TZS) and the Land of Styria represented by the Styrian Business Promotion Agency (SFG) and supported by UMIT - University for Health Sciences, Medical Informatics and Technology, Innsbruck Medical University, Tyrolean Health Insurance Fund and Tyrolean Health Company. NR 29 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD FEB 9 PY 2011 VL 11 AR 91 DI 10.1186/1471-2458-11-91 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 730XH UT WOS:000288070200001 PM 21306614 ER PT J AU Soto, O Cros, D AF Soto, Oscar Cros, Didier TI Direct Corticospinal Control of Force Derivative SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MAGNETIC BRAIN-STIMULATION; HUMAN MOTOR CORTEX; DORSAL INTEROSSEOUS MUSCLE; 2 DIFFERENT VIEWS; TRANSCRANIAL STIMULATION; ISOMETRIC CONTRACTIONS; CORTICOMOTONEURONAL CM; VOLUNTARY CONTRACTION; CORTICAL-NEURONS; MOVEMENT AB During simultaneous generation of static and dynamic forces, motor cortical signals only predict the dynamic components, suggesting a key role in the coding of force changes. However, such a role is obscured by uncertainties regarding the representation of dynamic force signals in corticospinal outputs. We used transcranial magnetic stimulation (TMS) of the motor cortex in humans during a task that dissociated the direction of instantaneous net force and that of force derivative. The direction of TMS-evoked force outputs was closely associated with that of the force derivative, and had no relationship with that of the net force generated simultaneously, even though the magnitude of the instantaneous net force largely exceeded that of the force derivative. This observation supports the hypothesis that during dynamic force generation, the motor cortex and the corticospinal system assume a pivotal role in coding the direction of force changes, through selective recruitment of spinal motoneurons. C1 [Soto, Oscar; Cros, Didier] Massachusetts Gen Hosp, Dept Neurol, Clin Neurophysiol Labs, Boston, MA 02114 USA. RP Cros, D (reprint author), 1 Hawthorne Pl,Suite 103-7, Boston, MA 02114 USA. EM dcros@partners.org NR 44 TC 2 Z9 2 U1 0 U2 5 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 FEB 9 PY 2011 VL 31 IS 6 BP 1944 EP 1948 DI 10.1523/JNEUROSCI.0056-10.2011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 721WV UT WOS:000287389400003 PM 21307232 ER PT J AU Choy, HA Kelley, MM Croda, J Matsunaga, J Babbitt, JT Ko, AI Picardeau, M Haake, DA AF Choy, Henry A. Kelley, Melissa M. Croda, Julio Matsunaga, James Babbitt, Jane T. Ko, Albert I. Picardeau, Mathieu Haake, David A. TI The Multifunctional LigB Adhesin Binds Homeostatic Proteins with Potential Roles in Cutaneous Infection by Pathogenic Leptospira interrogans SO PLOS ONE LA English DT Article ID IMMUNOGLOBULIN-LIKE PROTEINS; STAPHYLOCOCCUS-AUREUS; CLUMPING FACTOR; EXTRACELLULAR-MATRIX; MUCOSAL IMMUNOLOGY; CRYSTAL-STRUCTURE; HUMAN-FIBRINOGEN; GENE-EXPRESSION; TISSUE-REPAIR; MODEL AB Leptospirosis is a potentially fatal zoonotic disease in humans and animals caused by pathogenic spirochetes, such as Leptospira interrogans. The mode of transmission is commonly limited to the exposure of mucous membrane or damaged skin to water contaminated by leptospires shed in the urine of carriers, such as rats. Infection occurs during seasonal flooding of impoverished tropical urban habitats with large rat populations, but also during recreational activity in open water, suggesting it is very efficient. LigA and LigB are surface localized proteins in pathogenic Leptospira strains with properties that could facilitate the infection of damaged skin. Their expression is rapidly induced by the increase in osmolarity encountered by leptospires upon transition from water to host. In addition, the immunoglobulin-like repeats of the Lig proteins bind proteins that mediate attachment to host tissue, such as fibronectin, fibrinogen, collagens, laminin, and elastin, some of which are important in cutaneous wound healing and repair. Hemostasis is critical in a fresh injury, where fibrinogen from damaged vasculature mediates coagulation. We show that fibrinogen binding by recombinant LigB inhibits fibrin formation, which could aid leptospiral entry into the circulation, dissemination, and further infection by impairing healing. LigB also binds fibroblast fibronectin and type III collagen, two proteins prevalent in wound repair, thus potentially enhancing leptospiral adhesion to skin openings. LigA or LigB expression by transformation of a nonpathogenic saprophyte, L. biflexa, enhances bacterial adhesion to fibrinogen. Our results suggest that by binding homeostatic proteins found in cutaneous wounds, LigB could facilitate leptospirosis transmission. Both fibronectin and fibrinogen binding have been mapped to an overlapping domain in LigB comprising repeats 9-11, with repeat 11 possibly enhancing binding by a conformational effect. Leptospirosis patient antibodies react with the LigB domain, suggesting applications in diagnosis and vaccines that are currently limited by the strain-specific leptospiral lipopolysaccharide coats. C1 [Choy, Henry A.; Matsunaga, James; Babbitt, Jane T.; Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Choy, Henry A.; Kelley, Melissa M.; Matsunaga, James; Babbitt, Jane T.] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Croda, Julio; Ko, Albert I.] Brasilian Minist Hlth, Oswaldo Cruz Fdn, Goncalo Moniz Res Ctr, Salvador, BA, Brazil. [Croda, Julio] Fed Univ Grande Dourados, Fac Hlth Sci, Dourados, MS, Brazil. [Ko, Albert I.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Div Epidemiol Microbial Dis, New Haven, CT 06510 USA. [Picardeau, Mathieu] Inst Pasteur, Unite Biol Spirochetes, Paris, France. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Mol Genet Microbiol & Immunol, Los Angeles, CA USA. RP Choy, HA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM hachoy@ucla.edu RI Ko, Albert/P-2343-2015 FU National Institutes of Health [R01 AI34431, U01 AI088752, D43 TW00919, R01 AI052473]; VA Medical Research Funds; Institut Pasteur, Paris, France; French Ministry of Research [ANR-08-MIE-018]; Oswaldo Cruz Foundation [PDTIS RVR05] FX This study was supported by the National Institutes of Health (R01 AI34431, U01 AI088752, D43 TW00919, and R01 AI052473), VA Medical Research Funds (to D. A. H.), the Institut Pasteur, Paris, France, the French Ministry of Research (ANR-08-MIE-018), and the Fiocruz-Pasteur Scientific Cooperation Agreement, Oswaldo Cruz Foundation (PDTIS RVR05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 27 Z9 28 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2011 VL 6 IS 2 AR e16879 DI 10.1371/journal.pone.0016879 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 721NN UT WOS:000287361700049 PM 21347378 ER PT J AU Thankamony, SP Sackstein, R AF Thankamony, Sai P. Sackstein, Robert TI Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE G-protein; selectin; cell therapeutics; regenerative medicine ID BONE-MARROW; CHEMOKINE RECEPTORS; IN-VIVO; VASCULAR ENDOTHELIUM; MULTISTEP PARADIGM; SHEAR-FLOW; CD44; ADHESION; SIGNALS; RAP1 AB According to the multistep model of cell migration, chemokine receptor engagement (step 2) triggers conversion of rolling interactions (step 1) into firm adhesion (step 3), yielding transendothelial migration. We recently reported that glycosyltransferase-programmed stereosubstitution (GPS) of CD44 on human mesenchymal stem cells (hMSCs) creates the E-selectin ligand HCELL (hematopoietic cell E-selectin/L-selectin ligand) and, despite absence of CXCR4, systemically administered HCELL(+)hMSCs display robust osteotropism visualized by intravital microscopy. Here we performed studies to define the molecular effectors of this process. We observed that engagement of hMSC HCELL with E-selectin triggers VLA-4 adhesiveness, resulting in shear-resistant adhesion to ligand VCAM-1. This VLA-4 activation is mediated via a Rac1/Rap1 GTPase signaling pathway, resulting in transendothelial migration on stimulated human umbilical vein endothelial cells without chemokine input. These findings indicate that hMSCs coordinately integrate CD44 ligation and integrin activation, circumventing chemokine-mediated signaling, yielding a step 2-bypass pathway of the canonical multistep paradigm of cell migration. C1 [Thankamony, Sai P.; Sackstein, Robert] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Sackstein, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Thankamony, Sai P.; Sackstein, Robert] Harvard Univ, Sch Med, Harvard Skin Dis Res Ctr, Boston, MA 02115 USA. [Sackstein, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sackstein, R (reprint author), Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. EM rsackstein@rics.bwh.harvard.edu FU National Institutes of Health [HL073714, CA121335] FX The authors appreciate the helpful advice of Drs. Tanya Mayadas, Xavier Cullere, and Hans Widlund. This work was supported by National Institutes of Health R01 Grants HL073714 and CA121335, and is dedicated to the memory of Harold C. Sackstein. NR 52 TC 41 Z9 41 U1 2 U2 6 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 FEB 8 PY 2011 VL 108 IS 6 BP 2258 EP 2263 DI 10.1073/pnas.1018064108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YH UT WOS:000287084500019 PM 21257905 ER PT J AU Abdelwahid, E Smith, G AF Abdelwahid, Eltyeb Smith, Graham TI Promising antiapoptotic effects of helix B-surface peptide (HBSP) for treatment of heart diseases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID ERYTHROPOIETIN; ACTIVATION C1 [Abdelwahid, Eltyeb] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Smith, Graham] Queen Mary Univ London, Barts & Royal London Sch Med, London E1 4NS, England. RP Abdelwahid, E (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM eltyeb.abdelwahid@cbrc2.mgh.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 6 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 FEB 8 PY 2011 VL 108 IS 6 BP E17 EP E17 DI 10.1073/pnas.1012530108 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YH UT WOS:000287084500001 PM 21278330 ER PT J AU O'Donoghue, ML AF O'Donoghue, Michelle L. TI CYP2C19 Genotype and Proton Pump Inhibitors in Clopidogrel-Treated Patients Does It Take Two to Tango? SO CIRCULATION LA English DT Editorial Material DE Editorials; clopidogrel; proton pump inhibitors; CYP2C19, human ID CARDIOVASCULAR EVENTS; TRIAL; OMEPRAZOLE; OUTCOMES; RISK C1 Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM modonoghue@partners.org NR 23 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 8 PY 2011 VL 123 IS 5 BP 468 EP 470 DI 10.1161/CIRCULATIONAHA.110.006866 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 717CT UT WOS:000287021300008 PM 21262991 ER PT J AU Deshpande, V Nduaguba, A Zimmerman, SM Kehoe, SM MacConaill, LE Lauwers, GY Ferrone, C Bardeesy, N Zhu, AX Hezel, AF AF Deshpande, Vikram Nduaguba, Afamefuna Zimmerman, Stephanie M. Kehoe, Sarah M. MacConaill, Laura E. Lauwers, Gregory Y. Ferrone, Cristina Bardeesy, Nabeel Zhu, Andrew X. Hezel, Aram F. TI Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma SO BMC CANCER LA English DT Article ID BILIARY-TRACT CANCERS; GROWTH-FACTOR-RECEPTOR; INTRAHEPATIC CHOLANGIOCELLULAR CARCINOMA; TUMOR-SUPPRESSOR GENE; K-RAS; BETA-CATENIN; MICROSATELLITE INSTABILITY; P53 OVEREXPRESSION; SOMATIC MUTATIONS; BILE-DUCT AB Background: The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods: To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results: Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra- hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions: The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors. C1 [Deshpande, Vikram; Zimmerman, Stephanie M.; Lauwers, Gregory Y.; Ferrone, Cristina; Bardeesy, Nabeel; Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kehoe, Sarah M.; MacConaill, Laura E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Nduaguba, Afamefuna; Hezel, Aram F.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. RP Zhu, AX (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM AZHU@PARTNERS.ORG; aram_hezel@urmc.rochester.edu FU HHMI; NIH FX This work was supported by grants from the HHMI (AFH), and AFH is supported by an NIH K08 career development award. NR 39 TC 39 Z9 39 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 8 PY 2011 VL 11 AR 60 DI 10.1186/1471-2407-11-60 PG 7 WC Oncology SC Oncology GA 726RT UT WOS:000287744500001 PM 21303542 ER PT J AU Wang, TJ AF Wang, Thomas J. TI Assessing the Role of Circulating, Genetic, and Imaging Biomarkers in Cardiovascular Risk Prediction SO CIRCULATION LA English DT Article DE genetics; imaging; prevention; prognosis ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; INTIMA-MEDIA THICKNESS; ARTERY CALCIUM SCORE; BRAIN NATRIURETIC PEPTIDE; SERVICES TASK-FORCE; CLINICAL-TRIAL DESIGNS; ALL-CAUSE MORTALITY; MIDDLE-AGED MEN; ENDOTHELIAL DYSFUNCTION C1 Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Wang, TJ (reprint author), Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, GRB-800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org FU NHLBI NIH HHS [R01 HL083197, R01 HL083197-04, R01 HL086875, R01 HL086875-04, R01 HL098283, R01 HL098283-03, R01-HL-083197, R01-HL-083875, R01-HL098283]; NIDDK NIH HHS [R01 DK081572, R01 DK081572-03, R01-DK-081572] NR 121 TC 112 Z9 117 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 8 PY 2011 VL 123 IS 5 BP 551 EP 565 DI 10.1161/CIRCULATIONAHA.109.912568 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 717CT UT WOS:000287021300019 PM 21300963 ER PT J AU Held, C Asenblad, N Bassand, JP Becker, RC Cannon, CP Claeys, MJ Harrington, RA Horrow, J Husted, S James, SK Mahaffey, KW Nicolau, JC Scirica, BM Storey, RF Vintila, M Ycas, J Wallentin, L AF Held, Claes Asenblad, Nils Bassand, Jean Pierre Becker, Richard C. Cannon, Christopher P. Claeys, Marc J. Harrington, Robert A. Horrow, Jay Husted, Steen James, Stefan K. Mahaffey, Kenneth W. Nicolau, Jose C. Scirica, Benjamin M. Storey, Robert F. Vintila, Marius Ycas, Joseph Wallentin, Lars TI Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndromes; clopidogrel; coronary artery bypass grafting; ticagrelor ID ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; GRAFT-SURGERY; ASPIRIN; MANAGEMENT; INTERVENTION; ANTAGONIST; THERAPY; SAFETY; CURE AB Objectives The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy. Background Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial. Methods In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end. Results In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments. Conclusions In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding. (J Am Coll Cardiol 2011;57:672-84) (C) 2011 by the American College of Cardiology Foundation C1 [Held, Claes] Uppsala Univ, Dept Cardiol, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Held, Claes; Asenblad, Nils; James, Stefan K.; Wallentin, Lars] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Bassand, Jean Pierre] Univ Besancon, F-25030 Besancon, France. [Becker, Richard C.; Harrington, Robert A.; Mahaffey, Kenneth W.] Duke Clin Res Inst, Durham, NC USA. [Cannon, Christopher P.; Scirica, Benjamin M.