FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Sheridan, RL Goldstein, MA Stoddard, FJ Walker, TG AF Sheridan, Robert L. Goldstein, Mark A. Stoddard, Frederick J., Jr. Walker, T. Gregory TI A Boy with Hypothermia and Frostbite Stage 3 hypothermia. Stage 3 frostbite with diffuse distal small-vessel thrombosis and impending limb loss SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ALCOHOL-USE; ACCIDENTAL HYPOTHERMIA; ADOLESCENTS; INJURY; BEHAVIORS; AGE; INVOLVEMENT; DISORDERS; DRINKING; ONSET C1 [Sheridan, Robert L.; Stoddard, Frederick J., Jr.] Massachusetts Gen Hosp, Dept Surg, Burns Serv, Boston, MA 02114 USA. [Goldstein, Mark A.] Massachusetts Gen Hosp, Div Adolescent & Young Adult Med, Dept Pediat, Boston, MA 02114 USA. [Stoddard, Frederick J., Jr.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Walker, T. Gregory] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sheridan, Robert L.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Goldstein, Mark A.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Stoddard, Frederick J., Jr.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Walker, T. Gregory] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. RP Sheridan, RL (reprint author), Massachusetts Gen Hosp, Dept Surg, Burns Serv, Boston, MA 02114 USA. NR 34 TC 15 Z9 15 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 DEC 31 PY 2009 VL 361 IS 27 BP 2654 EP 2662 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 538JV UT WOS:000273181300015 PM 20042758 ER PT J AU Sinha, S Schwartz, MD Qin, AG Ross, JS AF Sinha, Sanjai Schwartz, Mark D. Qin, Angie Ross, Joseph S. TI Self-Reported and Actual Beta-Blocker Prescribing for Heart Failure Patients: Physician Predictors SO PLOS ONE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PRIMARY-CARE; MEDICATION UNDERUSE; MANAGEMENT; DIAGNOSIS; OUTCOMES; ASTHMA; PRACTITIONERS; CARVEDILOL; GUIDELINES AB Background: Beta-blockers reduce mortality among patients with systolic heart failure (HF), yet primary care provider prescription rates remain low. Objective: To examine the association between primary care physician characteristics and both self-reported and actual prescription of beta-blockers among patients with systolic HF. Design: Cross-sectional survey with supplementary retrospective chart review. Participants: Primary care providers at three New York City Veterans Affairs medical centers. Measurements: Main outcomes were: 1) self-reported prescribing of beta-blockers, and 2) actual prescribing of beta-blockers among HF patients. Physician HF practice patterns and confidence levels, as well as socio-demographic and clinical characteristics, were also assessed. Results: Sixty-nine of 101 physicians (68%) completed the survey examining self-reported prescribing of beta-blockers. Physicians who served as inpatient ward attendings self-reported significantly higher rates of beta-blocker prescribing among their HF patients when compared with physicians who did not attend (78% vs. 58%; p = 0.002), as did physicians who were very confident in managing HF patients when compared with physicians who were not (82% vs. 68%; p = 0.009). Fifty-one of these 69 surveyed physicians (74%) were successfully matched to 287 HF patients for whom beta-blocker prescribing data was available. Physicians with greater self-reported rates of prescribing beta-blockers were significantly more likely to actually prescribe beta-blockers ( p = 0.02); however, no other physician characteristics were significantly associated with actual prescribing of beta-blockers among HF patients. Conclusions: Physician teaching responsibilities and confidence levels were associated with self-reported beta-blocker prescribing among their HF patients. Educational efforts focused on improving confidence levels in HF care and increasing exposure to teaching may improve beta-blocker presciption in HF patients managed in primary care. C1 [Sinha, Sanjai; Ross, Joseph S.] James J Peters VA Med Ctr, Dept Med, Bronx, NY USA. [Sinha, Sanjai] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Schwartz, Mark D.; Qin, Angie] VA New York Harbor Healthcare Syst, Dept Med, New York, NY USA. [Schwartz, Mark D.; Qin, Angie] NYU, Sch Med, Dept Med, New York, NY USA. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY USA. RP Sinha, S (reprint author), James J Peters VA Med Ctr, Dept Med, Bronx, NY USA. EM Sanjai.Sinha@med.va.gov OI Schwartz, Mark/0000-0002-7123-0060 FU New Researcher Seed Grant, Dept. of Veterans Affairs, Veterans Integrated Service Network 3 Award FX Funding source: New Researcher Seed Grant, Dept. of Veterans Affairs, Veterans Integrated Service Network 3 Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 4 Z9 4 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 31 PY 2009 VL 4 IS 12 AR e8522 DI 10.1371/journal.pone.0008522 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538JK UT WOS:000273180200009 PM 20046824 ER PT J AU Nam, K Verdine, GL Karplus, M AF Nam, Kwangho Verdine, Gregory L. Karplus, Martin TI Analysis of an Anomalous Mutant of MutM DNA Glycosylase Leads to New Insights into the Catalytic Mechanism SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID FREE-ENERGY CALCULATIONS; BASE-EXCISION; LESION RECOGNITION; REPAIR AB To determine the factors involved in the specific recognition function of a bacterial. 8-oxoguanine (oxoG) DNA glycosylase MutM, a series of potentials of mean force and thermodynamic integration simulations were performed with the wild type and a single-point E3Q mutant of MutM bound to oxoG and G-containing DNA, respectively. Interestingly, the mutation of the catalytically important Glu3 (E3) residue to Gin (Q) significantly changes the free-energy surface so that oxoG can bind stably in the active site of the enzyme, Free-energy simulations with the protonated and deprotonated E3 residue further showed that the protonation of the catalytically important E3 residue plays a key role in distinguishing oxoG versus G in the active site by lowering the free energy of oxoG preferentially in the active site. The results suggest that MutM utilizes the thermodynamic recognition mechanism for stable binding of the lesion base in the active site of the enzyme in addition to kinetic discrimination at the early stage of the base extrusion for facilitated extrusion of oxoG. C1 [Nam, Kwangho; Verdine, Gregory L.; Karplus, Martin] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Chem Biol Initiat, Boston, MA 02115 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Karplus, Martin] Univ Strasbourg, ISIS, F-67000 Strasbourg, France. RP Verdine, GL (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM verdine@chemistry.harvard.edu; marci@tammy.harvard.edu FU NIH [CA100742, GM030804]; National Cancer Center FX This work was supported by grants from NIH to G.L.V. (CA100742) and M.K. (GM030804) and by a postdoctoral fellowship from National Cancer Center to K.N. NERSC and FAS at Harvard University provided computing resources. K.N. acknowledges Drs. J. Pu, V. Ovchinnikov, G. Zheng, and M. Spong and Ms. Y. Qi for helpful discussion. NR 17 TC 11 Z9 11 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 30 PY 2009 VL 131 IS 51 BP 18208 EP + DI 10.1021/ja907544b PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 543YA UT WOS:000273615800009 PM 19961158 ER PT J AU Biederman, J Petty, CR Ball, SW Fried, R Doyle, AE Cohen, D Henderson, C Faraone, SV AF Biederman, Joseph Petty, Carter R. Ball, Sarah W. Fried, Ronna Doyle, Alysa E. Cohen, Daniel Henderson, Carly Faraone, Stephen V. TI Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow-up study of grown up boys with persistent and remitting course SO PSYCHIATRY RESEARCH LA English DT Article DE Cognitive deficits; ADHD; Stability ID HYPERACTIVITY DISORDER; EXECUTIVE FUNCTIONS; CHILDREN; ADHD; PERFORMANCE; ADULTS; METAANALYSIS; NEUROPSYCHOLOGY; ADOLESCENTS; COMORBIDITY AB To investigate the longitudinal course of cognitive functions in boys with persistent and remittent attention deficit/hyperactivity disorder (ADHD) from childhood into young adult years. Males (n = 217) 15-31 years with and without ADHD were assessed at 3 time points over 10 years into young adulthood. Subjects were stratified into Remittent ADHD. and Persistent ADHD based on the course of ADHD. Cognitive domains included: 1) overall IQ(overall IQ, block design IQ, vocabulary IQ); 2) achievement scores in reading and math and measures of executive function (Wechsler arithmetic, digit span, digit symbol, Rey-Osterrieth, Wisconsin Card Sorting Test, and the Stroop Test). Cognitive outcomes were modeled as a function of group (Controls, Remittent ADHD, and Persistent ADHD), age, group by age interaction, and any demographic confounders using linear growth-curve models. There were no significant interaction effects of group by time. Main group effects indicated that persistent and remittent ADHD groups both had significantly lower scores on all cognitive outcomes compared with controls, and these did not differ between the ADHD subgroups Psychometrically defined cognitive deficits are relatively stable into young adult years and appear to be independent of the course of ADHD. More work is needed to help define the implications of these deficits in individuals with a remitting course of ADHD. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care YAW 6A 6900, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat Neurosci & Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care YAW 6A 6900, 32 Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Child Health and Human Development [5R01HD036317]; Neal-Kimmerly Fund for the Study of Cognition, Boston, MA, USA FX This study was supported by grant 5R01HD036317 from the National Institute of Child Health and Human Development. Support also came. in part, from the Neal-Kimmerly Fund for the Study of Cognition, Boston, MA, USA. NR 42 TC 43 Z9 47 U1 4 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 30 PY 2009 VL 170 IS 2-3 BP 177 EP 182 DI 10.1016/j.psychres.2008.09.010 PG 6 WC Psychiatry SC Psychiatry GA 533WD UT WOS:000272855200015 PM 19900713 ER PT J AU Biederman, J Petty, CR Ten Haagen, KS Small, J Doyle, AE Spencer, T Mick, E Monuteaux, MC Smoller, JW Faraone, SV AF Biederman, Joseph Petty, Carter R. Ten Haagen, Kristina S. Small, Jacqueline Doyle, Alysa E. Spencer, Thomas Mick, Eric Monuteaux, Michael C. Smoller, Jordan W. Faraone, Stephen V. TI Effect of candidate gene polymorphisms on the course of attention deficit hyperactivity disorder SO PSYCHIATRY RESEARCH LA English DT Article DE ADHD; Genetics; Dopamine; Serotonin ID FAMILY-BASED ASSOCIATION; DOPAMINE TRANSPORTER GENE; AGE-DEPENDENT DECLINE; DEFICIT/HYPERACTIVITY-DISORDER; D-4 RECEPTOR; ADHD INDIVIDUALS; SYSTEM GENES; METAANALYSIS; DRD4; SYMPTOMS AB The main aim of this study was to examine the association between attention-deficit hyperactivity disorder (ADHD)-associated genes and the course of ADHD. Subjects were derived from identically designed case-control family studies of boys and girls with ADHD and a genetic linkage study of families with children with ADHD. Caucasian probands and family members with ADHD and with available genetic data were included in this analysis (N = 563). The course of ADHD was compared in subjects with and without putative risk alleles (DRD4 7-repeat allele, DAT1 10-repeat allele, and 5HTTLPR long allele). The persistence of ADHD (full or subthreshold diagnosis in the last month) was plotted using Kaplan-Meier survival functions and tested with Cox proportional hazard models. Survival analyses revealed that by 25 years of age 76% of subjects with a DRD4 7-repeat allele were estimated to have significantly more persistent ADHD compared with 66% of subjects without the risk allele. In contrast, there were no significant associations between the course of ADHD and the DAT1 10-repeat allele (P = 0.94) and 5HTTLPR long allele. Our findings suggest that the DRD4 7-repeat allele is associated with a more persistent course of ADHD. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat, Yawkey Ctr, Pediat Psychopharmacol Dept, Boston, MA 02114 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat, Yawkey Ctr, Pediat Psychopharmacol Dept, Suite 6A, Boston, MA 02114 USA. EM jbiederman@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01HD037694, R01H-D037999, R01MH066877, R01MH050657, R01HD036317]; Alza, AstraZeneca; Bristol Myers Squibb; Eli Lilly and Co.; Janssen Pharmaceuticals Inc.; NARSAD; Stanley Foundation; Wyeth; National Institute of Mental Health (NIMH); National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse (NIDA); Glaxo-Smith Kline; Pfizer Pharmaceutical; McNeil Pharmaceutical; Novartis Pharmaceutical; NIMH; Hoffmann-La Roche, Inc; Enterprise Analysis Corp.; National Institute of Neurological Disorders and Stroke (NINDS) FX Mr. Carter R. Petty, Ms. Kristina Ten Haagen. Ms.Jacqueline Small, and Dr. Michael C. Monuteaux do not have any financial interests to disclose. NR 38 TC 22 Z9 22 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 30 PY 2009 VL 170 IS 2-3 BP 199 EP 203 DI 10.1016/j.psychres.2008.12.016 PG 5 WC Psychiatry SC Psychiatry GA 533WD UT WOS:000272855200018 PM 19906444 ER PT J AU Sinclair, SJ Siefert, CJ Shorey, HS Antonius, D Shiva, A Kehl-Fie, K Blais, MA AF Sinclair, Samuel J. Siefert, Caleb J. Shorey, Hal S. Antonius, Daniel Shiva, Andrew Kehl-Fie, Kendra Blais, Mark A. TI A psychometric evaluation of the Personality Assessment Inventory - short form clinical scales in an inpatient psychiatric sample SO PSYCHIATRY RESEARCH LA English DT Article DE Personality Assessment Inventory short-form; PAI-SF; Psychometric ID VALIDITY RATES; RELIABILITY; VALIDATION; PAI AB Few studies have assessed the psychometric properties of the Personality Assessment Inventory short-form (PAI-SF) clinical scales. and none have conducted these evaluations using participants from psychiatric inpatient units. The present study evaluated item-level tests of scaling assumptions of the PAI-SF using a large (N = 503) clinical sample of participants who completed the PAI during their admission to a psychiatric inpatient unit. Internal consistency reliability was high across scales. and tests of item-scale convergence and discrimination generally confirmed hypothesized item groupings. Scale-level correlations supported unique variance being measured by each scale. Finally. agreement between the PAI short- and full-form scales was found to be high. The results are discussed with regards to scale interpretation. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Sinclair, Samuel J.; Siefert, Caleb J.; Kehl-Fie, Kendra; Blais, Mark A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sinclair, Samuel J.; Siefert, Caleb J.; Kehl-Fie, Kendra; Blais, Mark A.] Harvard Univ, Sch Med, PEaRL, Boston, MA USA. [Shorey, Hal S.] Widener Univ, Inst Grad Clin Psychol, Chester, PA 19013 USA. [Antonius, Daniel; Shiva, Andrew] NYU, Sch Med, New York, NY USA. [Shiva, Andrew] CUNY John Jay Coll Criminal Justice, New York, NY 10019 USA. RP Sinclair, SJ (reprint author), Massachusetts Gen Hosp, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM jsincl@post.harvard.edu OI Shiva, Andrew/0000-0001-5069-239X NR 19 TC 8 Z9 8 U1 15 U2 22 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 30 PY 2009 VL 170 IS 2-3 BP 262 EP 266 DI 10.1016/j.psychres.2008.11.001 PG 5 WC Psychiatry SC Psychiatry GA 533WD UT WOS:000272855200030 PM 19879654 ER PT J AU Nery, FG Stanley, JA Chen, HH Hatch, JP Nicoletti, MA Monkul, ES Matsuo, K Caetano, SC Peluso, MA Najt, P Soares, JC AF Nery, Fabiano G. Stanley, Jeffrey A. Chen, Hua-Hsuan Hatch, John P. Nicoletti, Mark A. Monkul, Emel Serap Matsuo, Koji Caetano, Sheila C. Peluso, Marco A. Najt, Pablo Soares, Jair C. TI Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: A single voxel H-1 spectroscopy study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Major depressive disorder; Magnetic resonance spectroscopy; Prefrontal cortex; Pathophysiology; N-acetyl aspartate; Choline-containing compounds; Glutamate; Phosphocreatine/creatine ID MAGNETIC-RESONANCE-SPECTROSCOPY; GAMMA-AMINOBUTYRIC-ACID; N-ACETYL-ASPARTATE; IN-VIVO; MOOD DISORDERS; WHITE-MATTER; HUMAN BRAIN; GLUTAMATERGIC CONCENTRATIONS; UNIPOLAR DEPRESSION; GABA CONCENTRATIONS AB Few proton magnetic resonance spectroscopy (H-1 spectroscopy) studies have investigated the dorsolateral prefrontal cortex (DLPFC), a key region in the pathophysiology of major depressive disorder (MDD). We used H-1 spectroscopy to verify whether MDD patients differ from healthy controls (HQ in metabolite levels in this brain area. Thirty-seven unmedicated DSM-IV MDD patients were compared with 40 HC. Subjects underwent a short echo-time H-1 spectroscopy examination at 1.5 T, with an 8-cm(3) single voxel placed in the left DLPFC. Reliable absolute metabolite levels of N-acetyl aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol, glutamate plus glutamine (Glu+Gln), and glutamate were obtained using the unsuppressed water signal as an internal reference. Metabolite levels in the left DLPFC did not statistically differ between MDD patients and HC. We found an interaction between gender and diagnosis on PCr+Cr levels. Male MDD patients presented lower levels of PCr+Cr than male HC, and female MDD patients presented higher levels of PCr+Cr than female HC. Moreover, length of illness was inversely correlated with NAA levels. These findings suggest that there is not an effect of diagnosis on the left DLPFC neurochemistry. Possible effects of gender on PCr+Cr levels of MDD patients need to be further investigated. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Nicoletti, Mark A.; Soares, Jair C.] Univ N Carolina, CERT BD, Dept Psychiat, Sch Med, Chapel Hill, NC 27599 USA. [Nery, Fabiano G.; Hatch, John P.; Monkul, Emel Serap; Matsuo, Koji; Caetano, Sheila C.; Peluso, Marco A.; Najt, Pablo] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Nery, Fabiano G.; Monkul, Emel Serap; Matsuo, Koji; Caetano, Sheila C.; Peluso, Marco A.; Najt, Pablo] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Nery, Fabiano G.; Caetano, Sheila C.; Peluso, Marco A.] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo, Brazil. [Stanley, Jeffrey A.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Chen, Hua-Hsuan] Univ Cincinnati, Dept Radiol, Cincinnati, OH USA. [Hatch, John P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Orthodont, San Antonio, TX 78229 USA. RP Soares, JC (reprint author), Univ N Carolina, CERT BD, Dept Psychiat, Sch Med, 10616 Neurosci Hosp CB 7160, Chapel Hill, NC 27599 USA. EM jsoares@med.unc.edu RI Caetano, Sheila/H-5010-2012 OI Caetano, Sheila/0000-0001-8403-7078 FU UTHSCSA GCRC [M01-RR-01346]; Krus Endowed Chair in Psychiatry (UTHSCSA); Veterans Administration (VA Merit Review); CAPES Foundation (Brazil); CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil) [200006/04-5]; [MH 01736]; [MH 068662]; [RR 020571] FX This research was partly supported by grants MH 01736, MH 068662, RR 020571, UTHSCSA GCRC (M01-RR-01346), the Krus Endowed Chair in Psychiatry (UTHSCSA), the Veterans Administration (VA Merit Review), the CAPES Foundation (Brazil) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil - grant #200006/04-5). NR 63 TC 21 Z9 22 U1 3 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD DEC 30 PY 2009 VL 174 IS 3 BP 177 EP 183 DI 10.1016/j.pscychresns.2009.05.003 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 534OW UT WOS:000272908000003 PM 19910168 ER PT J AU Reed, M Benedetti, N Brand, R Newhouse, JP Hsu, J AF Reed, Mary Benedetti, Nancy Brand, Richard Newhouse, Joseph P. Hsu, John TI Perspectives from deductible plan enrollees: plan knowledge and anticipated care-seeking changes SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID DIRECTED HEALTH PLANS; SERVICES AB Background: Consumer directed health care proposes that patients will engage as informed consumers of health care services by sharing in more of their medical costs, often through deductibles. We examined knowledge of deductible plan details among new enrollees, as well as anticipated care-seeking changes in response to the deductible. Methods: In a large integrated delivery system with a range of deductible-based health plans which varied in services included or exempted from deductible, we conducted a mixed-method, cross-sectional telephone interview study. Results: Among 458 adults newly enrolled in a deductible plan (71% response rate), 51% knew they had a deductible, 26% knew the deductible amount, and 6% knew which medical services were included or exempted from their deductible. After adjusting for respondent characteristics, those with more deductible-applicable services and those with lower self-reported health status were significantly more likely to know they had a deductible. Among those who knew of their deductible, half anticipated that it would cause them to delay or avoid medical care, including avoiding doctor's office visits and medical tests, even services that they believed were medically necessary. Many expressed concern about their costs, anticipating the inability to afford care and expressing the desire to change plans. Conclusion: Early in their experience with a deductible, patients had limited awareness of the deductible and little knowledge of the details. Many who knew of the deductible reported that it would cause them to delay or avoid seeking care and were concerned about their healthcare costs. C1 [Reed, Mary; Benedetti, Nancy; Hsu, John] Ctr Hlth Policy Studies, Div Res, Oakland, CA 94612 USA. [Brand, Richard] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [Newhouse, Joseph P.; Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA. [Hsu, John] Massachusetts Gen Hosp, James J Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Reed, M (reprint author), Ctr Hlth Policy Studies, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM mary.e.reed@kp.org; nancyjb@stanford.edu; rjbrand@sbcglobal.net; newhouse@hcp.med.harvard.edu; john.t.hsu@kp.org FU Kaiser Foundation Research Institute; Commonwealth Fund FX This research was supported by Kaiser Foundation Research Institute and the Commonwealth Fund. Neither funding agencies nor the health system had any role in the design, analysis, interpretation, or decision to submit this manuscript for publication. The authors have no other relevant financial disclosures. NR 12 TC 4 Z9 4 U1 0 U2 0 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 DEC 29 PY 2009 VL 9 AR 244 DI 10.1186/1472-6963-9-244 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 549AH UT WOS:000274012500001 PM 20040076 ER PT J AU Robine, N Lau, NC Balla, S Jin, ZG Okamura, K Kuramochi-Miyagawa, S Blower, MD Lai, EC AF Robine, Nicolas Lau, Nelson C. Balla, Sudha Jin, Zhigang Okamura, Katsutomo Kuramochi-Miyagawa, Satomi Blower, Michael D. Lai, Eric C. TI A Broadly Conserved Pathway Generates 3 ' UTR-Directed Primary piRNAs SO CURRENT BIOLOGY LA English DT Article ID PIWI-INTERACTING RNAS; DROSOPHILA-MELANOGASTER; ARGININE METHYLATION; ENDOGENOUS SIRNAS; DNA METHYLATION; FAMILY-MEMBERS; SOMATIC-CELLS; HUMAN GENOME; BRAIN-TUMOR; TRAFFIC-JAM AB Background: Piwi-interacting RNAs (piRNAs) are similar to 24-30 nucleotide regulatory RNAs that are abundant in animal gonads and early embryos. The best-characterized piRNAs mediate a conserved pathway that restricts transposable elements, and these frequently engage a "ping-pong" amplification loop. Certain stages of mammalian testis also accumulate abundant piRNAs of unknown function, which derive from noncoding RNAs that are depleted in transposable element content and do not engage in ping-pong. Results: We report that the 3' untranslated regions (3'UTRs) of an extensive set of messenger RNAs (mRNAs) are processed into piRNAs in Drosophila ovaries, murine testes, and Xenopus eggs. Analysis of different mutants and Piwi-class immunoprecipitates indicates that their biogenesis depends on primary piRNA components, but not most ping-pong components. Several observations suggest that mRNAs are actively selected for piRNA production for regulatory purposes. First, genic piRNAs do not accumulate in proportion to the level of their host transcripts, and many highly expressed transcripts lack piRNAs. Second, piRNA-producing mRNAs in Drosophila and mouse are enriched for specific gene ontology categories distinct from those of simply abundant transcripts. Third, the protein output of traffic jam, whose 3'UTR generates abundant piRNAs, is increased in piwi mutant follicle clones. Conclusions: We reveal a conserved primary piRNA pathway that selects and metabolizes the 3'UTRs of a broad set of cellular transcripts, probably for regulatory purposes. These findings strongly increase the breadth of Argonaute-mediated small RNA systems in metazoans. C1 [Robine, Nicolas; Balla, Sudha; Jin, Zhigang; Okamura, Katsutomo; Lai, Eric C.] Sloan Kettering Inst, Dept Dev Biol, New York, NY 10065 USA. [Lau, Nelson C.; Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lau, Nelson C.; Blower, Michael D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kuramochi-Miyagawa, Satomi] Osaka Univ, Sch Med, Dept Pathol, Grad Sch Frontier Biosci,Res Inst Microbial Dis, Suita, Osaka 5650871, Japan. RP Lau, NC (reprint author), Brandeis Univ, Dept Biol, 415 S St, Waltham, MA 02454 USA. EM nlau@brandeis.edu; laie@mskcc.org OI Robine, Nicolas/0000-0001-5698-8183 FU National Institutes of Health [GM48405, GM086434, HD057298, R01-GM083300, U01-HG004261]; Burroughs Wellcome Fund; The Terry Fox Foundation [700132]; Japan Society for the Promotion of Science; Kimmel Cancer Foundation; Bressler Scholars Fund FX We thank Haruhiko and Mikiko Siomi for Piwi monoclonal antibody and open discussions. We are also grateful to Dorothea Godt for TJ antibody, to Haifan Lin for piwi stocks, to Kate Abruzzi and Michael Rosbash for reagents and assistance with Affymetrix gene profiling, and to Mark Borowsky and the MGH Illumina sequencing core for assistance in library sequencing. This work was partly supported by National Institutes of Health grant GM48405 to Robert Kingston and NIH grant GM086434 and a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund to M.D.B. Z.J. is a Research Fellow of The Terry Fox Foundation (#700132). K.O is supported by the Japan Society for the Promotion of Science. N.C.L. was funded by an NIH K99 grant (HD057298). Work in E.C.L.'s group was supported by the Kimmel Cancer Foundation, the Bressler Scholars Fund, and the NIH (R01-GM083300 and U01-HG004261). NR 42 TC 157 Z9 164 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD DEC 29 PY 2009 VL 19 IS 24 BP 2066 EP 2076 DI 10.1016/j.cub.2009.11.064 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 541JR UT WOS:000273411600019 PM 20022248 ER PT J AU Padmanabhan, A Lee, JS Ismat, FA Lu, MM Lawson, ND Kanki, JP Look, AT Epstein, JA AF Padmanabhan, Arun Lee, Jeong-Soo Ismat, Fraz A. Lu, Min Min Lawson, Nathan D. Kanki, John P. Look, A. Thomas Epstein, Jonathan A. TI Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cardiovascular; neurofibromin ID JUVENILE MYELOMONOCYTIC LEUKEMIA; MOUSE-TUMOR MODEL; ENDOTHELIAL-CELLS; MYELOPROLIFERATIVE DISORDER; LEARNING-DEFICITS; ADENYLYL-CYCLASE; RASA1 MUTATIONS; DROSOPHILA NF1; MICE; PROTEIN AB Von Recklinghausen neurofibromatosis is a common autosomal dominant genetic disorder characterized by benign and malignant tumors of neural crest origin. Significant progress in understanding the pathophysiology of this disease has occurred in recent years, largely aided by the development of relevant animal models. Von Recklinghausen neurofibromatosis is caused by mutations in the NF1 gene, which encodes neurofibromin, a large protein that modulates the activity of Ras. Here, we describe the identification and characterization of zebrafish nf1a and nf1b, orthologues of NF1, and show neural crest and cardiovascular defects resulting from morpholino knockdown, including vascular and cardiac valvular abnormalities. Development of a zebrafish model of von Recklinghausen neurofibromatosis will allow for structure-function analysis and genetic screens in this tractable vertebrate system. C1 [Padmanabhan, Arun; Lu, Min Min; Epstein, Jonathan A.] Univ Penn, Dept Cell & Dev Biol, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Padmanabhan, Arun; Lu, Min Min; Epstein, Jonathan A.] Univ Penn, Inst Regenerat Med, Philadelphia, PA 19104 USA. [Lee, Jeong-Soo; Kanki, John P.; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02114 USA. [Ismat, Fraz A.] Childrens Hosp Philadelphia, Dept Pediat, Div Cardiol, Philadelphia, PA 19104 USA. [Lawson, Nathan D.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. RP Look, AT (reprint author), 1154 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM thomas_look@dfci.harvard.edu; epsteinj@mail.med.upenn.edu FU National Institutes of Health [R01-HL062974, K08-HL075179]; Department of Defense [NF050175]; Sarnoff Cardiovascular Research Foundation; Children's Tumor Foundation FX We thank Jie He (University of Pennsylvania CDB Zebrafish Core) and Nicole Antonucci for assistance with animal husbandry, Andrea Stout (University of Pennsylvania CDB/CVI Microscopy Core) for assistance with microscopy, and Michael Pack and Mary Mullins for helpful discussions and reagents. This work was supported by National Institutes of Health Grants R01-HL062974 (to J.A.E.) and K08-HL075179 (to F.A.I.) and Department of Defense Grant NF050175 (to J.A.E. and A.T.L.). A.P. was supported by a fellowship from the Sarnoff Cardiovascular Research Foundation, and J.-S.L. was supported by a Young Investigator Award from the Children's Tumor Foundation. NR 50 TC 8 Z9 8 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 29 PY 2009 VL 106 IS 52 BP 22305 EP 22310 DI 10.1073/pnas.0901932106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700049 PM 19966217 ER PT J AU Estall, JL Ruas, JL Choi, CS Laznik, D Badman, M Maratos-Flier, E Shulman, GI Spiegelman, BM AF Estall, Jennifer L. Ruas, Jorge L. Choi, Cheol Soo Laznik, Dina Badman, Michael Maratos-Flier, Eleftheria Shulman, Gerald I. Spiegelman, Bruce M. TI PGC-1 alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb alpha axis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE liver; metabolism; diabetes; coactivator; fasting ID TRANSCRIPTIONAL COACTIVATOR PGC-1; IMPROVES INSULIN SENSITIVITY; PPAR-ALPHA; METABOLIC SYNDROME; ENERGY-EXPENDITURE; GLUCOSE-TOLERANCE; NUCLEAR RECEPTORS; FASTING RESPONSE; GAMMA; GLUCONEOGENESIS AB FGF21 is a hormone produced in liver and fat that dramatically improves peripheral insulin sensitivity and lipid metabolism. We show here that obese mice with genetically reduced levels of a key hepatic transcriptional coactivator, PGC-1 alpha, have improved whole-body insulin sensitivity with increased levels of hepatic and circulating FGF21. Gain-and loss-of-function studies in primary mouse hepatocytes show that hepatic FGF21 levels are regulated by the expression of PGC-1 alpha. Importantly, PGC-1 alpha-mediated reduction of FGF21 expression is dependent on Rev-Erb alpha and the expression of ALAS-1. ALAS-1 is a PGC-1 alpha target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erb alpha. Modulation of intracellular heme levels mimics the effect of PGC-1 alpha on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1 alpha. Thus, PGC-1 alpha can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand. C1 [Estall, Jennifer L.; Ruas, Jorge L.; Laznik, Dina; Spiegelman, Bruce M.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Estall, Jennifer L.; Ruas, Jorge L.; Laznik, Dina; Spiegelman, Bruce M.] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02115 USA. [Choi, Cheol Soo; Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Choi, Cheol Soo; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Choi, Cheol Soo; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Badman, Michael; Maratos-Flier, Eleftheria] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol,Dept Med, Boston, MA 02215 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu OI Ruas, Jorge/0000-0002-1110-2606 FU H. L. Holmes Award (National Research Council of Canada); Canadian Institutes of Health Research; National Institutes of Health [R01 DK-061562, R01 DK-40936, P30 DK-45735, U24 DK-59635] FX We thank Dr. Marc Montminy for the shPGC-1 alpha adenovirus, Dr. Mitch Lazar and Nan Wu for the human FLAG-Rev-Erb alpha construct, and Drs. Folliott Martin Fisher and Srikripa Devarakonda for helpful discussion. This work was supported by the H. L. Holmes Award (National Research Council of Canada) and a postdoctoral fellowship from the Canadian Institutes of Health Research (J.L.E.), and National Institutes of Health Grants R01 DK-061562 (to B. M. S.), and R01 DK-40936, P30 DK-45735, and U24 DK-59635 (to G. I. S.) support the work in this manuscript. NR 52 TC 67 Z9 69 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 29 PY 2009 VL 106 IS 52 BP 22510 EP 22515 DI 10.1073/pnas.0912533106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700084 PM 20018698 ER PT J AU Hug, BL Lipsitz, SR Seger, DL Karson, AS Wright, SC Bares, DW AF Hug, Balthasar L. Lipsitz, Stuart R. Seger, Diane L. Karson, Andrew S. Wright, Steven C. Bares, David W. TI Mortality and drug exposure in a 5-year cohort of patients with chronic liver disease SO SWISS MEDICAL WEEKLY LA English DT Article DE chronic liver disease; cirrhosis; drug exposure; mortality; MELD score; ambulatory; hospitalised; tertiary referral hospital; secondary referral hospital ID RANDOMIZED CONTROLLED-TRIALS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; STATIN THERAPY; UNITED-STATES; MODEL; INJURY; FAILURE; TRANSPLANTATION; HEPATOTOXICITY; METAANALYSIS AB Background: Chronic liver diseases are common in the general population. Drug treatment in this group may be challenging, as many drugs are hepatically metabolised and hepatotoxic. Objective: We aimed to assess the mortality of patients with chronic liver disease according to specific drug exposures and the three laboratory parameters creatinine, bilirubin and International Normalised Ratio (INR). Methods: We conducted a multicentre, 5-year retrospective cohort study in two tertiary university referral hospitals and a secondary referral hospital, using a research database to evaluate the crude and adjusted mortality. Results: Of 1159 362 individual patients 1.7% (n = 20 158) had chronic liver disease and in this group 36.8% had unspecified chronic non-alcoholic liver disease, 30.1% chronic hepatitis C and 11.9% cirrhosis of die liver. 8.4% of patients presented a diagnosis associated with alcohol. The 4-year survival rates were significantly higher in the group with the most normal laboratory values (94.3%) versus 34.5% in the group with elevated parameters (p < 0.001). Overall, drug exposure was not associated with higher mortality; in adjusted multivariate analysis the hazard ratio for anti-cancer drugs was 2.69 (95% CI 1.32-5.46). Of individual drugs, mortality hazard ratios for amiodarone, morphine oral, acetazolamide, sirolimus and lamivudine were 2.46 (95% CI 1.68-3.61), 2.26 (95% CI 1.78-2.86), 2.10 (95% CI 1.19-3.70), 1.81 (95% CI 1.02-3.21) and 1.72 (95% CI 1.17-2.53) respectively. Conclusions: Drug exposure In general was not associated with higher mortality except for a few categories. Mortality in patients with chronic liver disease was high and is associated with simple laboratory values. C1 [Hug, Balthasar L.; Seger, Diane L.; Bares, David W.