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Claeys, Marc J.] Univ Hosp, Edegem, Belgium. [Horrow, Jay; Ycas, Joseph] AstraZeneca Res & Dev, Wilmington, DE USA. [Husted, Steen] Arhus Univ Hosp, Aarhus, Denmark. [Nicolau, Jose C.] Univ Sao Paolo, Sch Med, Sao Paulo, Brazil. [Storey, Robert F.] Univ Sheffield, Sheffield, S Yorkshire, England. [Vintila, Marius] Carol Davila Univ Med Bucharest, Bucharest, Romania. RP Held, C (reprint author), Uppsala Univ, Dept Cardiol, Uppsala Clin Res Ctr, Dag Hammarskjolds 14B, S-75185 Uppsala, Sweden. EM claes.held@ucr.uu.se RI Nicolau, Jose/E-1487-2012; 刘, 李陆/H-8469-2015; OI Held, Claes/0000-0001-9402-7404 FU AstraZeneca FX Carol Davila University of Medicine Bucharest, Bucharest, Romania. The PLATO study was funded by AstraZeneca. For full author disclosures, please see the end of this article. NR 21 TC 191 Z9 204 U1 1 U2 13 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 FEB 8 PY 2011 VL 57 IS 6 BP 672 EP 684 DI 10.1016/j.jacc.2010.10.029 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 715JH UT WOS:000286880100006 PM 21194870 ER PT J AU Tallaj, JA Cadeiras, M AF Tallaj, Jose A. Cadeiras, Martin TI Mechanical Rescue of the Heart in Shock SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE assist devices; cardiogenic shock; heart failure; myocardial infarction ID ACUTE MYOCARDIAL-INFARCTION; VENTRICULAR ASSIST DEVICE; CARDIOGENIC-SHOCK; COUNTERPULSATION; DYSFUNCTION; MORTALITY; EFFICACY; FAILURE; SUPPORT; SAFETY AB Cardiogenic shock (CS) is a state of extreme hypoperfusion owing to pump failure manifested by altered mental status, cool extremities, and/or renal failure. This hypoperfusion leads to release of catecholamines and other inflammatory mediators, which further perpetuates myocardial ischemia and injury, resulting in additional impairment in systemic and tissue perfusion. Any cause of acute severe cardiac failure may lead to CS. C1 [Tallaj, Jose A.; Cadeiras, Martin] Univ Alabama, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Tallaj, Jose A.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL USA. RP Tallaj, JA (reprint author), Univ Alabama, Dept Med, Div Cardiol, THT 338,1900 Univ Blvd, Birmingham, AL 35294 USA. EM jtallaj@uab.edu NR 13 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 8 PY 2011 VL 57 IS 6 BP 697 EP 699 DI 10.1016/j.jacc.2010.10.015 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 715JH UT WOS:000286880100009 PM 21292128 ER PT J AU Van Dijk, KRA Sperling, RA AF Van Dijk, Koene R. A. Sperling, Reisa A. TI Defaulting on the default network Increased risk for dementia SO NEUROLOGY LA English DT Editorial Material ID INTRINSIC FUNCTIONAL CONNECTIVITY; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; MODE; MRI; MEMORY C1 [Sperling, Reisa A.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA 02115 USA. [Van Dijk, Koene R. A.; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Van Dijk, Koene R. A.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Sperling, Reisa A.] Harvard Univ, Sch Med, Boston, MA USA. RP Sperling, RA (reprint author), Massachusetts Gen Hosp, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, 221 Longwood Ave, Boston, MA 02115 USA. EM reisa@rics.bwh.harvard.edu RI Van Dijk, Koene/G-3317-2012; OI Van Dijk, Koene/0000-0001-6137-4282; Kennedy, Kristen/0000-0001-5373-9026 FU NIA NIH HHS [P01AG036694, R01AG027435] NR 15 TC 4 Z9 4 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 8 PY 2011 VL 76 IS 6 BP 498 EP 500 DI 10.1212/WNL.0b013e31820af975 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 718MN UT WOS:000287127100004 PM 21228298 ER PT J AU Wong, C Stylianopoulos, T Cui, JA Martin, J Chauhan, VP Jiang, W Popovic, Z Jain, RK Bawendi, MG Fukumura, D AF Wong, Cliff Stylianopoulos, Triantafyllos Cui, Jian Martin, John Chauhan, Vikash P. Jiang, Wen Popovic, Zoran Jain, Rakesh K. Bawendi, Moungi G. Fukumura, Dai TI Multistage nanoparticle delivery system for deep penetration into tumor tissue SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug delivery; cancer therapy; nanomedicine ID METASTATIC BREAST-CANCER; PHASE-III TRIAL; SOLID TUMORS; IN-VIVO; INTERSTITIAL TRANSPORT; GELATIN NANOPARTICLES; EXTRACELLULAR-MATRIX; SUBCUTANEOUS TUMORS; QUANTUM DOTS; DIFFUSION AB Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are approximate to 100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half-life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix. C1 [Wong, Cliff; Cui, Jian; Popovic, Zoran; Bawendi, Moungi G.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Stylianopoulos, Triantafyllos; Martin, John; Chauhan, Vikash P.; Jiang, Wen; Jain, Rakesh K.; Fukumura, Dai] Massachusetts Gen Hosp, Edwin L Steele Lab Tumor Biol, Dept Radiat Oncol, Boston, MA 02114 USA. [Stylianopoulos, Triantafyllos; Martin, John; Chauhan, Vikash P.; Jiang, Wen; Jain, Rakesh K.; Fukumura, Dai] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bawendi, MG (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA. EM mgb@mit.edu; dai@steele.mgh.harvard.edu RI Chauhan, Vikash/H-8172-2013; Martin, John/L-6892-2016; OI Chauhan, Vikash/0000-0001-9126-2302; Martin, John/0000-0002-9828-8203; Stylianopoulos, Triantafyllos/0000-0002-3093-1696; Jiang, Wen/0000-0001-9154-633X FU Dyax; AstraZeneca; MedImmune; AstraZeneca/MedImmune; Astellas-Fibrogen; Regeneron; Genzyme; MorphoSys; Noxxon Pharma; US National Cancer Institute [R01-CA126642, R01-CA085140, R01-CA115767, P01-CA080124, R01-CA096915]; MIT-Harvard NIH Center for Cancer Nanotechnology Excellence [1U54-CA119349]; MIT DCIF [CHE-980806, DBI-9729592]; ISN [W911NF-07-D-0004]; Susan G. Komen Foundation [KG091281]; US Department of Defense [W81XWH-10-1-0016] FX R.K.J. received commercial research grants from Dyax, AstraZeneca, and MedImmune; consultant fees from AstraZeneca/MedImmune, Dyax, Astellas-Fibrogen, Regeneron, Genzyme, MorphoSys, and Noxxon Pharma; and a speaker honorarium from Genzyme. R.K.J. owns stock in SynDevRx. No reagents or funding from these companies were used in these studies. There is no significant financial or other competing interest in the work.; We thank Patrick Boisvert for assistance with SEM imaging, Yves Boucher for help with zymography, Peigen Huang for the direction of gnotobiotic animal facility, Julia Kahn for animal model preparation, Eve Smith for cancer cell line preparation, Lisa Marshall for assistance with FCS, Li Miao for administrative support, Debby Pheasant for assistance with DLS, and Elisabeth Shaw for assistance with XPS. We thank Juwell Wu for assistance with image analysis and helpful discussions. This research was supported by US National Cancer Institute Grants R01-CA126642 (to R.K.J. and M.G.B.), R01-CA085140, R01-CA115767 (to R.K.J.), P01-CA080124 (to R.K.J. and D.F.), R01-CA096915 (to D.F.); MIT-Harvard NIH Center for Cancer Nanotechnology Excellence Grant 1U54-CA119349 (to M.G.B.); MIT DCIF Grants CHE-980806 and DBI-9729592; by ISN Grant W911NF-07-D-0004 (to M.G.B.); and The Susan G. Komen Foundation Grant KG091281 (to T.S.). R.K.J. is a recipient of Innovator Award W81XWH-10-1-0016 from the US Department of Defense Breast Cancer Research Program. NR 44 TC 334 Z9 339 U1 35 U2 273 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 FEB 8 PY 2011 VL 108 IS 6 BP 2426 EP 2431 DI 10.1073/pnas.1018382108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YH UT WOS:000287084500048 PM 21245339 ER PT J AU Yu, M Stott, S Toner, M Maheswaran, S Haber, DA AF Yu, Min Stott, Shannon Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI Circulating tumor cells: approaches to isolation and characterization SO JOURNAL OF CELL BIOLOGY LA English DT Review ID BREAST-CANCER PATIENTS; RESISTANT PROSTATE-CANCER; EPITHELIAL-MESENCHYMAL TRANSITION; MULTIPARAMETER FLOW-CYTOMETRY; HUMAN PERIPHERAL-BLOOD; BONE-MARROW; LUNG-CANCER; FREE DNA; COLORECTAL-CANCER; CARCINOMA-CELLS AB Circulating tumor cells (CTCs) shed from primary and metastatic cancers are admixed with blood components and are thus rare, making their isolation and characterization a major technological challenge. CTCs hold the key to understanding the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor genotypes during treatment and disease progression. Improvements in technologies to yield purer CTC populations amenable to better cellular and molecular characterization will enable a broad range of clinical applications, including early detection of disease and the discovery of biomarkers to predict treatment responses and disease progression. C1 [Yu, Min; Haber, Daniel A.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02129 USA. [Yu, Min; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Stott, Shannon; Toner, Mehmet] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA 02129 USA. RP Haber, DA (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02129 USA. EM dhaber@partners.org RI Zhou, Feng/E-9510-2011 FU Howard Hughes Medical Institute; NIBIB NIH HHS [P41 EB002503] NR 110 TC 420 Z9 434 U1 33 U2 271 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 FEB 7 PY 2011 VL 192 IS 3 BP 373 EP 382 DI 10.1083/jcb.201010021 PG 10 WC Cell Biology SC Cell Biology GA 727DX UT WOS:000287778900003 PM 21300848 ER PT J AU Wilken, R Veena, MS Wang, MB Srivatsan, ES AF Wilken, Reason Veena, Mysore S. Wang, Marilene B. Srivatsan, Eri S. TI Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma SO MOLECULAR CANCER LA English DT Review ID NF-KAPPA-B; BREAST-CANCER CELLS; MALIGNANT GLIOMA-CELLS; LIPOSOME-ENCAPSULATED CURCUMIN; ISCHEMIA-REPERFUSION INJURY; TYROSINE KINASE INHIBITOR; HUMAN NEUROBLASTOMA-CELLS; SOUTHWEST-ONCOLOGY-GROUP; NITRIC-OXIDE SYNTHASE; PHASE-II TRIAL AB Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-kappa B and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-alpha, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. C1 [Wilken, Reason; Veena, Mysore S.; Wang, Marilene B.; Srivatsan, Eri S.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Veena, Mysore S.; Srivatsan, Eri S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. RP Srivatsan, ES (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. EM esrivats@ucla.edu FU VAGLAHS; West Los Angeles Surgical Education Research Center; NIH [R21 CA116826-01]; Veterans Administration, Washington, DC FX We thank Eugene Han for help with figures. The study was supported by funds from VAGLAHS, West Los Angeles Surgical Education Research Center, NIH (R21 CA116826-01 to M. B. Wang) and Merit grant from the Veterans Administration, Washington, DC (E.S. Srivatsan). NR 217 TC 217 Z9 222 U1 13 U2 76 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD FEB 7 PY 2011 VL 10 AR 12 DI 10.1186/1476-4598-10-12 PG 19 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 729DX UT WOS:000287929900001 PM 21299897 ER PT J AU Konry, T Smolina, I Yarmush, JM Irimia, D Yarmush, ML AF Konry, Tania Smolina, Irina Yarmush, Joel M. Irimia, Daniel Yarmush, Martin L. TI Ultrasensitive Detection of Low-Abundance Surface-Marker Protein Using Isothermal Rolling Circle Amplification in a Microfluidic Nanoliter Platform SO SMALL LA English DT Article ID SINGLE-MOLECULE DETECTION; ENZYMATIC AMPLIFICATION; DNA; POLYMERASE; EXPRESSION; DROPLETS; CANCER; CELLS AB With advances in immunology and cancer biology, there is an unmet need for increasingly sensitive systems to monitor the expression of specific cell markers for the development of new diagnostic and therapeutic tools. To address this challenge, a highly sensitive labeling method that translates antigen-antibody recognition processes into DNA detection events that can be greatly amplified via isothermal rolling circle amplification (RCA) is applied. By merging the single-molecule detection power of RCA reactions with microfluidic technology, it is demonstrated that the identification of specific protein markers can be achieved on tumor-cell surfaces in miniaturized nanoliter reaction droplets. Furthermore, this combined approach of signal amplification in a microfluidic format could extend the utility of existing methods by reducing sample and reagent consumption and enhancing the sensitivities and specificities for various applications, including early diagnosis of cancer. C1 [Smolina, Irina] Boston Univ, Dept Biomed Engn, Ctr Adv Biotechnol, Boston, MA 02215 USA. [Konry, Tania; Irimia, Daniel; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Konry, Tania; Irimia, Daniel; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Konry, Tania; Irimia, Daniel; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Yarmush, Martin L.] New York Methodist Hosp, Dept Anesthesiol, Brooklyn, NY 11215 USA. RP Smolina, I (reprint author), Boston Univ, Dept Biomed Engn, Ctr Adv Biotechnol, 36 Cummington St, Boston, MA 02215 USA. EM IReis@sbi.org; ismolina@bu.edu OI Irimia, Daniel/0000-0001-7347-2082 FU NIH [1R21RR025371-01] FX We thank Ajay Shah for slides preparation and Dr. Jon Edd and Dr. Erkin Seker for technical assistance in the device operation. This work was supported by a NIH research grant (1R21RR025371-01) to I.S. NR 21 TC 31 Z9 34 U1 4 U2 38 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1613-6810 J9 SMALL JI Small PD FEB 7 PY 2011 VL 7 IS 3 BP 395 EP 400 DI 10.1002/smll.201001620 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 724WL UT WOS:000287607000016 PM 21294269 ER PT J AU Yu, LY Hales, CA AF Yu, Lunyin Hales, Charles A. TI Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats SO RESPIRATORY RESEARCH LA English DT Article ID CELL-DERIVED FACTOR-1-ALPHA; HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; MIGRATION; RECRUITMENT; INHIBITION; MICE; ENGRAFTMENT; HEPARIN; BLOOD AB Background: CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood. Methods: In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats. Results: We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats. Conclusions: The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment. C1 [Yu, Lunyin; Hales, Charles A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. RP Yu, LY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. EM lyu3@partners.org FU ATS/Pulmonary Hypertension Research Grant [PH-08-010]; NIH [HL39150]; Susannah Wood Fund FX This work was supported by ATS/Pulmonary Hypertension Research Grant PH-08-010 (L. Yu) and NIH grants HL39150 (C.A. Hales) and by Susannah Wood Fund. NR 50 TC 16 Z9 16 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD FEB 4 PY 2011 VL 12 AR 21 DI 10.1186/1465-9921-12-21 PG 11 WC Respiratory System SC Respiratory System GA 723RP UT WOS:000287524800001 PM 21294880 ER PT J AU Radhakrishnan, H Wu, WC Boas, D Franceschini, MA AF Radhakrishnan, Harsha Wu, Weicheng Boas, David Franceschini, Maria Angela TI Study of neurovascular coupling by modulating neuronal activity with GABA SO BRAIN RESEARCH LA English DT Article DE Neurovascular coupling; GABA; Diffuse optical imaging; Near infrared spectroscopy; EEG; Somatosensory evoked potential ID RAT SOMATOSENSORY CORTEX; CEREBRAL-BLOOD-FLOW; DIFFUSE OPTICAL MEASUREMENT; NEAR-INFRARED SPECTROSCOPY; ACTIVITY-DEPENDENT INCREASES; EVOKED-POTENTIALS; BARREL CORTEX; FUNCTIONAL MRI; HUMAN BRAIN; HEMODYNAMIC-RESPONSES AB Fundamental to the interpretation of neurovascular coupling is determining the neuronal activity that accounts for functional hyperemia. Recently, synaptic and not spiking activity has been found to be responsible for the hemodynamic response. Using pharmacological manipulation in rats, we want to further determine whether the cortical synaptic activity generated by the thalamic input or the subsequent synaptic activity related to secondary cortical processing is driving the hemodynamic response. In this study, we topically applied gamma-aminobutyric acid (GABA) in the somatosensory cortex and used electrical forepaw stimulation to evoke neural and vascular activity. In a group of 8 animals, using laminar electrophysiology, we verified that topical application of GABA for 20 mm does not affect layer IV synaptic activity but reduces subsequent activity in the supragranular and infragranular layers. In another group of 8 animals, we simultaneously measured the electrical and vascular responses with scalp electroencephalography (EEG) and diffuse optical imaging (DOI), respectively. We decomposed somatosensory evoked potentials (SEP) into three major components: P1, N1, and P2, where P1 represents the thalamic input activity originating in layer IV and N1 and P2 represent the subsequent cortical transmissions. We verified that GABA infusion in the somatosensory cortex does not significantly reduce the P1 SEP component but strongly reduces the N1 and P2 components. We found that GABA also elicits a large reduction in the hemodynamic responses, which correlate with the reduction in N1 and P2 components. These results suggest that the hemodynamic response is predominantly driven by cortico-cortical interactions and not by the initial thalamocortical activity in layer IV. (C) 2010 Elsevier B.V. All rights reserved. C1 [Radhakrishnan, Harsha; Wu, Weicheng; Boas, David; Franceschini, Maria Angela] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Photon Migrat Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. RP Radhakrishnan, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Photon Migrat Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, 149,13th St,Rm 2277, Charlestown, MA 02129 USA. EM harsha@nmr.mgh.harvard.edu RI Radhakrishnan, Harsha/K-5557-2012 FU US National Institutes of Health (NIH) [R01-EB001954] FX We thank Anna Devor, Diego Contreras, and Bruce Jenkins for valuable discussions and Michael Moskowitz and Nadege Roche for critical reading of the manuscript. This research is supported by the US National Institutes of Health (NIH) grant R01-EB001954. NR 66 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 4 PY 2011 VL 1372 BP 1 EP 12 DI 10.1016/j.brainres.2010.11.082 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 720PX UT WOS:000287293700001 PM 21145313 ER PT J AU Basu, U Meng, FL Keim, C Grinstein, V Pefanis, E Eccleston, J Zhang, TT Myers, D Wasserman, CR Wesemann, DR Januszyk, K Gregory, RI Deng, HT Lima, CD Alt, FW AF Basu, Uttiya Meng, Fei-Long Keim, Celia Grinstein, Veronika Pefanis, Evangelos Eccleston, Jennifer Zhang, Tingting Myers, Darienne Wasserman, Caitlyn R. Wesemann, Duane R. Januszyk, Kurt Gregory, Richard I. Deng, Haiteng Lima, Christopher D. Alt, Frederick W. TI The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates SO CELL LA English DT Article ID CLASS-SWITCH RECOMBINATION; ANTIBODY DIVERSIFICATION ENZYME; CHROMOSOMAL R-LOOPS; PROTEIN-KINASE-A; SOMATIC HYPERMUTATION; POLYMERASE-II; B-CELLS; MECHANISM; REGIONS; PHOSPHORYLATION AB Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA-processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID-and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity. C1 [Basu, Uttiya; Meng, Fei-Long; Eccleston, Jennifer; Zhang, Tingting; Myers, Darienne; Wasserman, Caitlyn R.; Wesemann, Duane R.; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Program Cellular & Mol Med,Dept Genet,Childrens H, Boston, MA 02115 USA. [Basu, Uttiya; Meng, Fei-Long; Eccleston, Jennifer; Zhang, Tingting; Myers, Darienne; Wasserman, Caitlyn R.; Wesemann, Duane R.; Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Childrens Hosp Boston,Dept Genet, Boston, MA 02115 USA. [Basu, Uttiya; Keim, Celia; Grinstein, Veronika; Pefanis, Evangelos] Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA. [Deng, Haiteng] Rockefeller Univ, Prote Res Ctr, New York, NY 10065 USA. [Gregory, Richard I.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Harvard Stem Cell Inst,Childrens Hosp Boston, Boston, MA 02115 USA. [Januszyk, Kurt; Lima, Christopher D.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Deng, Haiteng] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. RP Basu, U (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Program Cellular & Mol Med,Dept Genet,Childrens H, 300 Longwood Ave, Boston, MA 02115 USA. EM ub2121@columbia.edu; alt@enders.tch.harvard.edu OI Lima, Christopher/0000-0002-9163-6092 FU National Institute of Health [AI31541, GM079196]; Columbia University; Regeneron Pharmaceuticals; Cancer Biology training grant [CA09503-23]; Leukemia Research Foundation FX We thank Bjoern Schwer, Jason Rodriguez, Stephen Goff, Bruce Stillman, and Tasuku Honjo for providing reagents and/or protocols. We also thank Bjoern Schwer and Cosmas Giallourakis for critically reading the manuscript. This work was supported by National Institute of Health grants AI31541 (to F. W. A.) and GM079196 (to K.J. and C. D. L.); by Trustees of Columbia University Faculty startup funds (to U. B.); and by funds from Regeneron Pharmaceuticals (in support of E. P.). F.-L. M. is a fellow of Cancer Research Institute of New York. C. K. was supported by a Cancer Biology training grant CA09503-23. K.J. is a fellow of the American Cancer Society (PF-10-236-01-RMC). U. B. is a Special Fellow of the Leukemia and Lymphoma Society of America and the recipient of a New Investigator Award from the Leukemia Research Foundation. F. W. A. is an Investigator of the Howard Hughes Medical Institute. NR 80 TC 131 Z9 140 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 4 PY 2011 VL 144 IS 3 BP 353 EP 363 DI 10.1016/j.cell.2011.01.001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 716MK UT WOS:000286973100008 PM 21255825 ER PT J AU Koh, KP Yabuuchi, A Rao, S Huang, Y Cunniff, K Nardone, J Laiho, A Tahiliani, M Sommer, CA Mostoslavsky, G Lahesmaa, R Orkin, SH Rodig, SJ Daley, GQ Rao, A AF Koh, Kian Peng Yabuuchi, Akiko Rao, Sridhar Huang, Yun Cunniff, Kerrianne Nardone, Julie Laiho, Asta Tahiliani, Mamta Sommer, Cesar A. Mostoslavsky, Gustavo Lahesmaa, Riitta Orkin, Stuart H. Rodig, Scott J. Daley, George Q. Rao, Anjana TI Tet1 and Tet2 Regulate 5-Hydroxymethylcytosine Production and Cell Lineage Specification in Mouse Embryonic Stem Cells SO CELL STEM CELL LA English DT Article ID DNA METHYLATION; SELF-RENEWAL; TRANSCRIPTIONAL NETWORK; MYELOID CANCERS; GENOMIC DNA; 5-METHYLCYTOSINE; PLURIPOTENCY; CONVERSION; PROTEINS; ROLES AB TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs. C1 [Koh, Kian Peng; Huang, Yun; Tahiliani, Mamta; Lahesmaa, Riitta; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Yabuuchi, Akiko; Rao, Sridhar; Cunniff, Kerrianne; Orkin, Stuart H.; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Yabuuchi, Akiko; Rao, Sridhar; Cunniff, Kerrianne; Orkin, Stuart H.; Daley, George Q.] Harvard Stem Cell Inst, Dana Faber Canc Inst, Boston, MA 02115 USA. [Nardone, Julie] Cell Signaling Technol, Bioinformat, Danvers, MA 01923 USA. [Laiho, Asta; Lahesmaa, Riitta] Univ Turku, Turku Ctr Biotechnol, FI-20520 Turku, Finland. [Laiho, Asta; Lahesmaa, Riitta] Abo Akad Univ, FI-20520 Turku, Finland. [Sommer, Cesar A.; Mostoslavsky, Gustavo] Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA. [Sommer, Cesar A.; Mostoslavsky, Gustavo] Boston Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02118 USA. [Orkin, Stuart H.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Rodig, Scott J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Daley, George Q.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Koh, Kian Peng; Huang, Yun; Tahiliani, Mamta; Lahesmaa, Riitta; Rao, Anjana] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM arao@idi.harvard.edu RI Sommer, Cesar /H-9187-2013; OI Huang, Yun/0000-0001-5950-9168 FU NIH [AI44432, CA42471, RC1-DA028422, RO1-DK70055, RO1-DK59279, UO1-HL100001]; ARRA [RC2-HL102815]; Roche Foundation for Anemia Research; Alex's Lemonade Stand; Harvard Stem Cell Institute; American Heart Association; Academy of Finland; Sigrid Juselius Foundation; Burroughs Wellcome Fund; Leukemia and Lymphoma Society; Johnson Johnson; Verastem; Epizyme; iPierian; Solasia KK; MPM Capital, L.L.P. FX We thank P. Gadue and G. Keller for CD4-Foxa2/GFP-Bry ESCs, C. Unitt and staff at the Specialized Rodent Histopathology Services, Brigham and Women's Hospital for mouse histology and GFP staining, P. Junni at the Finnish Microarray and Sequencing Centre, Turku Centre for Biotechnology for sample processing and array hybridization, and K. E. Waraska at the Biopolymers facility, Harvard Medical School, for low-density array-based q-PCR. This work was funded by NIH grants AI44432, CA42471, and RC1-DA028422 (to A.R.); RO1-DK70055, RO1-DK59279, UO1-HL100001, and special funds from the ARRA stimulus package RC2-HL102815 (to GOD); the Roche Foundation for Anemia Research, Alex's Lemonade Stand, and the Harvard Stem Cell Institute (to GOD); an American Heart Association postdoctoral fellowship (to K.P.K); and grants from The Academy of Finland and The Sigrid Juselius Foundation (to R.L.). G.Q.D. is an affiliate member of the Broad Institute, a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. G.Q.D. is a member of the scientific advisory boards and holds stock in or receives consulting fees from the following companies: Johnson & Johnson, Verastem, Epizyme, iPierian, Solasia KK, and MPM Capital, L.L.P.. NR 48 TC 337 Z9 353 U1 7 U2 69 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 FEB 4 PY 2011 VL 8 IS 2 BP 200 EP 213 DI 10.1016/j.stem.2011.01.008 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 725GO UT WOS:000287633400013 PM 21295276 ER PT J AU Sturzu, AC Wu, SM AF Sturzu, Anthony C. Wu, Sean M. TI Developmental and Regenerative Biology of Multipotent Cardiovascular Progenitor Cells SO CIRCULATION RESEARCH LA English DT Review DE cardiovascular disease; stem cells; regeneration; cardiac development; cardiomyocytes ID CARDIAC STEM-CELLS; ADULT MAMMALIAN CARDIOMYOCYTES; BINDING CASSETTE TRANSPORTER; EPICARDIUM-DERIVED CELLS; SIDE POPULATION CELLS; MYOCARDIAL-INFARCTION; DEFINED FACTORS; SMOOTH-MUSCLE; BONE-MARROW; IN-VIVO AB Our limited ability to improve the survival of patients with heart failure is attributable, in part, to the inability of the mammalian heart to meaningfully regenerate itself. The recent identification of distinct families of multipotent cardiovascular progenitor cells from endogenous, as well as exogenous, sources, such as embryonic and induced pluripotent stem cells, has raised much hope that therapeutic manipulation of these cells may lead to regression of many forms of cardiovascular disease. Although the exact source and cell type remains to be clarified, our greater understanding of the scientific underpinning behind developmental cardiovascular progenitor cell biology has helped to clarify the origin and properties of diverse cells with putative cardiogenic potential. In this review, we highlight recent advances in the understanding of cardiovascular progenitor cell biology from embryogenesis to adulthood and their implications for therapeutic cardiac regeneration. We believe that a detailed understanding of cardiogenesis will inform future applications of cardiovascular progenitor cells in heart failure therapy and regenerative medicine. (Circ Res. 2011;108:353-364.) C1 [Sturzu, Anthony C.; Wu, Sean M.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Wu, Sean M.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Wu, SM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Cardiovasc Res Ctr, CPZN 3224 Simches Bldg,185 Cambridge St, Boston, MA 02114 USA. EM smwu@partners.org FU NIH [T32 HL07208-33, OD004411]; NIH/National Heart, Lung, and Blood Institute [HL081086, HL100408]; Harvard Stem Cell Institute FX A.C.S. is supported by NIH training grant T32 HL07208-33. S.M.W. is supported by grants from the NIH/National Heart, Lung, and Blood Institute (grants HL081086 and HL100408); NIH Director's New Innovator Award (OD004411); and Harvard Stem Cell Institute. NR 120 TC 41 Z9 45 U1 0 U2 7 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 FEB 4 PY 2011 VL 108 IS 3 BP 353 EP 364 DI 10.1161/CIRCRESAHA.110.227066 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 715YB UT WOS:000286930500012 PM 21293007 ER PT J AU da-Silva, WS Ribich, S Drigo, RAE Castillo, M Patti, ME Bianco, AC AF da-Silva, Wagner S. Ribich, Scott Arrojo e Drigo, Rafael Castillo, Melany Patti, Mary-Elizabeth Bianco, Antonio C. TI The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure SO FEBS LETTERS LA English DT Article DE Thyroid hormone; Deiodinase; Chemical chaperone; Oxygen consumption; Metabolism ID TYPE-2 IODOTHYRONINE DEIODINASE; RETICULUM-ASSOCIATED DEGRADATION; ADIPOSE-TISSUE; INSULIN; TRIIODOTHYRONINE; CONVERSION; THYROXINE; APOPTOSIS; STRESS; CELLS AB Exposure of cell lines endogenously expressing the thyroid hormone activating enzyme type 2 deiodinase (D2) to the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutiric acid (4-PBA) increases D2 expression, activity and T3 production. In brown adipocytes, TUDCA or 4-PBA induced T3-dependent genes and oxygen consumption (similar to 2-fold), an effect partially lost in D2 knockout cells. In wild type, but not in D2 knockout mice, administration of TUDCA lowered the respiratory quotient, doubled brown adipose tissue D2 activity and normalized the glucose intolerance associated with high fat feeding. Thus, D2 plays a critical role in the metabolic effects of chemical chaperones. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [da-Silva, Wagner S.; Ribich, Scott; Arrojo e Drigo, Rafael; Castillo, Melany; Bianco, Antonio C.] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33143 USA. [Patti, Mary-Elizabeth] Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Bianco, AC (reprint author), 1400 NW 10th St,Suite 816, Miami, FL 33136 USA. EM abianco@deiodinase.org RI Bianco, Antonio/A-4965-2008; da Silva, Wagner/A-7835-2008; Arrojo e Drigo, Rafael/F-6213-2010; OI Bianco, Antonio/0000-0001-7737-6813; da Silva, Wagner/0000-0002-0001-0386; Arrojo e Drigo, Rafael/0000-0001-7712-013X FU NIDDK [DK65055] FX We are grateful to John W. Harney for the outstanding technical assistance. Grant support from NIDDK(DK65055). W.S.S. is a fellow of the Pew Charitable Trusts Foundation. NR 32 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 4 PY 2011 VL 585 IS 3 BP 539 EP 544 DI 10.1016/j.febslet.2010.12.044 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 712HR UT WOS:000286657700015 PM 21237159 ER PT J AU Ting, DT Lipson, D Paul, S Brannigan, BW Akhavanfard, S Coffman, EJ Contino, G Deshpande, V Iafrate, AJ Letovsky, S Rivera, MN Bardeesy, N Maheswaran, S Haber, DA AF Ting, David T. Lipson, Doron Paul, Suchismita Brannigan, Brian W. Akhavanfard, Sara Coffman, Erik J. Contino, Gianmarco Deshpande, Vikram Iafrate, A. John Letovsky, Stan Rivera, Miguel N. Bardeesy, Nabeel Maheswaran, Shyamala Haber, Daniel A. TI Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers SO SCIENCE LA English DT Article ID PERVASIVE TRANSCRIPTION; HUMAN GENOMES; SMALL RNAS; DIFFERENTIATION; ELEMENTS; MOUSE; CELLS AB Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we showed that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDACs), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over that in normal tissue. In 15 of 15 human PDACs, alpha satellite transcripts were most abundant and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of the lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the long interspersed nuclear element 1 (LINE-1) retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions. The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection. C1 [Ting, David T.; Paul, Suchismita; Brannigan, Brian W.; Akhavanfard, Sara; Coffman, Erik J.; Contino, Gianmarco; Deshpande, Vikram; Iafrate, A. John; Rivera, Miguel N.; Bardeesy, Nabeel; Maheswaran, Shyamala; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ting, David T.; Paul, Suchismita; Brannigan, Brian W.; Akhavanfard, Sara; Coffman, Erik J.; Contino, Gianmarco; Deshpande, Vikram; Iafrate, A. John; Rivera, Miguel N.; Bardeesy, Nabeel; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Ting, David T.; Paul, Suchismita; Brannigan, Brian W.; Akhavanfard, Sara; Coffman, Erik J.; Contino, Gianmarco; Deshpande, Vikram; Iafrate, A. John; Rivera, Miguel N.; Bardeesy, Nabeel; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Ting, David T.; Paul, Suchismita; Brannigan, Brian W.; Akhavanfard, Sara; Coffman, Erik J.; Contino, Gianmarco; Deshpande, Vikram; Iafrate, A. John; Rivera, Miguel N.; Bardeesy, Nabeel; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. [Lipson, Doron; Letovsky, Stan] Helicos BioSci Corp, Cambridge, MA 02139 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM haber@helix.mgh.harvard.edu OI Contino, Gianmarco/0000-0001-5874-0405 FU Pancreatic Cancer Action Network-American Association for Cancer Research; Warshaw Institute for Pancreatic Cancer Research; Fond. Veronesi; Howard Hughes Medical Institute; National Cancer Institute [CA129933] FX This work was supported by a Pancreatic Cancer Action Network-American Association for Cancer Research Fellowship and the Warshaw Institute for Pancreatic Cancer Research (D.T.T.); Fond. Veronesi (G.C.); Howard Hughes Medical Institute (D.A.H. and M.N.R.); and National Cancer Institute CA129933 (D.A.H). We