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02120 USA. [Lipsitz, Stuart R.] Brigham & Womens Hosp, Dept Surg & Publ Hlth, Boston, MA 02120 USA. [Karson, Andrew S.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA USA. [Wright, Steven C.] Faulkner Hosp, Dept Internal Med, Boston, MA USA. RP Hug, BL (reprint author), Brigham & Womens Hosp, Div Gen Internal Med, Brigham Circle 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM bhug@uhbs.ch FU Freie Akademische Gesellschaft; Walter and Margarethe Lichtenstein Fund; University Hospital in Basel, Switzerland FX Dr Hug has received financial funding from the Freie Akademische Gesellschaft, the Walter and Margarethe Lichtenstein Fund and the University Hospital in Basel, Switzerland. NR 35 TC 16 Z9 16 U1 2 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 DEC 26 PY 2009 VL 139 IS 51-52 BP 737 EP 746 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 540VI UT WOS:000273367800003 PM 19924579 ER PT J AU Genethliou, N Panayiotou, E Panayi, H Orford, M Mean, R Lapathitis, G Gill, H Raoof, S De Gasperi, R Elder, G Kessaris, N Richardson, WD Malas, S AF Genethliou, Nicholas Panayiotou, Elena Panayi, Helen Orford, Michael Mean, Richard Lapathitis, George Gill, Herman Raoof, Sahir De Gasperi, Rita Elder, Gregory Kessaris, Nicoletta Richardson, William D. Malas, Stavros TI SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Sox1; Pax6; Nkx2.2; Hes1; Oligodendrocytes; Astrocytes; Notch signalling ID HOMEODOMAIN TRANSCRIPTION FACTOR; SONIC HEDGEHOG; OLIGODENDROCYTE DIFFERENTIATION; CELLS; PRECURSORS; MICE; GLIOGENESIS; NKX2.2; SPECIFICATION; NEUROGENESIS AB During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial (N/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss of Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate per se by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis. (C) 2009 Elsevier Inc. All rights reserved. C1 [Malas, Stavros] Cyprus Inst Neurol & Genet, Dev & Funct Genet Grp, CY-2370 Nicosia, Cyprus. [Genethliou, Nicholas; Panayiotou, Elena] Univ Cyprus, Dept Biol Sci, CY-1678 Nicosia, Cyprus. [De Gasperi, Rita; Elder, Gregory] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Kessaris, Nicoletta; Richardson, William D.] UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England. [Kessaris, Nicoletta; Richardson, William D.] UCL, Res Dept Cell & Dev Biol, London WC1E 6BT, England. RP Malas, S (reprint author), Cyprus Inst Neurol & Genet, Dev & Funct Genet Grp, Airport Ave 6, CY-2370 Nicosia, Cyprus. EM smalas@cing.ac.cy OI Kessaris, Nicoletta/0000-0003-1191-6009 FU European Union; UK Medical Research Council; Wellcome Trust FX We thank Johan Ericson, Anastasia Stoykova and Austin Smith for the mice and Michael Wegner for antibodies and plasmids. This work was supported by the European Union (SM) and the UK Medical Research Council and the Wellcome Trust (WDR and NK). NR 36 TC 9 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 25 PY 2009 VL 390 IS 4 BP 1114 EP 1120 DI 10.1016/j.bbrc.2009.08.154 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 531GB UT WOS:000272650800008 PM 19723505 ER PT J AU Hata, S Fujishige, S Araki, Y Kato, N Araseki, M Nishimura, M Hartmann, D Saftig, P Fahrenholz, F Taniguchi, M Urakami, K Akatsu, H Martins, RN Yamamoto, K Maeda, M Yamamoto, T Nakaya, T Gandy, S Suzuki, T AF Hata, Saori Fujishige, Sayaka Araki, Yoichi Kato, Naoko Araseki, Masahiko Nishimura, Masaki Hartmann, Dieter Saftig, Paul Fahrenholz, Falk Taniguchi, Miyako Urakami, Katsuya Akatsu, Hiroyasu Martins, Ralph N. Yamamoto, Kazuo Maeda, Masahiro Yamamoto, Tohru Nakaya, Tadashi Gandy, Sam Suzuki, Toshiharu TI Alcadein Cleavages by Amyloid beta-Precursor Protein (APP) alpha- and gamma-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzheimer Disease-related gamma-Secretase Dysfunction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRESENILIN-1 MUTATIONS; EARLY-ONSET; CONVERTING-ENZYME; METABOLISM; ASSOCIATION; MEMBRANE; FAMILY; PHOSPHORYLATION; DIFFERENTIATION; A-BETA(42) AB Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). Wedetermined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species A beta 42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects. C1 [Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Psychiat, New York, NY 10029 USA. [Hata, Saori; Fujishige, Sayaka; Araki, Yoichi; Kato, Naoko; Araseki, Masahiko; Yamamoto, Tohru; Nakaya, Tadashi; Suzuki, Toshiharu] Hokkaido Univ, Grad Sch Pharmaceut Sci, Dept Neurosci, Sapporo, Hokkaido 0600812, Japan. [Nishimura, Masaki] Shiga Univ Med Sci, Mol Neurosci Res Ctr, Neurol Unit, Otsu, Shiga 5202192, Japan. [Hartmann, Dieter] Univ Bonn, Dept Anat, D-53115 Bonn, Germany. [Saftig, Paul] Univ Kiel, Inst Biochem, D-2300 Kiel, Germany. [Fahrenholz, Falk] Johannes Gutenberg Univ Mainz, Inst Biochem, D-6500 Mainz, Germany. [Taniguchi, Miyako; Urakami, Katsuya] Tottori Univ, Fac Med, Sch Hlth Sci, Dept Regulat Biol, Yonago, Tottori 6838503, Japan. [Akatsu, Hiroyasu] Fukushimura Hosp, Choju Med Inst, Toyohashi, Aichi 4418124, Japan. [Martins, Ralph N.] Edith Cowan Univ, Sch Exercise Biomed & Hlth Sci, Sir James McCusker Alzheimers Dis Res Unit, Joondalup, WA 6027, Australia. [Martins, Ralph N.] Edith Cowan Univ, Sch Exercise Biomed & Hlth Sci, Ctr Excellence Alzheimers Dis Res & Care, Joondalup, WA 6027, Australia. [Yamamoto, Kazuo] Univ Tokyo, Grad Sch Frontier Sci, Dept Integrated Biosci, Kashiwa, Chiba 2778562, Japan. [Maeda, Masahiro] Immunobiol Labs Co Ltd, Fujioka 3750005, Japan. [Gandy, Sam] James J Peters Vet Adm Med Ctr, Bronx, NY 10468 USA. RP Gandy, S (reprint author), Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. EM samuel.gandy@mssm.edu; tsuzuki@pharm.hokudai.ac.jp RI Saftig, Paul/A-7966-2010; Hata, Saori /A-3829-2012; Yamamoto, Tohru/A-3801-2012; Suzuki, Toshiharu/B-5342-2013 OI Yamamoto, Tohru/0000-0002-1652-0233; FU National Institutes of Health, NIA [R01 AG23611, P01 AG10491, P50 AG005138]; Ministry of Education, Science, Culture, Sports, and Technology, Japan [20023001] FX This work was supported, in whole or in part, by National Institutes of Health, NIA, Grants R01 AG23611, P01 AG10491, and P50 AG005138 (to S. G.). This work was also supported in part by Grants-in-aid for Scientific Research on Priority Areas 20023001 (to T. S.) from the Ministry of Education, Science, Culture, Sports, and Technology, Japan. NR 31 TC 29 Z9 31 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 DEC 25 PY 2009 VL 284 IS 52 BP 36024 EP 36033 DI 10.1074/jbc.M109.057497 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 535LT UT WOS:000272970500004 PM 19864413 ER PT J AU Rajaiya, J Sadeghi, N Chodosh, J AF Rajaiya, Jaya Sadeghi, Neda Chodosh, James TI Specific NF kappa B subunit activation and kinetics of cytokine induction in adenoviral keratitis SO MOLECULAR VISION LA English DT Article ID NECROSIS-FACTOR-ALPHA; HUMAN CORNEAL FIBROBLASTS; P38 MAPK; ANTIGEN PRESENTATION; THERAPEUTIC TARGET; ACUTE-INFLAMMATION; TYPE-19 INFECTION; IMMUNE-RESPONSES; IL-8 EXPRESSION; GENE-EXPRESSION AB Purpose: Corneal inflammation associated with ocular adenoviral infection is caused by leukocytic infiltration of the subepithelial stroma in response to expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by infected corneal cells. We have shown that these two chemokines are activated by the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38 for IL-8, and Jun-terminal kinase (JNK) for MCP-1. It is also well established that transcription of each of these chemokines is tightly controlled by the nuclear factor kappa B (NF kappa B) transcription factor family. Therefore, we sought to better understand the differential regulation of chemokine expression by NF kappa B in adenoviral infection of the cornea. Methods: Primary keratocytes derived from human donor corneas were treated with signaling inhibitors and small interfering RNA specific to MAPKs, and infected with adenovirus for different time periods before analysis. Activation of specific NF kappa B subunits was analyzed by western blot, confocal microscopy, electromobility shift assay, and chromatin immunoprecipitation, and chemokine expression was quantified by enzyme-linked immunosorbent assay. Results: Upon adenoviral infection, NF kappa B p65, p50, and cREL subunits translocate to the nucleus. This translocation is blocked by inhibitors of specific MAPK signaling pathways. Confocal microscopy showed that inhibitors of the p38, JNK, and ERK pathways differentially inhibited NF kappa B nuclear translocation, while PP2, an inhibitor of Src family kinases, completely inhibited NF kappa B nuclear translocation. Western blot analysis revealed that activation of specific NF kappa B subunits was time dependent following infection. Chromatin immunoprecipitation experiments indicated that binding of NF kappa B p65 and p50 subunits to the IL-8 promoter upon viral infection was differentially reduced by chemical inhibitors of MAPKs. Electromobility shift assay and luciferase assay analysis revealed that transactivation of IL-8 occurred with binding by the NF kappa B p65 homodimer or NF kappa B p65/p50 heterodimer as early as 1 h post infection, whereas MCP-1 expression was dependent upon the NF kappa B cREL but not the p65 subunit, and occurred 4 h after IL-8 induction. Finally, knockdown of NF kappa B p65 by short interfering RNA abrogated IL-8 but not MCP-1 expression after adenoviral infection. Conclusion: The kinetics of NF kappa B subunit activation are partly responsible for the observed pattern of acute inflammation in the adenoviral-infected cornea. MAPKs differentially regulate chemokine expression in adenoviral keratitis by differential and time-dependent activation of specific NF kappa B subunits. C1 [Rajaiya, Jaya; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Howe Lab, Boston, MA 02114 USA. [Sadeghi, Neda] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Howe Lab, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU U.S. Public Health Service NIH [EY013124, P30EY014104]; Massachusetts Lions Eye Research Fund, Inc.; New England Corneal Transplant Research Fund; Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, New York, NY FX Supported in part by U.S. Public Health Service NIH grants EY013124 and P30EY014104, Massachusetts Lions Eye Research Fund, Inc., New England Corneal Transplant Research Fund, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, New York, NY. NR 54 TC 13 Z9 13 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD DEC 25 PY 2009 VL 15 IS 304-05 BP 2879 EP 2889 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 570SE UT WOS:000275697500001 PM 20038977 ER PT J AU Guibal, FC Alberich-Jorda, M Hirai, H Ebralidze, A Levantini, E Di Ruscio, A Zhang, P Santana-Lemos, BA Neuberg, D Wagers, AJ Rego, EM Tenen, DG AF Guibal, Florence C. Alberich-Jorda, Meritxell Hirai, Hideyo Ebralidze, Alexander Levantini, Elena Di Ruscio, Annalisa Zhang, Pu Santana-Lemos, Barbara A. Neuberg, Donna Wagers, Amy J. Rego, Eduardo M. Tenen, Daniel G. TI Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia SO BLOOD LA English DT Article ID PML-RAR-ALPHA; BINDING-PROTEIN-ALPHA; GENE-EXPRESSION PROFILES; HEMATOPOIETIC STEM-CELLS; TRANS-RETINOIC ACID; FACTOR-C/EBP-ALPHA; TRANSCRIPTION FACTOR; PML/RAR-ALPHA; GRANULOCYTIC DIFFERENTIATION; CHROMOSOMAL-ABNORMALITIES AB Acute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15: 17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor alpha. Treatment with retinoic acid leads to degradation of promyelocytic-retinoic acid receptor alpha protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer "stem" cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34(+), c-kit(+), Fc gamma RIII/II(+), Gr1(int)) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer-initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein alpha (C/EBP alpha) possibly through a methylation-dependent mechanism, indicating that C/EBP alpha deregulation contributes to transformation of APL cancer-initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease. (Blood. 2009; 114: 5415-5425) C1 [Guibal, Florence C.; Alberich-Jorda, Meritxell; Hirai, Hideyo; Ebralidze, Alexander; Levantini, Elena; Di Ruscio, Annalisa; Zhang, Pu; Tenen, Daniel G.] Harvard Univ, Ctr Life Sci, Sch Med, Boston, MA 02115 USA. [Guibal, Florence C.; Alberich-Jorda, Meritxell; Hirai, Hideyo; Ebralidze, Alexander; Levantini, Elena; Di Ruscio, Annalisa; Zhang, Pu; Wagers, Amy J.; Tenen, Daniel G.] Harvard Stem Cell Inst, Boston, MA USA. [Santana-Lemos, Barbara A.; Rego, Eduardo M.] Univ Sao Paulo, Div Hematol, Dept Internal Med, Med Sch Ribeirao Preto,Ctr Cell Based Therapy, Sao Paulo, Brazil. [Neuberg, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wagers, Amy J.] Harvard Univ, Sect Dev & Stem Cell Biol, Joslin Diabet Ctr, Dept Stem Cell & Regenerat Biol, Boston, MA 02115 USA. [Tenen, Daniel G.] Natl Univ Singapore, Canc Sci Inst, Singapore 117548, Singapore. RP Tenen, DG (reprint author), Harvard Univ, Ctr Life Sci, Sch Med, Rm 437,3 Blackfan Cir, Boston, MA 02115 USA. EM dtenen@bidmc.harvard.edu RI Celulas tronco, Inct/I-1921-2013; Rego, Eduardo/A-1058-2012; Alberich Jorda, Meritxell/G-3137-2014; OI Rego, Eduardo/0000-0003-1567-4086; Tenen, Daniel/0000-0002-6423-3888 FU National Institutes of Health [NIH/NCI POICA66996]; Harvard Stem Cell Institute; Fondation Recherche Medicale; European Hematology Association [19591126, 20592125, 21591246]; Shimizu Foundation; Flight Attendant Medical Research Institute; Italian Foundation for Cancer Research; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [01/07974-3, 01/08693-8]; BurroughsWellcome Fund; Associazione Italiana per la Ricerca sul Cancro FX This work was supported by the National Institutes of Health (NIH/NCI POICA66996) and the Harvard Stem Cell Institute (D. G. T.), the Fondation Recherche Medicale (F. C. G.), the European Hematology Association (M. A.-J.), Kakenhi (19591126, 20592125, and 21591246) and the Shimizu Foundation (Research Grant for 2006; H. H.), the Flight Attendant Medical Research Institute (E. L.), the Italian Foundation for Cancer Research (award Leonino Fontana e Maria Lionello; A. D. R.), and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo ( FAPESP; grants 01/07974-3 and 01/08693-8; B. A. S.-L.). This work was supported by the BurroughsWellcome Fund (CareerAward; A. J. W.). NR 58 TC 83 Z9 85 U1 1 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 24 PY 2009 VL 114 IS 27 BP 5415 EP 5425 DI 10.1182/blood-2008-10-182071 PG 11 WC Hematology SC Hematology GA 536UD UT WOS:000273068400005 PM 19797526 ER PT J AU Stewart, AK Richardson, PG San-Miguel, JF AF Stewart, A. Keith Richardson, Paul G. San-Miguel, Jesus F. TI How I treat multiple myeloma in younger patients SO BLOOD LA English DT Review ID STEM-CELL TRANSPLANTATION; HIGH-DOSE THERAPY; NEWLY-DIAGNOSED MYELOMA; CONSENSUS STATEMENT; COMPLETE RESPONSE; AUTOLOGOUS TRANSPLANTATION; INTERGROUPE FRANCOPHONE; CHROMOSOME-13 DELETION; CLINICAL-IMPLICATIONS; PLUS DEXAMETHASONE AB Therapeutic options for multiple myeloma (MM) patients have changed quickly in recent years and uncertainty has arisen about optimal approaches to therapy. A reasonable goal of MM treatment in younger "transplant eligible" patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control (and a potential "operational cure" in some). To achieve this goal we recommend induction therapy with multi-agent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteriods) which when employed together elicit frequent, rapid, and deep responses. We recommend consolidation with high-dose melphalan and autologous stem cell transplantation in the majority of patients willing and able to undergo this procedure and subsequent maintenance therapy in those failing to achieve a complete response or at high risk for early relapse based on prognostic, genetically defined risk factors. Defining genetic risk for early relapse is therefore an important aspect of early diagnostic testing and attention to minimizing expected toxicities once therapy begins is critical in ensuring the efficacy of modern combination therapy approaches. When access to newer drugs is restricted participation in clinical trials should be pursued. (Blood. 2009; 114: 5436-5443) C1 [Stewart, A. Keith] Mayo Clin Arizona, Scottsdale, AZ 85259 USA. [Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [San-Miguel, Jesus F.] Univ Salamanca, E-37008 Salamanca, Spain. RP Stewart, AK (reprint author), Mayo Clin Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM stewart.keith@mayo.edu RI 2009, Secribsal/A-1266-2012; OI SAN MIGUEL, JESUS/0000-0002-9183-4857 FU Millennium; Proteolix FX P. G. R. is on advisory boards for Millennium, Johnson and Johnson, and Celgene. A. K. S. is a consultant for Millennium and Proteolix, has received research support from Millennium, is on advisory boards for Celgene and Genzyme, and has received honoraria from Ortho Biotech. J. F. S.-M. is on advisory boards for Millennium, Celgene, and Janssen-Cilag. NR 72 TC 79 Z9 83 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 DEC 24 PY 2009 VL 114 IS 27 BP 5436 EP 5443 DI 10.1182/blood-2009-07-204651 PG 8 WC Hematology SC Hematology GA 536UD UT WOS:000273068400007 PM 19861683 ER PT J AU Kunert, S Meyer, I Fleischhauer, S Wannack, M Fiedler, J Shivdasani, RA Schulze, H AF Kunert, Stefan Meyer, Imke Fleischhauer, Silke Wannack, Martin Fiedler, Janine Shivdasani, Ramesh A. Schulze, Harald TI The microtubule modulator RanBP10 plays a critical role in regulation of platelet discoid shape and degranulation SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR NF-E2; BLOOD-PLATELETS; INTERNAL CONTRACTION; PROTEIN IMPORT; BETA-1 TUBULIN; RAN GTPASE; MEGAKARYOCYTES; MECHANISM; SUBSTRUCTURE; CYTOSKELETON AB Terminally mature megakaryocytes undergo dramatic cellular reorganization to produce hundreds of virtually identical platelets. A hallmark feature of this process is the generation of an elaborate system of branched protrusions called proplatelets. We recently identified RanBP10 as a tubulin-binding protein that is concentrated along polymerized micro-tubules in mature megakaryocytes. RanBP10 depletion in vitro caused the disturbance of polymerized filaments. Here we study the function of RanBP10 in vivo by generating deficient mice using a gene-trap approach. Mutant mice show normal platelet counts, and fetal liver-derived megakaryocytes reveal only slightly reduced proplatelet formation. However, ultrastructural analysis unveiled a significantly increased geometric axis ratio for resting platelets, and many platelets exhibited disorders in microtubule filament numbers and localization. Mutant mice showed a markedly prolonged bleeding time. Granule release, a process that depends on internal contraction of the microtubule marginal coil, also was reduced. Flow cytometry analysis revealed reduced expression of CD62P and CD63 after PAR4-peptide stimulation. These data suggest that RanBP10 plays an essential role in hemostasis and in maintaining microtubule dynamics with respect to both platelet shape and function. (Blood. 2009; 114: 5532-5540) C1 [Kunert, Stefan; Meyer, Imke; Fleischhauer, Silke; Wannack, Martin; Fiedler, Janine; Schulze, Harald] Charite, Klin Allgemeine Padiatrie, D-10098 Berlin, Germany. [Meyer, Imke; Fiedler, Janine] Freien Univ Berlin, Fachbereich Biol, Berlin, Germany. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA USA. RP Schulze, H (reprint author), Charite, Klin Allgemeine Padiatrie, Ziegelstr 5-9, D-10098 Berlin, Germany. EM harald.schulze@charite.de FU Deutsche Forschungsgemeinschaft [SCHU 1421/3-1, 3-2] FX This study was supported by the Deutsche Forschungsgemeinschaft SCHU 1421/3-1 and 3-2 (to H. S.). NR 44 TC 14 Z9 15 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 24 PY 2009 VL 114 IS 27 BP 5532 EP 5540 DI 10.1182/blood-2009-04-216804 PG 9 WC Hematology SC Hematology GA 536UD UT WOS:000273068400017 PM 19801445 ER PT J AU Moldovan, GL D'Andrea, AD AF Moldovan, George-Lucian D'Andrea, Alan D. TI FANCD2 Hurdles the DNA Interstrand Crosslink SO CELL LA English DT Editorial Material ID FANCONI-ANEMIA; REPAIR C1 [Moldovan, George-Lucian; D'Andrea, Alan D.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Radiat Oncol, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Radiat Oncol, 44 Binney St, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu OI George-Lucian, Moldovan/0000-0003-3825-149X FU NCI NIH HHS [P01 CA092584-09, P01CA092584, P01 CA092584]; NHLBI NIH HHS [R01 HL052725, R37 HL052725, R37 HL052725-16]; NIAID NIH HHS [U19 AI067751, U19 AI067751-05]; NIDDK NIH HHS [R01 DK043889, R01 DK043889-17] NR 9 TC 13 Z9 13 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 24 PY 2009 VL 139 IS 7 BP 1222 EP 1224 DI 10.1016/j.cell.2009.12.006 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 536MO UT WOS:000273048700009 PM 20064367 ER PT J AU Brass, AL Huang, IC Benita, Y John, SP Krishnan, MN Feeley, EM Ryan, BJ Weyer, JL van der Weyden, L Fikrig, E Adams, DJ Xavier, RJ Farzan, M Elledge, SJ AF Brass, Abraham L. Huang, I-Chueh Benita, Yair John, Sinu P. Krishnan, Manoj N. Feeley, Eric M. Ryan, Bethany J. Weyer, Jessica L. van der Weyden, Louise Fikrig, Erol Adams, David J. Xavier, Ramnik J. Farzan, Michael Elledge, Stephen J. TI The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus SO CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; RNA INTERFERENCE; GENE FAMILY; CELLS; ENDOCYTOSIS; EXPRESSION; SCREEN; TRANSCRIPTION; COMPLEXES; INFECTION AB Influenza viruses exploit host cell machinery to replicate, resulting in epidemics of respiratory illness. In turn, the host expresses antiviral restriction factors to defend against infection. To find host cell modifiers of influenza A H1N1 viral infection, we used a functional genomic screen and identified over 120 influenza A virus-dependency factors with roles in endosomal acidification, vesicular trafficking, mitochondrial metabolism, and RNA splicing. We discovered that the interferon-inducible transmembrane proteins IFITM1, 2, and 3 restrict an early step in influenza A viral replication. The IFITM proteins confer basal resistance to influenza A virus but are also inducible by interferons type I and II and are critical for interferon's virustatic actions. Further characterization revealed that the IFITM proteins inhibit the early replication of flaviviruses, including dengue virus and West Nile virus. Collectively this work identifies a family of antiviral restriction factors that mediate cellular innate immunity to at least three major human pathogens. C1 [Brass, Abraham L.; John, Sinu P.; Feeley, Eric M.; Ryan, Bethany J.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Brass, Abraham L.; John, Sinu P.; Feeley, Eric M.; Ryan, Bethany J.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Brass, Abraham L.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Benita, Yair; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Brass, Abraham L.; Elledge, Stephen J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Howard Hughes Med Inst,Dept Genet,Div Genet, Boston, MA 02115 USA. [Huang, I-Chueh; Weyer, Jessica L.; Farzan, Michael] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. [Krishnan, Manoj N.; Fikrig, Erol] Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06520 USA. [Fikrig, Erol] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. [van der Weyden, Louise; Adams, David J.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. RP Brass, AL (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. EM abrass@partners.org; farzan@hms.harvard.edu; selledge@genetics.med.harvard.edu RI Benita, Yair/E-3094-2012 FU NIH [AI 50031, AI070343, AI062773, DK060049, DK043351, U54 AI057159]; Cancer Research UK and the Wellcome Trust; Kay Kendall Leukaemia Foundation; New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases FX We thank the ICCB-Longwood; C. Shamu, S. Chang, S. Rudnicki, S. Johnston, K. Rudnicki, D. Wrobel, M. Ocana, and Z. Cooper; Ragon Institute; L. Whiteman, K. Hartman, A. Piechocka-Trocha, J. Proudfoot, and T. Diefenbach. We thank J. Philips, A. Mehle, M. Franti, F. Diaz-Griffero, J. Mabry (CDC), and J. Chou for helpful discussions. Funding support: A. L. B. wishes to express his gratitude to the Phillip T. and Susan M. Ragon Foundation for their generous support. A.L.B. (MGH GI Unit, Harvard Center for AIDS Research); M.N.K. and E.F. (NIH grants AI 50031 and AI070343); Y. B. and R.J.X. (CSIBD, CCIB, Genetics and Genomics Core, and NIH grants AI062773, DK060049, and DK043351); I.C.H. and M.F. (NERCE U54 AI057159). D.J.A. is supported by Cancer Research UK and the Wellcome Trust. L.v.d.W. is supported by a fellowship from the Kay Kendall Leukaemia Foundation. This study was supported by the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (NIH grant U54 AI057159 to D. Kasper). S. J. E. and E. F. are Investigators with the Howard Hughes Medical Institute. NR 46 TC 494 Z9 513 U1 4 U2 58 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 24 PY 2009 VL 139 IS 7 BP 1243 EP 1254 DI 10.1016/j.cell.2009.12.017 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 536MO UT WOS:000273048700013 PM 20064371 ER PT J AU Shapira, SD Gat-Viks, I Shum, BOV Dricot, A de Grace, MM Wu, LG Gupta, PB Hao, T Silver, SJ Root, DE Hill, DE Regev, A Hacohen, N AF Shapira, Sagi D. Gat-Viks, Irit Shum, Bennett O. V. Dricot, Amelie de Grace, Marciela M. Wu, Liguo Gupta, Piyush B. Hao, Tong Silver, Serena J. Root, David E. Hill, David E. Regev, Aviv Hacohen, Nir TI A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection SO CELL LA English DT Article ID DOUBLE-STRANDED-RNA; VIRUS-INFECTION; NS1 PROTEIN; ANTIVIRAL RESPONSES; GENE-EXPRESSION; RIG-I; REPLICATION; BINDING; SCREEN; ACTIVATION AB During the course of a viral infection, viral proteins interact with an array of host proteins and pathways. Here, we present a systematic strategy to elucidate the dynamic interactions between H1N1 influenza and its human host. A combination of yeast two-hybrid analysis and genome-wide expression profiling implicated hundreds of human factors in mediating viral-host interactions. These factors were then examined functionally through depletion analyses in primary lung cells. The resulting data point to potential roles for some unanticipated host and viral proteins in viral infection and the host response, including a network of RNA-binding proteins, components of WNT signaling, and viral polymerase subunits. This multilayered approach provides a comprehensive and unbiased physical and regulatory model of influenza-host interactions and demonstrates a general strategy for uncovering complex host-pathogen relationships. C1 [Shapira, Sagi D.; Gat-Viks, Irit; Shum, Bennett O. V.; de Grace, Marciela M.; Wu, Liguo; Gupta, Piyush B.; Silver, Serena J.; Root, David E.; Regev, Aviv; Hacohen, Nir] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Shapira, Sagi D.; de Grace, Marciela M.; Wu, Liguo; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Shapira, Sagi D.; Wu, Liguo; Hacohen, Nir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dricot, Amelie; Hao, Tong; Hill, David E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [de Grace, Marciela M.] Harvard Univ, Sch Med, Program Virol, Boston, MA 02115 USA. [Dricot, Amelie; Hao, Tong; Hill, David E.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Dricot, Amelie; Hao, Tong; Hill, David E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02142 USA. RP Regev, A (reprint author), MIT & Harvard, Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM aregev@broad.mit.edu; nhacohen@partners.org RI Hill, David/B-6617-2011 FU National Institutes of Health (NIH) [U01 AI074575, R01 HG001715, P50 HG004233]; NIH New Innovator Award; Ford Foundation Predoctoral Fellowship; EMBO Postdoctoral Fellowship; The Ellison Foundation; Howard Hughes Medical Institute; Burroughs Wellcome Fund; NIH Pioneer Award; Sloan Foundation; [U54 AI057159] FX We thank D. Lieber and K. Maciag for discussions and help with data analysis. We thank C. Shamu and S. Chiang at ICCB (HMS) for the siRNA library and expert advice, S. Gupta and the Broad's Genetic Analysis Platform for microarray processing, H. Le, A. Derr, B. Wong, and the staff at the Broad RNAi Platform for assistance with RNAi studies and analysis, L. Wu for the vRNA reporter plasmid, R. Cadagan and A. Garcia-Sastre for Delta NS1 virus, E. Fodor for PR8 plasmids, R. Lamb for Udorn plasmids, and S. Hart for assistance with artwork. This work was supported by National Institutes of Health (NIH) grant U01 AI074575 (N.H., D.R., and D.H.); U54 AI057159 and the NIH New Innovator Award (N.H.); Ford Foundation Predoctoral Fellowship (M.G.); EMBO Postdoctoral Fellowship (I.G.V.); The Ellison Foundation and NIH grants R01 HG001715 and P50 HG004233 (D.H.); and the Howard Hughes Medical Institute, a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, the NIH Pioneer Award, and the Sloan Foundation (A.R.). NR 34 TC 329 Z9 337 U1 5 U2 43 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 24 PY 2009 VL 139 IS 7 BP 1255 EP 1267 DI 10.1016/j.cell.2009.12.018 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 536MO UT WOS:000273048700014 PM 20064372 ER PT J AU Shen, XH Kim, WJ Fujiwara, Y Simon, MD Liu, YC Mysliwiec, MR Yuan, GC Lee, Y Orkin, SH AF Shen, Xiaohua Kim, Woojin Fujiwara, Yuko Simon, Matthew D. Liu, Yingchun Mysliwiec, Matthew R. Yuan, Guo-Cheng Lee, Youngsook Orkin, Stuart H. TI Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells SO CELL LA English DT Article ID MODEL-BASED ANALYSIS; TRANSCRIPTIONAL REPRESSION; CELLULAR-DIFFERENTIATION; HISTONE METHYLATION; TARGET GENES; PROTEIN; PLURIPOTENCY; DEMETHYLASE; NETWORK; CHROMATIN AB Trimethylation on histone H3 lysine 27 (H3K27me3) by Polycomb repressive complex 2 (PRC2) regulates the balance between self-renewal and differentiation of embryonic stem cells (ESCs). The mechanisms controlling the activity and recruitment of PRC2 are largely unknown. Here we demonstrate that the founding member of the Jumonji family, JMJ (JUMONJI or JARID2), is associated with PRC2, colocalizes with PRC2 and H3K27me3 on chromatin, and modulates PRC2 function. In vitro JMJ inhibits PRC2 methyltransferase activity, consistent with increased H3K27me3 marks at PRC2 targets in Jmj(-/-) ESCs. Paradoxically, JMJ is required for efficient binding of PRC2, indicating that the interplay of PRC2 and JMJ fine-tunes deposition of the H3K27me3 mark. During differentiation, activation of genes marked by H3K27me3 and lineage commitments are delayed in Jmj(-/-) ESCs. Our results demonstrate that dynamic regulation of Polycomb complex activity orchestrated by JMJ balances self-renewal and differentiation, highlighting the involvement of chromatin dynamics in cell-fate transitions. C1 [Shen, Xiaohua; Kim, Woojin; Fujiwara, Yuko; Orkin, Stuart H.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Shen, Xiaohua; Kim, Woojin; Fujiwara, Yuko; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Liu, Yingchun; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Yingchun; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Simon, Matthew D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Mysliwiec, Matthew R.; Lee, Youngsook] Univ Wisconsin, Sch Med & Publ Hlth, Dept Anat, Madison, WI 53706 USA. RP Orkin, SH (reprint author), Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU Claudia Adams Barr Program in Cancer Research; National Institutes of Health [HL67050]; American Heart Association [0615633Z] FX We thank T. Magnuson, K. Helin, Q. Yan, K. H. Hansen, and R. Fang for reagents; K.H. Hansen, A. Kuo, and O. Gozani for advice on peptide- binding assays; R. Tomaino and S. Gygi for performing mass spec sequencing; DFCI Microarray Core for processing microarray samples; T. Liu and X.S. Liu for assistance with MAT; Q. Yan, B. Wilson, J. Xu, and J. Perry for criticism. X.S. and G.Y. are supported by the Claudia Adams Barr Program in Cancer Research. M.D.S. is a HHWF fellow. Y.L. is supported by the National Institutes of Health grant HL67050 and M. R. M. by American Heart Association grant 0615633Z. S.H.O. is an investigator of the HHMI. NR 48 TC 248 Z9 252 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 24 PY 2009 VL 139 IS 7 BP 1303 EP 1314 DI 10.1016/j.cell.2009.12.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 536MO UT WOS:000273048700018 PM 20064376 ER PT J AU Hett, EC Hung, DT AF Hett, Erik C. Hung, Deborah T. TI Targeting Multiple Biofilm Pathways SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID SMALL-MOLECULE INHIBITORS; BACTERIAL BIOFILMS; BIOGENESIS C1 [Hett, Erik C.; Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Hett, Erik C.; Hung, Deborah T.] Broad Inst, Infect Dis Initiat, Cambridge, MA 02142 USA. [Hett, Erik C.; Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Hung, DT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM hung@molbio.mgh.havard.edu NR 8 TC 3 Z9 3 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD DEC 24 PY 2009 VL 16 IS 12 BP 1216 EP 1218 DI 10.1016/j.chembiol.2009.12.003 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541JI UT WOS:000273410700005 PM 20064430 ER PT J AU Vinciguerra, P D'Andrea, AD AF Vinciguerra, Patrizia D'Andrea, Alan D. TI FANCM: A Landing Pad for the Fanconi Anemia and Bloom's Syndrome Complexes SO MOLECULAR CELL LA English DT Editorial Material ID MITOSIS; PATHWAY; COLLABORATE; BLM C1 [Vinciguerra, Patrizia; D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu FU NCI NIH HHS [P01 CA092584, P01 CA092584-09, P01CA092584]; NHLBI NIH HHS [R37 HL052725] NR 10 TC 5 Z9 6 U1 0 U2 0 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 DEC 24 PY 2009 VL 36 IS 6 BP 916 EP 917 DI 10.1016/j.molcel.2009.12.007 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 537XS UT WOS:000273148300002 PM 20064455 ER PT J AU Stephens, PJ McBride, DJ Lin, ML Varela, I Pleasance, ED Simpson, JT Stebbings, LA Leroy, C Edkins, S Mudie, LJ Greenman, CD Jia, MM Latimer, C Teague, JW Lau, KW Burton, J Quail, MA Swerdlow, H Churcher, C Natrajan, R Sieuwerts, AM Martens, JWM Silver, DP Langerod, A Russnes, HEG Foekens, JA Reis-Filho, JS van't Veer, L Richardson, AL Borresen-Dale, AL Campbell, PJ Futreal, PA Stratton, MR AF Stephens, Philip J. McBride, David J. Lin, Meng-Lay Varela, Ignacio Pleasance, Erin D. Simpson, Jared T. Stebbings, Lucy A. Leroy, Catherine Edkins, Sarah Mudie, Laura J. Greenman, Chris D. Jia, Mingming Latimer, Calli Teague, Jon W. Lau, King Wai Burton, John Quail, Michael A. Swerdlow, Harold Churcher, Carol Natrajan, Rachael Sieuwerts, Anieta M. Martens, John W. M. Silver, Daniel P. Langerod, Anita Russnes, Hege E. G. Foekens, John A. Reis-Filho, Jorge S. van't Veer, Laura Richardson, Andrea L. Borresen-Dale, Anne-Lise Campbell, Peter J. Futreal, P. Andrew Stratton, Michael R. TI Complex landscapes of somatic rearrangement in human breast cancer genomes SO NATURE LA English DT Article ID TANDEM DUPLICATION; MYELOID-LEUKEMIA; COPY NUMBER; FUSION GENE; PATTERNS; TRANSLOCATIONS; IDENTIFICATION; ABERRATIONS; ETV6-NTRK3; MUTATION AB Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. C1 [Stephens, Philip J.; McBride, David J.; Lin, Meng-Lay; Varela, Ignacio; Pleasance, Erin D.; Simpson, Jared T.; Stebbings, Lucy A.; Leroy, Catherine; Edkins, Sarah; Mudie, Laura J.; Greenman, Chris D.; Jia, Mingming; Latimer, Calli; Teague, Jon W.; Lau, King Wai; Burton, John; Quail, Michael A.; Swerdlow, Harold; Churcher, Carol; Futreal, P. Andrew; Stratton, Michael R.