thank T. Raz, P. Kapranov, E. Giladi, and J. Whetstine for helpful discussions and K. Haigis and K. Wong for providing mouse colon and lung tumors, respectively. Massachusetts General Hospital and the authors (D.A.H., D.L., S.M., D.T.T.) have filed a patent application relating to detection of satellite and LINE sequences in human cancers. NR 23 TC 168 Z9 179 U1 2 U2 28 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 FEB 4 PY 2011 VL 331 IS 6017 BP 593 EP 596 DI 10.1126/science.1200801 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 715ZE UT WOS:000286933600056 PM 21233348 ER PT J AU Massimini, DF Warner, JJP Li, GA AF Massimini, Daniel F. Warner, Jon J. P. Li, Guoan TI Non-invasive determination of coupled motion of the scapula and humerus-An in-vitro validation SO JOURNAL OF BIOMECHANICS LA English DT Article DE Shoulder; Kinematics; Fluoroscopy; Radiostereometric; Validation ID PROFESSIONAL BASEBALL PITCHERS; GLENOHUMERAL JOINT KINEMATICS; ARTICULAR-CARTILAGE CONTACT; GEOMETRIC IMAGE DISTORTION; TISSUE ARTIFACT ASSESSMENT; SCAPULOHUMERAL RHYTHM; SHOULDER KINEMATICS; VIVO MEASUREMENT; ELEVATION; TRANSLATION AB Measuring the motion of the scapula and humerus with sub-millimeter levels of accuracy in six-degrees-of-freedom (6-DOF) is a challenging problem. The current methods to measure shoulder joint motion via the skin do not produce clinically significant levels of accuracy. Thus, the purpose of this study was to validate a non-invasive markerless dual fluoroscopic imaging system (DFIS) model-based tracking technique for measuring dynamic in-vivo shoulder kinematics. Our DFIS tracks the positions of bones based on their projected silhouettes to contours on recorded pairs of fluoroscopic images. For this study, we compared markerlessly tracking the bones of the scapula and humerus to track them with implanted titanium spheres using a radiostereometric analysis (RSA) while manually manipulating a cadaver specimen's arms. Additionally, we report the repeatability of the DFIS to track the scapula and humerus during dynamic shoulder motion. The difference between the markerless model-based tracking technique and the RSA was +/- 0.3 mm in translation and +/- 0.5 degrees in rotation. Furthermore, the repeatability of the markerless DFIS model-based tracking technique for the scapula and humerus was +/- 0.2 mm and +/- 0.4 degrees, respectively. The model-based tracking technique achieves an accuracy that is similar to an invasive RSA tracking technique and is highly suited for non-invasively studying the in-vivo motion of the shoulder. This technique could be used to investigate the scapular and humeral biomechanics in both healthy individuals and in patients with various pathologies under a variety of dynamic shoulder motions encountered during the activities of daily living. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Massimini, Daniel F.; Warner, Jon J. P.; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab, Boston, MA 02114 USA. [Massimini, Daniel F.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab, GRJ-1215,55 Fruit St, Boston, MA 02114 USA. EM gli1@partners.org RI Lempereur, Mathieu/G-5470-2012 NR 43 TC 18 Z9 18 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD FEB 3 PY 2011 VL 44 IS 3 BP 408 EP 412 DI 10.1016/j.jbiomech.2010.10.003 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 724BL UT WOS:000287551000008 PM 21055753 ER PT J AU Kim, JS Fan, CY Choi, D Jang, IK Lee, JM Kim, TH Park, SM Paik, SI Ko, YG Hong, MK Jang, Y Chung, N AF Kim, Jung-Sun Fan, Chunyu Choi, Donghoon Jang, Ik-Kyung Lee, Jung Myung Kim, Tae Hoon Park, Sang Min Paik, Sung Il Ko, Young-Guk Hong, Myeong-Ki Jang, Yangsoo Chung, Namsik TI Different patterns of neointimal coverage between acute coronary syndrome and stable angina after various types of drug-eluting stents implantation; 9-month follow-up optical coherence tomography study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Acute coronary syndrome; Drug-eluting stent; Tomography; Optical coherence ID LARGE 2-INSTITUTIONAL COHORT; ROUTINE CLINICAL-PRACTICE; MYOCARDIAL-INFARCTION; THROMBOSIS; PACLITAXEL; PLACEMENT AB Background: Acute coronary syndrome (ACS) is an independent risk factor for late stent thrombosis which might be related to the impaired vascular healing after drug-eluting stent (DES) due to the disruption of plaques and thrombus formation. Therefore, we investigated the vascular response after various DES implantations between ACS and stable angina pectoris (SAP) using optical coherence tomography (OCT). Methods: Ninety-one patients [49 ACS: 20 sirolimus-eluting (SES), 12 paclitaxel-eluting (PES) and 17 zotarolimus eluting stent (ZES) and 42 SAP: 15 SES, 12 PES and 15 ZES] underwent OCT at 9 months after stent implantation. Neointimal coverage and malapposition were evaluated in 21,939 struts in 2269-mm stented segments. Results: In the ACS group, the incidence of uncovered and malapposed struts was significantly higher (8.9 +/- 13.7 vs 2.9 +/- 6.2%, p=0.01 and 2.2 +/- 5.6 vs 0.5 +/- 2.0%, p=0.02). Among the three DESs tested, SES showed a significantly higher rate of uncovered struts in the ACS group (17.3 +/- 13.4 vs 4.4 +/- 6.2%, p=0.003). PES had a trend toward higher rate of uncovered and malapposed struts in the ACS groups (6.7 +/- 7.6 vs 4.0 +/- 9.0%, p=0.13) while ZES was similar in both groups. Conclusion: The patterns of neointimal coverage and malapposition at 9 months after DES implantation were different between ACS and SAP, and variable among the DES type between two groups. Therefore, the present study suggests that vascular response after DES implantation might be influenced by both clinical presentation and type of DES. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kim, Jung-Sun; Choi, Donghoon; Lee, Jung Myung; Kim, Tae Hoon; Park, Sang Min; Paik, Sung Il; Ko, Young-Guk; Hong, Myeong-Ki; Jang, Yangsoo; Chung, Namsik] Yonsei Univ, Coll Med, Div Cardiol, Yonsei Cardiovasc Ctr, Seoul 120752, South Korea. [Fan, Chunyu] ShanXi Med Univ, Hosp 1, Div Cardiol, Taiyuan, Peoples R China. [Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Choi, D (reprint author), Yonsei Univ, Coll Med, Div Cardiol, Yonsei Cardiovasc Ctr, 250 Seongsanno, Seoul 120752, South Korea. EM cdhlyj@yuhs.ac RI Jang, Yang Soo/D-4803-2012; OI Kim, Tae-Hoon/0000-0003-4200-3456 FU Ministry of Health & Welfare, Republic of Korea [A085136]; Yonsei University College of Medicine; Yonsei University; Cardiovascular Research Center, Seoul, Korea FX This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A085136) and was supported by a faculty research grant of Yonsei University College of Medicine for 2007 and by Yonsei University Research Fund of 2007 and Cardiovascular Research Center, Seoul, Korea. NR 30 TC 25 Z9 29 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 3 PY 2011 VL 146 IS 3 BP 341 EP 346 DI 10.1016/j.ijcard.2009.07.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 709SA UT WOS:000286460500015 PM 19709765 ER PT J AU Mitsiades, CS AF Mitsiades, Constantine S. TI How "immunomodulatory" are IMIDs? SO BLOOD LA English DT Editorial Material ID MULTIPLE-MYELOMA; LENALIDOMIDE; THALIDOMIDE C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Mitsiades, CS (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. NR 10 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 3 PY 2011 VL 117 IS 5 BP 1440 EP 1441 DI 10.1182/blood-2010-11-317156 PG 3 WC Hematology SC Hematology GA 715WV UT WOS:000286925500004 PM 21292783 ER PT J AU Mansoor, A Pittaluga, S Beck, PL Wilson, WH Ferry, JA Jaffe, ES AF Mansoor, Adnan Pittaluga, Stefania Beck, Paul L. Wilson, Wyndham H. Ferry, Judith A. Jaffe, Elaine S. TI NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; DELTA T-CELL; CELIAC-DISEASE; ADAPTIVE IMMUNITY; MUCOSAL; PROLIFERATION; SKIN; LYMPHOCYTES; DISORDER; INNATE AB Intestinal T-cell and natural killer (NK)-cell lymphomas are clinically aggressive and can be challenging to diagnose in small endoscopic biopsies. We describe 8 patients in whom atypical NK-cell lymphoproliferative lesions mimicked NK-or T-cell lymphoma. The patients (2 men; 6 women; ages 27-68 years) presented with vague gastrointestinal symptoms with lesions involving stomach, duodenum, small intestine, and colon. At endoscopy, the lesions exhibited superficial ulceration, edema, and hemorrhage. Biopsies revealed a mucosal infiltrate of atypical cells with an NK-cell phenotype (CD56(+)/TIA-1(+)/Granzyme B(+)/cCD3(+)), which displaced but did not invade the glandular epithelium. Epstein-Barr virus-encoded RNA in situ hybridization was negative, and T-cell receptor-gamma gene rearrangement showed no evidence of a clonal process. Based on an original diagnosis of lymphoma, 3 patients received aggressive chemotherapy followed by autologous bone marrow transplantation in 2. Five patients were followed without treatment. However, no patient developed progressive disease or died of lymphoma (median follow-up, 30 months). Repeat endoscopies in 6 of 8 patients showed persistence or recurrence of superficial gastrointestinal lesions. This unique entity mimics intestinal and NK-/T-cell lymphomas on endoscopic biopsies and can result in erroneous diagnosis, leading to aggressive chemotherapy. We propose the term "NK-cell enteropathy" for this syndrome of as yet unknown etiology. (Blood. 2011; 117(5): 1447-1452) C1 [Mansoor, Adnan] Calgary Lab Serv, Dept Pathol & Lab Med, Calgary, AB, Canada. [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Beck, Paul L.] Univ Calgary, Div Gastroenterol, Calgary, AB, Canada. [Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ferry, Judith A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Jaffe, ES (reprint author), NIH, Hematopathol Sect, Pathol Lab, 10 Ctr Dr,Bldg 10,Rm 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute FX This work was supported by the intramural research budget of the Center for Cancer Research, National Cancer Institute. NR 39 TC 42 Z9 45 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 FEB 3 PY 2011 VL 117 IS 5 BP 1447 EP 1452 DI 10.1182/blood-2010-08-302737 PG 6 WC Hematology SC Hematology GA 715WV UT WOS:000286925500009 PM 20966166 ER PT J AU Sivina, M Hartmann, E Kipps, TJ Rassenti, L Krupnik, D Lerner, S LaPushin, R Xiao, LC Huang, XL Werner, L Neuberg, D Kantarjian, H O'Brien, S Wierda, WG Keating, MJ Rosenwald, A Burger, JA AF Sivina, Mariela Hartmann, Elena Kipps, Thomas J. Rassenti, Laura Krupnik, Diana Lerner, Susan LaPushin, Ruth Xiao, Lianchun Huang, Xuelin Werner, Lillian Neuberg, Donna Kantarjian, Hagop O'Brien, Susan Wierda, William G. Keating, Michael J. Rosenwald, Andreas Burger, Jan A. TI CCL3 (MIP-1 alpha) plasma levels and the risk for disease progression in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; GENE MUTATION STATUS; T-CELLS; CD38 EXPRESSION; SURVIVAL; RECEPTOR; CHEMOKINES; ANTIGEN; ZAP-70; MICROENVIRONMENT AB B-cell receptor (BCR) signaling has been inferred as an important mechanism for disease progression in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. In response to BCR activation, CLL cells secrete the chemokine CCL3, which fosters interactions between CLL cells and the leukemia micro-environment. CCL3 secretion correlates with expression of the 70-kDa zeta-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with established prognostic markers and time from diagnosis to initial therapy. We found that CCL3 plasma concentrations were strongly associated with established prognostic markers. In a Cox proportional hazards regression model, CCL3 as well as established prognostic markers (immunoglobulin heavy chain variable-region mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly associated with time to treatment. Multivariable analysis revealed that CCL3 (hazard ratio [HR] = 2.33, P < .0001), advanced clinical stage (HR = 2.75, P = .0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P = .001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic markers. Collectively, CCL3 is a novel, robust, and independent prognostic marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore should become useful for risk assessment in patients with CLL. (Blood. 2011; 117(5): 1662-1669) C1 [Burger, Jan A.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Unit 428, Houston, TX 77230 USA. [Hartmann, Elena; Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Kipps, Thomas J.; Rassenti, Laura] Univ Calif San Diego, Dept Med, Chron Lymphocyt Leukemia Res Consortium, San Diego, CA 92103 USA. [Kipps, Thomas J.; Rassenti, Laura] Univ Calif San Diego, Dept Med, Div Hematol Oncol, San Diego, CA 92103 USA. [Xiao, Lianchun; Huang, Xuelin] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77230 USA. [Werner, Lillian; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Burger, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Unit 428, POB 301402, Houston, TX 77230 USA. EM jaburger@mdanderson.org FU CLL Global Research Foundation; ASCO Career Development Award; National Institutes of Health CLL Research Consortium [PO1-CA81534] FX This work was supported by CLL Global Research Foundation grants (W.W., A.R., and J.B.), an ASCO Career Development Award (J.B.), and National Institutes of Health CLL Research Consortium (grant PO1-CA81534). NR 38 TC 59 Z9 60 U1 1 U2 6 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 FEB 3 PY 2011 VL 117 IS 5 BP 1662 EP 1669 DI 10.1182/blood-2010-09-307249 PG 8 WC Hematology SC Hematology GA 715WV UT WOS:000286925500033 PM 21115978 ER PT J AU Liu, FL White, JA Antonescu, C Gusenleitner, D Quackenbush, J AF Liu, Fenglong White, Joseph A. Antonescu, Corina Gusenleitner, Daniel Quackenbush, John TI GCOD - GeneChip Oncology Database SO BMC BIOINFORMATICS LA English DT Article ID RENAL-CELL CARCINOMA; EXPRESSION; NORMALIZATION; DIOXYGENASE; TUMOR AB Background: DNA microarrays have become a nearly ubiquitous tool for the study of human disease, and nowhere is this more true than in cancer. With hundreds of studies and thousands of expression profiles representing the majority of human cancers completed and in public databases, the challenge has been effectively accessing and using this wealth of data. Description: To address this issue we have collected published human cancer gene expression datasets generated on the Affymetrix GeneChip platform, and carefully annotated those studies with a focus on providing accurate sample annotation. To facilitate comparison between datasets, we implemented a consistent data normalization and transformation protocol and then applied stringent quality control procedures to flag low-quality assays. Conclusion: The resulting resource, the GeneChip Oncology Database, is available through a publicly accessible website that provides several query options and analytical tools through an intuitive interface. C1 [White, Joseph A.; Antonescu, Corina; Gusenleitner, Daniel; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Liu, Fenglong] Monsanto Co, Middleton, WI 53562 USA. RP White, JA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM jwhite@jimmy.harvard.edu FU Dana-Farber Cancer Institute; NLM [5R01 LM008795-04]; NSF [DBI-0649614] FX This research was supported by institutional funds from the Dana-Farber Cancer Institute, NLM Grant # 5R01 LM008795-04, and NSF Grant # DBI-0649614. We thank Priya Karanam (pkaranam@jimmy.harvard.edu) for assistance with database maintenance and resolving data retrieval issues. NR 15 TC 10 Z9 10 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 3 PY 2011 VL 12 AR 46 DI 10.1186/1471-2105-12-46 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 726QW UT WOS:000287742200001 PM 21291543 ER PT J AU Shinagare, AB Cunto-Amesty, G Fennessy, FM AF Shinagare, Atul B. Cunto-Amesty, Gina Fennessy, Fiona M. TI Multiple inflammatory nodules: a differential diagnosis of new pulmonary nodules in oncology patients SO CANCER IMAGING LA English DT Article DE Sarcoma; pulmonary nodules; inflammatory nodules ID PSEUDOTUMOR AB New pulmonary nodules in an oncology patient are often considered metastatic unless proven otherwise. However, the possibility of an inflammatory cause needs to be considered in this setting. Clinicopathologic correlation is always needed in such cases to establish a diagnosis, especially before initiating a new treatment. The multiplicity of inflammatory nodules in this case, in the form of multiple pulmonary nodules and a spinal soft tissue mass, can be a considerable diagnostic challenge. The potential ramifications of not being familiar with inflammatory pseudotumors and not knowing when to suggest it involve unnecessary and incorrect patient treatment including chemotherapy, and may have medicolegal implications for the radiologist. Therefore all radiologists, especially those involved in oncologic imaging, need to be aware of this entity. C1 [Shinagare, Atul B.; Fennessy, Fiona M.