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Natrajan, Rachael; Reis-Filho, Jorge S.] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Mol Pathol Lab, London SW3 6JB, England. [Sieuwerts, Anieta M.; Martens, John W. M.; Foekens, John A.] Erasmus Univ, Med Ctr, Josephine Nefkens Inst, Dept Med Oncol, NL-3000 CA Rotterdam, Netherlands. [Silver, Daniel P.; Richardson, Andrea L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Langerod, Anita; Russnes, Hege E. G.; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Genet, N-0310 Oslo, Norway. [van't Veer, Laura] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Richardson, Andrea L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Borresen-Dale, Anne-Lise] Oslo Univ Hosp Radiumhosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. [Stratton, Michael R.] Inst Canc Res, Sutton SM2 5NG, Surrey, England. RP Stratton, MR (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. EM paf@sanger.ac.uk; mrs@sanger.ac.uk RI Russnes, Hege/N-6170-2015; Varela, Ignacio/G-1699-2016 OI Russnes, Hege/0000-0001-8724-1891; Varela, Ignacio/0000-0002-0969-506X FU Kay Kendall Leukaemia Fund [KKL282]; Human Frontiers [LT000561/2009-L]; NCI [CA089393]; Breakthrough Breast Cancer; Research Council of Norway [155218, 175240]; Wellcome Trust [077012/Z/05/Z] FX We are grateful to M. Lambros, F. Geyer and R. Vatcheva for their assistance in the FISH experiments. We would like to acknowledge the support of the Kay Kendall Leukaemia Fund under Grant KKL282, Human Frontiers Award reference LT000561/2009-L, the Dana-Farber/Harvard SPORE in breast cancer under NCI grant reference CA089393, Breakthrough Breast Cancer, the Research Council of Norway Grants no. 155218 and 175240, and the Wellcome Trust under grant reference 077012/Z/05/Z. NR 37 TC 481 Z9 492 U1 4 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 24 PY 2009 VL 462 IS 7276 BP 1005 EP U60 DI 10.1038/nature08645 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535UB UT WOS:000272996000036 PM 20033038 ER PT J AU Zhou, WJ Ercan, D Chen, L Yun, CH Li, DN Capelletti, M Cortot, AB Chirieac, L Iacob, RE Padera, R Engen, JR Wong, KK Eck, MJ Gray, NS Janne, PA AF Zhou, Wenjun Ercan, Dalia Chen, Liang Yun, Cai-Hong Li, Danan Capelletti, Marzia Cortot, Alexis B. Chirieac, Lucian Iacob, Roxana E. Padera, Robert Engen, John R. Wong, Kwok-Kin Eck, Michael J. Gray, Nathanael S. Jaenne, Pasi A. TI Novel mutant-selective EGFR kinase inhibitors against EGFR T790M SO NATURE LA English DT Article ID CELL LUNG-CANCER; PAN-ERBB INHIBITOR; TYROSINE KINASE; RESISTANCE; GEFITINIB; MUTATION; SENSITIVITY; DASATINIB; NILOTINIB; IMATINIB AB The clinical efficacy of epidermal growth factor receptor ( EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation(1-3). Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR(4,5). All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wildtype EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors. C1 [Zhou, Wenjun; Yun, Cai-Hong; Eck, Michael J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhou, Wenjun; Yun, Cai-Hong; Eck, Michael J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ercan, Dalia; Chen, Liang; Li, Danan; Capelletti, Marzia; Cortot, Alexis B.; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Ercan, Dalia; Chen, Liang; Li, Danan; Capelletti, Marzia; Cortot, Alexis B.; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chirieac, Lucian; Padera, Robert] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Iacob, Roxana E.; Engen, John R.] Northeastern Univ, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA. [Iacob, Roxana E.; Engen, John R.] Northeastern Univ, Dept Chem & Biol Chem, Boston, MA 02115 USA. [Wong, Kwok-Kin; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wong, Kwok-Kin; Jaenne, Pasi A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM Nathanael_Gray@dfci.harvard.edu; pjanne@partners.org OI wong, kwok kin/0000-0001-6323-235X FU National Institutes of Health [RO1CA11446, R01CA135257, R01CA080942, R01CA130876-02, R01CA116020, R01AG2400401, R01 CA122794, R01GM070590]; National Cancer Institute Lung SPORE [P50CA090578]; Cecily and Robert Harris Foundation; Uniting Against Lung Cancer; Flight Attendant Medical Research Institute; Hazel and Samuel Bellin Research Fund; Damon Runyon Foundation Cancer Innovation Award FX This study is supported by grants from the National Institutes of Health RO1CA11446 ( P. A. J.), R01CA135257 ( P. A. J.), R01CA080942 ( M. J. E.), R01CA130876-02 ( N. S. G.), R01CA116020 ( M. J. E.), R01AG2400401 (K.-K.W.), R01 CA122794 ( K.- K. W.), R01GM070590 ( J. R. E.), National Cancer Institute Lung SPORE P50CA090578 ( P. A. J. and K.- K. W.), the Cecily and Robert Harris Foundation ( K.- K. W.), Uniting Against Lung Cancer ( K.- K. W.), the Flight Attendant Medical Research Institute ( K.- K. W.)., the Hazel and Samuel Bellin Research Fund ( P. A. J.) and the Damon Runyon Foundation Cancer Innovation Award ( N. S. G.). This work is contribution 948 from the Barnett Institute. The authors thank Sai Advantium Pharma for performing the pharmacokinetic studies. NR 28 TC 405 Z9 420 U1 7 U2 95 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 24 PY 2009 VL 462 IS 7276 BP 1070 EP 1074 DI 10.1038/nature08622 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535UB UT WOS:000272996000050 PM 20033049 ER PT J AU Ma, QF AF Ma, Qiufu TI RETouching upon Mechanoreceptors SO NEURON LA English DT Editorial Material ID DRG NEURONS; INNERVATION; PAIN; NGF AB The rapidly adapting (RA) low-threshold mechanoreceptors respond to movement of the skin and vibration and are critical for the perception of texture and shape. In this issue of Neuron, two papers (Bourane et al. and Luo et al.) demonstrate that early-born Ret(+) sensory neurons are RA mechanoreceptors, whose peripheral nerve terminals are associated with Meissner corpuscles, longitudinal lanceolate endings, and Pacinian corpuscles. The studies further show that Ret signaling is essential for the development of these mechanoreceptors. C1 [Ma, Qiufu] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ma, Qiufu] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Ma, QF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM qiufu_ma@dfci.harvard.edu FU NIDCR NIH HHS [R01 DE018025, R01 DE018025-03, R01 DE018025-02, R01 DE018025-01A1]; NINDS NIH HHS [P01 NS047572-030003, P01 NS047572, P01 NS047572-020003, P01 NS047572-050003, P01 NS047572-01A10003, P01 NS047572-040003] NR 13 TC 1 Z9 2 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 24 PY 2009 VL 64 IS 6 BP 773 EP 776 DI 10.1016/j.neuron.2009.12.014 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 541ON UT WOS:000273425800002 PM 20064382 ER PT J AU Partridge, AH Winer, EP AF Partridge, Ann H. Winer, Eric P. TI On Mammography - More Agreement Than Disagreement SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SERVICES TASK-FORCE; BREAST-CANCER C1 [Partridge, Ann H.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 25 Z9 26 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 24 PY 2009 VL 361 IS 26 BP 2499 EP 2501 DI 10.1056/NEJMp0911288 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 535WX UT WOS:000273003700002 PM 19940286 ER PT J AU Uyeki, TM Sharma, A Branda, JA AF Uyeki, Timothy M. Sharma, Amita Branda, John A. TI A Man with Fever and Respiratory Failure 2009 influenza A (H1N1) virus infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CRITICALLY-ILL PATIENTS; ADENOVIRUS SEROTYPE 14; UNITED-STATES; SWINE INFLUENZA; HOSPITALIZED-PATIENTS; PNEUMONIC TULAREMIA; A(H1N1) INFECTION; DISTRESS-SYNDROME; DIAGNOSTIC-TESTS; MARTHAS-VINEYARD C1 [Uyeki, Timothy M.] Ctr Dis Control & Prevent, Epidemiol & Prevent Branch, Influenza Div, Atlanta, GA 30333 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sharma, Amita] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Uyeki, TM (reprint author), Ctr Dis Control & Prevent, Epidemiol & Prevent Branch, Influenza Div, Atlanta, GA 30333 USA. FU Diasorin FX Dr. Branda reports receiving grant support from Diasorin. No other potential conflict of interest relevant to this article was reported.; We thank Dr. Sandra Nelson for assistance in preparing the case presentation. NR 69 TC 3 Z9 3 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 DEC 24 PY 2009 VL 361 IS 26 BP 2558 EP 2569 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 535WX UT WOS:000273003700014 PM 20032326 ER PT J AU Kathiresan, S AF Kathiresan, Sekar TI Lp(a) Lipoprotein Redux - From Curious Molecule to Causal Risk Factor SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CORONARY-ARTERY-DISEASE; APOLIPOPROTEIN(A); ASSOCIATION; LOCI C1 [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02115 USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Kathiresan, Sekar] Broad Inst, Cambridge, MA USA. RP Kathiresan, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02115 USA. NR 16 TC 10 Z9 12 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 24 PY 2009 VL 361 IS 26 BP 2573 EP 2574 DI 10.1056/NEJMe0910792 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 535WX UT WOS:000273003700016 PM 20032327 ER PT J AU Liu, XQ Pawlyk, BS Adamian, M Olshevskaya, EV Dizhoor, AM Makino, CL Li, TS AF Liu, Xiaoqing Pawlyk, Basil S. Adamian, Michael Olshevskaya, Elena V. Dizhoor, Alexander M. Makino, Clint L. Li, Tiansen TI Increased Light Exposure Alleviates One Form of Photoreceptor Degeneration Marked by Elevated Calcium in the Dark SO PLOS ONE LA English DT Article ID DOMINANT CONE DEGENERATION; GUANYLATE-CYCLASE; RETINITIS-PIGMENTOSA; TRANSGENIC MICE; MOUSE MODEL; RHODOPSIN; MUTATION; DYSTROPHY; APOPTOSIS; DISEASE AB Background: In one group of gene mutations that cause photoreceptor degeneration in human patients, guanylyl cyclase is overactive in the dark. The ensuing excess opening of cGMP-gated cation channels causes intracellular calcium to rise to toxic levels. The Y99C mutation in guanylate cyclase-activating protein 1 (GCAP1) has been shown to act this way. We determined whether prolonged light exposure, which lowers cGMP levels through activation of phototransduction, might protect photoreceptors in a line of transgenic mice carrying the GCAP1-Y99C. Methodology/Principal Findings: We reared cohorts of GCAP1-Y99C transgenic mice under standard cyclic, constant dark and constant light conditions. Mouse eyes were analyzed by histology and by immunofluorescence for GFAP upregulation, a non-specific marker for photoreceptor degeneration. Full-field electroretinograms (ERGs) were recorded to assess retinal function. Consistent with our hypothesis, constant darkness accelerated disease, while continuous lighting arrested photoreceptor degeneration. Conclusions/Significance: In contrast to most forms of retinal degeneration, which are exacerbated by increased exposure to ambient light, a subset with mutations that cause overly active guanylyl cyclase and high intracellular calcium benefitted from prolonged light exposure. These findings may have therapeutic implications for patients with these types of genetic defects. C1 [Liu, Xiaoqing; Pawlyk, Basil S.; Adamian, Michael] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02115 USA. [Olshevskaya, Elena V.; Dizhoor, Alexander M.] Salus Univ, Penn Coll Optometry, Hafter Res Labs, Elkins Pk, PA USA. [Makino, Clint L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab, Boston, MA USA. [Li, Tiansen] NEI, Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. RP Liu, XQ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02115 USA. EM tiansen.li@nih.gov OI Makino, Clint/0000-0002-6005-9069 FU National Institutes of Health [EY10309, EY10581, EY11522, EY12944, EY14104]; Macular Vision Research Foundation; Foundation Fighting Blindness FX This work was supported by grants from the National Institutes of Health EY10309, EY10581 (TL), EY11522 (AD), EY12944 (CLM), EY14104 (core grant), the Macular Vision Research Foundation, and the Foundation Fighting Blindness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 24 PY 2009 VL 4 IS 12 AR e8438 DI 10.1371/journal.pone.0008438 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 537HN UT WOS:000273104000007 PM 20041177 ER PT J AU Landefeld, CS Winker, MA Chernof, B AF Landefeld, C. Seth Winker, Margaret A. Chernof, Bruce TI Clinical Care in the Aging Century-Announcing "Care of the Aging Patient: From Evidence to Action" SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Landefeld, C. Seth] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94118 USA. [Landefeld, C. Seth] San Francisco VA Med Ctr, San Francisco, CA USA. [Chernof, Bruce] SCAN Fdn, Long Beach, CA USA. RP Landefeld, CS (reprint author), Univ Calif San Francisco, Div Geriatr, 3333 Calif St,Ste 380, San Francisco, CA 94118 USA. EM sethl@medicine.ucsf.edu OI Winker, Margaret/0000-0002-4708-5641 NR 15 TC 12 Z9 12 U1 0 U2 6 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 DEC 23 PY 2009 VL 302 IS 24 BP 2703 EP 2704 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 535JU UT WOS:000272965300030 PM 20040562 ER PT J AU Kheirbek, T Kochanek, AR Alam, HB AF Kheirbek, Tareq Kochanek, Ashley R. Alam, Hasan B. TI Hypothermia in bleeding trauma: a friend or a foe? SO SCANDINAVIAN JOURNAL OF TRAUMA RESUSCITATION & EMERGENCY MEDICINE LA English DT Review ID UNCONTROLLED HEMORRHAGIC-SHOCK; EMERGENCY-DEPARTMENT THORACOTOMY; EXSANGUINATION CARDIAC-ARREST; HIGH-ENERGY PHOSPHATES; CEREBRAL-BLOOD-FLOW; N-TERMINAL KINASE; PROFOUND HYPOTHERMIA; MODERATE HYPOTHERMIA; SWINE MODEL; FLUID RESUSCITATION AB The induction of hypothermia for cellular protection is well established in several clinical settings. Its role in trauma patients, however, is controversial. This review discusses the benefits and complications of induced hypothermia--emphasizing the current state of knowledge and potential applications in bleeding patients. Extensive pre-clinical data suggest that in advanced stages of shock, rapid cooling can protect cells during ischemia and reperfusion, decrease organ damage, and improve survival. Yet hypothermia is a double edged sword; unless carefully managed, its induction can be associated with a number of complications. Appropriate patient selection requires a thorough understanding of the pre-clinical literature. Clinicians must also appreciate the enormous influence that temperature modulation exerts on various cellular mechanisms. This manuscript aims to provide a balanced view of the published literature on this topic. While many of the advantageous molecular and physiological effects of induced hypothermia have been outlined in animal models, rigorous clinical investigations are needed to translate these promising findings into clinical practice. C1 [Kheirbek, Tareq; Kochanek, Ashley R.; Alam, Hasan B.] Harvard Univ, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Sch Med,Dept Surg, Boston, MA 02115 USA. [Kheirbek, Tareq] Washington Hosp Ctr, Dept Surg, Washington, DC 20010 USA. RP Alam, HB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Sch Med,Dept Surg, Boston, MA 02115 USA. EM hbalam@partners.org; akochanek@partners.org; hbalam@partners.org FU National Institutes of Health FX Hypothermia research performed by Dr. Alam was supported by a research grant from the National Institutes of Health. NR 150 TC 24 Z9 26 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-7241 J9 SCAND J TRAUMA RESUS JI Scand. J. Trauma Resusc. Emerg. Med. PD DEC 23 PY 2009 VL 17 AR 65 DI 10.1186/1757-7241-17-65 PG 15 WC Emergency Medicine SC Emergency Medicine GA 665LI UT WOS:000283036200001 PM 20030810 ER PT J AU Fawzi, MCS Betancourt, TS Marcelin, L Klopner, M Munir, K Muriel, AC Oswald, C Mukherjee, JS AF Fawzi, Mary C. Smith Betancourt, Theresa S. Marcelin, Lilly Klopner, Michelle Munir, Kerim Muriel, Anna C. Oswald, Catherine Mukherjee, Joia S. TI Depression and post-traumatic stress disorder among Haitian immigrant students: implications for access to mental health services and educational programming SO BMC PUBLIC HEALTH LA English DT Article ID REFUGEE CHILDREN; ADOLESCENT REFUGEES; ALCOHOL-USE; PSYCHOLOGICAL DISTRESS; BLACK-ADOLESCENTS; AFRICAN-AMERICAN; RACIAL MISTRUST; TRAUMA; WAR; BEHAVIORS AB Background: Previous studies of Haitian immigrant and refugee youth have emphasized "externalizing" behaviors, such as substance use, high risk sexual behavior, and delinquency, with very little information available on "internalizing" symptoms, such as depression and anxiety. Analyzing stressors and "internalizing" symptoms offers a more balanced picture of the type of social and mental health services that may be needed for this population. The present study aims to: 1) estimate the prevalence of depression and post-traumatic stress disorder (PTSD) among Haitian immigrant students; and 2) examine factors associated with depression and PTSD to identify potential areas of intervention that may enhance psychosocial health outcomes among immigrant youth from Haiti in the U. S. Methods: A stratified random sample of Haitian immigrant students enrolled in Boston public high schools was selected for participation; 84% agreed to be interviewed with a standardized questionnaire. Diagnosis of depression and PTSD was ascertained using the best estimate diagnosis method. Results: The prevalence estimates of depression and PTSD were 14.0% and 11.6%; 7.9% suffered from comorbid PTSD and depression. Multivariate logistic regression demonstrated factors most strongly associated with depression ( history of father's death, self-report of schoolwork not going well, not spending time with friends) and PTSD (concern for physical safety, having many arguments with parents, history of physical abuse, and lack of safety of neighborhood). Conclusions: A significant level of depression and PTSD was observed. Stressors subsequent to immigration, such as living in an unsafe neighborhood and concern for physical safety, were associated with an increased risk of PTSD and should be considered when developing programs to assist this population. Reducing exposure to these stressors and enhancing access to social support and appropriate school-based and mental health services may improve educational attainment and psychosocial health outcomes among Haitian immigrant youth. C1 [Fawzi, Mary C. Smith; Mukherjee, Joia S.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Program Infect Dis & Social Change, Boston, MA 02115 USA. [Fawzi, Mary C. Smith; Marcelin, Lilly; Oswald, Catherine; Mukherjee, Joia S.] Partners Hlth, Boston, MA USA. [Betancourt, Theresa S.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Klopner, Michelle] Cambridge Hosp, Haitian Mental Hlth Clin, Cambridge, MA 02139 USA. [Munir, Kerim] Childrens Hosp, Boston, MA 02115 USA. [Muriel, Anna C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Fawzi, MCS (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Program Infect Dis & Social Change, Boston, MA 02115 USA. EM mksfawzi@msn.com; Theresa_Betancourt@harvard.edu; lil1216@yahoo.com; hcsmck@gwumc.edu; kerim.munir@childrens.harvard.edu; amuriel@partners.org; coswald@pih.org; jmukherjee@pih.org FU National Institute of Mental Health [RO3-MH52267] FX We would like to thank all of the youth who participated in this study. Special thanks are extended to William Beardslee, Nicole Cesar, Dumas Lafontant, Michelle Li, Dominic Maxwell, Richard Wong, Gwendolyn Zahner, as well as teachers and guidance staff at Boston Public Schools who provided assistance to this study. This study was funded by the National Institute of Mental Health (RO3-MH52267). NR 62 TC 8 Z9 8 U1 4 U2 15 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 DEC 22 PY 2009 VL 9 AR 482 DI 10.1186/1471-2458-9-482 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 544LD UT WOS:000273657300001 PM 20028506 ER PT J AU Kwolek, CJ Watkins, MT AF Kwolek, Christopher J. Watkins, Michael T. TI The INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) Trial The Need for Ongoing Analysis SO CIRCULATION LA English DT Editorial Material DE Editorials; aorta; aortic dissection; stents; remodeling; prognosis ID ENDOVASCULAR TREATMENT; ANEURYSM REPAIR; FALSE LUMEN; MULTICENTER C1 [Kwolek, Christopher J.; Watkins, Michael T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. RP Watkins, MT (reprint author), 15 Parkman St,Suite 440, Boston, MA 02114 USA. EM mtwatkins@partners.org NR 16 TC 6 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 22 PY 2009 VL 120 IS 25 BP 2513 EP 2514 DI 10.1161/CIRCULATIONAHA.109.911883 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 535LX UT WOS:000272970900001 PM 19996013 ER PT J AU Cauwels, A Buys, ES Thoonen, R Geary, L Delanghe, J Shiva, S Brouckaert, P AF Cauwels, Anje Buys, Emmanuel S. Thoonen, Robrecht Geary, Lisa Delanghe, Joris Shiva, Sruti Brouckaert, Peter TI Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CATALYTIC-ACTIVITY CONCENTRATIONS; SEPTIC SHOCK; OXIDATIVE STRESS; IN-VIVO; MITOCHONDRIAL-DNA; ENDOTOXIC-SHOCK; OXIDE SYNTHASE; NO; NECROSIS; DYSFUNCTION AB Nitrite (NO(2)(-)), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) alpha 1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection. C1 [Cauwels, Anje; Thoonen, Robrecht; Brouckaert, Peter] Flanders Inst Biotechnol, Dept Mol Biomed Res, B-9052 Ghent, Belgium. [Cauwels, Anje; Thoonen, Robrecht; Brouckaert, Peter] Univ Ghent, Univ Hosp, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Delanghe, Joris] Univ Ghent, Univ Hosp, Dept Clin Chem, B-9000 Ghent, Belgium. [Buys, Emmanuel S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Geary, Lisa; Shiva, Sruti] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Shiva, Sruti] Univ Pittsburgh, Sch Med, Vasc Med Inst, Pittsburgh, PA 15213 USA. RP Cauwels, A (reprint author), Flanders Inst Biotechnol, Dept Mol Biomed Res, B-9052 Ghent, Belgium. EM Anje.Cauwels@dmbr.UGent.be FU Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen; Universiteit Gent-Geconcerteerde Onderzoeks Acties; American Heart Association Northeast Affiliate; Massachusetts Biomedical Research Corporation FX This research was supported by the Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen and the Universiteit Gent-Geconcerteerde Onderzoeks Acties. A. Cauwels is a postdoctoral fellow of the FWO-Vlaanderen. E. S. Buys was supported by a postdoctoral fellowship award from the American Heart Association Northeast Affiliate and by a Tosteson postdoctoral fellowship from the Massachusetts Biomedical Research Corporation. NR 36 TC 44 Z9 46 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 2009 VL 206 IS 13 BP 2915 EP 2924 DI 10.1084/jem.20091236 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500009 PM 19934018 ER PT J AU Huang, JH Goedert, JJ Sundberg, EJ Cung, TDH Burke, PS Martin, MP Preiss, L Lifson, J Lichterfeld, M Carrington, M Yu, XG AF Huang, Jinghe Goedert, James J. Sundberg, Eric J. Cung, Thai Duong Hong Burke, Patrick S. Martin, Maureen P. Preiss, Liliana Lifson, Jeffrey Lichterfeld, Mathias Carrington, Mary Yu, Xu G. TI HLA-B*35-Px-mediated acceleration of HIV-1 infection by increased inhibitory immunoregulatory impulses SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-I MOLECULES; IMMUNODEFICIENCY VIRUS-REPLICATION; CD8(+) T-CELLS; MYELOMONOCYTIC CELLS; HLA; AIDS; RECEPTOR; INDIVIDUALS; RECOGNITION; PROGRESSION AB A subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1-specific CD8(+) T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1-infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1. C1 [Huang, Jinghe; Cung, Thai Duong Hong; Burke, Patrick S.; Yu, Xu G.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Huang, Jinghe; Cung, Thai Duong Hong; Burke, Patrick S.; Yu, Xu G.] Harvard Univ, Boston, MA 02129 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Sundberg, Eric J.] Boston Biomed Res Inst, Watertown, MA 02472 USA. [Martin, Maureen P.; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Lifson, Jeffrey] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Preiss, Liliana] Res Triangle Inst Int, Rockville, MD 20852 USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Yu, XG (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. EM xyu@partners.org RI Huang, Jinghe/O-1986-2015 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E, N02CP55504]; NIAID NIH HHS [AI078799, R01 AI078799]; PHS HHS [HHSN261200800001E, HHSN266200400088C] NR 25 TC 41 Z9 42 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 2009 VL 206 IS 13 BP 2959 EP 2966 DI 10.1084/jem.20091386 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500013 PM 20008523 ER PT J AU Kamizono, S Duncan, GS Seidel, MG Morimoto, A Hamada, K Grosveld, G Akashi, K Lind, EF Haight, JP Ohashi, PS Look, AT Mak, TW AF Kamizono, Shintaro Duncan, Gordon S. Seidel, Markus G. Morimoto, Akira Hamada, Koichi Grosveld, Gerard Akashi, Koichi Lind, Evan F. Haight, Jillian P. Ohashi, Pamela S. Look, A. Thomas Mak, Tak W. TI Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NATURAL-KILLER-CELL; XENOPUS-LAEVIS METAMORPHOSIS; PRO-B LYMPHOCYTES; TRANSCRIPTION FACTOR; THYROID-HORMONE; DEFICIENT MICE; E4BP4; GENE; EXPRESSION; PATHWAYS AB Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3(-/-)) mice. Nfil3(-/-) mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3(-/-) mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I-deficient cells in vivo and reductions in both interferon gamma production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage. C1 [Kamizono, Shintaro; Seidel, Markus G.; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Akashi, Koichi] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kamizono, Shintaro; Duncan, Gordon S.; Hamada, Koichi; Lind, Evan F.; Haight, Jillian P.; Ohashi, Pamela S.; Mak, Tak W.] Univ Hlth Network, Ontario Canc Inst, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2C1, Canada. [Ohashi, Pamela S.; Mak, Tak W.] Univ Toronto, Dept Immunol, Toronto, ON M5G 2C1, Canada. [Ohashi, Pamela S.; Mak, Tak W.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada. [Morimoto, Akira; Grosveld, Gerard] St Jude Childrens Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA. [Morimoto, Akira; Grosveld, Gerard] St Jude Childrens Hosp, Dept Genet, Memphis, TN 38105 USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM thomas_look@dfci.harvard.edu; tmak@uhnresearch.ca OI Seidel, Markus G/0000-0003-0981-8661 FU National Institutes of Health; Canadian Institute of Health Research; National Cancer Institute of Canada; International Research Fund of the Kyushu University School of Medicine Alumni, Japan FX Financial support for this project was provided by grants from the National Institutes of Health), Canadian Institute of Health Research, the National Cancer Institute of Canada, and the International Research Fund of the Kyushu University School of Medicine Alumni, Japan. NR 33 TC 151 Z9 153 U1 1 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 2009 VL 206 IS 13 BP 2977 EP 2986 DI 10.1084/jem.20092176 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500015 PM 19995955 ER PT J AU Francisco, LM Salinas, VH Brown, KE Vanguri, VK Freeman, GJ Kuchroo, VK Sharpe, AH AF Francisco, Loise M. Salinas, Victor H. Brown, Keturah E. Vanguri, Vijay K. Freeman, Gordon J. Kuchroo, Vijay K. Sharpe, Arlene H. TI PD-L1 regulates the development, maintenance, and function of induced regulatory T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; PROGRAMMED DEATH-1 LIGAND-1; GASTRIC EPITHELIAL-CELLS; CUTTING EDGE; DE-NOVO; CLINICAL-SIGNIFICANCE; TUMOR-IMMUNOTHERAPY; SUPPRESSOR FUNCTION; B7-H1 EXPRESSION; IMMUNE EVASION AB Both the programmed death (PD) 1-PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1(-/-) antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1-coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1(-/-)PD-L2(-/-)Rag(-/-) recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity. C1 [Francisco, Loise M.; Brown, Keturah E.; Vanguri, Vijay K.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Francisco, Loise M.; Vanguri, Vijay K.; Sharpe, Arlene H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kuchroo, Vijay K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Salinas, Victor H.] Harvard Univ, Cambridge, MA 02138 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU National Institutes of Health [AI38310, AI40614, PO1 56299]; National Multiple Sclerosis Society FX This work was supported by grants from the National Institutes of Health (AI38310 and AI40614 to A. H. Sharpe; PO1 56299 to A. H. Sharpe, V. K. Kuchroo, and G. J. Freeman) and The National Multiple Sclerosis Society (L. M. Francisco). NR 78 TC 508 Z9 542 U1 8 U2 47 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 2009 VL 206 IS 13 BP 3015 EP 3029 DI 10.1084/jem.20090847 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500018 PM 20008522 ER PT J AU Dimopoulos, MA Richardson, PG Schlag, R Khuageva, NK Shpilberg, O Kastritis, E Kropff, M Petrucci, MT Delforge, M Alexeeva, J Schots, R Masszi, T Mateos, MV Deraedt, W Liu, K Cakana, A van de Velde, H Miguel, JFS AF Dimopoulos, Meletios A. Richardson, Paul G. Schlag, Rudolf Khuageva, Nuriet K. Shpilberg, Ofer Kastritis, Efstathios Kropff, Martin Petrucci, Maria T. Delforge, Michel Alexeeva, Julia Schots, Rik Masszi, Tamas Mateos, Maria-Victoria Deraedt, William Liu, Kevin Cakana, Andrew van de Velde, Helgi Miguel, Jesus F. San TI VMP (Bortezomib, Melphalan, and Prednisone) Is Active and Well Tolerated in Newly Diagnosed Patients With Multiple Myeloma With Moderately Impaired Renal Function, and Results in Reversal of Renal Impairment: Cohort Analysis of the Phase III VISTA Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; MM PATIENTS; CYSTATIN-C; FAILURE; REGIMENS; REVERSIBILITY; DEXAMETHASONE; SAFETY; PATHOGENESIS; MULTICENTER AB Purpose To assess bortezomib plus melphalan and prednisone (VMP) and melphalan and prednisone (MP) in previously untreated patients with multiple myeloma (MM) with renal impairment enrolled on the phase III VISTA study, and to evaluate renal impairment reversibility. Patients and Methods Patients received nine 6-week cycles of VMP (bortezomib 1.3 mg/m(2), melphalan 9 mg/m(2), prednisone 60 mg/m(2)) or MP. Patients with serum creatinine higher than 2 mg/dL were excluded. Results In the VMP/MP arms, 6%/4%, 27%/30%, and 67%/66% of patients had baseline glomerular filtration rate (GFR) of <= 30, 31 to 50, and higher than 50 mL/min, respectively. Response rates were higher and time to progression (TTP) and overall survival (OS) longer with VMP versus MP across renal cohorts. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR < 50 or higher than 50 mL/min; OS appeared somewhat longer in patients with normal renal function in both arms. Renal impairment reversal (baseline GFR < 50 improving to > 60 mL/min) was seen in 49 (44%) of 111 patients receiving VMP versus 40 (34%) of 116 patients receiving MP. By multivariate analysis, younger age (< 75 years; P = .006) and less severe impairment (GFR >= 30 mL/min; P = .027) were associated with higher reversal rates. In addition, treatment with VMP approached significance (P = .07). In both arms, rates of grade 4 and 5 adverse events (AEs) and serious AEs appeared higher in patients with renal impairment; with VMP, rates of discontinuations/bortezomib dose reductions due to AEs did not appear affected. Conclusion VMP is a feasible, active, and well-tolerated treatment option for previously untreated patients with MM with moderate renal impairment, resulting in 44% renal impairment reversal. C1 [Dimopoulos, Meletios A.] Univ Athens, Alexandra Hosp, Dept Clin Therapeut, Sch Med, Athens, Greece. Dana Farber Canc Inst, Boston, MA 02115 USA. Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ USA. Praxisklin Dr Schlag, Wurzburg, Germany. Univ Munster, Munster, Germany. Rabin Med Ctr, Petah Tiqwa, Israel. Univ Roma La Sapienza, Rome, Italy. Belgian Hematol Soc, Myeloma Study Grp, Brussels, Belgium. SP Botkin Moscow City Clin Hosp, Moscow, Russia. Johnson & Johnson Pharmaceut Res & Dev, Beerse, Belgium. St Petersburg Clin City Hosp, St Petersburg, Russia. St Istvan & St Laszlo Hosp Budapest, Budapest, Hungary. Univ Salamance, CSIC, Inst Biol Mol & Celular Canc, Ctr Invest Canc,Hosp Univ Salamanca, Salamanca, Spain. RP Dimopoulos, MA (reprint author), Univ Athens, Alexandra Hosp, Dept Clin Therapeut, Sch Med, Athens, Greece. EM mdimop@med.uoa.gr RI 2009, Secribsal/A-1266-2012 FU Johnson & Johnson Pharmaceutical Research & Development LLC; Millennium Pharmaceuticals FX Supported by Johnson & Johnson Pharmaceutical Research & Development LLC and Millennium Pharmaceuticals. NR 38 TC 75 Z9 84 U1 0 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 DEC 20 PY 2009 VL 27 IS 36 BP 6086 EP 6093 DI 10.1200/JCO.2009.22.2232 PG 8 WC Oncology SC Oncology GA 534AI UT WOS:000272867500005 PM 19858394 ER PT J AU Damon, LE Johnson, JL Niedzwiecki, D Cheson, BD Hurd, DD Bartlett, NL LaCasce, AS Blum, KA Byrd, JC Kelly, M Stock, W Linker, CA Canellos, GP AF Damon, Lloyd E. Johnson, Jeffrey L. Niedzwiecki, Donna Cheson, Bruce D. Hurd, David D. Bartlett, Nancy L. LaCasce, Ann S. Blum, Kristie A. Byrd, John C. Kelly, Michael Stock, Wendy Linker, Charles A. Canellos, George P. TI Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Hematology CY DEC 09-12, 2006 CL Orlando, FL SP Amer Soc Hematol ID ANTI-CD20 MONOCLONAL-ANTIBODY; PROGRESSION-FREE SURVIVAL; NON-HODGKINS-LYMPHOMA; DOSE SEQUENTIAL CHEMOTHERAPY; PROSPECTIVE RANDOMIZED-TRIAL; MULTICENTER PHASE-II; 1ST REMISSION; EARLY CONSOLIDATION; HYPER-CVAD; FOLLOW-UP AB Purpose Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL. Patients and Methods The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab. Results There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%. Conclusion The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens. C1 [Damon, Lloyd E.] Univ Calif San Francisco, Med Ctr, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Canc & Leukemia Grp Stat Ctr B, Durham, NC 27710 USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Washington Univ, Sch Med, St Louis, MO USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. Univ Chicago, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Damon, LE (reprint author), Univ Calif San Francisco, Med Ctr, Helen Diller Comprehens Canc Ctr, 400 Parnassus Ave, San Francisco, CA 94143 USA. EM damonl@medicine.ucsf.edu RI Blum, Kristie/E-2768-2011 FU NCI NIH HHS [CA77440, CA03927, CA11789, CA31946, CA32291, CA33601, CA41287, CA77597, CA77658, U10 CA003927, U10 CA031946, U10 CA032291, U10 CA033601, U10 CA041287, U10 CA077440, U10 CA077597, U10 CA077658] NR 45 TC 106 Z9 109 U1 0 U2 6 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 DEC 20 PY 2009 VL 27 IS 36 BP 6101 EP 6108 DI 10.1200/JCO.2009.22.2554 PG 8 WC Oncology SC Oncology GA 534AI UT WOS:000272867500007 PM 19917845 ER PT J AU Morris, PG Dickler, M McArthur, HL Traina, T Sugarman, S Lin, N Moy, B Come, S Godfrey, L Nulsen, B Chen, C Steingart, R Rugo, H Norton, L Winer, E Hudis, CA Dang, CT AF Morris, Patrick G. Dickler, Maura McArthur, Heather L. Traina, Tiffany Sugarman, Steven Lin, Nancy Moy, Beverly Come, Steven Godfrey, Laura Nulsen, Benjamin Chen, Carol Steingart, Richard Rugo, Hope Norton, Larry Winer, Eric Hudis, Clifford A. Dang, Chau T. TI Dose-Dense Adjuvant Doxorubicin and Cyclophosphamide Is Not Associated With Frequent Short-Term Changes in Left Ventricular Ejection Fraction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HER2-POSITIVE BREAST-CANCER; RANDOMIZED-TRIALS; FOLLOW-UP; CHEMOTHERAPY; TRASTUZUMAB; PACLITAXEL; BEVACIZUMAB; THERAPY; SAFETY AB Purpose Doxorubicin and cyclophosphamide (AC) every 3 weeks has been associated with frequent asymptomatic declines in left ventricular ejection fraction (LVEF). Dose-dense (dd) AC followed by paclitaxel (P) is superior to the same regimen given every third week. Herein, we report the early cardiac safety of three sequential studies of ddAC alone or with bevacizumab (B). Patients and Methods Patients with HER2-positive breast cancer were treated on two trials: ddAC followed by P and trastuzumab (T) and ddAC followed by PT and lapatinib. Patients with HER2-normal breast cancer were treated with B and ddAC followed by B and nanoparticle albumin-bound P. Prospective LVEF measurement by multigated radionuclide angiography scan before and after every 2 week AC for 4 cycles and at month 6 from all three trials were aggregated to determine the early risks of cardiac dysfunction. Results From January 2005 to May 2008, 245 patients were enrolled. The median age was 47 years ( range, 27 to 75 years). Median LVEF pre-ddAC was 68% (range, 52% to 82%). LVEF post-ddAC was available in 241 patients (98%) and the median was unchanged at 68% (range, 47% to 81%). Per protocol no patients were ineligible for subsequent targeted biologic therapy based on LVEF decline post-ddAC. In addition, LVEF was available in 222 patients (92%) at 6 months, at which time the median LVEF was similar at 65% (range, 24% to 80%). Within 6 months of initiating chemotherapy, three patients (1.2%; 95% CI, 0.25% to 3.54%) developed CHF, all of whom received T. Conclusion Dose-dense AC with or without concurrent bevacizumab is not associated with frequent acute or short-term declines in LVEF. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Morris, PG (reprint author), Evelyn H Lauder Breast Ctr, 300 E 66th St, New York, NY 10065 USA. EM morrisp1@mskcc.org OI Norton, Larry/0000-0003-3701-9250 NR 21 TC 19 Z9 19 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2009 VL 27 IS 36 BP 6117 EP 6123 DI 10.1200/JCO.2008.20.2952 PG 7 WC Oncology SC Oncology GA 534AI UT WOS:000272867500009 PM 19901120 ER PT J AU Gonen, M Schrag, D Weiser, MR AF Goenen, Mithat Schrag, Deborah Weiser, Martin R. TI Nodal Staging Score: A Tool to Assess Adequate Staging of Node-Negative Colon Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL RESECTION SPECIMENS; LYMPH-NODES; MINIMUM NUMBER; ADJUVANT CHEMOTHERAPY; SURVIVAL; RECOMMENDATIONS; ACCURACY; RECOVERY; TRIAL AB Purpose Adequate nodal staging of colon cancer has been defined as pathologic examination of at least 12 lymph nodes. We sought to refine this definition by quantifying the likelihood that a pathologically node-negative patient has, indeed, no positive nodes. Patients and Methods Patients with stage I-III adenocarcinoma of the colon between 1994 and 2005 and had at least one lymph node pathologically examined were identified from the Surveillance, Epidemiology and End Results (SEER) database (n = 131,953). We estimated the sensitivity of the pathologic staging of locoregional spread using a beta-binomial model and developed the nodal staging score (NSS), which is the probability that a patient is correctly staged as node negative. NSS is a function of T stage and the number of examined nodes. Results The probability of missing a positive node that is in fact truly present is 29.7% if five nodes are examined, 20.0% if eight are examined, and drops to 13.6% for 12 nodes are examined. An NSS of 90% can be achieved by examining a single node for T1 and four nodes for T2 tumors. To maintain similar levels of NSS for T3, 13 nodes need to be examined and for T4 lesions, 21 nodes need to be examined. Graphical and tabular tools are provided to facilitate calculation of NSS and treatment decision making in practice. Conclusion The minimum number of examined nodes for adequate staging depends on the T stage. The score we developed indicates the adequacy of nodal staging for patients with no positive nodes and can assist clinical decision making in the patient without nodal metastasis. C1 [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Gonen, M (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave,Box 44, New York, NY 10065 USA. EM gonenm@mskcc.org RI Gonen, Mithat/E-4826-2012 NR 31 TC 34 Z9 36 U1 3 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 DEC 20 PY 2009 VL 27 IS 36 BP 6166 EP 6171 DI 10.1200/JCO.2009.23.7958 PG 6 WC Oncology SC Oncology GA 534AI UT WOS:000272867500016 PM 19901106 ER PT J AU Balch, CM Gershenwald, JE Soong, SJ Thompson, JF Atkins, MB Byrd, DR Buzaid, AC Cochran, AJ Coit, DG Ding, SL Eggermont, AM Flaherty, KT Gimotty, PA Kirkwood, JM McMasters, KM Mihm, MC Morton, DL Ross, MI Sober, AJ Sondak, VK AF Balch, Charles M. Gershenwald, Jeffrey E. Soong, Seng-jaw Thompson, John F. Atkins, Michael B. Byrd, David R. Buzaid, Antonio C. Cochran, Alistair J. Coit, Daniel G. Ding, Shouluan Eggermont, Alexander M. Flaherty, Keith T. Gimotty, Phyllis A. Kirkwood, John M. McMasters, Kelly M. Mihm, Martin C., Jr. Morton, Donald L. Ross, Merrick I. Sober, Arthur J. Sondak, Vernon K. TI Final Version of 2009 AJCC Melanoma Staging and Classification SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID AMERICAN JOINT COMMITTEE; PRIMARY CUTANEOUS MELANOMA; LYMPH-NODE BIOPSY; TUMOR MITOTIC RATE; PROGNOSTIC-FACTORS; METASTATIC MELANOMA; MICROSCOPIC SATELLITES; SENTINEL; SURVIVAL; SYSTEM AB Purpose To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. Methods The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Results Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. Conclusion Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010. C1 [Balch, Charles M.] Johns Hopkins Med Inst, Dept Surg Oncol & Dermatol, Baltimore, MD 21287 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Alabama, Birmingham, AL USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Univ Washington, Seattle, WA 98195 USA. Hosp Sirio Libanes, Sao Paulo, Brazil. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Erasmus Univ, Med Ctr, Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. Univ Penn, Philadelphia, PA 19104 USA. Univ Pittsburgh, Inst Canc, Med Ctr, Pittsburgh, PA USA. Univ Louisville, Med Ctr, Louisville, KY 40292 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Univ S Florida, Coll Med, Tampa, FL 33682 USA. Univ Sydney, Sydney Melanoma Unit, Sydney, NSW 2006, Australia. RP Balch, CM (reprint author), Johns Hopkins Med Inst, Dept Surg Oncol & Dermatol, 600 N Wolfe St,Osler 624, Baltimore, MD 21287 USA. EM balchch@jhmi.edu FU NCI NIH HHS [P30 CA013148, P50 CA093459] NR 34 TC 1882 Z9 1911 U1 12 U2 75 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 DEC 20 PY 2009 VL 27 IS 36 BP 6199 EP 6206 DI 10.1200/JCO.2009.23.4799 PG 8 WC Oncology SC Oncology GA 534AI UT WOS:000272867500020 PM 19917835 ER PT J AU O'Day, SJ Atkins, MB Boasberg, P Wang, HJ Thompson, JA Anderson, CM Gonzalez, R Lutzky, J Amatruda, T Hersh, EM Weber, JS AF O'Day, Steven J. Atkins, Michael B. Boasberg, Peter Wang, He-Jing Thompson, John A. Anderson, Clay M. Gonzalez, Rene Lutzky, Jose Amatruda, Thomas Hersh, Evan M. Weber, Jeffrey S. TI Phase II Multicenter Trial of Maintenance Biotherapy After Induction Concurrent Biochemotherapy for Patients With Metastatic Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLONY-STIMULATING-FACTOR; DOSE BOLUS INTERLEUKIN-2; INTERFERON-ALPHA; RANDOMIZED-TRIAL; SEQUENTIAL CHEMOIMMUNOTHERAPY; COOPERATIVE GROUP; ONCOLOGY-GROUP; CISPLATIN; CHEMOTHERAPY; DACARBAZINE AB Purpose Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. Patients and Methods One hundred thirty-three chemotherapy-naive patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. Results The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. Conclusion Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge. C1 [O'Day, Steven J.] Angeles Clin & Res Inst, John Wayne Canc Inst, Melanoma Program, Santa Monica, CA 90404 USA. Univ So Calif, Los Angeles, CA USA. Harvard Beth Israel Med Ctr, Boston, MA USA. Univ Washington, Seattle, WA 98195 USA. Univ Missouri, Columbia, MO USA. Univ Colorado, Denver, CO 80202 USA. Mt Sinai Hosp, Miami, FL USA. Humphrey Canc Ctr, Robbinsdale, MN USA. Univ Arizona, Tucson, AZ USA. RP O'Day, SJ (reprint author), Angeles Clin & Res Inst, John Wayne Canc Inst, Melanoma Program, 2001 Santa Monica Blvd,Suite 560 W, Santa Monica, CA 90404 USA. EM soday@theangelesclinic.org NR 29 TC 23 Z9 23 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 DEC 20 PY 2009 VL 27 IS 36 BP 6207 EP 6212 DI 10.1200/JCO.2008.20.3075 PG 6 WC Oncology SC Oncology GA 534AI UT WOS:000272867500021 PM 19917850 ER PT J AU Cullen, KJ Schumaker, L Nikitakis, N Goloubeva, O Tan, M Sarlis, NJ Haddad, RI Posner, MR AF Cullen, Kevin J. Schumaker, Lisa Nikitakis, Nikolaos Goloubeva, Olga Tan, Ming Sarlis, Nicholas J. Haddad, Robert I. Posner, Marshall R. TI beta-Tubulin-II Expression Strongly Predicts Outcome in Patients Receiving Induction Chemotherapy for Locally Advanced Squamous Carcinoma of the Head and Neck: A Companion Analysis of the TAX 324 Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 33rd Congress of the European-Society-for-Medical-Oncology CY SEP 12-16, 2008 CL Stockholm, SWEDEN SP European Soc Med Oncol ID CELL LUNG-CANCER; S-TRANSFERASE-PI; DEPENDENT ANION CHANNEL; POOR-PROGNOSIS; IMMUNOHISTOCHEMICAL ANALYSIS; BREAST-CANCER; CISPLATIN; P53; RESISTANCE; MARKERS AB Purpose TAX 324 was a phase III trial comparing induction chemotherapy (IC) with docetaxel, cisplatin, and fluorouracil (TPF) with cisplatin and fluorouracil (PF) followed by concomitant chemoradiotherapy in locally advanced squamous cell cancer of the head and neck (LASCCHN). This study evaluates a series of tumor markers in pretreatment biopsies from that trial TAX 324 and correlates expression with survival. Methods Pretherapy biopsy specimens were available for 265 of 501 participants. Expression of a series of six markers (p53, thymidylate synthase, glutathione s-transferase pi [GST-pi], Bcl 2, beta tubulin II [beta T-2], and HER2 neu) was evaluated by immunohistochemistry. Results For patients with low beta T-II expression, median overall survival (OS) was 58.6 months (95% CI, not reached [NR]), compared with 18.2 months for patients with high beta T-II expression (95% CI, 13.11 to 30.06: hazard ratio [HR], 2.39; 95% CI, 1.67 to 3.72; P < .0001). Progression-free survival in patients with low beta T-II expression was 43.2 months (95% CI, 24.4 to NR) versus 9.8 months (95% CI, 7.06 to 18.53) for high beta T-II expression, with a HR of 1.9 (95% CI, 1.43 to 2.77; P < .0001). The predictive value of beta T-II expression was greater in the TPF versus PF arm than in the PF arm. Conclusion Increased tumor expression of beta T-II is strongly associated with adverse outcome in LASCCHN patients treated with IC, and our data suggest low expression of beta T-II may predict patients most likely to benefit from induction TPF therapy. Further, simple models which combine expression of beta T-II with a carefully defined set of additional immunohistochemical markers may have significant prognostic impact for patients with LASCCHN. C1 [Cullen, Kevin J.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cullen, KJ (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, 22 S Greene St,Room N9E17, Baltimore, MD 21201 USA. EM kcullen@umm.edu NR 35 TC 32 Z9 32 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2009 VL 27 IS 36 BP 6222 EP 6228 DI 10.1200/JCO.2009.23.0953 PG 7 WC Oncology SC Oncology GA 534AI UT WOS:000272867500023 PM 19917838 ER PT J AU Li, JH Chian, RJ Ay, I Kashi, BB Celia, SA Tamrazian, E Pepinsky, RB Fishman, PS Brown, RH Francis, JW AF Li, Jianhong Chian, Ru-Ju Ay, Ilknur Kashi, Brenda B. Celia, Samuel A. Tamrazian, Eric Pepinsky, R. Blake Fishman, Paul S. Brown, Robert H., Jr. Francis, Jonathan W. TI Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Recombinant protein; GDNF; Tetanus toxin fragment C; Spinal cord; Intrathecal infusion; Intramuscular injection ID TOXIN FRAGMENT-C; MOTOR-NEURON DEGENERATION; INDUCED CELL-DEATH; NEUROTROPHIC FACTOR; TETANUS TOXIN; PARKINSONS-DISEASE; EXPRESSION SYSTEM; GROWTH-FACTOR; SPINAL-CORD; MICE AB With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFR alpha-1 in lumbar cord were not altered significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration. (C) 2009 Elsevier Inc. All rights reserved. C1 [Li, Jianhong; Chian, Ru-Ju; Ay, Ilknur; Kashi, Brenda B.; Celia, Samuel A.; Tamrazian, Eric; Brown, Robert H., Jr.; Francis, Jonathan W.] Massachusetts Gen Hosp, Dept Neurol, Cecil B Day Labr Neuromuscular Res, Charlestown, MA 02129 USA. [Pepinsky, R. Blake] Biogenldec Inc, Cambridge Ctr 14, Cambridge, MA 02142 USA. [Fishman, Paul S.] Baltimore Vet Affairs Med Ctr, Res Serv, Baltimore, MD 21201 USA. [Fishman, Paul S.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Francis, JW (reprint author), Massachusetts Gen Hosp, Dept Neurol, Cecil B Day Labr Neuromuscular Res, Bldg 114,16th St,Room 3003, Charlestown, MA 02129 USA. EM jwfrancisby@gmail.com RI li, jianhong/D-3483-2009 FU National Institute of Neurological Disorders and Stroke [RO1 NS038679]; Muscular Dystrophy Association; ALS Therapy Alliance FX The authors express their appreciation to Dr. Neil Fairweather for providing the cDNA for tetanus toxin fragment C, Dr. Ernest Terwilliger for providing the cDNA for rat GDNF, and Dr. Dana Hilt for information about the results of Amgen's clinical trial of GDNF in ALS patients. This work was supported by the National Institute of Neurological Disorders and Stroke (J.W.F., RJ.C., S.A.C., R.H.B.; RO1 NS038679), the Muscular Dystrophy Association (J.W.F., J.L.), the ALS Therapy Alliance (R.H.B., J.W.F., B.B.K., J.L., RJ.C.), Project ALS (R.H.B., J.W.F.), and AviTx, Inc (R.H.B., J.W.F.). NR 27 TC 10 Z9 12 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 DEC 18 PY 2009 VL 390 IS 3 BP 947 EP 951 DI 10.1016/j.bbrc.2009.10.083 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700109 PM 19852934 ER PT J AU Shah, A Tenzen, T McMahon, AP Woolf, PJ AF Shah, Abhik Tenzen, Toyoaki McMahon, Andrew P. Woolf, Peter J. TI Using mechanistic Bayesian networks to identify downstream targets of the Sonic Hedgehog pathway SO BMC BIOINFORMATICS LA English DT Article ID SIGNALING PATHWAY; GRAPHICAL MODELS; RETINOIC ACID; GENECHIP DATA; PROBE LEVEL; SHH; CELLS; EXPRESSION; BINDING; CANCER AB Background: The topology of a biological pathway provides clues as to how a pathway operates, but rationally using this topology information with observed gene expression data remains a challenge. Results: We introduce a new general-purpose analytic method called Mechanistic Bayesian Networks (MBNs) that allows for the integration of gene expression data and known constraints within a signal or regulatory pathway to predict new downstream pathway targets. The MBN framework is implemented in an open-source Bayesian network learning package, the Python Environment for Bayesian Learning (PEBL). We demonstrate how MBNs can be used by modeling the early steps of the sonic hedgehog pathway using gene expression data from different developmental stages and genetic backgrounds in mouse. Using the MBN approach we are able to automatically identify many of the known downstream targets of the hedgehog pathway such as Gas1 and Gli1, along with a short list of likely targets such as Mig12. Conclusions: The MBN approach shown here can easily be extended to other pathways and data types to yield a more mechanistic framework for learning genetic regulatory models. C1 [Shah, Abhik; Woolf, Peter J.] Univ Michigan, Bioinformat Program, Ann Arbor, MI 48109 USA. [Tenzen, Toyoaki] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Regenerat Med, Stowers Med Inst, Boston, MA 02114 USA. [Tenzen, Toyoaki; McMahon, Andrew P.] Harvard Stem Cell Inst, Boston, MA 02114 USA. [McMahon, Andrew P.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [McMahon, Andrew P.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Woolf, Peter J.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Woolf, Peter J.] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA. RP Woolf, PJ (reprint author), Univ Michigan, Bioinformat Program, Ann Arbor, MI 48109 USA. EM shahad@umich.edu; totenzen@gmail.com; amcmahon@mcb.harvard.edu; pwoolf@umich.edu FU NIH [U54-DA-021519, 5 R37 NS033642] FX PJW and AS are supported by NIH grant U54-DA-021519. Work in APMs laboratory was supported by a grant from the NIH 5 R37 NS033642. NR 36 TC 3 Z9 3 U1 0 U2 7 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 DEC 18 PY 2009 VL 10 AR 433 DI 10.1186/1471-2105-10-433 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 546UR UT WOS:000273838900002 PM 20021670 ER PT J AU Laajala, TD Raghav, S Tuomela, S Lahesmaa, R Aittokallio, T Elo, LL AF Laajala, Teemu D. Raghav, Sunil Tuomela, Soile Lahesmaa, Riitta Aittokallio, Tero Elo, Laura L. TI A practical comparison of methods for detecting transcription factor binding sites in ChIP-seq experiments SO BMC GENOMICS LA English DT Article ID RNA-POLYMERASE-II; PROTEIN-DNA INTERACTIONS; EMBRYONIC STEM-CELLS; GENOME-WIDE ANALYSIS; DISCOVERY; PATHWAYS; PROGRAM; NETWORK; ALPHA AB Background: Chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) is increasingly being applied to study transcriptional regulation on a genome-wide scale. While numerous algorithms have recently been proposed for analysing the large ChIP-seq datasets, their relative merits and potential limitations remain unclear in practical applications. Results: The present study compares the state-of-the-art algorithms for detecting transcription factor binding sites in four diverse ChIP-seq datasets under a variety of practical research settings. First, we demonstrate how the biological conclusions may change dramatically when the different algorithms are applied. The reproducibility across biological replicates is then investigated as an internal validation of the detections. Finally, the predicted binding sites with each method are compared to high-scoring binding motifs as well as binding regions confirmed in independent qPCR experiments. Conclusions: In general, our results indicate that the optimal choice of the computational approach depends heavily on the dataset under analysis. In addition to revealing valuable information to the users of this technology about the characteristics of the binding site detection approaches, the systematic evaluation framework provides also a useful reference to the developers of improved algorithms for ChIP-seq data. C1 [Laajala, Teemu D.; Raghav, Sunil; Tuomela, Soile; Lahesmaa, Riitta; Aittokallio, Tero; Elo, Laura L.] Turku Ctr Biotechnol, FI-20521 Turku, Finland. [Tuomela, Soile] Turku Grad Sch Biomed Sci, FI-20520 Turku, Finland. [Lahesmaa, Riitta] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Aittokallio, Tero; Elo, Laura L.] Univ Turku, Dept Math, FI-20014 Turku, Finland. RP Elo, LL (reprint author), Turku Ctr Biotechnol, FI-20521 Turku, Finland. EM tlaajala@cc.hut.fi; sunil.raghav@btk.fi; soile.tuomela@btk.fi; riitta.lahesmaa@btk.fi; tero.aittokallio@utu.fi; laura.elo@utu.fi RI Aittokallio, Tero/B-6583-2009; OI Aittokallio, Tero/0000-0002-0886-9769; Elo, Laura/0000-0001-5648-4532 FU Academy of Finland [116639, 115939, 126063, 120569, 127575]; Sigrid Juselius Foundation; Juvenile Diabetes Research Foundation (JDRF); Centre for International Mobility FX Marjo Hakkarainen, Marjo Linja and Sarita Heinonen are acknowledged for excellent technical help and David Hawkins and Omid Rasool for fruitful discussions. This work was supported by the Academy of Finland [116639, 115939, 126063 to RL, 120569 to TA, 127575 to LLE]; the Sigrid Juselius Foundation; the Juvenile Diabetes Research Foundation (JDRF); and the Centre for International Mobility (CIMO-SITRA fellowship). NR 34 TC 70 Z9 72 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 18 PY 2009 VL 10 AR 618 DI 10.1186/1471-2164-10-618 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 543JF UT WOS:000273571200001 PM 20017957 ER PT J AU Knipscheer, P Raschle, M Smogorzewska, A Enoiu, M Ho, TV Scharer, OD Elledge, SJ Walter, JC AF Knipscheer, Puck Raeschle, Markus Smogorzewska, Agata Enoiu, Milica Ho, The Vinh Schaerer, Orlando D. Elledge, Stephen J. Walter, Johannes C. TI The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair SO SCIENCE LA English DT Article ID MONOUBIQUITINATED FANCD2; S-PHASE; PROTEINS AB Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised. C1 [Knipscheer, Puck; Walter, Johannes C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Raeschle, Markus] Max Planck Inst Biochem, Dept Mol Cell Biol, D-82152 Martinsried, Germany. [Smogorzewska, Agata; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Smogorzewska, Agata; Elledge, Stephen J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Smogorzewska, Agata] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Enoiu, Milica; Schaerer, Orlando D.] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland. [Ho, The Vinh; Schaerer, Orlando D.] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [Ho, The Vinh; Schaerer, Orlando D.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. RP Walter, JC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM johannes_walter@hms.harvard.edu RI Smogorzewska, Agata/B-8891-2011; Scharer, Orlando/B-8908-2008 OI Scharer, Orlando/0000-0003-2425-2715 FU NIH [GM62267]; Leukemia and Lymphoma Society [1406-07]; New York State of Science, Technology and Academic Research (NYSTAR) [C040069]; Swiss Cancer League [OCS-01413-08-2003]; Dutch Cancer Society [T32CA09216]; Burroughs Wellcome Fund; Max Planck Institute FX This work was supported by NIH grant GM62267 and Leukemia and Lymphoma Society Award 1406-07 to J. C. W.; New York State of Science, Technology and Academic Research (NYSTAR) Faculty Development Award C040069 and Swiss Cancer League grant OCS-01413-08-2003 to O. D. S.; and a Dutch Cancer Society fellowship to P. K. A. S. was supported by T32CA09216 to the Pathology Department at the Massachusetts General Hospital and by the Burroughs Wellcome Fund. S. J. E. is an investigator of the Howard Hughes Medical Institute. We thank M. Hoatlin for the Xenopus FANCD2 cDNA, K. Cimprich for phospho-Rad1 antibody, and the Walter laboratory for feedback. M. R. thanks S. Jentsch and the Max Planck Institute for generous support. The Xenopus FANCI cDNA sequence was deposited to the National Center for Biotechnology Information, NIH, database (accession no. GU144566). NR 17 TC 242 Z9 246 U1 1 U2 22 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 DEC 18 PY 2009 VL 326 IS 5960 BP 1698 EP 1701 DI 10.1126/science.1182372 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533QJ UT WOS:000272839000054 PM 19965384 ER PT J AU Vanderwerf, SM Svahn, J Olson, S Rathbun, RK Harrington, C Yates, J Keeble, W Anderson, DC Anur, P Pereira, NF Pilonetto, DV Pasquini, R Bagby, GC AF Vanderwerf, Scott M. Svahn, Johanna Olson, Susan Rathbun, R. Keaney Harrington, Christina Yates, Jane Keeble, Winifred Anderson, David C. Anur, Praveen Pereira, Noemi F. Pilonetto, Daniela V. Pasquini, Ricardo Bagby, Grover C. TI TLR8-dependent TNF-alpha overexpression in Fanconi anemia group C cells SO BLOOD LA English DT Article ID NECROSIS-FACTOR-ALPHA; DEPENDENT PROTEIN-KINASE; DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTORS; INTERFERON-GAMMA; HEMATOPOIETIC-CELLS; IFN-GAMMA; IN-VITRO; APOPTOTIC RESPONSES; SIGNALING PATHWAYS AB Tumor necrosis factor alpha (TNF-alpha) production is abnormally high in Fanconi anemia (FA) cells and contributes to the hematopoietic defects seen in FA complementation group C-deficient (Fancc(-/-)) mice. Applying gene expression microarray and proteomic methods to studies on FANCC-deficient cells we found that genes encoding proteins directly involved in ubiquitinylation are overrepresented in the signature of FA bone marrow cells and that ubiquitinylation profiles of FA-C and complemented cells were substantially different. Finding that Toll-like receptor 8 (TLR8) was one of the proteins ubiquitinylated only in mutant cells, we confirmed that TLR8 (or a TLR8-associated protein) is ubiquitinylated in mutant FA-C cells and that TNF-alpha production in mutant cells depended upon TLR8 and the canonical downstream signaling intermediates interleukin 1 receptor-associated kinase (IRAK) and I kappa B kinase-alpha/beta. FANCC-deficient THP-1 cells and macrophages from Fancc(-/-) mice overexpressed TNF-alpha in response to TLR8 agonists but not other TLR agonists. Ectopically expressed FANCC point mutants were capable of fully complementing the mitomycin-C hypersensitivity phenotype of FA-C cells but did not suppress TNF-alpha overproduction. In conclusion, FANCC suppresses TNF-alpha production in mononuclear phagocytes by suppressing TLR8 activity and this particular function of FANCC is independent of its function in protecting the genome from cross-linking agents. (Blood. 2009; 114: 5290-5298) C1 [Vanderwerf, Scott M.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. [Svahn, Johanna] Osped Gaslini, Dept Pediat Hematol Oncol, Genoa, Italy. [Olson, Susan; Bagby, Grover C.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Rathbun, R. Keaney; Yates, Jane; Keeble, Winifred; Bagby, Grover C.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Vanderwerf, Scott M.; Rathbun, R. Keaney; Yates, Jane; Keeble, Winifred; Bagby, Grover C.] Portland VA Med Ctr, NW VA Canc Res Ctr, Portland, OR 97239 USA. [Harrington, Christina] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Harrington, Christina; Bagby, Grover C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Anderson, David C.] Univ Oregon, Dept Mol Biol, Eugene, OR 97403 USA. [Anur, Praveen] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Pereira, Noemi F.; Pilonetto, Daniela V.; Pasquini, Ricardo] Univ Fed Parana, Bone Marrow Transplantat Serv, BR-80060000 Curitiba, Parana, Brazil. RP Vanderwerf, SM (reprint author), Portland VA Med Ctr, NW VA Canc Res Ctr, Mailstop R&D30,Bldg 104,Rm 6206,3710 SW US Vet Ho, Portland, OR 97239 USA. EM vanderws@ohsu.edu OI Pilonetto, Daniela/0000-0002-3045-5028 FU National Heart, Lung and Blood Institute; National Cancer Institute; Department of Veterans Affairs; Fanconi Anemia Research Fund Inc. FX This study was supported in part by the National Heart, Lung and Blood Institute, the National Cancer Institute, the Department of Veterans Affairs, and the Fanconi Anemia Research Fund Inc. NR 47 TC 36 Z9 37 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 DEC 17 PY 2009 VL 114 IS 26 BP 5290 EP 5298 DI 10.1182/blood-2009-05-222414 PG 9 WC Hematology SC Hematology GA 533ZA UT WOS:000272863800009 PM 19850743 ER PT J AU Juszczynski, P Chen, LF O'Donnell, E Polo, JM Ranuncolo, SM Dalla-Favera, R Melnick, A Shipp, MA AF Juszczynski, Przemyslaw Chen, Linfeng O'Donnell, Evan Polo, Jose M. Ranuncolo, Stella M. Dalla-Favera, Riccardo Melnick, Ari Shipp, Margaret A. TI BCL6 modulates tonic BCR signaling in diffuse large B-cell lymphomas by repressing the SYK phosphatase, PTPROt SO BLOOD LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; ANTIGEN RECEPTOR; EXPRESSION; GENE; SURVIVAL; PHOSPHORYLATION; PROMOTER; CLONING; TARGET AB Tonic B-cell receptor (BCR) signaling is a key survival pathway during normal B-cell ontogenesis and in a subset of diffuse large B-cell lymphomas (DLBCLs). We previously demonstrated that BCR-dependent DLBCL cell lines and primary tumors underwent apoptosis after treatment with an ATP-competitive inhibitor of the BCR-associated spleen tyrosine kinase (SYK). These "BCR-type" tumors also have more abundant expression of the transcriptional repressor, BCL6, and increased sensitivity to BCL6 inhibition. Herein, we evaluated potential connections between BCL6-mediated transcriptional repression and SYK-dependent BCR signaling. In transcriptionally profiled normal B-cell subsets (naive, germinal center, and memory B cells) and in primary DLBCLs, there were reciprocal patterns of expression of BCL6 and the SYK tyrosine phosphatase PTPROt. BCL6 repressed PTPROt transcription via a direct interaction with functional BCL6 binding sites in the PTPROt promoter. Enforced expression of BCL6 in normal naive B cells and RNAi-mediated depletion of BCL6 in germinal center B cells directly modulated PTPROt expression. In "BCR-type" DLBCLs, BCL6 depletion increased PTPROt expression and decreased phosphorylation of SYK and the downstream adaptor protein BLNK. Because BCL6 augments BCR signaling and BCL6 and SYK are both promising therapeutic targets in many DLBCLs, combined inhibition of these functionally related pathways warrants further study. (Blood. 2009; 114: 5315-5321) C1 [Juszczynski, Przemyslaw; Chen, Linfeng; O'Donnell, Evan; Shipp, Margaret A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Polo, Jose M.; Ranuncolo, Stella M.; Melnick, Ari] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Dalla-Favera, Riccardo] Columbia Univ, Inst Canc Genet, Dept Pathol & Genet & Dev, New York, NY USA. RP Shipp, MA (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM margaret_shipp@dfci.harvard.edu FU National Institutes of Health [5 PO1 CA092625]; LLS SCOR [7391-07] FX This paper was funded by National Institutes of Health grant 5 PO1 CA092625 and LLS SCOR grant 7391-07. NR 29 TC 39 Z9 40 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 DEC 17 PY 2009 VL 114 IS 26 BP 5315 EP 5321 DI 10.1182/blood-2009-02-204362 PG 7 WC Hematology SC Hematology GA 533ZA UT WOS:000272863800012 PM 19855081 ER PT J AU Vidal, M AF Vidal, Marc TI A unifying view of 21st century systems biology SO FEBS LETTERS LA English DT Article; Proceedings Paper CT 146th Nobel Symposium on Systems Biology CY JUN 25-27, 2009 CL Drobak, NORWAY DE Systems biology; Network biology; Interactome network ID ESCHERICHIA-COLI; GENETIC-CONTROL; COMPLEX NETWORKS; CELL; DIFFERENTIATION; BIOSYNTHESIS; INTERACTOME; ROBUSTNESS; MECHANISM; GROWTH AB The idea that multi-scale dynamic complex systems formed by interacting macromolecules and metabolites, cells, organs and organisms underlie some of the most fundamental aspects of life was proposed by a few visionaries half a century ago. We are witnessing a powerful resurgence of this idea made possible by the availability of nearly complete genome sequences, ever improving gene annotations and interactome network maps, the development of sophisticated informatic and imaging tools, and importantly, the use of engineering and physics concepts such as control and graph theory. Alongside four other fundamental "great ideas" as suggested by Sir Paul Nurse, namely, the gene, the cell, the role of chemistry in biological processes, and evolution by natural selection, systems-level understanding of "What is Life" may materialize as one of the major ideas of biology. (c) 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, CCSB, 44 Binney St, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu NR 37 TC 53 Z9 56 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 17 PY 2009 VL 583 IS 24 BP 3891 EP 3894 DI 10.1016/j.febslet.2009.11.024 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 538TX UT WOS:000273208000003 PM 19913537 ER PT J AU Steele, JW Kim, SH Cirrito, JR Verges, DK Restivo, JL Westaway, D Fraser, P Hyslop, PS Sano, M Bezprozvanny, I Ehrlich, ME Holtzman, DM Gandy, S AF Steele, John W. Kim, Soong H. Cirrito, John R. Verges, Deborah K. Restivo, Jessica L. Westaway, David Fraser, Paul Hyslop, Peter St George Sano, Mary Bezprozvanny, Ilya Ehrlich, Michelle E. Holtzman, David M. Gandy, Sam TI Acute dosing of latrepirdine (Dimebon (TM)), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo SO MOLECULAR NEURODEGENERATION LA English DT Article ID PRECURSOR PROTEIN; SYNAPTIC PLASTICITY; COGNITIVE DEFICITS; TRANSGENIC MICE; HUMAN BRAIN; A-BETA; DISEASE; OLIGOMERS; SYNAPSES; ACCUMULATION AB Background: Recent reports suggest that latrepirdine (Dimebon T, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-beta (A beta) peptide in the brain, and A beta-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular A beta using in vitro and in vivo experimental systems. Results: We evaluated extracellular levels of A beta in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 mu M). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 mu M or 10 mu M). Drug-naive Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of A beta in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 mu M) and led to more modest increases in extracellular A beta(x-42) levels (+ 10%; p = 0.001); of note, however, was the observation that extracellular A beta(x-40) levels did not change. Conclusions: Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular A beta as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular A beta levels must now be determined. C1 [Cirrito, John R.; Verges, Deborah K.; Restivo, Jessica L.; Holtzman, David M.] Washington Univ, Hope Ctr Neurol Disorders, Dept Neurol, Sch Med, St Louis, MO 63110 USA. [Cirrito, John R.; Verges, Deborah K.; Restivo, Jessica L.; Holtzman, David M.] Washington Univ, Alzheimers Dis Res Ctr, Sch Med, St Louis, MO 63110 USA. [Steele, John W.; Kim, Soong H.; Ehrlich, Michelle E.; Gandy, Sam] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Steele, John W.; Kim, Soong H.; Sano, Mary; Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Steele, John W.; Kim, Soong H.; Sano, Mary; Ehrlich, Michelle E.; Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Westaway, David] Univ Alberta, Ctr Pr & Prot Folding Dis, Edmonton, AB T6G 2M8, Canada. [Fraser, Paul; Hyslop, Peter St George] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. [Hyslop, Peter St George] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0XY, England. [Sano, Mary; Gandy, Sam] James J Peters VA Med Ctr, Dept Neurol, Bronx, NY 10468 USA. [Bezprozvanny, Ilya] Univ Texas SW, Dept Physiol, Dallas, TX 75390 USA. [Ehrlich, Michelle E.] Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. RP Holtzman, DM (reprint author), Washington Univ, Hope Ctr Neurol Disorders, Dept Neurol, Sch Med, St Louis, MO 63110 USA. EM john.steele@mssm.edu; soongho.kim@mssm.edu; cirritoj@neuro.wustl.edu; vergesd@neuro.wustl.edu; restivoj@neuro.wustl.edu; david.westaway@ualberta.ca; paul.fraser@utoronto.ca; p.hyslop@utoronto.ca; mary.sano@mssm.edu; ilya.bezprozvanny@utsouthwestern.edu; michelle.ehrlich@mssm.edu; holtzman@neuro.wustl.edu; samuel.gandy@mssm.edu FU National Institute of General Medical Sciences [T32GM062754]; National Institute on Aging [P01 AG10491, K01 AG29524]; Cure Alzheimer's Fund; Zenith Award; Alzheimer's Association; NINDS [R01 NS056224]; Canadian Institutes for Health Research; Alzheimer's Society of Ontario FX Support: JWS is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. JWS, SHK, and SG; and JRC (National Institute on Aging grant P01 AG10491 and K01 AG29524, respectively); JWS, SHK, and SG; and JRC and DMH (Cure Alzheimer's Fund); DMH [Zenith Award] and IB (Alzheimer's Association); IB (NINDS R01 NS056224); PF (Canadian Institutes for Health Research and the Alzheimer's Society of Ontario). Swedish APP N2a cell line was the generous gift of Dr. Gopal Thinakaran (University of Chicago). The authors would like to thank Loren E. Khan-Vaughan and Justine Bonet for their assistance with animal colony management. NR 41 TC 26 Z9 27 U1 0 U2 3 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 DEC 17 PY 2009 VL 4 AR 51 DI 10.1186/1750-1326-4-51 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 545ZR UT WOS:000273777300001 PM 20017949 ER PT J AU O'Gara, PT Shepard, JO Yared, K Sohani, AR Butcher, BW Rosenberg, ES Newton-Cheh, C Abramson, JS AF O'Gara, Patrick T. Shepard, Jo-Anne O. Yared, Kibar Sohani, Aliyah R. Butcher, Brad W. Rosenberg, Eric S. Newton-Cheh, Christopher Abramson, Jeremy S. TI Case 39-2009: A 28-Year-Old Pregnant Woman with Acute Cardiac Failure. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Medical Case Conference 2008 CY SEP, 2008 CL Los Angeles, CA ID B-CELL LYMPHOMA; HODGKIN LYMPHOMA; HEART-DISEASE; MANAGEMENT; INVOLVEMENT; GUIDELINES; RISK C1 [O'Gara, Patrick T.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Yared, Kibar] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [O'Gara, Patrick T.; Yared, Kibar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shepard, Jo-Anne O.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP O'Gara, PT (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. NR 19 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 17 PY 2009 VL 361 IS 25 BP 2462 EP 2473 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 533CE UT WOS:000272798900013 PM 20018968 ER PT J AU Dec, GW AF Dec, G. William TI Anemia and Iron Deficiency -- New Therapeutic Targets in Heart Failure?. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 9 TC 9 Z9 10 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 17 PY 2009 VL 361 IS 25 BP 2475 EP 2477 DI 10.1056/NEJMe0910313 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 533CE UT WOS:000272798900014 PM 19920053 ER PT J AU Bruckner, RJ Mansy, SS Ricardo, A Mahadevan, L Szostak, JW AF Bruckner, R. J. Mansy, S. S. Ricardo, A. Mahadevan, L. Szostak, J. W. TI Flip-Flop-Induced Relaxation of Bending Energy: Implications for Membrane Remodeling SO BIOPHYSICAL JOURNAL LA English DT Article ID LAURDAN FLUORESCENCE; MODEL MEMBRANES; VESICLES; CURVATURE; CHOLESTEROL; PROTEINS; FISSION; PHASE; ACID; CYCLODEXTRIN AB Cellular and organellar membranes are dynamic materials that underlie many aspects of cell biology. Biological membranes have long been thought of as elastic materials with respect to bending deformations. A wealth of theory and experimentation on pure phospholipid membranes provides abundant support for this idea. However, biological membranes are not composed solely of phospholipids-they also incorporate a variety of amphiphilic molecules that undergo rapid transbilayer flip-flop. Here we describe several experimental systems that demonstrate deformation-induced molecular flip-flop. First we use a fluorescence assay to track osmotically controlled membrane deformation in single component fatty acid vesicles, and show that the relaxation of the induced bending stress is mediated by fatty acid flip-flop. We then look at two-component phospholipid/cholesterol composite vesicles. We use NMR to show that the steady-state rate of interleaflet diffusion of cholesterol is fast relative to biological membrane remodeling. We then use a Forster resonance energy transfer assay to detect the transbilayer movement of cholesterol upon deformation. We suggest that our results can be interpreted by modifying the area difference elasticity model to account for the time-dependent relaxation of bending energy. Our findings suggest that rapid interleaflet diffusion of cholesterol may play a role in membrane remodeling in vivo. We suggest that the molecular characteristics of sterols make them evolutionarily preferred mediators of stress relaxation, and that the universal presence of sterols in the membranes of eukaryotes, even at low concentrations, reflects the importance of membrane remodeling in eukaryotic cells. C1 [Bruckner, R. J.; Mansy, S. S.; Ricardo, A.; Szostak, J. W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Bruckner, R. J.; Mansy, S. S.; Ricardo, A.; Szostak, J. W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Mahadevan, L.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Mahadevan, L.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Bruckner, R. J.; Mansy, S. S.; Ricardo, A.; Szostak, J. W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM szostak@molbio.mgh.harvard.edu RI Mansy, Sheref/E-6266-2010; OI Mansy, Sheref/0000-0003-2382-198X FU NASA-Exobiology [NNX07AJ09G]; Harvard Origins of Life Initiative FX This work was supported in part by NASA-Exobiology grant NNX07AJ09G. R.J.B. was supported by a fellowship from the Harvard Origins of Life Initiative. J.W. S. is an investigator at the Howard Hughes Medical Institute. NR 37 TC 50 Z9 50 U1 1 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC 16 PY 2009 VL 97 IS 12 BP 3113 EP 3122 DI 10.1016/j.bpj.2009.09.025 PG 10 WC Biophysics SC Biophysics GA 532QV UT WOS:000272765400008 PM 20006948 ER PT J AU Rose, SA Turchin, A Grant, RW Meigs, JB AF Rose, Stephanie A. Turchin, Alexander Grant, Richard W. Meigs, James B. TI Documentation of body mass index and control of associated risk factors in a large primary care network SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID AMERICAN-DIABETES-ASSOCIATION; WEIGHT MANAGEMENT; BLOOD-PRESSURE; OBESITY; DISEASE; RECOMMENDATIONS; OVERWEIGHT; ADULTS; METAANALYSIS; CHOLESTEROL AB Background: Body mass index (BMI) will be a reportable health measure in the United States (US) through implementation of Healthcare Effectiveness Data and Information Set (HEDIS) guidelines. We evaluated current documentation of BMI, and documentation and control of associated risk factors by BMI category, based on electronic health records from a 12-clinic primary care network. Methods: We conducted a cross-sectional analysis of 79,947 active network patients greater than 18 years of age seen between 7/05-12/06. We defined BMI category as normal weight (NW, 18-24.9 kg/m(2)), overweight (OW, 25-29.9), and obese (OB, >= 30). We measured documentation (yes/no) and control (above/below) of the following three risk factors: blood pressure (BP) <= 130/<= 85 mmHg, low-density lipoprotein (LDL) <= 130 mg/dL (3.367 mmol/L), and fasting glucose <100 mg/dL (5.55 mmol/L) or casual glucose <200 mg/dL (11.1 mmol/L). Results: BMI was documented in 48,376 patients (61%, range 34-94%), distributed as 30% OB, 34% OW, and 36% NW. Documentation of all three risk factors was higher in obesity (OB = 58%, OW = 54%, NW = 41%, p for trend <0.0001), but control of all three was lower (OB = 44%, OW = 49%, NW = 62%, p = 0.0001). The presence of cardiovascular disease (CVD) or diabetes modified some associations with obesity, and OB patients with CVD or diabetes had low rates of control of all three risk factors (CVD: OB = 49%, OW = 50%, NW = 56%; diabetes: OB = 42%, OW = 47%, NW = 48%, p < 0.0001 for adiposity-CVD or diabetes interaction). Conclusions: In a large primary care network BMI documentation has been incomplete and for patients with BMI measured, risk factor control has been poorer in obese patients compared with NW, even in those with obesity and CVD or diabetes. Better knowledge of BMI could provide an opportunity for improved quality in obesity care. C1 [Rose, Stephanie A.] Univ Kentucky, Div Gen Internal Med, Lexington, KY 40536 USA. [Turchin, Alexander] Harvard Univ, Clin Informat Res & Dev, Boston, MA 02115 USA. [Turchin, Alexander] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Grant, Richard W.; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Rose, SA (reprint author), Univ Kentucky, Div Gen Internal Med, 740 S Limestone St,Kentucky Clin K507, Lexington, KY 40536 USA. EM sro226@uky.edu; aturchin@partners.org; rgrant@partners.org; jmeigs@partners.org OI Grant, Richard/0000-0002-6164-8025 FU Institutional National Research Service Award [5 T32 HP11001-19]; NIDDK Career Development Award [K23 DK067452, K24 DK080140]; GlaxoSmithKline; sanofi-aventis FX We thank Peter Shrader and Amy Cohen for their assistance with the analysis, and Daniel Singer, M. D., for review and comment on an earlier draft of the manuscript. Dr. Rose was supported by an Institutional National Research Service Award #5 T32 HP11001-19. Dr. Grant was supported by an NIDDK Career Development Award (K23 DK067452). Dr. Meigs was supported by NIDDK K24 DK080140. Dr. Meigs currently has research grants from GlaxoSmithKline and sanofi-aventis, and has consulting agreements with GlaxoSmithKline, sanofi-aventis, Interleukin Genetics, Kalypsis, and Outcomes Science. This work has been presented in poster form at the New England Regional Society of General Internal Medicine Conference in March of 2008, the Massachusetts Medical Society Poster Symposium in April of 2008, where it was the Second Prize Winner for Clinical Research, the Massachusetts General Hospital Clinical Research Day in May of 2008, and the Obesity Society Annual Meeting on October 6, 2008. NR 34 TC 7 Z9 7 U1 0 U2 0 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 DEC 16 PY 2009 VL 9 AR 236 DI 10.1186/1472-6963-9-236 PG 13 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 549AD UT WOS:000274011900001 PM 20015391 ER PT J AU Katz, RV Jean-Charles, G Green, BL Kressin, NR Claudio, C Wang, MQ Russell, SL Outlaw, J AF Katz, Ralph V. Jean-Charles, Germain Green, B. Lee Kressin, Nancy R. Claudio, Cristina Wang, MinQi Russell, Stefanie L. Outlaw, Jason TI Identifying the Tuskegee Syphilis Study: implications of results from recall and recognition questions SO BMC PUBLIC HEALTH LA English DT Article ID AFRICAN-AMERICANS; BIOMEDICAL-RESEARCH; MEDICAL-RESEARCH; LEGACY PROJECT; PARTICIPATE; WILLINGNESS; RACE; MINORITIES; DISTRUST; TRUST AB Background: This analysis assessed whether Blacks, Whites and Puerto-Rican (PR) Hispanics differed in their ability to identify the Tuskegee Syphilis Study (TSS) via open-ended questions following lead-in recognition and recall questions. Methods: The Tuskegee Legacy Project (TLP) Questionnaire was administered via a Random-Digit Dial (RDD) telephone survey to a stratified random sample of Black, White and PR Hispanic adults in three U.S. cities. Results: The TLP Questionnaire was administered to 1,162 adults (356 African-Americans, 313 PR Hispanics, and 493 non-Hispanic Whites) in San Juan, PR, Baltimore, MD and New York City, NY. Recall question data revealed: 1) that 89% or more of Blacks, Whites, and PR Hispanics were not able to name or definitely identify the Tuskegee Syphilis Study by giving study attributes; and, 2) that Blacks were the most likely to provide an open-ended answer that identified the Tuskegee Syphilis Study as compared to Whites and PR Hispanics (11.5% vs 6.3% vs 2.9%, respectively) (p = 0.002). Even when probed by a recognition question, only a minority of each racial/ethnic group (37.1%, 26.9%, and 8.6%, for Blacks, Whites and PR Hispanics, respectively) was able to clearly identify the TSS (p < 0.001). Conclusions: The two major implications of these findings for health disparity researchers are 1) that it is unlikely that detailed knowledge of the Tuskegee Syphilis Study has any current widespread influence on the willingness of minorities to participate in biomedical research, and 2) that caution should be applied before assuming that what community leaders 'know and are aware of' is equally 'well known' within their community constituencies. C1 [Katz, Ralph V.; Russell, Stefanie L.; Outlaw, Jason] NYU, Coll Dent, Dept Epidemiol & Hlth Promot, New York, NY 10012 USA. [Jean-Charles, Germain] SUNY Buffalo, Dept Oral Maxillofacial Pathol, Sch Dent Med, Buffalo, NY 14214 USA. [Green, B. Lee] H Lee Moffitt Canc Ctr & Res Inst, Off Inst Divers, Tampa, FL 33612 USA. [Kressin, Nancy R.] Boston Univ, Sch Med, Healthcare Dispar Res Unit, Gen Internal Med Sect, Boston, MA 02130 USA. [Kressin, Nancy R.] VA Boston Healthcare Syst, Dept Vet Affairs Hlth Serv, Res & Dev Serv, Boston, MA 02130 USA. [Claudio, Cristina] Univ Puerto Rico, Sch Dent, Dept Community Dent, San Juan, PR 00936 USA. [Wang, MinQi] Univ Maryland, Sch Publ Hlth, Dept Publ & Community Hlth, College Pk, MD 20742 USA. [Outlaw, Jason] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Katz, RV (reprint author), NYU, Coll Dent, Dept Epidemiol & Hlth Promot, 250 Pk Ave S, New York, NY 10012 USA. EM ralph.katz@nyu.edu; gj8@buffalo.edu; greenbl@moffitt.usf.edu; nkressin@bu.edu; cristina.claudio@upr.edu; mqw@umd.edu; stefanie.russell@nyu.edu; outlaw@jasonoutlaw.com OI Kressin, Nancy/0000-0003-2767-4286 FU National Institute of Dental and Craniofacial Research (NIDCR) at the NIH [U54 DE 14257]; NYU Oral Cancer RAAHP* Center [T32 DE DE007255]; NYU Oral Epidemiology Comprehensive Training Program FX This study was funded by the National Institute of Dental and Craniofacial Research (NIDCR) at the NIH via 2 grants: 1) U54 DE 14257, the NYU Oral Cancer RAAHP* Center (* = Research on Adolescent and Adult Health Promotion), an Oral Health Disparities Research Center; and, 2) T32 DE DE007255, the NYU Oral Epidemiology Comprehensive Training Program. NR 35 TC 3 Z9 3 U1 1 U2 7 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 DEC 16 PY 2009 VL 9 AR 468 DI 10.1186/1471-2458-9-468 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 541HZ UT WOS:000273407200002 PM 20015361 ER PT J AU McKenna, JT Cordeira, JW Jeffrey, BA Ward, CP Winston, S McCarley, RW Strecker, RE AF McKenna, J. T. Cordeira, J. W. Jeffrey, B. A. Ward, C. P. Winston, S. McCarley, R. W. Strecker, R. E. TI c-Fos protein expression is increased in cholinergic neurons of the rodent basal forebrain during spontaneous and induced wakefulness SO BRAIN RESEARCH BULLETIN LA English DT Article DE Sleep; Wake; EEG; Rat; Stress; Acetylcholine ID REPEATED SOCIAL STRESS; EARLY GENE-EXPRESSION; RAT-BRAIN; SLEEP-DEPRIVATION; NUCLEUS BASALIS; RECOVERY SLEEP; NONCHOLINERGIC PROJECTIONS; DISCHARGE PROPERTIES; THALAMIC NUCLEI; NERVOUS-SYSTEM AB It has been proposed that cholinergic neurons of the basal forebrain (BF) may play a role in vigilance state control. Since not all vigilance states have been studied, we evaluated cholinergic neuronal activation levels across spontaneously occurring states of vigilance, as well as during sleep deprivation and recovery sleep following sleep deprivation. Sleep deprivation was performed for 2 h at the beginning of the light (inactive) period, by means of gentle sensory stimulation. In the rodent BF, we used immunohistochemical detection of the c-Fos protein as a marker for activation, combined with labeling for choline acetyl-transferase (ChAT) as a marker for cholinergic neurons. We found c-Fos activation in BF cholinergic neurons was highest in the group undergoing sleep deprivation (12.9% of cholinergic neurons), while the spontaneous wakefulness group showed a significant increase (9.2%), compared to labeling in the spontaneous sleep group (1.8%) and a sleep deprivation recovery group (0.8%). A subpopulation of cholinergic neurons expressed c-Fos during spontaneous wakefulness, when possible confounds of the sleep deprivation procedure were minimized (e.g., stress and sensory stimulation). Double-labeling in the sleep deprivation treatment group was significantly elevated in select subnuclei of the BF (medial septum/vertical limb of the diagonal band, horizontal limb of the diagonal band, and the magnocellular preoptic nucleus), when compared to spontaneous wakefulness. These findings support and provide additional confirming data of previous reports that cholinergic neurons of BF play a role in vigilance state regulation by promoting wakefulness. Published by Elsevier Inc. C1 [McKenna, J. T.; Cordeira, J. W.; Jeffrey, B. A.; Ward, C. P.; Winston, S.; McCarley, R. W.; Strecker, R. E.] VA Boston Healthcare Syst, Brockton, MA 02301 USA. [McKenna, J. T.; Cordeira, J. W.; Jeffrey, B. A.; Ward, C. P.; Winston, S.; McCarley, R. W.; Strecker, R. E.] Harvard Univ, Sch Med, Dept Psychiat, Brockton, MA 02401 USA. [Cordeira, J. W.] Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA. [Ward, C. P.] Univ Houston Clear Lake City, Dept Psychol, Houston, TX 77058 USA. RP McKenna, JT (reprint author), VA Boston Healthcare Syst, VAMC Res 151-C,940 Belmont St,Bldg 44,Rm 111, Brockton, MA 02301 USA. EM james_mckenna@hms.harvard.edu; Joshua.Cordeira@tufts.edu; briannejeffrey@hrca.harvard.edu; WardChris@UHCL.edu; stuart_winston@hms.harvard.edu; robert_mccarley@hms.harvard.edu; robert_strecker@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Ward, Christopher/0000-0001-9932-3894; Jeffrey, Brianne/0000-0002-3337-4434 FU U.S. Department of Veterans Affairs Medical Research Awards; NIH [HL060292, MH039683, HL07901, MH070156] FX We thank Gina Ciovacco, Amanda Cookson, Stephanie Cummings, Ryan Lydon, and Lance Morin for technical assistance, and John Franco for care of the animals. This research was supported by U.S. Department of Veterans Affairs Medical Research Awards to RWM and RES; NIH HL060292, NIH MH039683; NIH HL07901 and NIH MH070156 to JTM. NR 63 TC 12 Z9 13 U1 0 U2 2 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 DEC 16 PY 2009 VL 80 IS 6 BP 382 EP 388 DI 10.1016/j.brainresbull.2009.08.015 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 520MC UT WOS:000271847600010 PM 19716862 ER PT J AU Lieb, W Beiser, AS Vasan, RS Tan, ZS Au, R Harris, TB Roubenoff, R Auerbach, S DeCarli, C Wolf, PA Seshadri, S AF Lieb, Wolfgang Beiser, Alexa S. Vasan, Ramachandran S. Tan, Zaldy S. Au, Rhoda Harris, Tamara B. Roubenoff, Ronenn Auerbach, Sanford DeCarli, Charles Wolf, Philip A. Seshadri, Sudha TI Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HIPPOCAMPAL SYNAPTIC PLASTICITY; CENTRAL-NERVOUS-SYSTEM; COGNITIVE FUNCTION; CENTRAL OBESITY; HEART-DISEASE; RISK; DEMENTIA; NEUROPATHOLOGY; MORTALITY; NEURONS AB Context The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). Objective To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. Design, Setting, and Participants Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. Main Outcome Measure Incidence of dementia and AD during follow-up until December 31, 2007. Results During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. Conclusion Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults. JAMA. 2009;302(23):2565-2572 C1 [Beiser, Alexa S.; Au, Rhoda; Auerbach, Sanford; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Lieb, Wolfgang; Beiser, Alexa S.; Vasan, Ramachandran S.; Wolf, Philip A.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. [Tan, Zaldy S.] Brigham & Womens Hosp, Boston VA Healthcare Syst, Boston, MA 02115 USA. [Tan, Zaldy S.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Roubenoff, Ronenn] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B602, Boston, MA 02118 USA. EM suseshad@bu.edu RI Lieb, Wolfgang/C-1990-2012; OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [N01-HC-25195, N01HV28178, RO1DK080739, 2K24HL04334]; National Heart, Lung, and Blood Institute; National Institute on Aging [R01 AG16495, AG08122, AG033193, AG031287]; National Institute of Neurological Disorders and Stroke [R01 NS17950] FX This work was supported by contracts N01-HC-25195, N01HV28178, RO1DK080739, and 2K24HL04334 (awarded to Dr Vasan) from the National Institutes of Health and the National Heart, Lung, and Blood Institute; grants R01 AG16495, AG08122, AG033193, and AG031287 from the National Institute on Aging; and grant R01 NS17950 from the National Institute of Neurological Disorders and Stroke. NR 45 TC 172 Z9 175 U1 2 U2 18 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 DEC 16 PY 2009 VL 302 IS 23 BP 2565 EP 2572 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 532HK UT WOS:000272737200024 PM 20009056 ER PT J AU Stanley, SA Hung, DT AF Stanley, Sarah A. Hung, Deborah T. TI Toward a Systems-Level Analysis of Infection Biology: A New Method for Conducting Genetic Screens in Human Cells SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID FUNCTIONAL GENOMIC SCREEN; RNAI SCREEN; VIRUS-REPLICATION; HOST; IDENTIFICATION; INTERFERENCE; PATHOGEN; TOXIN AB Loss-of-function genetic screens have facilitated great strides in our understanding of the biology of model organisms but have not been possible in diploid human cells. A recent report by Brummelkamp's group in Science describes the use of insertional mutagenesis to generate loss-of-function alleles in a largely haploid human cell line and demonstrates the versatility of this method in screens designed to investigate the host/pathogen interaction. This approach has strengths that are complementary to existing strategies and will facilitate progress toward a systems-level understanding of infectious disease and ultimately the development of new therapeutics. C1 [Hung, Deborah T.] Broad Inst, Infect Dis Initiat, Cambridge, MA 02142 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Hung, DT (reprint author), Broad Inst, Infect Dis Initiat, Cambridge, MA 02142 USA. EM dhung@broadinstitute.org FU Intramural NIH HHS NR 17 TC 0 Z9 0 U1 2 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 16 PY 2009 VL 1 IS 11 AR 11ps13 DI 10.1126/scitranslmed.3000550 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 590XZ UT WOS:000277263100003 PM 20371455 ER PT J AU Kumarasamy, A Schmitt, I Nave, AH Reiss, I van der Horst, I Dony, E Roberts, JD de Krijger, RR Tibboel, D Seeger, W Schermuly, RT Eickelberg, O Morty, RE AF Kumarasamy, Arun Schmitt, Isabelle Nave, Alexander H. Reiss, Irwin van der Horst, Irene Dony, Eva Roberts, Jesse D., Jr. de Krijger, Ronald R. Tibboel, Dick Seeger, Werner Schermuly, Ralph T. Eickelberg, Oliver Morty, Rory E. TI Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE lung development; septation; TGF-beta; transforming growth factor ID VENTILATED PRETERM INFANTS; ELASTIN CROSS-LINKING; MESSENGER-RNA LEVELS; BRONCHOPULMONARY DYSPLASIA; PULMONARY MICROVASCULATURE; MECHANICAL VENTILATION; MOLECULAR SIGNATURE; NEONATAL MICE; NEWBORN MICE; DISEASE AB Rationale Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-beta) was preemptively blocked in mice exposed to hyperoxia using TGF-beta-neutralizing antibodies. lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxi1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygen-injured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-beta signaling drove aberrant lox, but not loxi1 or lox/2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-beta signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD. C1 [Kumarasamy, Arun; Schmitt, Isabelle; Nave, Alexander H.; Dony, Eva; Seeger, Werner; Schermuly, Ralph T.; Morty, Rory E.] Univ Giessen, Lung Ctr, Dept Internal Med, D-35392 Giessen, Germany. [de Krijger, Ronald R.] Erasmus Univ, Med Ctr, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [Reiss, Irwin; van der Horst, Irene; Tibboel, Dick] Erasmus Univ, Med Ctr, Josephine Nefkens Inst, Dept Pediat Surg, Rotterdam, Netherlands. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Schermuly, Ralph T.] Max Planck Inst Heart & Lung Res, Dept Lung Dev & Remodelling, Bad Nauheim, Germany. [Eickelberg, Oliver] Helmholz Zentrum, Inst Lung Biol & Dis, Munich, Germany. RP Morty, RE (reprint author), Univ Giessen, Lung Ctr, Dept Internal Med, Aulweg 123,Room 6-11, D-35392 Giessen, Germany. EM rory.morty@innere.med.uni-giessen.de RI Eickelberg, Oliver/A-5461-2013 OI Eickelberg, Oliver/0000-0001-7170-0360 FU von Behring-Rontgen Foundation [51-0031]; University Medical Center Giessen and Marburg [62589035]; Sophia Kinderziekenhuis Fonds [521]; Deutsche Forschungsgemeinschaft through: Collaborative Research Centre [547]; Clinical Research Group [118]; Excellence Cluster [147]; [MO 1789/1] FX Supported in part by research grants 51-0031 from the von Behring-Rontgen Foundation (R.E.M.), 62589035 from the University Medical Center Giessen and Marburg (R.E.M.); 521 from the Sophia Kinderziekenhuis Fonds (I.R., I.v.d.H., and D.T.); and by the Deutsche Forschungsgemeinschaft through: Collaborative Research Centre 547 "Cardio-Pulmonary Circulation" (W.S., R.T.S. and O.E.); Clinical Research Group 118 "Pulmonary Fibrosis" (I.R., W.S., R.T.S., and O.E.), and Excellence Cluster 147 "Cardio-Pulmonary System" (W.S., R.T.S., O.E., and R.E.M.), and MO 1789/1 (R.E.M.). NR 56 TC 38 Z9 39 U1 0 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 15 PY 2009 VL 180 IS 12 BP 1239 EP 1252 DI 10.1164/rccm.200902-0215OC PG 14 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 534IG UT WOS:000272889200011 PM 19797161 ER PT J AU Nathan, DM AF Nathan, David M. TI The Role of Glycemia Management in the Prevention of Cardiovascular Disease-Starting Over? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID BLOOD-GLUCOSE CONTROL; DIABETES-MELLITUS; RISK-FACTORS; FOLLOW-UP; COMPLICATIONS; ASSOCIATION; METAANALYSIS; RETINOPATHY; HEMOGLOBIN; STATEMENT C1 Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Ctr Diabet, 50 Staniford St, Boston, MA 02114 USA. EM dnathan@partners.org NR 19 TC 3 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 15 PY 2009 VL 151 IS 12 BP 888 EP 889 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 532ET UT WOS:000272728900008 PM 20008764 ER PT J AU Milad, MR Pitman, RK Ellis, CB Gold, AL Shin, LM Lasko, NB Zeidan, MA Handwerger, K Orr, SP Rauch, SL AF Milad, Mohammed R. Pitman, Roger K. Ellis, Cameron B. Gold, Andrea L. Shin, Lisa M. Lasko, Natasha B. Zeidan, Mohamed A. Handwerger, Kathryn Orr, Scott P. Rauch, Scott L. TI Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Amygdala; classical; conditioning; hippocampus; posttraumatic; magnetic resonance imaging; prefrontal cortex; stress disorders ID VENTROMEDIAL PREFRONTAL CORTEX; CHILDHOOD SEXUAL-ABUSE; SCRIPT-DRIVEN IMAGERY; ANTERIOR CINGULATE FUNCTION; CORTICOLIMBIC BLOOD-FLOW; FEAR EXTINCTION; ANXIETY DISORDER; BRAIN ACTIVATION; PTSD; AMYGDALA AB Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD control subjects underwent a 2-day fear conditioning and extinction protocol in a 3-T functional magnetic resonance imaging scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: The SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of functional magnetic resonance imaging data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC and greater activation in dACC were observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment. C1 [Milad, Mohammed R.; Pitman, Roger K.; Ellis, Cameron B.; Gold, Andrea L.; Shin, Lisa M.; Lasko, Natasha B.; Zeidan, Mohamed A.; Orr, Scott P.; Rauch, Scott L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shin, Lisa M.; Handwerger, Kathryn] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Orr, Scott P.] Res Serv, Dept Vet Affairs, Med Ctr, Manchester, NH USA. [Milad, Mohammed R.] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Milad, MR (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 149 13th St,CNY 2614, Charlestown, MA 02129 USA. EM milad@nmr.mgh.harvard.edu OI Gold, Andrea/0000-0003-4447-776X FU National Institute of Mental Health [1R21MH072156-1]; National Alliance for Research; Massachusetts General Hospital (MGH) for Brain Stimulation Therapy from Medtronics; MGH for vegal nerve stimulation from Cyberonics; MGH on anxiolytic action from Cephalon; Novartis FX Scott Rauch's financial disclosures are as follows: be received funded research through Massachusetts General Hospital (MGH) for Brain Stimulation Therapy from Medtronics; funded research through MGH for vegal nerve stimulation from Cyberonics; and funded reseaach through MGH on anxiolytic action from Cephalon. He also received honoraria from Novartis for consultation on emerging treatments' : Neurogen for his participation as a consultant on emerging trends in anxiety associated with insomnia.: Sepracor for his consultation on fear/conditioning/extinction and from Primedia for his participation in developing a continuing education activity; and Medtronics for his attendance of the Advisory Board Meeting on the Anatomy and Neuroscience of anxiety and depression. Note that no direct conflict is anticipated. All relationships are listed for full disclosure. The remaining authors reported no biomedical financial interests or potential conflicts of interest. NR 65 TC 410 Z9 417 U1 13 U2 84 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 DEC 15 PY 2009 VL 66 IS 12 BP 1075 EP 1082 DI 10.1016/j.biopsych.2009.06.026 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 530NL UT WOS:000272599500002 PM 19748076 ER PT J AU Elman, I Lowen, S Frederick, BB Chi, W Becerra, L Pitman, RK AF Elman, Igor Lowen, Steven Frederick, Blaise B. Chi, Won Becerra, Lino Pitman, Roger K. TI Functional Neuroimaging of Reward Circuitry Responsivity to Monetary Gains and Losses in Posttraumatic Stress Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Corpus striatum; functional magnetic resonance imaging; motivation; posttraumatic; reward; stress disorders ID MESIAL PREFRONTAL CORTEX; DOPAMINE-RECEPTOR DRD2; EVENT-RELATED FMRI; DORSAL STRIATUM; INDUCED ANHEDONIA; DECISION-MAKING; ANIMAL-MODELS; LOSS AVERSION; PTSD; SYSTEM AB Background: Clinical impressions and preclinical work suggest that posttraumatic stress disorder (PTSD) might be associated with dysfunctional reward processing. To pursue this issue, we administered a validated passive-viewing monetary reward task during functional magnetic resonance imaging (fMRI) to subjects with chronic PTSD and to mentally healthy individuals. \Methods: The protocol evaluated fMRI signal changes that anticipated or accompanied monetary gains and losses under varying conditions of controlled expectation. The "expectancy phase" entailed presentation of a promising, unpromising, or intermediate Wheel of Fortune-type spinner, whereas the "outcome phase" was defined by the arrow landing on one of three sectors of that spinner, thereby determining the subjects' gain or loss for that trial. Results: Neuroimaging data from 20 PTSD and 26 healthy subjects withstood quality control procedures and were included. In voxelwise and anatomically defined region-of-interest analyses, when gains were contrasted to losses, between-group comparison revealed smaller bilateral striatal activations in the PTSD subjects. In the PTSD group, less striatal activation to gains versus losses was associated with more self-reported motivational and social deficits. Conclusions: The present data support the hypothesis that PTSD is associated with abnormal processing of monetary outcomes and that this alteration might be related to some aspects of emotional numbing. C1 [Elman, Igor] Harvard Univ, McLean Hosp, Sch Med, Clin Psychopathol Lab, Belmont, MA 02478 USA. [Elman, Igor; Lowen, Steven; Frederick, Blaise B.; Becerra, Lino] McLean Hosp, Brain Imaging Ctr, Belmont, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Boston, MA USA. [Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Elman, I (reprint author), Harvard Univ, McLean Hosp, Sch Med, Clin Psychopathol Lab, 115 Mill St, Belmont, MA 02478 USA. EM ielman@partners.org RI Frederick, Blaise/G-6098-2012 OI Frederick, Blaise/0000-0001-5832-5279 FU National Institute on Drug Abuse [DA017959, DA16612] FX This work, was supported by Grants DA017959 (IE) and DA16612 (SL) from the National Institute on Drug Abuse. We gratefully, acknowledge Dr. Yavin Shaham for his very insightful comments on The manuscript and Dr. David Borsook for help consultation. Ms. Evelyne Tschibelu assisted with the preparation of this manuscript NR 73 TC 50 Z9 50 U1 1 U2 16 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 DEC 15 PY 2009 VL 66 IS 12 BP 1083 EP 1090 DI 10.1016/j.biopsych.2009.06.006 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 530NL UT WOS:000272599500003 PM 19640506 ER PT J AU New, AS Hazlett, EA Newmark, RE Zhang, J Triebwasser, J Meyerson, D Lazarus, S Trisdorfer, R Goldstein, KE Goodman, M Koenigsberg, HW Flory, JD Siever, LJ Buchsbaum, MS AF New, Antonia S. Hazlett, Erin A. Newmark, Randall E. Zhang, Jane Triebwasser, Joseph Meyerson, David Lazarus, Sophie Trisdorfer, Roanna Goldstein, Kim E. Goodman, Marianne Koenigsberg, Harold W. Flory, Janine D. Siever, Larry J. Buchsbaum, Monte S. TI Laboratory Induced Aggression: A Positron Emission Tomography Study of Aggressive Individuals with Borderline Personality Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Brain imaging; emotion; Point Subtraction Aggression Paradigm; PSAP ID NONVIOLENT MALE PAROLEES; ORBITAL FRONTAL-CORTEX; GLUCOSE-METABOLISM; PSYCHOMETRIC MEASUREMENTS; IMPULSIVE AGGRESSION; BRAIN ABNORMALITIES; SPECTRUM DISORDERS; BRODMANN AREAS; RHESUS-MONKEYS; FDG-PET AB Background: Borderline personality disorder (BPD) is often associated with symptoms of impulsive aggression, which poses a threat to patients themselves and to others. Preclinical studies show that orbital frontal cortex (OFC) plays a role in regulating impulsive aggression. Prior work has found OFC dysfunction in BPD. Methods: We employed a task to provoke aggressive behavior, the Point Subtraction Aggression Paradigm (PSAP), which has never previously been used during functional brain imaging. Thirty-eight BPD patients with intermittent explosive disorder (BPD-IED) and 36 age-matched healthy control subjects (HCs) received (18)fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) on two occasions with a provocation and nonprovocation version of the PSAP. Mean relative glucose metabolism was measured throughout the cortex, and difference scores (provoked - nonprovoked) were calculated. A whole brain exploratory analysis for the double difference of BPD-IED - HC for provoked - nonprovoked was also conducted. Results: BPD-IED patients were significantly more aggressive than HCs on the PSAP. BPD-IED patients also increased relative glucose metabolic rate (rGMR) in OFC and amygdala when provoked, while HCs decreased rGMR in these areas, However, HCs increased rGMR in anterior, medial, and dorsolateral prefrontal regions during provocation more than BPD-IED patients. Conclusions: Patients responded aggressively and showed heightened rGMR in emotional brain areas, including amygdala and OFC, in response to provocation but not in more dorsal brain regions associated with cognitive control of aggression. In contrast, HCs increased rGMR in dorsal regions of PFC during aggression provocation, brain regions involved in top-down cognitive control of aggression, and, more broadly, of emotion. C1 [New, Antonia S.; Triebwasser, Joseph; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [New, Antonia S.; Hazlett, Erin A.; Zhang, Jane; Triebwasser, Joseph; Lazarus, Sophie; Trisdorfer, Roanna; Goldstein, Kim E.; Goodman, Marianne; Koenigsberg, Harold W.; Flory, Janine D.; Siever, Larry J.; Buchsbaum, Monte S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Newmark, Randall E.] Boston Univ, Dept Neurosci, Boston, MA 02215 USA. [Meyerson, David] Depaul Univ, Dept Psychol, Chicago, IL 60604 USA. [Flory, Janine D.] CUNY, Queens Coll, Dept Psychol, New York, NY 10021 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. RP New, AS (reprint author), James J Peters Vet Affairs Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM antonia.new@mssm.edu FU James J. Peters Veterans Affairs Medical Center; National Institutes of Health (NIH) [1-R01-MH067918-01, 1-R01-MH07911, 5-M01 RR00071]; National Center for Research Resources FX This work was supported by the James J. Peters Veterans Affairs Medical Center and by a grant to ASN from the National Institutes of Health (NIH) (1-R01-MH067918-01) and to EAH (1-R01-MH07911) and by 5-M01 RR00071 for the Mount Sinai General Clinical Research Center from the National Center for Research Resources at the NIH. NR 64 TC 69 Z9 71 U1 1 U2 8 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 DEC 15 PY 2009 VL 66 IS 12 BP 1107 EP 1114 DI 10.1016/j.biopsych.2009.07.015 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 530NL UT WOS:000272599500006 PM 19748078 ER PT J AU Faridi, MH Maiguel, D Barth, CJ Stoub, D Day, R Schurer, S Gupta, V AF Faridi, Mohd. Hafeez Maiguel, Dony Barth, Constantinos J. Stoub, Darren Day, Ruth Schuerer, Stephan Gupta, Vineet TI Identification of novel agonists of the integrin CD11b/CD18 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Integrin; Mac-1; CD11b/CD18; Inflammation; Cell-adhesion; Cell-based assay; High-throughput screening; Agonist ID A-DOMAIN; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; LIGAND-BINDING; I-DOMAIN; ADHESION; MAC-1; DISCOVERY; RECEPTOR; SUBUNIT AB We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC(50) of 10.5 mu M and in vitro selectivity for binding to the recombinant alpha A-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding alpha A-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Schuerer, Stephan] Univ Miami, Dept Pharmacol, Miami, FL 33176 USA. [Faridi, Mohd. Hafeez; Maiguel, Dony; Barth, Constantinos J.; Gupta, Vineet] Peggy & Harold Katz Family Drug Discovery Ctr, Div Nephrol & Hypertens, Dept Med, Miami, FL 33176 USA. [Gupta, Vineet] Univ Miami, Dept Biochem & Mol Biol, Miami, FL 33176 USA. [Stoub, Darren; Day, Ruth] Rollins Coll, Dept Chem, Winter Pk, FL 32789 USA. [Schuerer, Stephan] Univ Miami, Ctr Computat Sci, Miami, FL 33176 USA. [Gupta, Vineet] Harvard Univ, Sch Med, Div Nephrol, Massachusetts Gen Hosp, Boston, MA 02129 USA. RP Schurer, S (reprint author), Univ Miami, Dept Pharmacol, Miami, FL 33176 USA. EM sschuerer@med.miami.edu; vgupta2@med.miami.edu OI Gupta, Vineet/0000-0001-6987-2550 FU NIH [DK068253, NS053659]; The Edward W. and Stella C. Van Houten Memorial Fund; Center for Computational Science at the University of Miami [162] FX This work was supported in part by NIH Grants DK068253 and NS053659 and by The Edward W. and Stella C. Van Houten Memorial Fund. We thank Dr. Jun Y. Park and Dr. Jack Rosa for generous help and discussions with the cell-based assays; Dr. Caroline Shamu and the rest of the ICCB staff for their support in the implementation of the HTS assay and Prof. M. Amin Arnaout for helpful discussions. This work was supported with resources of the Center for Computational Science at the University of Miami (# 162). We also thank Istvan Kolossvary from DEShaw Research for help setting up Desmond. NR 29 TC 11 Z9 11 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2009 VL 19 IS 24 BP 6902 EP 6906 DI 10.1016/j.bmcl.2009.10.077 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 518VU UT WOS:000271724200016 PM 19879752 ER PT J AU Collins, MP Souza, PE Liu, CF Heagerty, PJ Amtmann, D Yueh, B AF Collins, Margaret P. Souza, Pamela E. Liu, Chuan-Fen Heagerty, Patrick J. Amtmann, Dagmar Yueh, Bevan TI Hearing aid effectiveness after aural rehabilitation - individual versus group (HEARING) trial: RCT design and baseline characteristics SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID HEALTH MAINTENANCE ORGANIZATION; BEHAVIORAL TREATMENT APPROACH; RANDOMIZED CONTROLLED-TRIAL; CHRONIC CARE CLINICS; 2-YEAR FOLLOW-UP; COMMUNICATION PROFILE; HANDICAP INVENTORY; AUDIOLOGICAL REHABILITATION; DIABETES EDUCATION; GROUP VISITS AB Background: Hearing impairment is the most common body system disability in veterans. In 2008, nearly 520,000 veterans had a disability for hearing loss through the Department of Veterans Affairs (VA). Changes in eligibility for hearing aid services, along with the aging population, contributed to a greater than 300% increase in the number of hearing aids dispensed from 1996 to 2006. In 2006, the VA committed to having no wait times for patient visits while providing quality clinically-appropriate care. One approach to achieving this goal is the use of group visits as an alternative to individual visits. We sought to determine: 1) if group hearing aid fitting and follow-up visits were at least as effective as individual visits, and 2) whether group visits lead to cost savings through the six month period after the hearing aid fitting. We describe the rationale, design, and characteristics of the baseline cohort of the first randomized clinical trial to study the impact of group versus individual hearing aid fitting and follow-up visits. Methods: Participants were recruited from the VA Puget Sound Health Care System Audiology Clinic. Eligible patients had no previous hearing aid use and monaural or binaural air-conduction hearing aids were ordered at the evaluation visit. Participants were randomized to receive the hearing aid fitting and the hearing aid follow-up in an individual or group visit. The primary outcomes were hearing-related function, measured with the first module of the Effectiveness of Aural Rehabilitation (Inner EAR), and hearing aid adherence. We tracked the total cost of planned and unplanned audiology visits over the 6-month interval after the hearing aid fitting. Discussion: A cohort of 659 participants was randomized to receive group or individual hearing aid fitting and follow-up visits. Baseline demographic and self-reported health status and hearing-related measures were evenly distributed across the treatment arms. Outcomes after the 6-month follow-up period are needed to determine if group visits were as least as good as those for individual visits and will be reported in subsequent publication. C1 [Collins, Margaret P.; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, Hlth Serv Res Dev Ctr Excellence, Seattle, WA 98101 USA. [Collins, Margaret P.] VA Puget Sound Hlth Care Syst, Rehabil Care Serv, Seattle, WA 98108 USA. [Souza, Pamela E.] Northwestern Univ, Dept Commun Sci & Disorders, Evanston, IL 60208 USA. [Liu, Chuan-Fen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Amtmann, Dagmar] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Yueh, Bevan] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, Minneapolis, MN 55455 USA. RP Collins, MP (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv Res Dev Ctr Excellence, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM margaret.collins@va.gov; p-souza@northwestern.edu; Chuan-Fen.Liu@va.gov; heagerty@u.washington.edu; dagmara@u.washington.edu; byueh@umn.edu OI Yueh, Bevan/0000-0003-1380-1053 FU Health Services Research & Development Service of the Veterans Health Administration [SLI 04-2653] FX This work is supported by a grant from the Health Services Research & Development Service of the Veterans Health Administration (SLI 04-2653). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the United States government, or other affiliated institutions. NR 76 TC 5 Z9 5 U1 2 U2 11 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 DEC 15 PY 2009 VL 9 AR 233 DI 10.1186/1472-6963-9-233 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 543JR UT WOS:000273573100001 PM 20003515 ER PT J AU Sepucha, KR Barry, MJ AF Sepucha, Karen R. Barry, Michael J. TI Making Patient-Centered Cancer Care a Reality SO CANCER LA English DT Editorial Material ID DECISION C1 [Sepucha, Karen R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. RP Sepucha, KR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. NR 6 TC 2 Z9 2 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2009 VL 115 IS 24 BP 5610 EP 5611 DI 10.1002/cncr.24824 PG 2 WC Oncology SC Oncology GA 529UX UT WOS:000272545400002 PM 19957353 ER PT J AU Siegel, AB Zhu, AX AF Siegel, Abby B. Zhu, Andrew X. TI Metabolic Syndrome and Hepatocellular Carcinoma Two Growing Epidemics With a Potential Link SO CANCER LA English DT Review DE hepatocellular carcinoma; metabolic syndrome; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis ID NONALCOHOLIC FATTY LIVER; BODY-MASS INDEX; HEPATITIS-C VIRUS; PLACEBO-CONTROLLED TRIAL; PROSTATE-CANCER RISK; GROWTH-FACTOR-I; CRYPTOGENIC CIRRHOSIS; INSULIN-RESISTANCE; UNITED-STATES; BREAST-CANCER AB Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Although many risk factors for HCC are well defined, including hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol, most series have indicated that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer. The majority of "cryptogenic" HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome. The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer with respect to both increased risk of disease and worsened outcome. In this review, the authors focused on the relation between metabolic syndrome and HCC. They investigated the increased risks of HCC among individuals with features of metabolic syndrome, potentially worsened cancer outcomes in these patients, possible pathogenic mechanisms to explain these relations, and treatment options for those with NAFLD and its progressive counterpart, nonalcoholic steatohepatitis. It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC. Cancer 2009;115:5651-61. (C) 2009 American Cancer Society. C1 [Siegel, Abby B.] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Siegel, Abby B.] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY USA. [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med,Tucker Gosnell Ctr Gastrointestinal Canc, Boston, MA 02114 USA. RP Siegel, AB (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, 622 W 168th St,PH-14, New York, NY 10032 USA. EM aas54@columbia.edu FU National Institutes of Health [KL2 RR024157-03]; Steven J. Levinson Medical Research Foundation FX Supported in part by a K12 award from the National Institutes of Health (KL2 RR024157-03) and by the Steven J. Levinson Medical Research Foundation. NR 109 TC 173 Z9 178 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2009 VL 115 IS 24 BP 5651 EP 5661 DI 10.1002/cncr.24687 PG 11 WC Oncology SC Oncology GA 529UX UT WOS:000272545400009 PM 19834957 ER PT J AU Winer, EP AF Winer, E. P. TI The Evolving Role of Adjuvant Chemotherapy. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Winer, E. P.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 484S EP 484S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700012 ER PT J AU Harris, JR AF Harris, J. R. TI How Will the '4:1 Ratio' Change with Increasingly Effective Systemic Therapy. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Harris, J. R.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 486S EP 486S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700022 ER PT J AU Goss, PE Ingle, JN Martino, S Robert, N Muss, H Shepherd, L Pritchard, KI Livingston, RB Davidson, N Perez, EA Cameron, D Whelan, T Palmer, A Tu, D AF Goss, P. E. Ingle, J. N. Martino, S. Robert, N. Muss, H. Shepherd, L. Pritchard, K., I Livingston, R. B. Davidson, N. Perez, E. A. Cameron, D. Whelan, T. Palmer, A. Tu, D. TI Outcomes of Women Who Were Premenopausal at Diagnosis of Early Stage Breast Cancer in the NCIC CTG MA17 Trial. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX SP Amer Assoc Canc Res, Canc Therapy & Res Ctr C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 32224 USA. Mayo Clin, Rochester, MN USA. Angeles Clin & Res Inst, Los Angeles, CA USA. Inova Fairfax Hosp, Falls Church, VA USA. Univ N Carolina, Chapel Hill, NC USA. Natl Canc Inst Canada, Kingston, ON, Canada. Univ Toronto, Toronto, ON, Canada. Univ Arizona, Tucson, AZ USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Mayo Clin, Jacksonville, FL USA. Univ Leeds, Leeds, W Yorkshire, England. McMaster Univ, Hamilton, ON, Canada. RI Whelan, Timothy/D-3185-2017 NR 0 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 487S EP 487S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700025 ER PT J AU Golshan, M Garber, J Gelman, R Tung, N Smith, BL Troyan, S Greenberg, CC Winer, EP Ryan, PD AF Golshan, M. Garber, J. Gelman, R. Tung, N. Smith, B. L. Troyan, S. Greenberg, C. C. Winer, E. P. Ryan, P. D. TI Surgical Complications and the Use of Neoadjuvant Bevacizumab SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 496S EP 496S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700048 ER PT J AU Blackwell, KL Burstein, HJ Sledge, GW Stein, S Ellis, C Casey, M Baselga, J O'Shaughnessy, J AF Blackwell, K. L. Burstein, H. J. Sledge, G. W. Stein, S. Ellis, C. Casey, M. Baselga, J. O'Shaughnessy, J. TI Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Duke Univ, Med Ctr, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. GlaxoSmithKline Inc, Collegeville, PA USA. Vall Hebron Univ Hosp, Barcelona, Spain. US Oncol, Dallas, TX USA. NR 0 TC 8 Z9 8 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 DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 499S EP 499S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700057 ER PT J AU Stal, O Jerevall, PL Ma, XJ Li, H Salunga, R Erlander, M Sgroi, D Holmlund, B Skoog, L Fornander, T AF Stal, O. Jerevall, P-L Ma, X-J Li, H. Salunga, R. Erlander, M. Sgroi, D. Holmlund, B. Skoog, L. Fornander, T. TI Validation of Prognostic Utility of HOXB13:IL17BR and Molecular Grade Index in Early Stage Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Linkoping Univ, Linkoping, Sweden. bioTheranostics, San Diego, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Karolinska Inst, Stockholm, Sweden. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 504S EP 504S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700070 ER PT J AU Juul, N Wang, Y Kim, JY Eklund, AC Li, Q Carlton, VEH Gerlinger, M Swanton, C Garber, JE Silver, DP Faham, M Richardson, AL Szallasi, Z Wang, ZC AF Juul, N. Wang, Y. Kim, J-Y Eklund, A. C. Li, Q. Carlton, V. E. H. Gerlinger, M. Swanton, C. Garber, J. E. Silver, D. P. Faham, M. Richardson, A. L. Szallasi, Z. Wang, Z. C. TI A Genomic-Profile Derived Summary Measure of Chromosomal Breakpoints Predicts Response to Treatment with the DNA-Damaging Agent Cisplatin. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Tech Univ Denmark, DK-2800 Lyngby, Denmark. Affymetrix Inc, Santa Clara, CA USA. London Res Inst, London, England. MLC Diagnosis, Menlo Pk, CA USA. Harvard Univ, Childrens Hosp, Informat Program, Harvard Mit Div Hlth Sci & Technol,Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 509S EP 510S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920700082 ER PT J AU Pierce, LJ Phillips, KAM Griffith, KA Buys, SS Gaffney, DK Moran, MS Haffty, BG Ben-David, MA Garber, JE Merajver, S Balmanya, J Meirovitz, A Domchek, SM AF Pierce, L. J. Phillips, K-A M. Griffith, K. A. Buys, S. S. Gaffney, D. K. Moran, M. S. Haffty, B. G. Ben-David, M. A. Garber, J. E. Merajver, S. Balmanya, J. Meirovitz, A. Domchek, S. M. TI Local Therapy in BRCA1/2 Carriers with Operable Breast Cancer: Comparison of Breast Conservation and Mastectomy. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ Michigan, Sch Med, Ann Arbor, MI USA. Peter MacCallum Canc Ctr, Melbourne, Australia. Huntsman Canc Inst, Salt Lake City, UT USA. Yale Univ, Sch Med, New Haven, CT USA. UMDNJ RWJMS Canc Inst New Jersey, New Brunswick, NJ USA. Chaim Sheba Med Ctr, Ramat Gan, Israel. Dana Farber Canc Inst, Boston, MA 02115 USA. Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. Abramson Canc Ctr, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 537S EP 537S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700159 ER PT J AU Ruddy, KJ Gelber, S Tamimi, R Mayer, EL Schapira, L Come, SE Meyer, ME Winer, EP Partridge, AH AF Ruddy, K. J. Gelber, S. Tamimi, R. Mayer, E. L. Schapira, L. Come, S. E. Meyer, M. E. Winer, E. P. Partridge, A. H. TI Prevalence and Predictors of Distress in Young Women with Newly Diagnosed Early Stage Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 559S EP 559S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700223 ER PT J AU Kuter, I Anderson, E Emeribe, U Finlay, F Nicholson, RI Gee, J AF Kuter, I Anderson, E. Emeribe, U. Finlay, F. Nicholson, R., I Gee, J. TI Comparison of Methods for Detection of Fulvestrant-Induced Changes in Breast Tumor Estrogen and Progesterone Receptor Expression in a Neoadjuvant Trial (NEWEST) SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. AstraZeneca, Macclesfield, Cheshire, England. AstraZeneca, Wilmington, DE USA. Tenovus Ctr Canc Res, Cardiff, S Glam, Wales. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 566S EP 567S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920700243 ER PT J AU Lee, CN Belkora, J Wetschler, M Chang, Y Feibelmann, S Moy, B Partridge, A Sepucha, K AF Lee, C. N. Belkora, J. Wetschler, M. Chang, Y. Feibelmann, S. Moy, B. Partridge, A. Sepucha, K. TI The Quality of Decisions about Adjuvant Chemotherapy for Early Stage Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ N Carolina, Chapel Hill, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 619S EP 620S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920701116 ER PT J AU Ma, XJ Bandaru, R Letzkus, M Philips, P Barrett, JC Erlander, M Goetz, M Sgroi, D Gardner, H Baselga, J AF Ma, X-J Bandaru, R. Letzkus, M. Philips, P. Barrett, J. C. Erlander, M. Goetz, M. Sgroi, D. Gardner, H. Baselga, J. TI HOXB13 May Predict Response to Neoadjuvant Letrozole in Patients with Estrogen Receptor-Positive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Biotheranostics Inc, San Diego, CA USA. Mayo Clin, Rochester, MN USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Novartis Inst Biomed Res, Boston, MA USA. Novartis Pharma AG, Basel, Switzerland. Vall Hebron Univ Hosp, Barcelona, Spain. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 631S EP 632S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920701152 ER PT J AU Flores, LM Kindelberger, DW Ligon, AH Cappeletti, M Fiorentino, M Loda, M Cibas, ES Janne, PA Krop, IE AF Flores, L. M. Kindelberger, D. W. Ligon, A. H. Cappeletti, M. Fiorentino, M. Loda, M. Cibas, E. S. Janne, P. A. Krop, I. E. TI Comparison of the Cellsearch Profile Kit (CPK) with the Standard Cellsearch Epithelial Kit (CEK) Demonstrates the CPK Produces Higher Circulating Tumor Cell (CTC) Yields and Is Better Suited for Use in Obtaining CTC's for Molecular Characterization. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 647S EP 647S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701201 ER PT J AU Morris, PG Chen, C Lin, N Moy, B Come, S Abbruzzi, A Patil, S Winer, E Norton, L Hudis, CA Dang, CT AF Morris, P. G. Chen, C. Lin, N. Moy, B. Come, S. Abbruzzi, A. Patil, S. Winer, E. Norton, L. Hudis, C. A. Dang, C. T. TI Dose-Dense (dd) Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel (P) with Trastuzumab (T) and Lapatinib (L) in Early Breast Cancer (EBC); Troponin I and C-Reactive Protein as Biomarkers of Cardiotoxicity. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 MSKCC, New York, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 675S EP 675S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701285 ER PT J AU Lee, CN Belkora, J Cosenza, C Chang, Y Levin, C Moy, B Partridge, A Sepucha, K AF Lee, C. N. Belkora, J. Cosenza, C. Chang, Y. Levin, C. Moy, B. Partridge, A. Sepucha, K. TI Decisions about Breast Reconstruction after Mastectomy: Patient Involvement, Knowledge, and Preferences. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ N Carolina, Chapel Hill, NC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Fdn Informed Med Decis Making, Boston, MA USA. Univ Massachusetts, Boston, MA 02125 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 680S EP 681S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920701300 ER PT J AU Harris, LN Parker, J Broadwater, G Schulz, V Halligan, K Geyda, K Seidman, A Berry, D Winer, E Hudis, C Krasnitz, A Hicks, J Tuck, DP Perou, C AF Harris, L. N. Parker, J. Broadwater, G. Schulz, V Halligan, K. Geyda, K. Seidman, A. Berry, D. Winer, E. Hudis, C. Krasnitz, A. Hicks, J. Tuck, D. P. Perou, C. TI Genome-Wide Profiling of Archived Material from CALGB 9840 and 9342 for Paclitaxel (P) and Trastuzumab (T) Response Biomarkers Using Gene Expression and Copy Number Analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Yale Univ, New Haven, CT USA. Univ N Carolina, Chapel Hill, NC USA. Duke Univ, Durham, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Cold Spring Harbor Labs, Long Isl City, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 716S EP 717S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920701407 ER PT J AU Goss, PE Mamounas, EP Jakesz, R Markopoulos, C Dowsett, M Peto, R Godwin, J Davies, C AF Goss, P. E. Mamounas, E. P. Jakesz, R. Markopoulos, C. Dowsett, M. Peto, R. Godwin, J. Davies, C. TI Aromatase Inhibitors (AIs) Versus Not (Placebo/Observation) as Late Extended Adjuvant Therapy for Postmenopausal Women with Early Stage Breast Cancer (BC): Overviews of Randomized Trials of AIs after similar to 5 Years of Tamoxifen SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Aultmann Canc Ctr, Canton, OH USA. Med Univ Vienna, Vienna, Austria. Univ Athens, Sch Med, GR-11527 Athens, Greece. Royal Marsden Hosp, London SW3 6JJ, England. EBCTCG, Oxford, England. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 733S EP 733S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701455 ER PT J AU Kornblith, AB Archer, L Lan, L Kimmick, G Partridge, A Casey, R Bennett, S Hudis, C Winer, E Cohen, HJ Muss, HB AF Kornblith, A. B. Archer, L. Lan, L. Kimmick, G. Partridge, A. Casey, R. Bennett, S. Hudis, C. Winer, E. Cohen, H. J. Muss, H. B. TI Quality of Life of Early Stage Breast Cancer Patients 65 Years Old or Older Randomized to Standard Chemotherapy or Capecitabine: A Cancer and Leukemia Group B Study (CALGB 49907). SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Raleigh, NC USA. Yale Univ, Sch Nursing, New Haven, CT 06536 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 776S EP 776S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701580 ER PT J AU Zaman, K Thurlimann, B Huober, J Schonenberger, A Pagani, O Luthi, JM Simcock, M Giobbie-Hurder, A Genton, C Aebi, S AF Zaman, K. Thuerlimann, B. Huober, J. Schoenenberger, A. Pagani, O. Luethi, J.-M. Simcock, M. Giobbie-Hurder, A. Genton, C. Aebi, S. TI Modelling Bone Mineral Density in Swiss Breast Cancer Patients Treated with Letrozole, Tamoxifen and Sequences of Letrozole and Tamoxifen in the BIG 1-98 Study (SAKK 21/07). SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 CHU Vaudois, CEPO, Lausanne, Switzerland. Kantonsspital, Aarau, Switzerland. Kantonsspital, Breast Ctr, St Gallen, Switzerland. Oncol Inst So Switzerland, Lugano, Switzerland. Hosp, Thun, Switzerland. SAKK Coordinating Ctr, Bern, Switzerland. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. Univ Hosp Bern, CH-3010 Bern, Switzerland. Behalf Swiss Grp Clin Canc Res SAKK, Bern, Switzerland. RI Aebi, Stefan/F-2004-2010 OI Aebi, Stefan/0000-0002-3383-9449 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 777S EP 777S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701582 ER PT J AU Hickish, T Wheatley, D Lin, N Carey, L Houston, S Mendelson, D Solca, F Uttenreuther-Fischer, M Jones, H Winer, E AF Hickish, T. Wheatley, D. Lin, N. Carey, L. Houston, S. Mendelson, D. Solca, F. Uttenreuther-Fischer, M. Jones, H. Winer, E. TI Use of BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor To Treat Patients with HER2-Positive Metastatic Breast Cancer after Failure of Treatment with Trastuzumab SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Royal Bournemouth Hosp, Bournemouth, Dorset, England. Royal Cornwall Hosp, Truro, England. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ N Carolina, Chapel Hill, NC USA. Royal Surrey Cty Hosp, Guildford, Surrey, England. Premiere Oncol Arizona, Scottsdale, AZ USA. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. Boehringer Ingelheim GmbH & Co KG, Biberach, Germany. Boehringer Ingelheim Ltd, Bracknell, Berks, England. NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 785S EP 785S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702019 ER PT J AU Swaby, RF Wang, M Sparano, JA Bhalla, K Meropol, NJ Falkson, CI Pellegrino, CM Klein, P Goldstein, LJ Sledge, GW AF Swaby, R. F. Wang, M. Sparano, J. A. Bhalla, K. Meropol, N. J. Falkson, C., I Pellegrino, C. M. Klein, P. Goldstein, L. J. Sledge, Jr G. W. TI A Phase II Study of the Histone Deacetylase Inhibitor, Vorinostat, in Combination with Trastuzumab in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER-2 Amplified Breast Cancer Resistant to Transtuzumab-Containing Therapy: (E1104) a Trial of the Eastern Cooperative Oncology Group SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Montefiore Hosp, Bronx, NY USA. Med Coll Georgia, Augusta, GA 30912 USA. Univ Alabama, Birmingham, AL USA. St Vincents Comp Canc Ctr, New York, NY USA. Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 793S EP 793S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702043 ER PT J AU Krop, I LoRusso, P Miller, KD Modi, S Yardley, D Rodriguez, G Agresta, S Zheng, M Amler, L Rugo, H AF Krop, I LoRusso, P. Miller, K. D. Modi, S. Yardley, D. Rodriguez, G. Agresta, S. Zheng, M. Amler, L. Rugo, H. TI A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody-Drug Conjugate, in Patients Previously Treated with Lapatinib, Trastuzumab, and Chemotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Karmanos Canc Inst, Detroit, MI USA. Indiana Univ Melvin Bren Simon, Indianapolis, IN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Sarah Cannon Res Inst, Nashville, TN USA. S Texas Oncol Hematol, San Antonio, TX USA. Genentech Inc, San Francisco, CA 94080 USA. UCSF Comprehens Canc Ctr, San Francisco, CA USA. NR 0 TC 4 Z9 5 U1 0 U2 5 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 DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 795S EP 795S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702049 ER PT J AU Burstein, HJ Sun, Y Dirix, L Jiang, Z Paridaens, R Tan, AR Awada, A Ranade, A Jiao, S Schwartz, G Powell, C Turnbull, K Vermette, J Zacharchuk, C Badwe, R AF Burstein, H. J. Sun, Y. Dirix, L. Jiang, Z. Paridaens, R. Tan, A. R. Awada, A. Ranade, A. Jiao, S. Schwartz, G. Powell, C. Turnbull, K. Vermette, J. Zacharchuk, C. Badwe, R. TI Gastrointestinal and Cardiovascular Safety Profiles of Neratinib Monotherapy in Patients with Advanced ErbB2-Positive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Chinese Acad Med Sci, Canc Hosp, Beijing 100037, Peoples R China. Oncol Ctr AZ St Augustinus, Antwerp, Belgium. 307 Hosp Chinese Peoples Liberat Army, Beijing, Peoples R China. Univ Hosp Gasthuisberg, Louvain, Belgium. Canc Inst New Jersey, New Brunswick, NJ USA. Inst Jules Bordet, B-1000 Brussels, Belgium. Deenanath Mangeshkar Hosp, Pune, Maharashtra, India. Chinese Peoples Liberat Army Gen Hosp, Beijing, Peoples R China. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Wyeth Res, Cambridge, MA USA. Tata Mem Hosp, Bombay 400012, Maharashtra, India. NR 0 TC 0 Z9 0 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 DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 797S EP 798S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920702055 ER PT J AU Gonzalez-Malerva, LG Park, J Zou, L Hu, Y Moradpour, Z Pearlberg, J Harlow, E LaBaer, J AF Gonzalez-Malerva, L. G. Park, J. Zou, L. Hu, Y. Moradpour, Z. Pearlberg, J. Harlow, E. LaBaer, J. TI Autophagy and Tamoxifen Resistance in Breast Cancer. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Biodesign Inst, Tempe, AZ USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 810S EP 811S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920702094 ER PT J AU Kaplan, J Schnitt, S Collins, L Wang, Y Garber, J Tung, N AF Kaplan, J. Schnitt, S. Collins, L. Wang, Y. Garber, J. Tung, N. TI Estrogen Rececptor (ER)-Positive Breast Cancers in BRCA1 Mutation Carriers: Mutation-Related or Sporadic? SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 819S EP 819S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702121 ER PT J AU Collins, LC Gelber, S Ruddy, K Tamimi, RM Come, S Marotti, J Schapira, L Kereakoglow, S Brachtel, EF Winer, E Partridge, A AF Collins, L. C. Gelber, S. Ruddy, K. Tamimi, R. M. Come, S. Marotti, J. Schapira, L. Kereakoglow, S. Brachtel, E. F. Winer, E. Partridge, A. TI Pathologic Features and Biomarker Expression among Young Women with Breast Cancer: Results from the Young Women's Breast Cancer Study SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Channing Inst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 825S EP 825S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702135 ER PT J AU Seewaldt, V Wilke, LG Zalles, C Archer, L Yee, L Kulkarni, S Wood, M Garber, J Ibarra-Drendall, C AF Seewaldt, V Wilke, L. G. Zalles, C. Archer, L. Yee, L. Kulkarni, S. Wood, M. Garber, J. Ibarra-Drendall, C. TI Reproducibility of Random Periareolar Fine Needle Aspiration in a Multi-Institutional Cancer and Leukemia Group B (CALGB) Cross-Sectional Study SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Duke Univ, Durham, NC USA. Ohio State Univ, Columbus, OH 43210 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Univ Vermont, Burlington, VT 05405 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 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 DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 832S EP 832S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702155 ER PT J AU Hayashida, T Takahashi, F Chiba, N Brachtel, E Jinno, H Kitagawa, Y Maheswaran, S AF Hayashida, T. Takahashi, F. Chiba, N. Brachtel, E. Jinno, H. Kitagawa, Y. Maheswaran, S. TI HOXB9 Promotes the Acquisition of Tumorigenic Phenotypes in Mammary Epithelial Cells. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Massachusetts Gen Hosp, Charlestown, MA USA. Keio Univ, Sch Med, Shinjyuku Ku, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 871S EP 872S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920702267 ER PT J AU Pieters, A Duda, DG Steller, EJ Fukumura, D Jain, RK AF Pieters, A. Duda, D. G. Steller, E. J. Fukumura, D. Jain, R. K. TI The Role of Stromal Cells in Tumor Metastases. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 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 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 DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 874S EP 874S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702273 ER PT J AU van der Voet, M Lorson, MA Srinivasan, DG Bennett, KL van den Heuvel, S AF van der Voet, Monique Lorson, Monique A. Srinivasan, Dayalan G. Bennett, Karen L. van den Heuvel, Sander TI C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation SO CELL CYCLE LA English DT Article DE C. elegans; cyclin B1; cyclin B3; mitosis; meiosis; cell cycle; chromosome congression; chromosome segregation ID B-TYPE CYCLINS; CLEAVAGE PLANE SPECIFICATION; MAMMALIAN-CELL-CYCLE; CAENORHABDITIS-ELEGANS; S-PHASE; A-TYPE; SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; COMPLEX; MITOSIS AB Mitotic cyclins in association with the Cdk1 protein kinase regulate progression through mitosis in all eukaryotes. Here, we address to what extent mitotic cyclins in the nematode Caenorhabditis elegans provide overlapping functions or distinct biological activities. C. elegans expresses a single A-type cyclin (CYA-1), three typical B-type cyclins (CYB-1, CYB-2.1 and CYB-2.2), and one B3-subfamily member (CYB-3). While we observed clear redundancies between the cyb genes, cyb-1 and cyb-3 also contribute specific essential functions in meiosis and mitosis. CYB-1 and CYB-3 show similar temporal and spatial expression, both cyclins localize prominently to the nucleus, and both associate with CDK-1 and display histone H1 kinase activity in vitro. We demonstrate that inhibition of cyb-1 by RNAi interferes with chromosome congression and causes aneuploidy. In contrast, cyb-3(RNAi) embryos fail to initiate sister chromatid separation. Inhibition of both cyclins simultaneously results in a much earlier and more dramatic arrest. However, only the combination of cyb-1, cyb-3 and cyb2.1/cyb-2.2 RNAi fully resembles cdk-1 inhibition. This combination of redundant and specific phenotypes supports that in vivo phosphorylation of certain Cdk targets can be achieved by multiple Cdk1/cyclin complexes, while phosphorylation of other targets requires a unique Cdk1/cyclin combination. C1 [van der Voet, Monique; van den Heuvel, Sander] Univ Utrecht, Utrecht, Netherlands. [Lorson, Monique A.; Srinivasan, Dayalan G.; van den Heuvel, Sander] Massachusetts Gen Hosp, Canc Res Ctr, Charlestown, MA USA. [Lorson, Monique A.; Srinivasan, Dayalan G.; van den Heuvel, Sander] Harvard Univ, Sch Med, Charlestown, MA USA. [Bennett, Karen L.] Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO USA. RP van den Heuvel, S (reprint author), Univ Utrecht, Utrecht, Netherlands. EM S.J.L.vandenHeuvel@uu.nl RI van den Heuvel, Sander/B-8892-2011; van der Voet, Monique/F-5772-2012 OI van der Voet, Monique/0000-0002-8829-1767 FU NIH [RO1 GM057990]; Medical Foundation; William Starr Fellowship FX We thank Andy Golden for CDK-1/NCC-1 specific antibodies, Masakane Yamashita for anti-PSTAIRE antibodies, and Yuji Kohara for cyb-2.1 cDNA. We acknowledge Mike Boxem for critically reading the manuscript. This work was supported by the NIH, RO1 GM057990 to S.v.d.H., by a postdoctoral fellowship from the Medical Foundation to M. A. L., and by a William Starr Fellowship to D. G. S. NR 52 TC 21 Z9 28 U1 1 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD DEC 15 PY 2009 VL 8 IS 24 BP 4091 EP 4102 DI 10.4161/cc.8.24.10171 PG 12 WC Cell Biology SC Cell Biology GA 539CZ UT WOS:000273232300027 PM 19829076 ER PT J AU McGeachie, M Ramoni, RLB Mychaleckyj, JC Furie, KL Dreyfuss, JM Liu, YM Herrington, D Guo, XQ Lima, JA Post, W Rotter, JI Rich, S Sale, M Ramoni, MF AF McGeachie, Michael Ramoni, Rachel L. Badovinac Mychaleckyj, Josyf C. Furie, Karen L. Dreyfuss, Jonathan M. Liu, Yongmei Herrington, David Guo, Xiuqing Lima, Joao A. Post, Wendy Rotter, Jerome I. Rich, Stephen Sale, Michele Ramoni, Marco F. TI Integrative Predictive Model of Coronary Artery Calcification in Atherosclerosis SO CIRCULATION LA English DT Article DE atherosclerosis; genetics; risk factors ID OPERATING CHARACTERISTIC CURVES; PROTEIN-KINASE; RECEPTOR; DISEASE; GENE; POLYMORPHISMS; INHIBITION; EXPRESSION; MESA; ASSOCIATION AB Background-Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results-We assessed 712 individuals for the presence or absence of coronary artery calcification and assessed their genotypes for 2882 single-nucleotide polymorphisms. With the use of these single-nucleotide polymorphisms and relevant clinical data, a Bayesian network that predicts the presence of coronary calcification was constructed. The model contained 13 single-nucleotide polymorphisms (from genes AGTR1, ALOX15, INSR, PRKAB1, IL1R2, ESR2, KCNK1, FBLN5, PPARA, VEGFA, PON1, TDRD6, PLA2G7, and 1 ancestry informative marker) and 5 clinical variables (sex, age, weight, smoking, and diabetes mellitus) and achieved 85% predictive accuracy, as measured by area under the receiver operating characteristic curve. This is a significant (P<0.001) improvement on models that use just the single-nucleotide polymorphism data or just the clinical variables. Conclusions-We present an investigation of joint genetic and clinical factors associated with atherosclerosis that shows predictive results for both cases, as well as enhanced performance for their combination. (Circulation. 