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Shinagare, Atul B.; Fennessy, Fiona M.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Cunto-Amesty, Gina] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Shinagare, AB (reprint author), 33 Pond Ave,Apt B 514, Brookline, MA 02445 USA. EM ashinagare@partners.org NR 13 TC 1 Z9 1 U1 0 U2 0 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD FEB 3 PY 2011 VL 10 IS 1 BP 205 EP 208 DI 10.1102/1470-7330.2010.0031 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 826CG UT WOS:000295328400001 PM 21300598 ER PT J AU Diep, CQ Ma, DD Deo, RC Holm, TM Naylor, RW Arora, N Wingert, RA Bollig, F Djordjevic, G Lichman, B Zhu, H Ikenaga, T Ono, F Englert, C Cowan, CA Hukriede, NA Handin, RI Davidson, AJ AF Diep, Cuong Q. Ma, Dongdong Deo, Rahul C. Holm, Teresa M. Naylor, Richard W. Arora, Natasha Wingert, Rebecca A. Bollig, Frank Djordjevic, Gordana Lichman, Benjamin Zhu, Hao Ikenaga, Takanori Ono, Fumihito Englert, Christoph Cowan, Chad A. Hukriede, Neil A. Handin, Robert I. Davidson, Alan J. TI Identification of adult nephron progenitors capable of kidney regeneration in zebrafish SO NATURE LA English DT Article ID TRANSGENIC ZEBRAFISH; GENES; MORPHOGENESIS; PRONEPHROS; REPORTER AB Loss of kidney function underlies many renal diseases(1). Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones(2,3). By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury(4,5), providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10-30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies. C1 [Diep, Cuong Q.; Ma, Dongdong; Deo, Rahul C.; Holm, Teresa M.; Naylor, Richard W.; Wingert, Rebecca A.; Cowan, Chad A.; Handin, Robert I.; Davidson, Alan J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ma, Dongdong; Handin, Robert I.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Wingert, Rebecca A.; Cowan, Chad A.; Handin, Robert I.; Davidson, Alan J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Bollig, Frank; Englert, Christoph] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany. [Zhu, Hao] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ikenaga, Takanori; Ono, Fumihito] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Englert, Christoph] Friedrich Schiller Univ, D-07743 Jena, Germany. [Cowan, Chad A.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hukriede, Neil A.] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15260 USA. [Diep, Cuong Q.; Deo, Rahul C.; Holm, Teresa M.; Naylor, Richard W.; Arora, Natasha; Wingert, Rebecca A.; Djordjevic, Gordana; Lichman, Benjamin; Cowan, Chad A.; Davidson, Alan J.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Davidson, AJ (reprint author), Univ Auckland, Sch Med Sci, Dept Mol Med & Pathol, Auckland 1142, New Zealand. EM a.davidson@auckland.ac.nz OI Ikenaga, Takanori/0000-0002-7321-9703; Zhu, Hao/0000-0002-8417-9698; Lichman, Benjamin/0000-0002-0033-1120 FU Harvard Stem Cell Institute; American Society of Nephrology; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [P50DK074030] FX We thank E. C. Liao for help with suturing, and R. Ethier and L. Gyr for zebrafish care. A.J.D. was supported by the Harvard Stem Cell Institute, the American Society of Nephrology and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (P50DK074030). NR 23 TC 105 Z9 108 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 3 PY 2011 VL 470 IS 7332 BP 95 EP U108 DI 10.1038/nature09669 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 715LQ UT WOS:000286886400041 PM 21270795 ER PT J AU Miller, FG Joffe, S AF Miller, Franklin G. Joffe, Steven TI Equipoise and the Dilemma of Randomized Clinical Trials SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID METASTATIC COLORECTAL-CANCER; ESTROGEN PLUS PROGESTIN; THERAPEUTIC MISCONCEPTION; 1ST-LINE CHEMOTHERAPY; RESPONSE RATES; BREAST-CANCER; SURVIVAL; BENEFIT; MELANOMA; ETHICS C1 [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Joffe, Steven] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. OI Joffe, Steven/0000-0002-0667-7384 NR 35 TC 78 Z9 78 U1 0 U2 8 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 FEB 3 PY 2011 VL 364 IS 5 BP 476 EP 480 DI 10.1056/NEJMsb1011301 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 715LL UT WOS:000286885900016 PM 21288100 ER PT J AU Ferguson-Smith, AC Patti, ME AF Ferguson-Smith, Anne C. Patti, Mary-Elizabeth TI You Are What Your Dad Ate SO CELL METABOLISM LA English DT Editorial Material ID IN-UTERO; MAMMALS; DIET; RATS AB Maternal nutrition and metabolism are critical determinants of adult offspring health. Recent reports describe adverse offspring outcomes associated with the father's diet, indicating nongenetic inheritance of paternal experience. Determining underlying mechanisms may require reconsideration of our understanding of the heritability of epigenetic states. C1 [Ferguson-Smith, Anne C.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [Ferguson-Smith, Anne C.] Singapore Inst Clin Sci, Brenner Ctr Mol Med, Singapore, Singapore. [Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Patti, Mary-Elizabeth] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Ferguson-Smith, AC (reprint author), Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3EG, England. EM afsmith@mole.bio.cam.ac.uk; mary.elizabeth.patti@joslin.harvard.edu RI Ferguson-Smith, Anne/G-7534-2011 NR 9 TC 38 Z9 39 U1 0 U2 8 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 FEB 2 PY 2011 VL 13 IS 2 BP 115 EP 117 DI 10.1016/j.cmet.2011.01.011 PG 3 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 722KR UT WOS:000287431600001 PM 21284975 ER PT J AU Schleinitz, D Kloting, N Bottcher, Y Wolf, S Dietrich, K Tonjes, A Breitfeld, J Enigk, B Halbritter, J Korner, A Schon, MR Jenkner, J Tseng, YH Lohmann, T Dressler, M Stumvoll, M Bluher, M Kovacs, P AF Schleinitz, Dorit Kloeting, Nora Boettcher, Yvonne Wolf, Sara Dietrich, Kerstin Toenjes, Anke Breitfeld, Jana Enigk, Beate Halbritter, Jan Koerner, Antje Schoen, Michael R. Jenkner, Jost Tseng, Yu-Hua Lohmann, Tobias Dressler, Miriam Stumvoll, Michael Blueher, Matthias Kovacs, Peter TI Genetic and Evolutionary Analyses of the Human Bone Morphogenetic Protein Receptor 2 (BMPR2) in the Pathophysiology of Obesity SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; HAPLOTYPE RECONSTRUCTION; PHYLOGENETIC ANALYSIS; MAXIMUM-LIKELIHOOD; INSULIN-SECRETION; DIABETES-MELLITUS; POPULATION; EXPRESSION; VARIANTS; CELLS AB Objective: Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity. Research Design and Methods: Evolutionary analyses (dN/dS, Fst, iHS) were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs) were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined. Results: The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and <30 kg/m(2)) and 80 obese (BMI>30 kg/m(2)) compared with 44 lean subjects (BMI<25 kg/m(2)) (P<0.001). In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118) were associated with obesity (adjusted P<0.05). Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P=0.01) on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue. Conclusion: Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity. C1 [Schleinitz, Dorit; Dietrich, Kerstin; Breitfeld, Jana; Enigk, Beate; Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kloeting, Nora; Boettcher, Yvonne; Wolf, Sara; Toenjes, Anke; Halbritter, Jan; Stumvoll, Michael; Blueher, Matthias] Univ Leipzig, Dept Med, Leipzig, Germany. [Toenjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Koerner, Antje] Univ Leipzig, Univ Hosp Children & Adolescents, Leipzig, Germany. [Schoen, Michael R.; Jenkner, Jost] Municipal Clin Karlsruhe, Clin Visceral Surg, Karlsruhe, Germany. [Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Lohmann, Tobias; Dressler, Miriam] Municipal Clin, Dresden, Germany. RP Schleinitz, D (reprint author), Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. EM bluma@medizin.uni-leipzig.de; peter.kovacs@medizin.uni-leipzig.de RI Korner, Antje/B-3988-2015; OI Korner, Antje/0000-0001-6001-0356; Schon, Michael/0000-0002-0698-4130 FU Federal Ministry of Education and Research, Competence Network Obesity [FKZ 01GI0829]; NGFNplus [FKZ 01GI0827]; Deutsche Forschungsgemeinschaft (DFG); German Diabetes Association [BL 833/1-1, Stu192/6-1, KO 3512/1-1, KO 3880/1-1]; National Institutes of Health (USA) [R01 DK077097, P30 DK040561]; DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland) FX This work was supported by grants from the Federal Ministry of Education and Research, Competence Network Obesity (FKZ 01GI0829), the NGFNplus (FKZ 01GI0827), Deutsche Forschungsgemeinschaft (DFG), the Clinical Research Group "Atherobesity'' KFO 152 (projects BL 833/1-1 to MB, and Stu192/6-1 (MS), KO 3512/1-1 to AK, KO 3880/1-1 to PK), from the German Diabetes Association (to DS and PK), from the National Institutes of Health (USA) grants R01 DK077097 and P30 DK040561 (to YHT) and DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland; to MS, PK, MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 15 Z9 16 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 2 PY 2011 VL 6 IS 2 AR e16155 DI 10.1371/journal.pone.0016155 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717IF UT WOS:000287036200008 PM 21311592 ER PT J AU Shervin, N Dorrwachter, J Bragdon, CR Shervin, D Zurakowski, D Malchau, H AF Shervin, Nina Dorrwachter, Janet Bragdon, Charles R. Shervin, David Zurakowski, David Malchau, Henrik TI Comparison of Paper and Computer-Based Questionnaire Modes for Measuring Health Outcomes in Patients Undergoing Total Hip Arthroplasty SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID REPLACEMENT; PENCIL; SCORE AB Background: Health status questionnaires are important, especially with the growing interest in outcome studies. However, these questionnaires continue to be administered in their original paper format. We hypothesized that total hip arthroplasty outcome data derived with computer-based questionnaires do not differ significantly from those derived with established paper-based formats. Methods: From January 2006 to January 2007, the clinic schedules of four attending arthroplasty surgeons were screened weekly to identify patients who could potentially be included in the study. Charts were reviewed for subjects who were scheduled for or had received primary total hip arthroplasty. Patients were recruited during their office visit or when they attended a preoperative educational class, and five health status questionnaires (the Harris hip score, WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index], SF-36 [Short Form-36], EQ-5D [EuroQol-5D], and UCLA [University of California at Los Angeles] activity score) were administered in three formats: paper, touch screen, and web-based. Repeated-measures analysis of variance and Pearson correlations were used to compare the questionnaire modes for the Harris hip score (normally distributed data), and the Friedman test and Spearman correlations were used to compare the modes for the other health status scores (non-normally distributed data). The study was designed with 90% power for detecting 10% differences between modes in the entire series of sixty-one patients and with 82% and 87% power in preoperative and postoperative subgroups, respectively. Results: The mean age was sixty-three years, with thirty-seven male and twenty-four female patients in the study. Forty-seven hips (77%) had osteoarthritis as the primary diagnosis. No significant differences were detected, for any of the five health outcome systems, among the paper, touch screen, and web-based modes, and there were highly significant correlations among all questionnaire modes in the entire series of patients and in the preoperative and postoperative subgroups (p < 0.001). Conclusions: The scores obtained with the paper, touch screen, and web-based modes of the five questionnaires demonstrated excellent agreement. Thus, touch screen and web-based formats can be used to collect and track patient outcome data. Use of electronic formats of these questionnaires will facilitate a more efficient and reliable data collection process. C1 [Shervin, Nina] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthopaed Biomech & Biomat Lab, Boston, MA 02114 USA. RP Shervin, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthopaed Biomech & Biomat Lab, Jackson Bldg 1126,55 Fruit St, Boston, MA 02114 USA. EM hmalchau@partners.org NR 19 TC 18 Z9 18 U1 0 U2 3 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD FEB 2 PY 2011 VL 93A IS 3 BP 285 EP 293 DI 10.2106/JBJS.I.01104 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 721DY UT WOS:000287335000007 PM 21266642 ER PT J AU Courchesne, SL Karch, C Pazyra-Murphy, MF Segal, RA AF Courchesne, Stephanie L. Karch, Christoph Pazyra-Murphy, Maria F. Segal, Rosalind A. TI Sensory Neuropathy Attributable to Loss of Bcl-w SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SMALL-FIBER NEUROPATHY; CELL-CYCLE ENTRY; WALLERIAN DEGENERATION; MITOCHONDRIAL FISSION; AXONAL DEGENERATION; GROWTH-FACTOR; APOPTOSIS; DEATH; EXPRESSION; SURVIVAL AB Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small-diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w(-/-) mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w(-/-) sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w(-/-) mice as an animal model of small fiber sensory neuropathy and provide new insight regarding the role of Bcl-w and of mitochondria in preventing axonal degeneration. C1 [Courchesne, Stephanie L.; Karch, Christoph; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Courchesne, Stephanie L.; Karch, Christoph; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Courchesne, Stephanie L.; Karch, Christoph; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Segal, RA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu FU National Institutes of Health (NIH) [R01 NS050674, P30-HD-18655] FX This work was supported by National Institutes of Health (NIH) Grant R01 NS050674 (R.A.S.). S.L.C. is a Stuart H.Q. and Victoria Quan Fellow at Harvard Medical School. Confocal microscopy imaging was performed at the Mental Retardation Developmental Disability Research Center Imaging Core, Children's Hospital Boston (NIH Grant P30-HD-18655), and stereology imaging was performed at the Harvard NeuroDiscovery Optical Imaging Center. We thank Grant MacGregor (University of California, Irvine, Irvine, California) for the generous gift of bcl-w-/- mice. We thank members of Qiufu Ma's laboratory for helpful advice and discussion. We thank Jennifer Kalscheuer, Danny Lee, and Aymeric Hans for assistance, and Katharina Cosker and Sara Fenstermacher for discussion and manuscript suggestions. The research that is the basis of this paper was conducted before S.L.C. started employment at NIH. NR 50 TC 27 Z9 27 U1 0 U2 3 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 FEB 2 PY 2011 VL 31 IS 5 BP 1624 EP 1634 DI 10.1523/JNEUROSCI.3347-10.2011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 715WE UT WOS:000286922100010 PM 21289171 ER PT J AU Miyazono, S Isayama, T Makino, CL AF Miyazono, Sadaharu Isayama, Tomoki Makino, Clint L. TI Vitamin A as an Activator and Sensitizing Chromophore for Rhodopsin SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 