2009; 120: 2448-2454.) C1 [McGeachie, Michael; Ramoni, Marco F.] Harvard Univ, Sch Med, Harvard Partners Ctr Genet & Genom, Boston, MA 02115 USA. [McGeachie, Michael; Dreyfuss, Jonathan M.; Ramoni, Marco F.] Harvard MIT Div Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA USA. [Ramoni, Rachel L. Badovinac] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Mychaleckyj, Josyf C.; Rich, Stephen; Sale, Michele] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Mychaleckyj, Josyf C.; Rich, Stephen] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Furie, Karen L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Herrington, David] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Guo, Xiuqing; Rotter, Jerome I.] Cedars Sinai, Inst Med Genet, Los Angeles, CA USA. [Lima, Joao A.; Post, Wendy] Johns Hopkins Univ, Div Cardiol, Donald W Reynolds Cardiovasc Clin Res Ctr, Baltimore, MD USA. [Rich, Stephen; Sale, Michele] Univ Virginia, Dept Med, Charlottesville, VA USA. [Sale, Michele] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. RP Ramoni, MF (reprint author), Harvard Univ, Sch Med, Harvard Partners Ctr Genet & Genom, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM ms5fe@virginia.edu; marco_ramoni@harvard.edu FU National Institutes of Health [T32-HL-007427, U01-HL-065899, R01-HL-071205, R21-DA-025168]; [N01-HC-95159]; [N01-HC-95165]; [N01-HC-95169] FX This research was supported in part by National Institutes of Health grants T32-HL-007427, U01-HL-065899, R01-HL-071205, and R21-DA-025168 and by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169. NR 46 TC 20 Z9 21 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 15 PY 2009 VL 120 IS 24 BP 2448 EP 2454 DI 10.1161/CIRCULATIONAHA.109.865501 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 531WR UT WOS:000272704000008 PM 19948975 ER PT J AU Loureiro, R Bezerra, HG Sarwar, A Pale, R Houser, S Cury, RC AF Loureiro, Ricardo Bezerra, Hiram G. Sarwar, Ammar Pale, Rodrigo Houser, Stuart Cury, Ricardo C. TI Tuberculous Pseudoaneurysms of the Thoracic Aorta Comprehensive Evaluation by Cardiovascular Magnetic Resonance SO CIRCULATION LA English DT Editorial Material C1 [Loureiro, Ricardo; Bezerra, Hiram G.; Sarwar, Ammar; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol & Cardiac, MRI PET CT Program, Boston, MA 02114 USA. [Houser, Stuart] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Loureiro, R (reprint author), Hosp Coracao Brasil, Dept Radiol, Complexo Hosp Santa Luzia,SQSW 104,Bloco F, BR-70670000 Brasilia, DF, Brazil. EM rlradiol@globo.com NR 2 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 15 PY 2009 VL 120 IS 24 BP E285 EP E287 DI 10.1161/CIRCULATIONAHA.108.782177 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 531WR UT WOS:000272704000016 PM 20008736 ER PT J AU Hammerman, PS Janne, PA Johnson, BE AF Hammerman, Peter S. Jaenne, Pasi A. Johnson, Bruce E. TI Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CHEMOTHERAPY-NAIVE PATIENTS; PREVIOUSLY TREATED PATIENTS; PROSPECTIVE PHASE-II; ACQUIRED-RESISTANCE; GENE-MUTATIONS; EGFR MUTATIONS; PROLONGED SURVIVAL; GEFITINIB THERAPY; KRAS MUTATIONS; T790M MUTATION AB Gefitinib and erlotinib are ATP competitive inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and are approved around the world for the treatment of patients with non-small cell lung cancer (NSCLC). Somatic mutations in the EGFR are found in 10 to 40% of patients with NSCLC. Patients with sensitizing somatic mutations of EGFR treated with gefitinib or erlotinib have an initial clinical response of 60 to 80%, approximately twice as high as the responses associated with the administration of conventional platinum-based chemotherapy. However, the efficacy of EGFR tyrosine kinase inhibitors (TKI) is limited by either primary (de novo) or acquired resistance after therapy and investigations to define the mechanisms of resistance are active areas of ongoing preclinical and clinical studies. Primary resistance is typically caused by other somatic mutations in genes such as KRAS, which also have an impact on the EGFR signaling pathway or by mutations in the EGFR gene that are not associated with sensitivity to EGFR-TKIs. Two established mechanisms of acquired resistance are caused by additional mutations in the EGFR gene acquired during the course of treatment that change the protein-coding sequence or by amplification of another oncogene signaling pathway driven by the MET oncogene. This review focuses on characterized mechanisms of resistance to the EGFR TKIs and efforts to overcome the problem of resistance aimed at improving the therapy of patients with NSCLC. (Clin Cancer Res 2009;15(24):7502-9) C1 [Hammerman, Peter S.; Jaenne, Pasi A.; Johnson, Bruce E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hammerman, Peter S.; Jaenne, Pasi A.; Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Hammerman, Peter S.; Jaenne, Pasi A.; Johnson, Bruce E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D1234C,44 Binney St, Boston, MA 02115 USA. EM bejohnson@partners.org NR 67 TC 81 Z9 82 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2009 VL 15 IS 24 BP 7502 EP 7509 DI 10.1158/1078-0432.CCR-09-0189 PG 8 WC Oncology SC Oncology GA 533VM UT WOS:000272853500009 ER PT J AU Gramza, AW Corless, CL Heinrich, MC AF Gramza, Ann W. Corless, Christopher L. Heinrich, Michael C. TI Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; SOFT-TISSUE SARCOMAS; C-KIT MUTATIONS; IMATINIB MESYLATE; MOUSE MODEL; DIFFERENTIAL-DIAGNOSIS; STRUCTURAL BASIS; DOSE IMATINIB; CARNEY TRIAD; PHASE-III AB Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. These concepts are directly relevant to the development of targeted molecular therapy for other solid tumors. (Clin Cancer Res 2009;15(24):7510-8) C1 [Gramza, Ann W.; Corless, Christopher L.; Heinrich, Michael C.] Portland VA Med Ctr, Portland, OR USA. [Gramza, Ann W.; Corless, Christopher L.; Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Heinrich, MC (reprint author), R&D-19,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM heinrich@ohsu.edu FU Department of Veterans Affairs; Life Raft Group; GIST Cancer Research Fund FX In part from a Merit Review Grant from the Department of Veterans Affairs (M.C. Heinrich), as well as the Life Raft Group (C.L. Corless, M.C. Heinrich), and GIST Cancer Research Fund (C.L. Corless, M.C. Heinrich). NR 88 TC 89 Z9 95 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2009 VL 15 IS 24 BP 7510 EP 7518 DI 10.1158/1078-0432.CCR-09-0190 PG 9 WC Oncology SC Oncology GA 533VM UT WOS:000272853500010 ER PT J AU Poeta, ML Manola, J Goldenberg, D Forastiere, A Califano, JA Ridge, JA Goodwin, J Kenady, D Saunders, J Westra, W Sidransky, D Koch, WM AF Poeta, M. Luana Manola, Judith Goldenberg, David Forastiere, Arlene Califano, Joseph A. Ridge, John A. Goodwin, Jarrard Kenady, Daniel Saunders, John Westra, William Sidransky, David Koch, Wayne M. TI The Ligamp TP53 Assay for Detection of Minimal Residual Disease in Head and Neck Squamous Cell Carcinoma Surgical Margins SO CLINICAL CANCER RESEARCH LA English DT Article ID P53 GENE; CANCER; MUTATIONS; RECURRENCE; DIAGNOSIS; TUMORS; TISSUES AB Purpose: Detect tumor-related DNA using LigAmp in histologically clear margins and associate results with clinical outcome. Experimental Design: Patients with head and neck cancer were registered for molecular analysis of surgical margins. Adequacy of resection was ensured using histologic margin analysis. Further margins were then harvested and DNA extracted. TP53 mutations in tumor were determined using Affymetrix p53 GeneChip. Margins were analyzed by Ligamp in comparison with standard curves for quantification of mutant DNA. Ligation used two oligonucleotides to isolate DNA targeting the mutation. Ligated DNA was amplified using real-time PCR. The quantity of mutation in the margin was determined as percent of mutant species relative to plasmid and relative to tumor. Cutpoints were identified and defined groups were evaluated for local failure-free, cancer-specific, and overall survival. Study margins were examined for presence of tumor by light microscopy. Results: Tissue from 95 patients with common mutations was analyzed. Fifteen experienced local recurrence. Cutpoints of 0.15% for mutant species relative to plasmid and 0.5% for mutant species relative to tumor were chosen as most selective of recurrent cases. LigAmp had slightly better area under the receiver operator characteristic curve (P = 0.09) than light microscopy correctly predicting 9 of 15 recurrent tumors. There were 6 false negative cases and 26 false positive results. No statistically significant distinctions were observed in cancer-specific or overall survival in this limited cohort. Conclusions: Ligamp provides quantifiable, sensitive detection of mutant DNA in histologically normal margins. Detection of mutant species in margins may identify patients at risk of local recurrence. (Clin Cancer Res 2009;15(24):7658-65) C1 [Poeta, M. Luana; Forastiere, Arlene; Califano, Joseph A.; Westra, William; Sidransky, David; Koch, Wayne M.] Johns Hopkins Univ, Baltimore, MD USA. [Saunders, John] Greater Baltimore Med Ctr, Baltimore, MD USA. [Manola, Judith] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldenberg, David] Penn State Hershey Med Ctr, Hershey, PA USA. [Ridge, John A.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Goodwin, Jarrard] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Kenady, Daniel] Univ Kentucky, Lexington, KY USA. [Poeta, M. Luana] Univ Bari, Ctr Excellence Comparat Genom CEGBA, Dept Gen & Environm Physiol, Bari, Italy. RP Koch, WM (reprint author), 601 N Caroline St, Baltimore, MD 21287 USA. EM wkoch@jhmi.edu FU NIH/NIDCR [R01 DE013152]; Public Health Service [CA23318, CA66636, CA21115, CA16116, CA27525]; National Cancer Institute; Department of Health and Human Services FX NIH/NIDCR R01 DE013152. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service grants CA23318, CA66636, CA21115, CA16116, and CA27525 and from the National Cancer Institute, NIH and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 24 TC 21 Z9 21 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2009 VL 15 IS 24 BP 7658 EP 7665 DI 10.1158/1078-0432.CCR-09-1433 PG 8 WC Oncology SC Oncology GA 533VM UT WOS:000272853500027 PM 19996217 ER PT J AU Snyder, BD Cordio, MA Nazarian, A Kwak, SD Chang, DJ Entezari, V Zurakowski, D Parker, LM AF Snyder, Brian D. Cordio, Marsha A. Nazarian, Ara Kwak, S. Daniel Chang, David J. Entezari, Vahid Zurakowski, David Parker, Leroy M. TI Noninvasive Prediction of Fracture Risk in Patients with Metastatic Cancer to the Spine SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; BONE METASTASES; PATHOLOGICAL FRACTURE; COMPUTED-TOMOGRAPHY; THORACIC VERTEBRAE; DEFECTS; MANAGEMENT; STRENGTH; FAILURE; DENSITY AB Purpose: Skeletal metastases affect up to 85% of breast cancer patients by the time of their death. This prospective in vivo study evaluated the diagnostic performance of computed tomography-based structural rigidity analysis (CTRA) to predict vertebral fracture risk in breast cancer patients with skeletal metastasis and in comparison with the current standard of care. Experimental Design: Torso CT scans of 94 women with vertebral metastatic breast cancer were obtained as part of routine screening for lung and liver metastases. The load-bearing capacity (LBC) and axial (EA) and bending (EI) rigidities of vertebrae T8 to L5 were calculated from CT images. The LBC was normalized by patient body mass index (BMI) to account for height and mass variations. Vertebral fracture risk was also calculated using the current radiographic-based criteria based on lesion size and location. The actual occurrence of a new vertebral fracture was assessed radiographically over the ensuing 4 months. Results: Eleven vertebral fractures occurred in 10 patients. The structural parameters EA, El, LBC, and LBC/BMI were all 100% sensitive and 55%, 53%, 44%, and 70% specific to predict fracture risk, respectively. Although radiographic criteria correctly predicted all fracture cases (100% sensitive), only 48 of the 236 spinal segments that did not have a fracture were correctly predicted not to fracture (20% specific). Conclusions: CTRA, using CT scans as part of routine screening for lung and liver metastasis, is shown to be as sensitive as, and significantly more specific than, the current radiographic criteria for predicting vertebral fracture in breast cancer patients with skeletal metastasis. (Clin Cancer Res 2009;15(24):7676-83) C1 [Snyder, Brian D.; Cordio, Marsha A.; Nazarian, Ara; Kwak, S. Daniel; Chang, David J.; Entezari, Vahid] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. [Snyder, Brian D.; Zurakowski, David] Boston Childrens Hosp, Dept Anesthesia, Boston, MA USA. [Snyder, Brian D.; Zurakowski, David] Boston Childrens Hosp, Dept Orthopaed Surg, Boston, MA USA. [Nazarian, Ara; Parker, Leroy M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Snyder, BD (reprint author), Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, 330 Brookline Ave,RN 115, Boston, MA 02215 USA. EM bsnyder@bidmc.harvard.edu RI Entezari , Vahid/B-5459-2013 FU NIH [CA40211]; Susan Komen Foundation FX NIH grant CA40211 and Susan Komen Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 49 TC 27 Z9 27 U1 1 U2 3 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 DEC 15 PY 2009 VL 15 IS 24 BP 7676 EP 7683 DI 10.1158/1078-0432.CCR-09-0420 PG 8 WC Oncology SC Oncology GA 533VM UT WOS:000272853500029 PM 19996215 ER PT J AU Ziakas, PD Mylonakis, E AF Ziakas, Panayiotis D. Mylonakis, Eleftherios TI 4 Months of Rifampin Compared with 9 Months of Isoniazid for the Management of Latent Tuberculosis Infection: A Meta-analysis and Cost-Effectiveness Study That Focuses on Compliance and Liver Toxicity SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; TREATMENT COMPLETION; PREVENTIVE THERAPY; DRUG-RESISTANCE; ADVERSE EVENTS; HEPATOTOXICITY; PYRAZINAMIDE; EPIDEMIOLOGY; HOMELESS; REGIMENS AB Background. One-third of the world's population is infected with tuberculosis, and 9 months of isoniazid monotherapy is the treatment of choice for latent tuberculosis infection. However, this approach has been associated with hepatotoxicity and poor compliance. A shorter (4-month) rifampin regimen has been evaluated in recent clinical trials. Methods. We performed a meta-analysis of the published studies to compare compliance, toxicity, and cost-effectiveness between the 2 strategies. Pooled effects were calculated as risk ratios (RRs) by means of random-effects and fixed-effects models. Results. Pooled data from 3586 patients suggested that 4-month rifampin therapy was associated with a significant reduction in the risk of noncompletion (RR for random-effects model, 0.53; 95% confidence interval [CI], 0.44-0.63). Noncompletion rates were lower among patients who received 4-month rifampin therapy (range, 8.6%-28.4%), compared with noncompletion rates among patients who received 9-month isoniazid therapy (range, 24.1%-47.4%). Also, rates of hepatotoxicity (defined as grade 3 or 4 liver failure leading to drug discontinuation) were lower for patients who received 4-month rifampin therapy (range, 0%-0.7%), compared with the corresponding rates for patients who received 9-month isoniazid therapy (range, 1.4%-5.2%), and rifampin was associated with significant reduction in the risk of hepatotoxicity (RR for fixed-effects model, 0.12; 95% CI, 0.05-0.30). Notably, with the data from our meta-analysis, we calculated that the 4-month rifampin strategy is also cost-effective and results in $213 savings per patient treated ($90/patient when doctor fees are not included). Conclusions. The improved compliance, safety, and cost associated with the 4-month rifampin therapy suggest that the efficacy of this approach needs to be evaluated in detail. An extended posttreatment follow-up in future studies will clarify the unresolved issue of tuberculosis reactivation rates. C1 [Ziakas, Panayiotis D.; Mylonakis, Eleftherios] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Ziakas, Panayiotis D.] Univ Athens, Sch Med, Dept Hematol, GR-10679 Athens, Greece. RP Mylonakis, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, 55 Fruit St,Gray Jackson 5,Rm GRJ 504, Boston, MA 02114 USA. EM emylonakis@partners.org FU Astellas Pharma FX Potential conflicts of interest. E. M. is a member of the speakers' bureau for Pfizer and has received research funding from Astellas Pharma. P. D. Z.: no conflicts. NR 39 TC 49 Z9 53 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2009 VL 49 IS 12 BP 1883 EP 1889 DI 10.1086/647944 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 523KA UT WOS:000272070800017 PM 19911936 ER PT J AU Ciaranello, AL Chang, YC Margulis, AV Bernstein, A Bassett, IV Losina, E Walensky, RP AF Ciaranello, Andrea L. Chang, Yuchiao Margulis, Andrea V. Bernstein, Adam Bassett, Ingrid V. Losina, Elena Walensky, Rochelle P. TI Effectiveness of Pediatric Antiretroviral Therapy in Resource-Limited Settings: A Systematic Review and Meta-analysis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED CHILDREN; CD4 CELL RESPONSE; HIV-1-INFECTED CHILDREN; OPPORTUNISTIC INFECTIONS; CLINICAL-OUTCOMES; INCOME COUNTRIES; UNITED-KINGDOM; FOLLOW-UP; HAART; MORTALITY AB Background. Responses to antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected children in resource-limited settings have recently been reported, but outcomes vary. We sought to derive pooled estimates of the 12-month rate of virologic suppression (HIV RNA, <400 copies/mL) and gain in CD4 cell percentage (Delta CD4%) for children initiating ART in resource-limited settings. Methods. We conducted a systematic review and meta-analysis of published reports of HIV RNA and CD4 outcomes for treatment-naive children aged 0-17 years old by means of the Medline, EMBASE (Excerpta Medica Database), and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the Cochrane Clinical Trials Register. Pooled estimates of the reported proportion with HIV RNA <400 copies/mL and Delta CD4% after 12 months of ART were derived using patient-level estimates and fixed-and random-effects models. To approximate intention-to-treat analyses, in sensitivity analyses children with missing 12-month data were assumed to have HIV RNA>400 copies/mL or Delta CD4% of zero. Results. In patient-level estimates after 12 months of ART, the pooled proportion with virologic suppression was 70% (95% confidence interval [CI], 67%-73%); the pooled Delta CD4% was 13.7% (95% CI, 11.8%-15.7%). Results from the fixed-and random-effects models were similar. In approximated intention-to-treat analyses, the pooled estimates decreased to 53% with virologic suppression (95% CI, 50%-55%) and to a Delta CD4% of 8.5% (95% CI, 5.5%-11.4%). Conclusions. Pooled estimates of reported virologic and immunologic benefits after 12 months of ART among HIV-infected children in resource-limited settings are comparable with those observed among children in developed settings. Consistency in reporting on reasons for missing data will aid in the evaluation of ART outcomes in resource-limited settings. C1 [Ciaranello, Andrea L.; Bassett, Ingrid V.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Chang, Yuchiao; Bassett, Ingrid V.; Losina, Elena; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Margulis, Andrea V.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bernstein, Adam] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Walensky, Rochelle P.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. RP Ciaranello, AL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM aciaranello@partners.org RI Margulis, Andrea/G-2833-2013; OI Margulis, Andrea/0000-0001-7388-6082; Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Allergy and Infectious Disease [T32 AI07433, R01 AI058736, R37 AI420061, K23 AI068458, P30 AI 60354]; National Institute of Diabetes and Digestive and Kidney Diseases [T32 DK07703]; Harvard School of Public Health Pharmacoepidemiology Program Training Fund; Doris Duke Charitable Foundation; Elizabeth Glaser Pediatric AIDS Foundation FX Financial support. National Institute of Allergy and Infectious Disease (T32 AI07433 to A. L. C.; R01 AI058736 to A. L. C., E. L., and R. P. W.; R37 AI420061 to A. L. C., E. L., and R. P. W.; K23 AI068458 to I. V. B.; and P30 AI 60354 to A. L. C., Y. C., and E. L.); the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK07703 to A. B.); the Harvard School of Public Health Pharmacoepidemiology Program Training Fund (to A. V. M.); the Doris Duke Charitable Foundation (Clinical Scientist Development Award to R. P. W.); and the Elizabeth Glaser Pediatric AIDS Foundation (to A. L. C. and R. P. W.). NR 55 TC 60 Z9 60 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2009 VL 49 IS 12 BP 1915 EP 1927 DI 10.1086/648079 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 523KA UT WOS:000272070800023 PM 19916798 ER PT J AU Delous, M Hellman, NE Gaude, HM Silbermann, F Le Bivic, A Salomon, R Antignac, C Saunier, S AF Delous, Marion Hellman, Nathan E. Gaude, Helori-Mael Silbermann, Flora Le Bivic, Andre Salomon, Remi Antignac, Corinne Saunier, Sophie TI Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6 SO HUMAN MOLECULAR GENETICS LA English DT Article ID CELL POLARITY; JUVENILE NEPHRONOPHTHISIS; LENTIVIRUS VECTOR; TIGHT JUNCTIONS; PRIMARY CILIA; TGF-BETA; INTERACTS; DISEASE; GENE; MUTATIONS AB Nephronophthisis (NPH) is an autosomal recessive disorder characterized by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end-stage renal failure. The disease is caused by mutations in NPHP1-9 genes, which encode the nephrocystins, proteins localized to cell-cell junctions and centrosome/primary cilia. Here, we show that nephrocystin mRNA expression is dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation and disorganized multi-lumen structures when grown in a three-dimensional collagen matrix. Some of these phenotypes are similar to those reported for cells depleted of the TJ proteins PALS1 or Par3, and interestingly, we demonstrate a physical interaction between these nephrocystins and PALS1 as well as their partners PATJ and Par6 and show their partial co-localization in human renal tubules. Taken together, these results demonstrate that the nephrocystins play an essential role in epithelial cell organization, suggesting a plausible mechanism by which the in vivo histopathologic features of NPH might develop. C1 [Delous, Marion; Hellman, Nathan E.; Gaude, Helori-Mael; Silbermann, Flora; Salomon, Remi; Antignac, Corinne; Saunier, Sophie] INSERM, Hop Necker Enfants Malad, U574, F-75015 Paris, France. [Delous, Marion; Hellman, Nathan E.; Gaude, Helori-Mael; Silbermann, Flora; Salomon, Remi; Antignac, Corinne; Saunier, Sophie] Univ Paris 05, Paris, France. [Hellman, Nathan E.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA USA. [Le Bivic, Andre] CNRS, Fac Sci Luminy, IBDML, LNCC,Equipe Iabellisee,UMR6216, Marseille, France. [Antignac, Corinne] Hop Necker Enfants Malad, Dept Genet, AP HP, Paris, France. RP Saunier, S (reprint author), INSERM, Hop Necker Enfants Malad, U574, 149 Rue Sevres, F-75015 Paris, France. EM sophie.saunier@inserm.fr FU Institut National de la Sante et de la Recherche Me dicale (INSERM); Ministere de l'Education Nationale de la Recherche et de la Technologie (MRT); Fondation pour la Recherche Medicale (FRM) [DEQ20071210558]; Association pour l'Utilisation du Rein Artificiel (AURA); Agence National de la Recherche (ANR) [R07089KS]; Fulbright grant; Centre National de la Recherche Scientifique (CNRS); French National Agency (ANR Crumbs); 'Equipe labellise e par la Ligue Nationale contre le Cancer'; Universite Paris Descartes FX This work was supported by the Institut National de la Sante et de la Recherche Me dicale (INSERM), the Ministere de l'Education Nationale de la Recherche et de la Technologie (MRT), the Fondation pour la Recherche Medicale (FRM, PhD grant of M. D.; S. S. is laureate of the 'Equipe FRM' grant DEQ20071210558), the Association pour l'Utilisation du Rein Artificiel (AURA) and the Agence National de la Recherche (ANR, S. S. and R. S. grant R07089KS). N. E. H. was the recipient of a Fulbright grant. A. L. B. is supported by Centre National de la Recherche Scientifique (CNRS) and by the French National Agency (ANR Crumbs) and is a 'Equipe labellise e par la Ligue Nationale contre le Cancer'. Funding to pay the Open Access publication charges for this article was provided by Universite Paris Descartes. NR 33 TC 42 Z9 42 U1 1 U2 2 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 DEC 15 PY 2009 VL 18 IS 24 BP 4711 EP 4723 DI 10.1093/hmg/ddp434 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 523ME UT WOS:000272077200003 PM 19755384 ER PT J AU Murnane, MJ Cai, JG Shuja, S McAneny, D Klepeis, V Willett, JB AF Murnane, Mary Jo Cai, Jinguo Shuja, Sania McAneny, David Klepeis, Veronica Willett, John B. TI Active MMP-2 effectively identifies the presence of colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer diagnosis; colorectal carcinomas; active MMP-2 ID GELATINASE-A MMP-2; HUMAN COLON-CANCER; MATRIX METALLOPROTEINASES; IV COLLAGENASES; PROGNOSTIC-SIGNIFICANCE; ENHANCED PRODUCTION; TISSUE INHIBITORS; ACTIVATION; EXPRESSION; METASTASIS AB Fully active MMP-2 is expressed at such low levels in human tissues that studies often fail to confirm its value as a cancer marker despite strong associations with malignancy. Our study utilized careful extraction, accurate activity measurements, standardization to purified controls and a new statistical metric to determine whether active MMP-2 is an effective indicator of colorectal cancer compared to pro-MMP-2 or pro-MMP-9. MMP-2 and MMP-9 activities were analyzed in matched normal and cancer samples from 269 patients by gelatin zymography, computer-assisted image analysis, serial dilutions of strong samples and standardization to controls. An index of effect size was designed for comparative evaluation of active MMP-2, pro-MMP-2 and pro-MMP-9 activities. For each gelatinase, mean activity and protein levels/mg soluble protein in normal mucosa and colorectal cancer were calculated for the first time with respect to commercial standards. Active MMP-2 activity, detected in 99% of colorectal cancers, was higher in 95% of cancers (on average 10-fold) than in normal mucosa. Levels of pro-MMP-2 and pro-MMP-9, but not active MMP-9, activities were also significantly higher in cancers versus normal. However, active MMP-2 activity provided the most effective test for the presence of cancer (p < 0.0.0001) with an effect size statistically significantly larger than for either pro-MMP-2 or pro-MMP-9. Receiver operating characteristic (ROC) curves demonstrated that a cut-off for active MMP-2 of >44 SDU activity/mg soluble protein (>180 pg/mg), which is three times mean normal levels, would permit detection of colorectal cancer with an estimated sensitivity of 84% and estimated specificity of 93%. (C) 2009 UICC C1 [Murnane, Mary Jo; Cai, Jinguo] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Murnane, Mary Jo] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Shuja, Sania] Univ Florida, Coll Med, Dept Pathol, Jacksonville, FL USA. [McAneny, David] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Klepeis, Veronica] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Willett, John B.] Harvard Univ, Grad Sch Educ, Cambridge, MA 02138 USA. RP Murnane, MJ (reprint author), Boston Univ, Sch Med, Dept Pathol & Lab Med, 670 Albany St,4th Floor, Boston, MA 02118 USA. EM mmurnane@bu.edu OI McAneny, David/0000-0002-6405-0424; Willett, John/0000-0001-7183-350X FU NIH [R21 CA81515, R21 CA100837]; Cancer Research and Prevention Foundation FX Grant sponsor: NIH: Grant numbers: R21 CA81515, R21 CA100837; Grant sponsor: Cancer Research and Prevention Foundation. NR 47 TC 20 Z9 22 U1 7 U2 14 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2009 VL 125 IS 12 BP 2893 EP 2902 DI 10.1002/ijc.24682 PG 10 WC Oncology SC Oncology GA 523CJ UT WOS:000272049000018 PM 19551856 ER PT J AU Pantaleo, MA Astolfi, A Di Battista, M Heinrich, MC Paterini, P Scotlandi, K Santini, D Catena, F Manara, MC Nannini, M Maleddu, A Saponara, M Lolli, C Formica, S Biasco, G AF Pantaleo, Maria A. Astolfi, Annalisa Di Battista, Monica Heinrich, Michael C. Paterini, Paola Scotlandi, Katia Santini, Donatella Catena, Fausto Manara, Maria C. Nannini, Margherita Maleddu, Alessandra Saponara, Maristella Lolli, Cristian Formica, Serena Biasco, Guido TI Insulin-like growth factor 1 receptor expression in wild-type GISTs: A potential novel therapeutic target SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gastrointestinal stromal tumours; insulin-like growth factor 1 receptor; KIT receptor; PDGFRA ID GASTROINTESTINAL STROMAL TUMORS; MUTATIONS; PATHWAY; DISEASE; CANCER AB Aberrations of the Insulin-like Growth Factor (IGF) system have been found in association with a variety of cancer types. The potential role of IGF1R has been postulated in a small subset of GISTs, but until now the implications of its aberrations have not been defined. The aim of the study was to examine the IGF1R status in patients with gastric GIST in regard to KIT and PDGFRA genotype. Fresh resection specimens were collected from 8 primary tumours [2 wild-type (WT) and 6 mutant cases]. IGF1R was studied as gene expression profiling with Affymetrix GeneChip HG-U133Plus 2.0 arrays and as genomic copy number with SNP array analysis Affymetrix Genome Wide Human SNP 6.0 arrays, and at protein level with western blotting (WB) and immunohistochemistry (IHC). The unsupervised analysis of gene expression profiling of our patients merged with a data set from gastric GISTs identified 2 patients out of 8 with different expression of IGF1R. The data were confirmed by WB and IHC. In particular, IGF1R was upregulated in 2 young patients (<30-years old), who had both WT disease and metastases at diagnosis. The SNP array analysis showed that none of the tumours had IGF1R amplification. GISTs are characterized by abnormalities of the KIT and PDGFRA receptors that affect prognosis and response to tyrosine kinase inhibitors. Both young adult with WT GIST had the overexpression of IGF1R at mRNA and protein level. These results further confirm the hypothesis that IGF1R may be a potential therapeutic target in GISTs lacking KIT and PDGFRA mutations. (C) 2009 UICC C1 [Pantaleo, Maria A.; Di Battista, Monica; Nannini, Margherita; Maleddu, Alessandra; Saponara, Maristella; Lolli, Cristian; Biasco, Guido] Univ Bologna, St Orsola Malpighi Hosp, Dept Hematol & Oncol Sci LA Seragnoli, I-40138 Bologna, Italy. [Pantaleo, Maria A.; Astolfi, Annalisa; Paterini, Paola; Formica, Serena; Biasco, Guido] Univ Bologna, Interdept Ctr Canc Res G Prodi, I-40138 Bologna, Italy. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Dept Med, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Scotlandi, Katia; Manara, Maria C.] Ist Ortoped Rizzoli, Lab Ric Oncol, CRS Sviluppo Terapie Biomol, Bologna, Italy. [Santini, Donatella] Univ Bologna, St Orsola Malpighi Hosp, Pathol Unit, I-40138 Bologna, Italy. [Catena, Fausto] Univ Bologna, St Orsola Malpighi Hosp, Emergency Surg & Transplant Dept, I-40138 Bologna, Italy. RP Pantaleo, MA (reprint author), Univ Bologna, St Orsola Malpighi Hosp, Dept Hematol & Oncol Sci LA Seragnoli, Via Massarenti 9, I-40138 Bologna, Italy. EM maria.pantaleo@unibo.it RI Saponara, Maristella/J-9904-2016; nannini, margherita/J-9866-2016; OI Saponara, Maristella/0000-0003-0715-171X; PANTALEO, MARIA ABBONDANZA/0000-0002-0177-6957; NANNINI, MARGHERITA/0000-0002-2103-1960; astolfi, annalisa/0000-0002-2732-0747 FU Fondazione Cassa di Risparmio of Bologna (CARISBO); Vanini-Cavagnino (Interdepartmental Centre for Cancer Research "G. Prodi"); University of Bologna, Italy FX Grant sponsors: Fondazione Cassa di Risparmio of Bologna (CARISBO), Vanini-Cavagnino (Interdepartmental Centre for Cancer Research "G. Prodi"), University of Bologna, Italy. NR 16 TC 51 Z9 53 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2009 VL 125 IS 12 BP 2991 EP 2994 DI 10.1002/ijc.24595 PG 4 WC Oncology SC Oncology GA 523CJ UT WOS:000272049000030 PM 19672856 ER PT J AU Wang, R Lagakos, SW AF Wang, Rui Lagakos, Stephen W. TI On the Use of Adjusted Cross-Sectional Estimators of HIV Incidence SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE BED; detuned ELISA; sensitive/less sensitive tests ID CAPTURE ENZYME-IMMUNOASSAY; INCIDENCE RATES; INFECTION; ANTIBODIES; STRATEGY; AFRICA; TESTS AB Objective: To elucidate when and how cross-sectional estimators of HIV incidence rates based on a sensitive and less sensitive diagnostic test should be adjusted. Methods: Evaluate the statistical properties of unadjusted and adjusted cross-sectional estimators of HIV incidence, including the adjusted estimators considered by McDougal et al, for the 2 settings where (a) all infected subjects eventually become reactive to the less sensitive test, and (b) a subset of infected subjects indefinitely remain nonreactive to the less sensitive test. Derive the maximum likelihood estimator of incidence for the latter setting and use analytical results and simulation studies to compare the performance of the various estimators. Results: When every infected subject would eventually become reactive to the less sensitive test, the McDougal adjusted estimator is uniformly less precise than the unadjusted estimator and more susceptible to bias. When a subset of the infected population would indefinitely remain nonreactive to the less sensitive test, the McDougal adjusted estimator is less precise than the maximum likelihood estimator, which coincides with an estimator developed by McWalter and Welte using a mathematical modeling approach. When the assumed model is incorrect, the unadjusted estimator overestimates incidence, whereas the maximum likelihood estimator can be biased in either direction. Conclusions: The standard unadjusted cross-sectional estimator of HIV incidence should be used when all infected individuals would eventually become reactive to the less sensitive test. When a subset of individuals would indefinitely remain nonreactive to the less sensitive test, the maximum likelihood estimator for this setting should be used. Characterizing the proportion of individuals who would indefinitely remain nonreactive is crucial for accurate estimation of HIV incidence. C1 [Wang, Rui; Lagakos, Stephen W.