55th Annual Meeting of the Biophysical-Society CY MAR 05-09, 2011 CL Baltimore, MD SP Biophys Soc C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 2 PY 2011 VL 100 IS 3 SU 1 BP 22 EP 22 PG 1 WC Biophysics SC Biophysics GA 972PF UT WOS:000306288600113 ER PT J AU Kural, C Boulant, S Kirchhausen, T AF Kural, Comert Boulant, Steeve Kirchhausen, Tomas TI Real-Time Imaging of Clathrin Dynamics in Three Dimensions SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 55th Annual Meeting of the Biophysical-Society CY MAR 05-09, 2011 CL Baltimore, MD SP Biophys Soc C1 [Kural, Comert; Boulant, Steeve; Kirchhausen, Tomas] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 2 PY 2011 VL 100 IS 3 SU 1 BP 30 EP 30 PG 1 WC Biophysics SC Biophysics GA 972PF UT WOS:000306288600155 ER PT J AU Wu, J Ruas, JL Estall, JL Rasbach, KA Choi, JH Ye, L Bostrom, P Tyra, HM Crawford, RW Campbell, KP Rutkowski, DT Kaufman, RJ Spiegelman, BM AF Wu, Jun Ruas, Jorge L. Estall, Jennifer L. Rasbach, Kyle A. Choi, Jang Hyun Ye, Li Bostroem, Pontus Tyra, Heather M. Crawford, Robert W. Campbell, Kevin P. Rutkowski, D. Thomas Kaufman, Randal J. Spiegelman, Bruce M. TI The Unfolded Protein Response Mediates Adaptation to Exercise in Skeletal Muscle through a PGC-1 alpha/ATF6 alpha Complex SO CELL METABOLISM LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; ER STRESS; CELL FUNCTION; TRANSCRIPTION; PGC-1; COACTIVATORS; EXPRESSION; INCREASES; PATHWAYS; DISEASE AB Exercise has been shown to be effective for treating obesity and type 2 diabetes. However, the molecular mechanisms for adaptation to exercise training are not fully understood. Endoplasmic reticulum (ER) stress has been linked to metabolic dysfunction. Here we show that the unfolded protein response (UPR), an adaptive response pathway that maintains ER homeostasis upon luminal stress, is activated in skeletal muscle during exercise and adapts skeletal muscle to exercise training. The transcriptional coactivator PGC-1 alpha, which regulates several exercise-associated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6 alpha. Efficient recovery from acute exercise is compromised in ATF6 alpha(-/-) mice. Blocking ER-stress-related cell death via deletion of CHOP partially rescues the exercise intolerance phenotype in muscle-specific PGC-1 alpha KO mice. These findings suggest that modulation of the UPR through PGC1 alpha represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits. C1 [Wu, Jun; Ruas, Jorge L.; Estall, Jennifer L.; Rasbach, Kyle A.; Choi, Jang Hyun; Ye, Li; Bostroem, Pontus; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Wu, Jun; Ruas, Jorge L.; Estall, Jennifer L.; Rasbach, Kyle A.; Choi, Jang Hyun; Ye, Li; Bostroem, Pontus; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kaufman, Randal J.] Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Kaufman, Randal J.] Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. [Tyra, Heather M.; Rutkowski, D. Thomas] Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. [Crawford, Robert W.; Campbell, Kevin P.] Univ Iowa, Howard Hughes Med Inst, Carver Coll Med, Iowa City, IA 52242 USA. [Crawford, Robert W.; Campbell, Kevin P.] Univ Iowa, Howard Hughes Med Inst, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Crawford, Robert W.; Campbell, Kevin P.] Univ Iowa, Howard Hughes Med Inst, Dept Neurol, Iowa City, IA 52242 USA. [Crawford, Robert W.; Campbell, Kevin P.] Univ Iowa, Howard Hughes Med Inst, Dept Internal Med, Iowa City, IA 52242 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu RI Choi, Jang Hyun/B-3055-2012; OI Ruas, Jorge/0000-0002-1110-2606 FU National Institutes of Health (NIH) [DK61562, DK54477, 1137, DK042394, R01 HL052173, P01 HL057346]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK084058]; Wellstone Muscular Dystrophy Cooperative Research Center [U54 NS053672]; Howard Hughes Medical Institute; American Heart Association [POST2010078] FX We thank Dina Laznik and Kevin Brannan for excellent technical assistance. We thank Dr. Umut Ozcan for the adenovirus expressing ATF6 alpha N. We thank members of the Spiegelman laboratory for helpful comments, especially Drs. Patrick Seale and Melin Khandekar. This work was supported by National Institutes of Health (NIH) grants (to B.M.S., DK61562 and DK54477). Portions of this work were supported by NIH 1137 DK042394, R01 HL052173, and P01 HL057346 to R.J.K. and R01 DK084058 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to D.T.R. This work was supported in part by the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center grant 1 U54 NS053672 (to K.P.C.). K.P.C. is an investigator of the Howard Hughes Medical Institute. J.W. was supported by a postdoctoral fellowship from the American Heart Association (Founders Affiliate #09POST2010078). J.W. and B.M.S. conceived and designed the experiments. J.W., J.L.R., J.L.E., K.A.R., J.H.C., L.Y., P.B., H.M.T., and R.W.C. performed the experiments. J.W. and B.M.S. analyzed the data and wrote the paper. Work with ATF6 alpha-/- and IRE1 alpha deleted myotubes was done with the laboratory of R.J.K. Work with ATF6 alpha-/- mice was done with the laboratories of K.P.C. and D.T.R. NR 27 TC 91 Z9 97 U1 2 U2 17 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 FEB 2 PY 2011 VL 13 IS 2 BP 160 EP 169 DI 10.1016/j.cmet.2011.01.003 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 722KR UT WOS:000287431600009 PM 21284983 ER PT J AU Axon, RN Williams, MV AF Axon, R. Neal Williams, Mark V. TI Hospital Readmission as an Accountability Measure SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INPATIENT CARE; QUALITY; ASSOCIATION C1 [Axon, R. Neal] Ralph H Johnson VAMC, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. [Axon, R. Neal] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC USA. [Williams, Mark V.] Northwestern Univ, Feinberg Sch Med, Div Hosp Med, Chicago, IL 60611 USA. RP Axon, RN (reprint author), 135 Rutledge Ave,MSC 591, Charleston, SC 29425 USA. EM axon@musc.edu NR 10 TC 135 Z9 135 U1 0 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 2 PY 2011 VL 305 IS 5 BP 504 EP 505 DI 10.1001/jama.2011.72 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 714LI UT WOS:000286810700026 PM 21285430 ER PT J AU Holschneider, DP Bradesi, S Mayer, EA AF Holschneider, Daniel P. Bradesi, Sylvie Mayer, Emeran A. TI The role of experimental models in developing new treatments for irritable bowel syndrome SO EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Review DE functional gastrointestinal disorders; intestinal transit; neuroimaging; visceral pain ID C-FOS EXPRESSION; 5-HT3 RECEPTOR ANTAGONIST; FUNCTIONAL GASTROINTESTINAL DISORDERS; REGIONAL BRAIN ACTIVATION; KAPPA-AGONIST FEDOTOZINE; ROBALZOTAN TARTRATE MONOHYDRATE; NOXIOUS COLORECTAL DISTENSION; LUMBOSACRAL SPINAL-CORD; COLONIC DISTENSION; VISCERAL PAIN AB Irritable bowel syndrome (IBS) is characterized by chronic, recurrent abdominal pain and altered bowel habits and is currently defined by symptom criteria and the absence of detectable organic disease. The underlying pathophysiology remains incompletely understood. Despite considerable efforts by the scientific community and the pharmaceutical industry to develop novel pharmacological treatments aimed at chronic visceral pain, the traditional approach to identifying and evaluating novel drugs for this target have largely failed to translate into effective IBS treatments. However, several novel drugs aimed at normalizing bowel movements have produced clinical effects, not only on the primary target, but also on pain and discomfort. While some of the commonly used experimental animal models for the pain dimension of IBS have some face and construct validity, the predictive validity of most of the models is either unknown, or has been disappointing. A reverse translational approach is proposed, which is based on identification and characterization of brain endophenotypes in patients, followed by translation of these endophenotypes for pharmacological studies in rodent models. C1 [Holschneider, Daniel P.; Bradesi, Sylvie; Mayer, Emeran A.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Holschneider, Daniel P.] Univ So Calif, Dept Psychiat, Los Angeles, CA USA. [Holschneider, Daniel P.] Univ So Calif, Dept Behav Sci Neurol Cell & Neurobiol, Los Angeles, CA USA. [Bradesi, Sylvie; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, UCLA Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. [Bradesi, Sylvie; Mayer, Emeran A.] Univ Calif Los Angeles, Sch Med, Dept Physiol, UCLA Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. [Bradesi, Sylvie; Mayer, Emeran A.] Univ Calif Los Angeles, Sch Med, Dept Psychiat, UCLA Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. RP Bradesi, S (reprint author), VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. EM sbradesi@ucla.edu FU NIH [DK 48351, DK 64539, DA026597] FX The work discussed in this paper is supported by NIH grants DK 48351, DK 64539, DA026597. The authors have 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. NR 133 TC 13 Z9 14 U1 2 U2 3 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4124 J9 EXPERT REV GASTROENT JI Expert Rev. Gastroenterol. Hepatol. PD FEB PY 2011 VL 5 IS 1 BP 43 EP 57 DI 10.1586/EGH.10.88 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 861SL UT WOS:000298039400011 PM 21309671 ER PT J AU Biagtan, MJ Viswanathan, RK Mathur, SK AF Biagtan, M. J. Viswanathan, R. K. Mathur, S. K. TI The Chronic Urticaria Index as a Predictor of Responsiveness to Therapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Biagtan, M. J.; Viswanathan, R. K.; Mathur, S. K.] Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. [Mathur, S. K.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB104 EP AB104 DI 10.1016/j.jaci.2010.12.417 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400400 ER PT J AU Blumenthal, KG Patil, S Ling, M Long, A AF Blumenthal, K. G. Patil, S. Ling, M. Long, A. TI The Importance of Vancomycin in Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Blumenthal, K. G.; Patil, S.; Ling, M.; Long, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB198 EP AB198 DI 10.1016/j.jaci.2010.12.787 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400769 ER PT J AU Ford, LS Bloom, KA Nowak-Wegrzyn, AH Chase, AZ Hertzberg, EH Bencharitiwong, R Shreffler, WG Sampson, HA AF Ford, L. S. Bloom, K. A. Nowak-Wegrzyn, A. H. Chase, A. Z. Hertzberg, E. H. Bencharitiwong, R. Shreffler, W. G. Sampson, H. A. TI Basophil Reactivity, IgE and IgG(4) Among Subjects with Various Levels of Milk Tolerance SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Ford, L. S.; Bloom, K. A.; Nowak-Wegrzyn, A. H.; Chase, A. Z.; Hertzberg, E. H.; Bencharitiwong, R.; Sampson, H. A.] Mt Sinai Sch Med, New York, NY USA. [Shreffler, W. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB29 EP AB29 DI 10.1016/j.jaci.2010.12.125 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400109 ER PT J AU Ling, M Begun, J Patil, S Hamilos, DL AF Ling, M. Begun, J. Patil, S. Hamilos, D. L. TI Eosinophilic Cholangiopathy Presenting With Peripheral Eosinophilia and Hepatic Mass SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Ling, M.; Begun, J.; Patil, S.; Hamilos, D. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB108 EP AB108 DI 10.1016/j.jaci.2010.12.433 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400415 ER PT J AU Lu, TX Fabry, V Lim, E Cole, ET Orkin, SH Rothenberg, ME AF Lu, T. X. Fabry, V. Lim, E. Cole, E. T. Orkin, S. H. Rothenberg, M. E. TI MicroRNA-21 Deficiency Leads to an Attenuated Asthma Response in Mice SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Lu, T. X.; Fabry, V.; Lim, E.; Cole, E. T.; Rothenberg, M. E.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Orkin, S. H.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB220 EP AB220 DI 10.1016/j.jaci.2010.12.877 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400858 ER PT J AU Parikh, N Verma, P Lee, S Klaustermeyer, WB AF Parikh, N. Verma, P. Lee, S. Klaustermeyer, W. B. TI Inhaler Use and Effect on Asthma Control SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Parikh, N.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Verma, P.; Lee, S.; Klaustermeyer, W. B.] Univ Calif Los Angeles, Div Allergy Immunol, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB159 EP AB159 DI 10.1016/j.jaci.2010.12.631 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400613 ER PT J AU Patil, S Ling, M Wilson, MT Long, A Hesterberg, P Wong, JT Banerji, A AF Patil, S. Ling, M. Wilson, M. T. Long, A. Hesterberg, P. Wong, J. T. Banerji, A. TI Repeat Skin Testing Improves Risk Stratification For Platinum-based Chemotherapy Desensitizations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Patil, S.; Ling, M.; Wilson, M. T.; Long, A.; Hesterberg, P.; Wong, J. T.; Banerji, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB143 EP AB143 DI 10.1016/j.jaci.2010.12.569 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400551 ER PT J AU Ruiter, B Shreffler, WG AF Ruiter, B. Shreffler, W. G. TI Human Dendritic Cells Stimulated with Peanut Extract Express High Levels of RALDH2 and Induce RA-Sensitive Genes in Naive T Cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Ruiter, B.; Shreffler, W. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB263 EP AB263 DI 10.1016/j.jaci.2010.12.1047 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846401161 ER PT J AU Verma, P Randhawa, I Klaustermeyer, WB AF Verma, P. Randhawa, I. Klaustermeyer, W. B. TI Severe Geriatric Asthma: Efficacy of Omalizumab in a VA population SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Verma, P.; Klaustermeyer, W. B.] Univ Calif Los Angeles, Div Allergy Immunol, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB160 EP AB160 DI 10.1016/j.jaci.2010.12.634 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400616 ER PT J AU Viswanathan, RK Biagtan, MJ Kelly, JT Moss, MH Mathur, SK AF Viswanathan, R. K. Biagtan, M. J. Kelly, J. T. Moss, M. H. Mathur, S. K. TI Phenotypic Profile of Potential Responders to Omalizumab in Chronic Idiopathic Urticaria SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Viswanathan, R. K.; Biagtan, M. J.; Kelly, J. T.; Moss, M. H.; Mathur, S. K.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Mathur, S. K.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB103 EP AB103 DI 10.1016/j.jaci.2010.12.414 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400397 ER PT J AU Selinger, S Restrepo, MI Copeland, LA Pugh, MJV Nakashima, B Downs, JR Anzueto, A Mortensen, EM AF Selinger, Scott Restrepo, Marcos I. Copeland, Laurel A. Pugh, Mary Jo V. Nakashima, Brandy Downs, John R. Anzueto, Antonio Mortensen, Eric M. TI Pneumonia in the Elderly Hospitalized in the Department of Veteran Affairs Health Care System SO MILITARY MEDICINE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; VALIDATION; FACILITIES; MORTALITY; OUTCOMES; THERAPY; IMPACT AB Pneumonia is a major cause of hospital admissions and deaths worldwide. Our aim was to examine the trends in admissions for pneumonia in the Department of Veterans Affairs (VA). We examined data for the fiscal years 2002 through 2007 on patients aged 65 years and older hospitalized with pneumonia by using VA administrative databases. The numbers of hospital admissions for pneumonia were relatively stable during this period. However, length of hospital stay and 30- and 90-day mortality decreased during this period. The proportion of patients admitted to the intensive care unit remained relatively constant, but fewer received mechanical ventilation; there was substantial increase in noninvasive ventilation. In the VA, pneumonia-related admissions are being managed more effectively even as the overall number of admissions remains stable. C1 [Selinger, Scott; Downs, John R.; Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Gen Internal Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Copeland, Laurel A.; Pugh, Mary Jo V.; Nakashima, Brandy; Downs, John R.; Anzueto, Antonio; Mortensen, Eric M.] VERDICT S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. RP Selinger, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Gen Internal Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RI Restrepo, Marcos/H-4442-2014; OI Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU National Institute of Nursing Research [R01NR0I0828]; Department of Veteran Affairs Veterans Integrated Service Network [17]; National Health Institute [KL2 RR025766]; Veterans Health Administration [MRP-05-145] FX This project was supported by grant number R01NR0I0828 from the National Institute of Nursing Research. Dr. Restrepo is supported by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and National Health Institute Grant KL2 RR025766. Dr. Copeland is supported by Veterans Health Administration Grant MRP-05-145. The funding agencies had no role in conducting the study or in the preparation, review, or approval of the manuscript. NR 21 TC 0 Z9 0 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD FEB PY 2011 VL 176 IS 2 BP 214 EP 217 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 825BL UT WOS:000295245800020 PM 21366087 ER PT J AU Stroffolini, T Deuffic-Burban, S Deltenre, P Buti, M Parkes, J Muhlberger, N Siebert, U Moreno, C Hatzakis, A Rosenberg, W Zeuzem, S Mathurin, P AF Stroffolini, T. Deuffic-Burban, S. Deltenre, P. Buti, M. Parkes, J. Muehlberger, N. Siebert, U. Moreno, C. Hatzakis, A. Rosenberg, W. Zeuzem, S. Mathurin, P. TI HCV burden in Europe: Impact of national treatment practices on future HCV-related morbidity and mortality through a modeling approach SO DIGESTIVE AND LIVER DISEASE LA English DT Meeting Abstract C1 [Stroffolini, T.; Mathurin, P.] Policlin Umberto 1, Dipartimento Malattie Infett & Tropicali, Rome, Italy. [Deuffic-Burban, S.] INSERM, U995, F-59045 Lille, France. [Deuffic-Burban, S.; Mathurin, P.] Univ Lille Nord France, EA 2694, Lille, France. [Deltenre, P.] CHU Lille, Hop Huriez, Serv Hepatogastroenterol, F-59037 Lille, France. [Deltenre, P.] Hop Jolimont, Serv Hepatogastroenterol, Haine St Paul, Belgium. [Buti, M.] Univ Valle Hebron, Gen Hosp, Liver Unit, Dept Internal Med Hepatol, Barcelona, Spain. [Parkes, J.] Univ Southampton, Sch Med, Southampton, Hants, England. [Muehlberger, N.; Siebert, U.] Univ Hlth Sci Med Informat & Technol, UMIT, Innsbruck, Austria. [Siebert, U.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Moreno, C.] ULB, Hop Erasme, Dept Gastroenterol & Hepatopancreatol, Brussels, Belgium. [Hatzakis, A.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Rosenberg, W.] UCL, Inst Hepatol, London, England. [Zeuzem, S.] Goethe Univ Hosp, Frankfurt, Germany. [Buti, M.] Inst Salud Carlos III, Ciber ehd, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD FEB PY 2011 VL 43 SU 2 BP S70 EP S70 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 808ZW UT WOS:000294021500018 ER PT J AU Silver, AL Yager, P Purohit, P Noviski, N Hartnick, CJ AF Silver, Amanda L. Yager, Phoebe Purohit, Prashant Noviski, Natan Hartnick, Christopher J. TI Dexmedetomidine Use in Pediatric Airway Reconstruction SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT AAO-HNSF Annual Meeting and OTO EXPO CY SEP 25-29, 2010 CL Boston, MA SP AAO, HNSF DE dexmedetomidine; pediatric; airway reconstruction; laryngotracheal reconstruction; laryngeal cleft repair ID PROPOFOL INFUSION SYNDROME; HIGH-DOSE DEXMEDETOMIDINE; LARYNGOTRACHEAL RECONSTRUCTION; INTENSIVE-CARE; SEDATION AB Objective. Assess the postoperative use of dexmedetomidine (Precedex) in pediatric patients following airway reconstruction. Study Design. Historical cohort study. Setting. Tertiary medical center. Subjects and Methods. A retrospective review of 24 children undergoing laryngotracheal reconstruction (LTR) or laryngeal cleft repair (LCR) was conducted. Twelve children were treated with standard sedation protocols where dexmedetomidine was administered in lieu of propofol (Diprivan); 12 age-, gender-, and procedure-matched controls were selected. Subjects were divided into groups based on duration of postoperative intubation for cross-comparison; group 1 was intubated <24 hours, group 2 was intubated 2 to 6 days, and group 3 was intubated 7 days or longer. Baseline heart rate and blood pressure measurements were compared to hourly measurements for the first 6 hours following initiation of dexmedetomidine or mechanical ventilation in the control group. Number of supportive respiratory interventions, adverse events, self-extubations, premature termination of dexmedetomidine, amount of muscle relaxants, agents to treat withdrawal, and length of stay were evaluated. Results. Ten patients undergoing LTR and 2 patients undergoing LCR receiving dexmedetomidine were compared to 10 LTR and 2 LCR control patients. Overall, dexmedetomidine was well tolerated and without significant adverse effects, particularly in cases of short-term intubation or as a bridge to extubation. Conclusion. In cases requiring short-term intubation following airway reconstruction, dexmedetomidine may offer a safe alternative to propofol by providing readily reversible sedation during the periextubation period. Further studies are needed to determine the safety, efficacy, dosing, and potential complications of longer term dexmedetomidine administration in pediatric airway reconstruction. C1 [Silver, Amanda L.; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Silver, Amanda L.; Hartnick, Christopher J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Yager, Phoebe; Noviski, Natan] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Purohit, Prashant] Univ Hawaii, Pediat Residency Program, Honolulu, HI 96822 USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu NR 19 TC 5 Z9 6 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD FEB PY 2011 VL 144 IS 2 BP 262 EP 267 DI 10.1177/0194599810391397 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808RV UT WOS:000293997000023 PM 21493428 ER PT J AU Taft, CT Watkins, LE Stafford, J Street, AE Monson, CM AF Taft, Casey T. Watkins, Laura E. Stafford, Jane Street, Amy E. Monson, Candice M. TI Posttraumatic Stress Disorder and Intimate Relationship Problems: A Meta-Analysis SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE PTSD; intimate relationships; couples; trauma ID VIETNAM COMBAT VETERANS; IRAQI FREEDOM VETERANS; TRAUMA-EXPOSED ADULTS; PARTNER VIOLENCE; DOMESTIC VIOLENCE; CONFLICT-TACTICS; MARITAL SATISFACTION; FORMER PRISONERS; SYMPTOMS; FAMILY AB Objective: The authors conducted a meta-analysis of empirical studies investigating associations between indices of posttraumatic stress disorder (PTSD) and intimate relationship problems to empirically synthesize this literature. Method: A literature search using PsycINFO, Medline, Published International Literature on Traumatic Stress (PILOTS), and Dissertation Abstracts was performed. The authors identified 31 studies meeting inclusion criteria. Results: True score correlations (p) revealed medium-sized associations between PTSD and intimate relationship discord (p = .38, N = 7,973, K = 21), intimate relationship physical aggression perpetration (p = .42, N = 4,630, K = 19), and intimate relationship psychological aggression perpetration (p = .36, N = 1,501, K = 10). The strength of the association between PTSD and relationship discord was higher in military (vs. civilian) samples, and when the study was conducted in the United States (vs. other country), and the study represented a doctoral dissertation (vs. published article). The strength of the association between PTSD and physical aggression was higher in military (vs. civilian) samples, males (vs. females), community (vs. clinical) samples, studies examining PTSD symptom severity (vs. diagnosis), when the physical aggression measure focused exclusively on severe violence (vs. a more inclusive measure), and the study was published (vs. dissertation). For the PTSD psychological aggression association, 98% of the variance was accounted for by methodological artifacts such as sampling and measurement error; consequently, no moderators were examined in this relationship. Conclusions: Findings highlight a need for the examination of models explaining the relationship difficulties associated with PTSD symptomatology and interventions designed to treat problems in both areas. C1 [Taft, Casey T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Taft, Casey T.; Street, Amy E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Stafford, Jane] Univ S Carolina, Dept Psychol, Aiken, SC USA. [Street, Amy E.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Monson, Candice M.] Ryerson Univ, Dept Psychol, Toronto, ON, Canada. RP Taft, CT (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, 116B-4,150 S Huntington Ave, Boston, MA 02130 USA. EM casey.taft@va.gov FU NIMH NIH HHS [K08 MH7311701A2] NR 73 TC 124 Z9 127 U1 13 U2 49 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD FEB PY 2011 VL 79 IS 1 BP 22 EP 33 DI 10.1037/a0022196 PG 12 WC Psychology, Clinical SC Psychology GA 714ZD UT WOS:000286849300003 PM 21261431 ER PT J AU Kovach, AE Lam, Q Dias-Santagata, D Sadow, PM AF Kovach, A. E. Lam, Q. Dias-Santagata, D. Sadow, P. M. TI Molecular Analysis of Adrenal Cortical Carcinomas in Clinical and Histologic Context SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 577 BP 138A EP 138A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000017 ER PT J AU Fan, XS Chen, JY Feng, AN Wu, HY Gold, JS Huang, Q AF Fan, X. S. Chen, J. Y. Feng, A. N. Wu, H. Y. Gold, J. S. Huang, Q. TI HER2 Protein Over-Expression in Proximal and Distal Gastric Cancers: An Immunohistochemical and Clinicopathological Comparison Study of 957 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Nanjing Drum Tower Hosp, Nanjing, Jiangsu, Peoples R China. VA Boston Healthcare Syst, W Roxbury, MA USA. Harvard Univ, Sch Med, W Roxbury, MA USA. RI Gold, Jason/O-5112-2014 OI Gold, Jason/0000-0002-2925-4755 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 620 BP 148A EP 148A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000060 ER PT J AU Huang, Q Gold, JK Wu, HY Fan, XS Feng, AN Shi, J AF Huang, Q. Gold, J. K. Wu, H. Y. Fan, X. S. Feng, A. N. Shi, J. TI Pancreatic Acinar-Like Adenocarcinoma of the Proximal Stomach Involving the Esophagus in Chinese Patients: A Clinicopathological Study of 41 Cases from a Single High-Volume Hospital in China. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP US & Canadian Acad Pathol (USCAP) C1 Nanjing Drum Tower Hosp, Nanjing, Peoples R China. VA Boston Healthcare Syst, W Roxbury, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 640 BP 152A EP 152A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000080 ER PT J AU Kim, A Park, MK Kim, KB Kim, JY Shin, N Choi, KU Park, DY Lauwers, GY AF Kim, A. Park, M-K Kim, K-B Kim, J-Y Shin, N. Choi, K-U Park, D. Y. Lauwers, G. Y. TI P53 Expression and Proliferation Index Measured by Ki-67 Immunostaining in Gastric Pit Dysplasia. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Pusan Natl Univ Hosp, Pusan, South Korea. Pusan Natl Univ, Sch Med, Pusan, South Korea. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 654 BP 156A EP 156A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000094 ER PT J AU Lisovsky, M Mino-Kenudson, M Lefferts, J Courville, E Zaki, B Calvo, LN Hong, TS Tsongalis, GJ Lawyers, GY Srivastava, A AF Lisovsky, M. Mino-Kenudson, M. Lefferts, J. Courville, E. Zaki, B. Calvo, L. N. Hong, T. S. Tsongalis, G. J. Lawyers, G. Y. Srivastava, A. TI MGMT (O6-MethylguanineDNA Methyltransferase) Is Inactivated in a Significant Subset of Distal Esophageal Adenocarcinomas: Implications for Neoadjuvant Chemoradiation Therapy. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 660 BP 157A EP 157A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000100 ER PT J AU Lisovsky, M Jiang, Z Lawyers, GY AF Lisovsky, M. Jiang, Z. Lawyers, G. Y. TI Oncofetal Protein IMP3 as a Predictor of Prognosis in Gastric Adenocarcinoma. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. UMassMem Med Ctr, Worcester, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 659 BP 157A EP 157A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000099 ER PT J AU Nosho, K Dranoff, G Fuchs, C Ogino, S AF Nosho, K. Dranoff, G. Fuchs, C. Ogino, S. TI Tumor-Infiltrating CD45RO+-Cell Density, but Not CD3+, CD8+, or FOXP3+-Cell Density, Has a Prognostic Role in Colorectal Cancer, Independent of Molecular Features SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 672 BP 160A EP 160A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000112 ER PT J AU Ogino, S Tanaka, N Fuchs, C AF Ogino, S. Tanaka, N. Fuchs, C. TI Multivariate Negative Binomial Regression Identifies Length of Colorectal Resection, Proximal Tumor Location, T3N0M0 Stage, Academic Setting, and Tumor PIK3CA Mutation as Independent Predictors of Lymph Node Count SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 675 BP 160A EP 161A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000115 ER PT J AU Ogino, S Fuchs, C Huttenhower, C AF Ogino, S. Fuchs, C. Huttenhower, C. TI LINE-1 Extreme Hypomethylator Is a New Distinct Molecular Subtype Associated with Young Age and Poor Prognosis: Bioinformatic Analysis of 1190 Colorectal Cancers SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 676 BP 161A EP 162A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000116 ER PT J AU Rege, TA Wagner, AJ Corless, CL Hornick, JL AF Rege, T. A. Wagner, A. J. Corless, C. L. Hornick, J. L. TI "Pediatric-Type" Gastrointestinal Stromal Tumors in Adults: Distinctive Histology Predicts Genotype and Clinical Behavior. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 690 BP 165A EP 165A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000130 ER PT J AU Shimizu, M Aida, J Brown, IS Greenson, JK Jouret-Mourin, A Kawachi, H Lennerz, JK Nagata, K Takubo, K Vieth, M Lauwers, GY AF Shimizu, M. Aida, J. Brown, I. S. Greenson, J. K. Jouret-Mourin, A. Kawachi, H. Lennerz, J. K. Nagata, K. Takubo, K. Vieth, M. Lauwers, G. Y. TI Evaluation of Esophageal Biopsies for Squamous Intraepithelial Neoplasia: Differences between Japan and the West. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Saitama Med Univ, Int Med Ctr, Hidaka, Japan. Tokyo Metropolitan Inst Gerontol, Tokyo, Japan. Sullivan Nicolaides Pathol, Brisbane, Qld, Australia. Univ Michigan, Ann Arbor, MI 48109 USA. Catholic Univ Louvain, B-1200 Brussels, Belgium. Tokyo Med & Dent Univ, Tokyo, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Klinikum Bayreuth, Bayreuth, Germany. RI Brown, Ian/R-7763-2016 OI Brown, Ian/0000-0001-6329-2547 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 701 BP 167A EP 167A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000141 ER PT J AU Virk, RK Lauwers, GY Deshpande, V AF Virk, R. K. Lauwers, G. Y. Deshpande, V. TI The Significance of IGG4 in Inflammatory Bowel Disease SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 UMass Mem Med Ctr, Worcester, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 719 BP 172A EP 172A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000159 ER PT J AU Wang, H Chen, Y Deshpande, V AF Wang, H. Chen, Y. Deshpande, V. TI Heterogeneity in Signaling Pathways of Gastrointestinal Neuroendocrine Cell Tumors: A Critical Look at Notch Signaling Pathway SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Univ Delaware, Newark, DE USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 721 BP 172A EP 173A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000161 ER PT J AU Berger, MF Lawrence, MS Demichelis, F Getz, G Rubin, MA Garraway, LA AF Berger, M. F. Lawrence, M. S. Demichelis, F. Getz, G. Rubin, M. A. Garraway, L. A. TI Characterization of Complex Chromosomal Aberrations in Primary Prostate Cancer Genomes SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Broad Inst, Weill Cornell Med Coll, Prostate Genome Consortium, Cambridge, England. Weill Cornell Med Coll, New York, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 752 BP 179A EP 179A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000192 ER PT J AU Flavin, R Hendrickson, W Krunz, L Judson, G Lis, R Bailey, D Fiorentino, M Finn, S Martin, N Stark, J Pettersson, A Sinnott, J Penny, K Fall, K Giovannucci, E Rubin, M Kantoff, P Stampfer, M Loda, M Mucci, L AF Flavin, R. Hendrickson, W. Krunz, L. Judson, G. Lis, R. Bailey, D. Fiorentino, M. Finn, S. Martin, N. Stark, J. Pettersson, A. Sinnott, J. Penny, K. Fall, K. Giovannucci, E. Rubin, M. Kantoff, P. Stampfer, M. Loda, M. Mucci, L. TI SPINK1 Protein Expression and Prostate Cancer Progression SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 810 BP 192A EP 192A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000250 ER PT J AU He, W Cheville, JC Sadow, PM Gopalan, A Fine, SW Al-Ahmadie, HA Chen, Y Oliva, E Russo, P Reuter, VE Tickoo, SK AF He, W. Cheville, J. C. Sadow, P. M. Gopalan, A. Fine, S. W. Al-Ahmadie, H. A. Chen, Y. Oliva, E. Russo, P. Reuter, V. E. Tickoo, S. K. TI Pathologic Characteristics and Clinical Outcome of Renal Epithelioid Angiomyolipoma: A Multi-Institutional Experience Based on Primary Tumor Resections SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Mayo Clin, Rochester, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 829 BP 196A EP 197A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000269 ER PT J AU Kao, CS Idrees, MT Young, RH Ulbright, TM AF Kao, C-S Idrees, M. T. Young, R. H. Ulbright, T. M. TI Solid Pattern of Testicular Yolk Sac Tumor: A Morphologic and Immunohistochemical Study of 52 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Indiana Univ, Sch Med, Indianapolis, IN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 853 BP 202A EP 202A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000293 ER PT J AU Pettersson, A Flavin, R Stark, J Fiorentino, M Pollak, A Penney, K Sesso, HD Gleave, M Bismar, TA Perner, S Finn, S Rubin, MA Ma, J Giovannucci, E Stampfer, M Kantoff, P Loda, M Mucci, L AF Pettersson, A. Flavin, R. Stark, J. Fiorentino, M. Pollak, A. Penney, K. Sesso, H. D. Gleave, M. Bismar, T. A. Perner, S. Finn, S. Rubin, M. A. Ma, J. Giovannucci, E. Stampfer, M. Kantoff, P. Loda, M. Mucci, L. TI TMPRSS2:ERG Rearrangement and Markers of Metabolic Signaling Pathways Implicated in Prostate Carcinogenesis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 [Pettersson, A.; Flavin, R.; Stark, J.; Fiorentino, M.; Pollak, A.; Penney, K.; Sesso, H. D.; Gleave, M.; Bismar, T. A.; Perner, S.; Finn, S.; Rubin, M. A.; Ma, J.; Giovannucci, E.; Stampfer, M.; Kantoff, P.; Loda, M.; Mucci, L.] Dana Farber Harvard Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 917 BP 217A EP 218A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000357 ER PT J AU Ryan, RJ Wu, S Borger, D Iafrate, J Wu, CL Le, L AF Ryan, R. J. Wu, S. Borger, D. Iafrate, J. Wu, C-L Le, L. TI The Lymphoma-Associated EZH2 Codon 641 Mutation Is Not Detected in Localized Prostate Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 [Ryan, R. J.; Wu, S.; Borger, D.; Iafrate, J.; Wu, C-L; Le, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 933 BP 221A EP 221A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000373 ER PT J AU Stampfer, MJ Penney, K Sinnott, J Flavin, R Stark, J Finn, S Giovannucci, E Sesso, H Loda, M Mucci, L Fiorentino, M AF Stampfer, M. J. Penney, K. Sinnott, J. Flavin, R. Stark, J. Finn, S. Giovannucci, E. Sesso, H. Loda, M. Mucci, L. Fiorentino, M. TI Does Gleason Grade Progress over Time? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 [Stampfer, M. J.; Penney, K.; Sinnott, J.; Flavin, R.; Stark, J.; Finn, S.; Giovannucci, E.; Sesso, H.; Loda, M.; Mucci, L.; Fiorentino, M.] Dana Farber Harvard Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 952 BP 225A EP 225A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000392 ER PT J AU Stark, JR Finn, SP Ma, J Sinnott, JA Schumacher, F Lis, R Penney, KL Kasperzyk, JL Sesso, HD Stampfer, MJ Giovannucci, EL Loda, M Mucci, LA AF Stark, J. R. Finn, S. P. Ma, J. Sinnott, J. A. Schumacher, F. Lis, R. Penney, K. L. Kasperzyk, J. L. Sesso, H. D. Stampfer, M. J. Giovannucci, E. L. Loda, M. Mucci, L. A. TI Adiponectin Receptor 2 Expression Predicts Lethal Prostate Cancer SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Dublin, Trin Coll, Dublin, Ireland. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Calif Los Angeles, Keck Sch Med, Los Angeles, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 954 BP 226A EP 226A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000394 ER PT J AU Al-Agha, OM Huwait, HP Chow, C Yang, W Senz, JE Kalloger, SG Huntsman, DH Young, R Gilks, CB AF Al-Agha, O. M. Huwait, H. P. Chow, C. Yang, W. Senz, J. E. Kalloger, S. G. Huntsman, D. H. Young, R. Gilks, C. B. TI Anti-FOXL2 Antibody Is a Sensitive and Specific Diagnostic Marker for Ovarian Sex Cord-Stromal Tumors. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Vancouver Gen Hosp, Vancouver, BC, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 988 BP 234A EP 234A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000428 ER PT J AU Azueta, A Gatius, S Velasco, A Santacana, M Pallares, J Clarke, B Oliva, E Matias-Guiu, X AF Azueta, A. Gatius, S. Velasco, A. Santacana, M. Pallares, J. Clarke, B. Oliva, E. Matias-Guiu, X. TI Dedifferentiated Carcinoma of the Endometrium and the Ovary: A Molecular Study of 8 Cases. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Univ Lleida, Hosp Univ Arnau Vilanova, IRB Lleida, Lleida, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. Toronto Gen Hosp, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 999 BP 236A EP 236A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000439 ER PT J AU Biscuola, M De Vijver, KV Castilla, MA Romero-Perez, L Lopez-Garcia, MA Palacios, J Oliva, E AF Biscuola, M. De Vijver, K. Van Castilla, M. A. Romero-Perez, L. Lopez-Garcia, M. A. Palacios, J. Oliva, E. TI Molecular Alterations in Endometrial Carcinosarcomas (ECS). SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Hosp Univ Virgen Rocio IBIS, Inst Biomed Sevilla, Seville, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Romero-Perez, Laura/C-8314-2015; Castilla, M Angeles/C-9454-2015 OI Romero-Perez, Laura/0000-0003-3196-4382; NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1004 BP 237A EP 238A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000444 ER PT J AU Castilla, MA Moreno-Bueno, G Romero-Perez, L Van De Vijver, K Biscuola, M Lopez-Garcia, MA Prat, J Matias-Guiu, X Cano, A Oliva, E Palacios, J AF Castilla, M. A. Moreno-Bueno, G. Romero-Perez, L. Van De Vijver, K. Biscuola, M. Lopez-Garcia, M. A. Prat, J. Matias-Guiu, X. Cano, A. Oliva, E. Palacios, J. TI Micro-RNA Signature of the Epithelial-Mesenchymal Transition in Endometrial Carcinosarcoma. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Hosp Univ Virgen Rocio IBIS, Seville, Spain. IdiPAZ Inst Invest La Paz, Inst Invest Biomed Alberto Sols CSIC UAM, Madrid, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. Hosp San Pau, Barcelona, Spain. Hosp Arnau Vilanova, Lleida, Spain. RI Romero-Perez, Laura/C-8314-2015; Castilla, M Angeles/C-9454-2015 OI Romero-Perez, Laura/0000-0003-3196-4382; NR 0 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1015 BP 240A EP 240A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000455 ER PT J AU Chiang, S Ali, R Lee, CH Gilks, B Oliva, E AF Chiang, S. Ali, R. Lee, C-H Gilks, B. Oliva, E. TI Frequency of Known Translocations Detected by Fluorescence In Situ Hybridization in Endometrial and Endometrioid Stromal Tumors (ESTs): A Study of 57 Patients. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. BC Canc Agcy, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1020 BP 241A EP 241A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000460 ER PT J AU Chiang, S Gilks, B Huntsman, DG Oliva, E AF Chiang, S. Gilks, B. Huntsman, D. G. Oliva, E. TI Immunohistochemical and Mutational Analysis of FOXL2 in Uterine Tumors Resembling Ovarian Sex-Cord Tumors. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. BC Canc Agcy, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1021 BP 241A EP 241A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000461 ER PT J AU Gilks, CB Oliva, E Soslow, R AF Gilks, C. B. Oliva, E. Soslow, R. TI Poor Interobserver Reproducibility in the Diagnosis of High-Grade Endometrial Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Vancouver Gen Hosp, Vancouver, BC, Canada. BC Childrens & Womens Hosp, Vancouver, BC, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1049 BP 248A EP 248A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000489 ER PT J AU Karst, AM Levanon, K Hirsch, MS Drapkin, R AF Karst, A. M. Levanon, K. Hirsch, M. S. Drapkin, R. TI Transformation of Fallopian Tube Epithelial Cells Leads to High-Grade Tumor Formation in a Xenograft Mouse Model SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Chaim Sheba Med Ctr, Sheba Canc Res Ctr, Ramat Gan, Israel. Brigham & Womens Hosp, Ramat Gan, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1063 BP 249A EP 249A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000495 ER PT J AU Karst, AM Levanon, K Duraisamy, S Liu, JF Hirsch, MS Drapkin, R AF Karst, A. M. Levanon, K. Duraisamy, S. Liu, J. F. Hirsch, M. S. Drapkin, R. TI Stathmin 1, a Marker of PI3K Pathway Activation and Regulator of Microtubule Dynamics, Is Expressed in Early Serous Ovarian Carcinomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Chaim Sheba Med Ctr, Sheba Canc Res Ctr, Ramat Gan, Israel. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1064 BP 249A EP 249A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000496 ER PT J AU Lim, D Gilks, B Longacre, T Nucci, MR Soslow, RA Oliva, E AF Lim, D. Gilks, B. Longacre, T. Nucci, M. R. Soslow, R. A. Oliva, E. TI Interobserver Variability in the Interpretation of Tumor Cell Necrosis (TCN) in Uterine Leiomyosarcoma (LMS). SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Natl Univ Hlth Syst, Singapore, Singapore. Vancouver Gen Hosp, Vancouver, BC, Canada. Stanford Univ, Stanford, CA 94305 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1086 BP 256A EP 256A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000526 ER PT J AU Lim, D Wang, WL Lee, CH Dodge, T Gilks, B Oliva, E AF Lim, D. Wang, W-L Lee, C-H Dodge, T. Gilks, B. Oliva, E. TI Old Versus New FIGO Staging Systems in Predicting Overall Survival in Patients with Uterine Leiomyosarcoma: A Study of 86 Cases. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Natl Univ Hlth Syst, Singapore, Singapore. Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. Vancouver Gen Hosp, Vancouver, BC, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1085 BP 256A EP 256A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000525 ER PT J AU Ning, G Laury, AR Quick, CM Hirsch, MS Drapkin, R Mehra, KK Mehrad, M McKeon, FD Crum, CP Xian, W AF Ning, G. Laury, A. R. Quick, C. M. Hirsch, M. S. Drapkin, R. Mehra, K. K. Mehrad, M. McKeon, F. D. Crum, C. P. Xian, W. TI Co-Ordinated Dysregulation of PAX2, ALDH1 and EZH2 in Tubal Serous Carcinogenesis. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Lukes Roosevelt Hosp, New York, NY USA. Washington Univ, St Louis, MO USA. A Star Inst Med Biol, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1110 BP 262A EP 262A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000550 ER PT J AU Tarragona, J Santacana, M Valls, J Oliva, E Palacios, J Matias-Guiu, X AF Tarragona, J. Santacana, M. Valls, J. Oliva, E. Palacios, J. Matias-Guiu, X. TI Stem Cell Marker Expression in Endometrial Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Univ Lleida, IRB Lleida, Hosp Univ Arnau Vilanova, Lleida, Spain. Hosp Virgen Rocio, Seville, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1140 BP 268A EP 268A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000580 ER PT J AU Zaino, R Zhu, J Abendroth, C Yemelyanova, A Oliva, E Lim, D Hagemann, IS Montone, K Delair, D Saslow, R AF Zaino, R. Zhu, J. Abendroth, C. Yemelyanova, A. Oliva, E. Lim, D. Hagemann, I. S. Montone, K. Delair, D. Saslow, R. TI Stage II Endometrial Carcinoma: Endocervical Gland Spread Is Not Reproducibly Distinguished from Endocervical Stromal Invasion. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Johns Hopkins Med Ctr, Hershey Med Ctr, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. U Penn, Philadelphia, PA USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1157 BP 272A EP 272A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000597 ER PT J AU Courville, EL Lew, M Sadow, PM AF Courville, E. L. Lew, M. Sadow, P. M. TI Retrospective Review of Tonsil Specimens: Experiential Assessment of a Clinical Practice. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1178 BP 277A EP 277A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000618 ER PT J AU Carvajal, A Sua, L Silva, N Pittaluga, S Royo, C Sargent, RL Climent, F Jacobs, SA Delabie, J Naresh, K Bagg, A Harris, NL Swerdlow, SH Jaffe, ES Campo, E AF Carvajal, A. Sua, L. Silva, N. Pittaluga, S. Royo, C. Sargent, R. L. Climent, F. Jacobs, S. A. Delabie, J. Naresh, K. Bagg, A. Harris, N. L. Swerdlow, S. H. Jaffe, E. S. Campo, E. TI "In Situ" Mantle Cell Lymphoma (MCL), an Incidental Finding with an Indolent Clinical Course SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Hosp Clin Barcelona, Barcelona, Spain. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Oslo Univ Hosp, Oslo, Norway. Hammersmith Hosp, London, England. Hosp Univ Penn, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NCI, Bethesda, MD 20892 USA. RI Royo, Cristina/H-3193-2015 OI Royo, Cristina/0000-0002-1214-4656 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1228 BP 289A EP 289A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000668 ER PT J AU Chiu, A Chen, YB Pinkus, GS Hasserjian, RP AF Chiu, A. Chen, Y-B Pinkus, G. S. Hasserjian, R. P. TI Acute Graft-Versus-Host Disease Is Associated with Increased Bone Remodeling and Impaired B-Cell Development Suggesting Effects on the Osteoblastic Niche. SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1237 BP 291A EP 291A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000677 ER PT J AU Hasserjian, RP Chi, YO Hu, Y Kluk, M Attar, E Wang, SA AF Hasserjian, R. P. Chi, Y. Ok Hu, Y. Kluk, M. Attar, E. Wang, S. A. TI Therapy-Related Myelodysplastic Syndrome (MDS) Lacking High-Risk Karyotype Resembles De Novo Disease and Differs from Conventional Therapy-Related MDS SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. UMass Med Ctr, Worcester, MA USA. UT MD Anderson Canc Ctr, Houston, TX USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1275 BP 300A EP 300A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000715 ER PT J AU Katz, SG LaBelle, JL Godes, M Fisher, JK Bird, GH Walensky, LD AF Katz, S. G. LaBelle, J. L. Godes, M. Fisher, J. K. Bird, G. H. Walensky, L. D. TI Stapled BIM BH3 Helix Restores Apoptosis in BIM-Null Mantle Cell Lymphoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1295 BP 304A EP 305A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000735 ER PT J AU Nardi, V Kluk, M Attar, E Winkfield, K Hasserjian, RP AF Nardi, V. Kluk, M. Attar, E. Winkfield, K. Hasserjian, R. P. TI AML and MDS Following Radiation Therapy Are Similar to De Novo Disease and Differ from Other Therapy-Related Myeloid Neoplasms SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1322 BP 309A EP + PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000758 ER PT J AU Nardi, V Rochelle-Keyes, H Peterson, T Loda, M Rosina, L Raje, N Sohani, AR Sabatini, DM Hasserjian, RP AF Nardi, V. Rochelle-Keyes, H. Peterson, T. Loda, M. Rosina, L. Raje, N. Sohani, A. R. Sabatini, D. M. Hasserjian, R. P. TI Activation of the PI3K/Akt Pathway in Plasma Cell Myeloma Is Associated with MAF and DEPTOR Overexpression and Favorable Response to Therapy SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Whitehead Inst, Cambridge, MA 02142 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2011 VL 91 SU 1 MA 1323 BP 311A EP 311A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 773CQ UT WOS:000291285000763 ER EF