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wang, Rui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Wang, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM rwang@hsph.harvard.edu FU National Institutes of Health [AI24643] FX Supported by grant AI24643 from the National Institutes of Health. NR 18 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2009 VL 52 IS 5 BP 538 EP 547 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 526SO UT WOS:000272314100002 PM 19881357 ER PT J AU Izard, J Renken, C Hsieh, CE Desrosiers, DC Dunham-Ems, S La Vake, C Gebhardt, LL Limberger, RJ Cox, DL Marko, M Radolf, JD AF Izard, Jacques Renken, Christian Hsieh, Chyong-Ere Desrosiers, Daniel C. Dunham-Ems, Star La Vake, Carson Gebhardt, Linda L. Limberger, Ronald J. Cox, David L. Marko, Michael Radolf, Justin D. TI Cryo-Electron Tomography Elucidates the Molecular Architecture of Treponema pallidum, the Syphilis Spirochete SO JOURNAL OF BACTERIOLOGY LA English DT Review ID OUTER-MEMBRANE PROTEINS; FRACTURE ELECTRON-MICROSCOPY; BORRELIA-BURGDORFERI LIPOPROTEINS; FILAMENT-DEFICIENT MUTANT; LIMITED SURFACE EXPOSURE; LYME-DISEASE SPIROCHETE; GRAM-NEGATIVE BACTERIA; PERIPLASMIC FLAGELLA; ESCHERICHIA-COLI; BINDING PROTEINS AB Cryo-electron tomography (CET) was used to examine the native cellular organization of Treponema pallidum, the syphilis spirochete. T. pallidum cells appeared to form flat waves, did not contain an outer coat and, except for bulges over the basal bodies and widening in the vicinity of flagellar filaments, displayed a uniform periplasmic space. Although the outer membrane (OM) generally was smooth in contour, OM extrusions and blebs frequently were observed, highlighting the structure's fluidity and lack of attachment to underlying periplasmic constituents. Cytoplasmic filaments converged from their attachment points opposite the basal bodies to form arrays that ran roughly parallel to the flagellar filaments along the inner surface of the cytoplasmic membrane (CM). Motile treponemes stably attached to rabbit epithelial cells predominantly via their tips. CET revealed that T. pallidum cell ends have a complex morphology and assume at least four distinct morphotypes. Images of dividing treponemes and organisms shedding cell envelope-derived blebs provided evidence for the spirochete's complex membrane biology. In the regions without flagellar filaments, peptidoglycan (PG) was visualized as a thin layer that divided the periplasmic space into zones of higher and lower electron densities adjacent to the CM and OM, respectively. Flagellar filaments were observed overlying the PG layer, while image modeling placed the PG-basal body contact site in the vicinity of the stator-P-collar junction. Bioinformatics and homology modeling indicated that the MotB proteins of T. pallidum, Treponema denticola, and Borrelia burgdorferi have membrane topologies and PG binding sites highly similar to those of their well-characterized Escherichia coli and Helicobacter pylori orthologs. Collectively, our results help to clarify fundamental differences in cell envelope ultrastructure between spirochetes and gram-negative bacteria. They also confirm that PG stabilizes the flagellar motor and enable us to propose that in most spirochetes motility results from rotation of the flagellar filaments against the PG. C1 [Desrosiers, Daniel C.; Dunham-Ems, Star; La Vake, Carson; Radolf, Justin D.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06030 USA. [Radolf, Justin D.] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Izard, Jacques] Forsyth Inst, Dept Mol Genet, Boston, MA 02135 USA. [Izard, Jacques] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Renken, Christian; Hsieh, Chyong-Ere; Gebhardt, Linda L.; Limberger, Ronald J.; Marko, Michael] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Cox, David L.] Ctr Dis Control & Prevent, Div STD Prevent, Lab Reference & Res Branch, Atlanta, GA 30333 USA. RP Radolf, JD (reprint author), Univ Connecticut, Ctr Hlth, Dept Med, 263 Farmington Ave, Farmington, CT 06030 USA. EM JRadolf@up.uchc.edu RI Izard, Jacques/A-6074-2012; OI Izard, Jacques/0000-0002-5904-5436 FU NIH [AI-26756, DE017106]; NIH-NICRR [P41 RR01212] FX This work was supported by NIH grants AI-26756 (J.D.R.) and DE017106 (J.I.) and by NIH-NICRR grant P41 RR01212, which supports the Wadsworth Center's Resource for Biological Complexity as a national biotechnological resource. NR 125 TC 40 Z9 41 U1 1 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD DEC 15 PY 2009 VL 191 IS 24 BP 7566 EP 7580 DI 10.1128/JB.01031-09 PG 15 WC Microbiology SC Microbiology GA 522WI UT WOS:000272030400020 PM 19820083 ER PT J AU Pomerantseva, I Krebs, N Hart, A Neville, CM Huang, AY Sundback, CA AF Pomerantseva, Irina Krebs, Nicholas Hart, Alison Neville, Craig M. Huang, Albert Y. Sundback, Cathryn A. TI Degradation behavior of poly(glycerol sebacate) SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE degradation; enzyme; mechanical properties; elastomer; lipase ID EPSILON-CAPROLACTONE POLYMER; NERVE GUIDE; BIODEGRADABLE ELASTOMER; IN-VITRO; TISSUE; CYTOCOMPATIBILITY; COPOLYMERS; PUTRESCINE; SCAFFOLDS; CARBONATE AB Poly(glycerol sebacate) (PGS), a promising scaffold material for soft tissue engineering applications, is a soft, tough elastomer with excellent biocompatibility. However, the rapid in vivo degradation rate of PGS limits its use as a scaffold material. To determine the impact of crosslink density on degradation rate, a family of PGS materials was synthesized by incrementally increasing the curing time from 42 to 144 h, at 120 degrees C and 10 mTorr vacuum. As expected, PGS became a stiffer, tougher, and stronger elastomer with increasing curing time. PGS disks were Subcutaneously implanted into rats and periodically harvested only mild tissue responses were observed and the biocompatibility remained excellent. Regardless of crosslink density, surface erosion degradation was observed. The sample dimensions linearly decreased with implantation time, and the mass loss rates were constant after 1-week implantation. As surface erosion degradation frequently correlates with enzymatic digestion, parallel in vitro digestion studies were conducted in lipase solutions which hydrolyze ester bonds. Enzymatic digestion played a significant role in degrading PGS, and the mass-loss rates were not a function of curing time. Alternative chemistry approaches will be required to decrease the enzymatic hydrolysis rate of the ester bonds in PGS polymers. (C) 2008 Wiley Periodicals, Inc. J Biomed Mater Res 91A: 1038-1047, 2009 C1 [Pomerantseva, Irina; Krebs, Nicholas; Hart, Alison; Neville, Craig M.; Huang, Albert Y.; Sundback, Cathryn A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. RP Sundback, CA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, CPZN 4809,185 Cambridge St, Boston, MA 02114 USA. EM csundback@partners.org FU Center for Integration of Medicine and Innovative Technology (CIMIT) FX Contract grant sponsor: Center for Integration of Medicine and Innovative Technology (CIMIT) NR 23 TC 59 Z9 60 U1 4 U2 33 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1549-3296 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD DEC 15 PY 2009 VL 91A IS 4 BP 1038 EP 1047 DI 10.1002/jbm.a.32327 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 525EN UT WOS:000272196900010 PM 19107788 ER PT J AU Ali, M Auger, RR Slocumb, NL Morgenthaler, TI AF Ali, Mohsin Auger, R. Robert Slocumb, Nancy L. Morgenthaler, Timothy I. TI Idiopathic Hypersomnia: Clinical Features and Response to Treatment SO JOURNAL OF CLINICAL SLEEP MEDICINE LA English DT Article DE Idiopathic hypersomnia; treatment; modafinil; methylphenidate; stimulants ID CENTRAL ORIGIN; NARCOLEPSY AB Objective: A recent American Academy of Sleep Medicine publication identified a need for research regarding idiopathic hypersomnia. We describe various clinical and polysomnographic features of patients with idiopathic hypersomnia, with an emphasis on response to pharmacotherapy. Methods: A retrospective review of our database initially identified 997 patients, utilizing "idiopathic hypersomnia," "hypersomnia NOS," and "primary hypersomnia" as keywords. The charts of eligible patients were examined in detail, and data were abstracted and analyzed. Response to treatment was graded utilizing an internally developed scale. Results: Eighty-five patients were ultimately identified (65% female). Median (interquartile range) ages of onset and diagnosis were 19.6 (15.5) and 33.7 (15.5), respectively. During a median follow-up duration of 2.4 (4.7) years, 65% of patients demonstrated a "complete response" to phamnacotherapy as assessed by the authors' grading schema. Methylphenidate was most commonly used as a first-line agent prior to December 1998, but subsequently, modafinil became the most common first drug. At the last recorded follow-up visit, 92% of patients were on monotherapy, with greater representation of methylphenidate versus modafinil (51% vs. 32%). Among these patients, methylphenidate produced a higher percentage of "complete" or "partial" responses than modafinil, although statistical significance was not reached (38/40 [95%] vs 22/25 [88%], respectively, p = 0.291). Conclusions: The majority of patients with idiopathic hypersomnia respond well to treatment. Methylphenidate is chosen more often than modafinil as final monotherapy in the treatment of idiopathic hypersomnia, despite the fact that it is less commonly used initially. Further prospective comparisons of medications should be explored. C1 [Auger, R. Robert; Slocumb, Nancy L.; Morgenthaler, Timothy I.] Mayo Clin, Ctr Sleep Med, Rochester, MN USA. [Auger, R. Robert] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Morgenthaler, Timothy I.] Mayo Clin, Dept Internal Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Ali, Mohsin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ali, Mohsin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Morgenthaler, TI (reprint author), Mayo Ctr Sleep Med, Gonda 17W,200 1st St SW, Rochester, MN 55905 USA. EM tmorgenthaler@mayo.edu OI Morgenthaler, Timothy/0000-0002-2614-3793 NR 13 TC 29 Z9 29 U1 0 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 1550-9389 J9 J CLIN SLEEP MED JI J. Clin. Sleep Med. PD DEC 15 PY 2009 VL 5 IS 6 BP 562 EP 568 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 532WG UT WOS:000272780400012 PM 20465024 ER PT J AU Li, JM Southerland, LT Lu, Y Darlak, KA Giver, CR McMillin, DW Harris, WAC Jaye, DL Waller, EK AF Li, Jian-Ming Southerland, Lauren T. Lu, Ying Darlak, Kataryna A. Giver, Cynthia R. McMillin, Douglas W. Harris, Wayne A. C. Jaye, David L. Waller, Edmund K. TI Activation, Immune Polarization, and Graft-versus-Leukemia Activity of Donor T Cells Are Regulated by Specific Subsets of Donor Bone Marrow Antigen-Presenting Cells in Allogeneic Hemopoietic Stem Cell Transplantation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; COLONY-STIMULATING FACTOR; HOST-DISEASE; IN-VIVO; ADAPTIVE IMMUNITY; LANGERHANS CELLS; LYMPHOID ORGANS; MOUSE; RESPONSES; PRECURSORS AB We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage(-)CD11c(+) APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage(-)CD11c(+)CD11b(-) APC (CD11b(-) APC) in combination with c-kit(+)Sca-1(+)lineage(-) hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4(+) and CD8(+) T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage(-)CD11c(+)CD11b(+) APCs (CD11b(+) APC), or grafts containing only HSC and T cells. Transplanting CD11b(-) APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b(+) APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b- APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1(+)) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b(+) APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity. The Journal of Immunology, 2009, 183: 7799-7809. C1 [Waller, Edmund K.] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol Oncol, Atlanta, GA 30322 USA. [Southerland, Lauren T.] Duke Univ, Sch Med, Durham, NC 27710 USA. [McMillin, Douglas W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jaye, David L.] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. RP Waller, EK (reprint author), Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol Oncol, 1365C Clifton Rd NE,Room C4002, Atlanta, GA 30322 USA. EM ewaller@emory.edu FU National Institute of Health [R01 CA-74364-03, NHLBI P01HI086773]; National Marrow Donor Program; SuperGen Corporation; When Everyone Survives Foundation, Inc. FX This work was supported by National Institute of Health Grants R01 CA-74364-03 (to E.K.W.) and NHLBI P01HI086773 (to C.D.H. and E.K.W.) and an Amy Strelzer Manasevit fellowship sponsored by the National Marrow Donor Program and the SuperGen Corporation and a research fund from When Everyone Survives Foundation, Inc. (J.-M.L.). NR 63 TC 16 Z9 18 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 7799 EP 7809 DI 10.4049/jimmunol.0900155 PG 11 WC Immunology SC Immunology GA 533YE UT WOS:000272861300023 PM 19933853 ER PT J AU Currie, AJ Prosser, A McDonnell, A Cleaver, AL Robinson, BWS Freeman, GJ van der Most, RG AF Currie, Andrew J. Prosser, Amy McDonnell, Alison Cleaver, Amanda L. Robinson, Bruce W. S. Freeman, Gordon J. van der Most, Robbert G. TI Dual Control of Antitumor CD8 T Cells through the Programmed Death-1/Programmed Death-Ligand 1 Pathway and Immunosuppressive CD4 T Cells: Regulation and Counterregulation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; TUMOR-SPECIFIC CD8; IN-VIVO; DENDRITIC CELLS; INDUCIBLE COSTIMULATOR; SOLID TUMORS; EFFECTOR; EXPRESSION; RESPONSES; PD-1 AB Tumors have evolved multiple mechanisms to evade immune destruction. One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1; B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. However, PD-L1 blockade only marginally affected tumor growth and was associated with the emergence of activated programmed death-1(+) ICOS(+) CD4 T cells in tumor-draining lymph nodes, whereas few activated CD8 T cells were present. Full activation of antitumor CD8 T cells, characterized as programmed death-1(+) ICOS(+) Ki-67(+) and displaying CTL activity, was only observed when CD4 T cells were depleted, suggesting that a population of suppressive CD4 T cells exists. ICOS(+) foxp3(+) regulatory T cells were found to be regulated through PD-L1, identifying one potentially suppressive CD4 T cell population. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies. The Journal of Immunology, 2009, 183: 7898-7908. C1 [Currie, Andrew J.; Prosser, Amy; McDonnell, Alison; Cleaver, Amanda L.; Robinson, Bruce W. S.; van der Most, Robbert G.] Univ Western Australia, Natl Ctr Asbestos Related Dis, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP van der Most, RG (reprint author), GSK Biol, Rue Inst 89, B-1330 Rixensart, Belgium. EM robbertvdm@gmail.com RI Flow, CMCA/C-4191-2013; Robinson, Bruce/N-1900-2014; Currie, Andrew/C-2778-2015 FU Raine Medical Research Foundation, Perth, Australia FX This work was supported by a priming grant from the Raine Medical Research Foundation, Perth, Australia (to R.G.V.M.). NR 44 TC 24 Z9 24 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 DEC 15 PY 2009 VL 183 IS 12 BP 7898 EP 7908 DI 10.4049/jimmunol.0901060 PG 11 WC Immunology SC Immunology GA 533YE UT WOS:000272861300034 PM 20007574 ER PT J AU Akilov, OE Ustyugova, IV Zhi, L Hasan, T Wu, MX AF Akilov, Oleg E. Ustyugova, Irina V. Zhi, Liang Hasan, Tayyaba Wu, Mei X. TI Enhanced Susceptibility to Leishmania Infection in Resistant Mice in the Absence of Immediate Early Response Gene X-1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; NECROSIS-FACTOR-ALPHA; DEPENDENT KILLING MECHANISM; CUTANEOUS LEISHMANIASIS; MAJOR INFECTION; NITRIC-OXIDE; BALB/C MICE; ACTIVATED MACROPHAGES; NATURAL MODEL; IFN-GAMMA AB Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both gamma delta T and CD4(+) cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-alpha production in both macrophages and T cells, resulting in a high intralesional load, of parasites-and delayed healing of the lesion, both of which were reversed by TNF-alpha treatment. These findings indicate the crucial role of IL-17 and TNF-alpha in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses. The Journal of Immunology, 2009, 183: 7994-8003. C1 [Akilov, Oleg E.; Ustyugova, Irina V.; Zhi, Liang; Hasan, Tayyaba; Wu, Mei X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Akilov, OE (reprint author), Univ Pittsburgh, Dept Dermatol, 200 Lothrop St,Presby S Tower,Suite 3880, Pittsburgh, PA 15213 USA. EM oea2@pitt.edu FU National Institutes of Health [AI050822, AI070785]; Department of Defense Medical Free Electron Laser Program [FA9550-04-1-0079] FX This work was supported by National Institutes of Health Grants AI050822 and AI070785 (to M.X.W.) and by Department of Defense Medical Free Electron Laser Program Grant FA9550-04-1-0079 (to T.H.). NR 44 TC 12 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 7994 EP 8003 DI 10.4049/jimmunol.0900866 PG 10 WC Immunology SC Immunology GA 533YE UT WOS:000272861300044 PM 19923449 ER PT J AU Strle, K Drouin, EE Shen, SQ El Khoury, J McHugh, G Ruzic-Sabljic, E Strle, F Steere, AC AF Strle, Klemen Drouin, Elise E. Shen, Shiqian El Khoury, Joseph McHugh, Gail Ruzic-Sabljic, Eva Strle, Franc Steere, Allen C. TI Borrelia burgdorferi Stimulates Macrophages to Secrete Higher Levels of Cytokines and Chemokines than Borrelia afzelii or Borrelia garinii SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CONFIRMED ERYTHEMA MIGRANS; EARLY LYME-DISEASE; SENSU-LATO; MESSENGER-RNA; SKIN; BLOOD; ACRODERMATITIS; ACTIVATION; EXPRESSION; RECEPTORS AB To delineate the inflammatory potential of the 3 pathogenic species of Borrelia burgdorferi sensu lato, we stimulated monocyte-derived macrophages from healthy human donors with 10 isolates each of B. burgdorferi, Borrelia afzelii, or Borrelia garinii recovered from erythema migrans skin lesions of patients with Lyme borreliosis from the United States or Slovenia. B. burgdorferi isolates from the United States induced macrophages to secrete significantly higher levels of interleukin (IL)-8, CCL3, CCL4, IL-6, IL-10, and tumor necrosis factor than B. garinii or B. afzelii isolates. Consistent with this response in cultured macrophages, chemokine and cytokine levels in serum samples of patients from whom the isolates were obtained were significantly greater in B. burgdorferi-infected patients than in B. afzelii-or B. garinii-infected patients. These results demonstrate in vitro and in vivo that B. burgdorferi has greater inflammatory potential than B. afzelii and B. garinii, which may account in part for variations in the clinical manifestations of Lyme borreliosis. C1 [Strle, Klemen; Drouin, Elise E.; Shen, Shiqian; El Khoury, Joseph; McHugh, Gail; Steere, Allen C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02114 USA. [El Khoury, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Ruzic-Sabljic, Eva] Univ Ljubljana, Inst Microbiol & Immunol, Ljubljana, Slovenia. [Strle, Franc] Univ Med Ctr Ljubljana, Dept Infect Dis, Ljubljana, Slovenia. RP Strle, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, 55 Fruit St,CNY149-8301, Boston, MA 02114 USA. EM kstrle@partners.org FU National Institutes of Health [AR-20358]; Centers for Disease Control and Prevention [CCU110291]; English, Bonter, Mitchell Foundation; Eshe Fund; Lyme/Arthritis Research Fund at Massachusetts General Hospital; Walter J. and Lille A. Berbecker Foundation; Ministry of Science and Technology of the Republic of Slovenia [Ministry of Science and Technology of the Republic of Slovenia (P30296] FX Financial support: The National Institutes of Health (AR-20358), the Centers for Disease Control and Prevention (CCU110291), the English, Bonter, Mitchell Foundation, the Eshe Fund, and the Lyme/Arthritis Research Fund at Massachusetts General Hospital. K. S. received support from a scholarship from the Walter J. and Lille A. Berbecker Foundation for the study of Lyme disease. F. S. received funding from the Ministry of Science and Technology of the Republic of Slovenia (P30296). NR 30 TC 36 Z9 36 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2009 VL 200 IS 12 BP 1936 EP 1943 DI 10.1086/648091 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 520UH UT WOS:000271874000018 PM 19909078 ER PT J AU Murphy, SA Cannon, CP Wiviott, SD McCabe, CH Braunwald, E AF Murphy, Sabina A. Cannon, Christopher P. Wiviott, Stephen D. McCabe, Carolyn H. Braunwald, Eugene TI Reduction in Recurrent Cardiovascular Events With Intensive Lipid-Lowering Statin Therapy Compared With Moderate Lipid-Lowering Statin Therapy After Acute Coronary Syndromes From the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE statin; acute coronary syndrome; lipid lowering; clinical trial ID C-REACTIVE PROTEIN; CHOLESTEROL; PARTICIPANTS; METAANALYSIS; PANEL AB Objectives In addition to reducing first events in patients after an acute coronary syndrome (ACS), we hypothesized that high-dose atorvastatin 80 mg would also reduce recurrent cardiovascular events, and therefore total events, compared with pravastatin 40 mg during the 2-year follow-up. Background In the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial, more intensive lipid lowering with high-dose atorvastatin reduced the first occurrence of the primary end point (death, myocardial infarction, unstable angina requiring rehospitalization, stroke, or revascularization >= 30 days) compared with moderate lipid lowering with pravastatin. Methods Poisson regression analysis was performed to compare the number of occurrences of the primary end point between high-dose atorvastatin and pravastatin in the PROVE IT-TIMI 22 trial. Results As previously reported, first primary end point events were reduced by 16% with atorvastatin 80 mg versus pravastatin 40 mg (n = 464 vs. n = 537, respectively; p = 0.005). Additional events were also reduced by 19% with atorvastatin 80 mg (n = 275 vs. n = 340, respectively; p = 0.009). Overall, there were 138 fewer primary efficacy events with atorvastatin 80 mg versus pravastatin 40 mg (n = 739 vs. n = 877, respectively; rate ratio: 0.85, 95% confidence interval: 0.77 to 0.94, p = 0.001). Conclusions Although analytic techniques commonly used in clinical outcomes trials censor patients who experience a component of the primary composite end point, total cardiovascular events are important to patients, clinicians, and health care payers. Maintaining low levels of low-density lipoprotein cholesterol is central to preventing additional atherosclerotic development and subsequent cardiovascular events. Atorvastatin 80 mg, a more intensive low-density lipoprotein cholesterol lowering agent, reduced both first and subsequent primary end point events compared with pravastatin 40 mg after ACS. (J Am Coll Cardiol 2009; 54: 2358-62) (C) 2009 by the American College of Cardiology Foundation C1 [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, TIMI Study Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, Dept Med, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org FU Bristol-Myers Squibb; Accumetrics; AstraZeneca; Bristol-Myers Squibb/Sanofi Partnership; GlaxoSmithKline; Intekrin Therapeutics; Merck; Merck/Schering-Plough Partnership; Novartis; Takeda FX The TIMI Study Group received research grants from Bristol-Myers Squibb to conduct the PROVE IT-TIMI 22 trial. Dr. Cannon receives research grants/support from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering-Plough Partnership, Novartis, and Takeda; and is a clinical advisor with equity in Automedics Medical Systems. Dr. Wiviott has received speaking honoraria from Pfizer, Merck, AstraZeneca, and Bristol-Myers Squibb; and consulting fees from Bristol-Myers Squibb. Dr. McCabe has received grant support from Bristol-Myers Squibb (for the PROVE IT trial) and Schering-Plough. Dr. Braunwald has received grant support from Bristol-Myers Squibb (for the PROVE IT-TIMI 22 trial), Schering-Plough, and Merck; and has received honoraria and is an advisory board member of Schering-Plough and Merck. NR 16 TC 69 Z9 75 U1 0 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 DEC 15 PY 2009 VL 54 IS 25 BP 2358 EP 2362 DI 10.1016/j.jacc.2009.10.005 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 532SA UT WOS:000272768600003 PM 20082923 ER PT J AU Matthews, KA Crawford, SL Chae, CU Everson-Rose, SA Sowers, MF Sternfeld, B Sutton-Tyrrell, K AF Matthews, Karen A. Crawford, Sybil L. Chae, Claudia U. Everson-Rose, Susan A. Sowers, Mary Fran Sternfeld, Barbara Sutton-Tyrrell, Kim TI Are Changes in Cardiovascular Disease Risk Factors in Midlife Women Due to Chronological Aging or to the Menopausal Transition? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE menopause; risk factors; lipids; inflammation; race ID CORONARY-HEART-DISEASE; HEALTHY WOMEN; NATION SWAN; AGE; POPULATION; STANDARDIZATION; PREMENOPAUSAL; CHOLESTEROL; HORMONE; WEIGHT AB Objectives This prospective study examined whether changes in traditional and novel coronary heart disease (CHD) risk factors are greater within a year of the final menstrual period (FMP), relative to changes that occur before or after that interval, in a multiethnic cohort. Background Understanding the influence of menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian samples. Methods SWAN (Study of Women's Health Across the Nation) is a prospective study of the menopausal transition in 3,302 minority (African American, Hispanic, Japanese, or Chinese) and Caucasian women. After 10 annual examinations, 1,054 women had achieved an FMP not due to surgery and without hormone therapy use before FMP. Measured CHD risk factors included lipids and lipoproteins, glucose, insulin, blood pressure, fibrinogen, and C-reactive protein. We assessed which of 2 models provided a better fit with the observed risk factor changes over time in relation to the FMP: a linear model, consistent with chronological aging, or a piecewise linear model, consistent with ovarian aging. Results Only total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B demonstrated substantial increases within the 1-year interval before and after the FMP, consistent with menopause-induced changes. This pattern was similar across ethnic groups. The other risk factors were consistent with a linear model, indicative of chronological aging. Conclusions Women experience a unique increase in lipids at the time of the FMP. Monitoring lipids in perimenopausal women should enhance primary prevention of CHD. (J Am Coll Cardiol 2009; 54: 2366-73) (C) 2009 by the American College of Cardiology Foundation C1 [Matthews, Karen A.] Univ Pittsburgh, Dept Psychiat & Psychol, Pittsburgh, PA 15213 USA. [Matthews, Karen A.; Sutton-Tyrrell, Kim] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Crawford, Sybil L.] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Biostat Res Grp, Worcester, MA USA. [Chae, Claudia U.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Chae, Claudia U.] Harvard Univ, Sch Med, Boston, MA USA. [Everson-Rose, Susan A.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Sowers, Mary Fran] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Sternfeld, Barbara] Kaiser Permanente, Div Res, Oakland, CA USA. RP Matthews, KA (reprint author), Univ Pittsburgh, Dept Psychiat & Psychol, 3811 OHara St, Pittsburgh, PA 15213 USA. EM matthewska@upmc.edu FU National Institutes of Health (NIH); Department of Health and Human Services, through the National Institute on Aging (NIA); National Institute of Nursing Research (NINR); NIH Office of Research on Women's Health (ORWH) [NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495] FX SWAN (Study of Women's Health Across the Nation) has grant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women's Health (ORWH) (grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, and AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH. NR 35 TC 158 Z9 161 U1 0 U2 7 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 DEC 15 PY 2009 VL 54 IS 25 BP 2366 EP 2373 DI 10.1016/j.jacc.2009.10.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 532SA UT WOS:000272768600005 PM 20082925 ER PT J AU Ladapo, JA Jaffer, FA Hoffmann, U Thomson, CC Bamberg, F Dec, W Cutler, DM Weinstein, MC Gazelle, GS AF Ladapo, Joseph A. Jaffer, Farouc A. Hoffmann, Udo Thomson, Carey C. Bamberg, Fabian Dec, William Cutler, David M. Weinstein, Milton C. Gazelle, G. Scott TI Clinical Outcomes and Cost-Effectiveness of Coronary Computed Tomography Angiography in the Evaluation of Patients With Chest Pain SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery disease; coronary computed tomography angiography; cost-effectiveness; economics; outcomes research ID SOLITARY PULMONARY NODULES; RANDOMIZED CONTROLLED-TRIALS; ARTERY-DISEASE; DIAGNOSTIC-ACCURACY; NONCARDIAC FINDINGS; BYPASS-SURGERY; CT ANGIOGRAPHY; HEART-DISEASE; ELUTING STENTS; 1ST EXPERIENCE AB Objectives The aim of this study was to project clinical outcomes, health care costs, and cost-effectiveness of coronary computed tomography angiography (CCTA), as compared with conventional diagnostic technologies, in the evaluation of patients with stable chest pain and suspected coronary artery disease (CAD). Background CCTA has recently been found to be effective in the evaluation of patients with suspected CAD, but investigators have raised concerns related to radiation exposure, incidental findings, and nondiagnostic exams. Methods With published data, we developed a computer simulation model to project clinical outcomes, health care costs, and cost-effectiveness of CCTA, compared with conventional testing modalities, in the diagnosis of CAD. Our target population included 55-year-old patients who present to their primary care physicians with stable chest pain. Results All diagnostic strategies yielded similar health outcomes, but performing CCTA-with or without stress testing or performing stress single-photon emission computed tomography-marginally minimized adverse events and maximized longevity and quality-adjusted life-years (QALYs). Health outcomes associated with these strategies were comparable, with CCTA in men and women yielding the greatest QALYs but only by modest margins. Overall differences were small, and performing the most effective test-compared with the least effective-decreased adverse event rates by 3% in men and women. Comparable increases in longevity and QALYs were 2 months and 0.1 QALYs in men and 1 month and 0.03 QALYs in women. CCTA raised overall costs, partly through the follow-up of incidental findings, and when performed with stress testing, its incremental cost-effectiveness ratio ranged from $26,200/QALY in men to $35,000/QALY in women. Health outcomes were marginally less favorable in women when radiation risks were considered. Conclusions CCTA is comparable to other diagnostic studies and might hold good clinical value, but large randomized controlled trials are needed to guide policy. (J Am Coll Cardiol 2009; 54: 2409-22) (C) 2009 by the American College of Cardiology Foundation C1 [Ladapo, Joseph A.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. [Ladapo, Joseph A.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Jaffer, Farouc A.; Dec, William] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo; Bamberg, Fabian; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Thomson, Carey C.] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Bamberg, Fabian] Univ Munich, Dept Clin Radiol, Univ Hosp Grosshadern, Munich, Germany. [Cutler, David M.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Cutler, David M.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Weinstein, Milton C.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Ladapo, JA (reprint author), Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM jladapo@bidmc.harvard.edu OI Jaffer, Farouc/0000-0001-7980-384X; Ladapo, Joseph/0000-0002-8518-4800 FU NEMA FX Dr. Gazelle received research funding from NEMA (ended July 2009). NR 65 TC 44 Z9 45 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 15 PY 2009 VL 54 IS 25 BP 2409 EP 2422 DI 10.1016/j.jacc.2009.10.012 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 532SA UT WOS:000272768600012 PM 20082932 ER PT J AU Uchiyama, S Goto, S Matsumoto, M Nagai, R Origasa, H Yamazaki, T Shigematsu, H Shimada, K Yamada, N Bhatt, DL Steg, PG Ikeda, Y AF Uchiyama, Shinichiro Goto, Shinya Matsumoto, Masayasu Nagai, Ryozo Origasa, Hideki Yamazaki, Tsutomu Shigematsu, Hiroshi Shimada, Kazuyuki Yamada, Nobuhiro Bhatt, Deepak L. Steg, P. Gabriel Ikeda, Yasuo CA REACH Registry Investigators TI Cardiovascular event rates in patients with cerebrovascular disease and atherothrombosis at other vascular locations: Results from 1-year outcomes in the Japanese REACH Registry SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Atherothrombosis; Cerebrovascular disease; Coronary artery disease; Epidemiology; Japan; Peripheral artery disease ID PERIPHERAL ARTERIAL-DISEASE; TRANSIENT ISCHEMIC ATTACK; ANTIPLATELET THERAPY; SECONDARY PREVENTION; ATRIAL-FIBRILLATION; RISK-FACTORS; DOUBLE-BLIND; STROKE; CLOPIDOGREL; PREVALENCE AB The REduction of Atherothrombosis for Continued Health (REACH) Registry is a large, international, prospective cohort of patients with atherothrombosis or multiple (>= 3) risk factors (MRFs) for atherothrombosis. Japanese patients (n = 5193) were enrolled into the REACH registry between August and December 2004. One-year event rate in patients with cerebrovascular disease (CVD) was compared with that of patients with symptomatic atherothrombosis at other locations. After one year (n = 5021), patients with CVD (n = 1962) experienced a higher rate of non-fatal strokes than patients with coronary artery disease (CAD), peripheral artery disease (PAD) or MRFs alone (2.77% vs. 1.28%, 2.07% and 1.56%, respectively), but a lower rate of non-fatal myocardial infarction (0.45% vs. 131%, 0.77% and 0.66%, respectively). Patients with CVD plus disease in >= 1 other vascular bed had higher rates of cardiovascular events than patients with CVD alone. Overall, event rates including non-fatal stroke, non-fatal myocardial infarction and cardiovascular death were higher for patients with CVD and PAD than for patients with CVD and CAD. Asymptormatic carotid stenosis >= 70% and ankle-brachial index < 0.9 were significant predisposing factors for stroke. Patients with CVD and co-existing atherothrombotic diseases had a high risk of recurrent events, including events arising in other vascular beds than originally diagnosed. (C) 2009 Elsevier B.V. All rights reserved. C1 [Uchiyama, Shinichiro] Tokyo Womens Med Univ, Sch Med, Dept Neurol, Shinjuku Ku, Tokyo 1628666, Japan. [Goto, Shinya] Tokai Univ, Sch Med, Dept Med, Kanagawa 2591100, Japan. [Matsumoto, Masayasu] Hiroshima Univ, Grad Sch Biomed Sci, Dept Clin Neurosci & Therapeut, Hiroshima, Japan. [Nagai, Ryozo] Univ Tokyo, Dept Cardiol, Tokyo, Japan. [Origasa, Hideki] Toyama Univ, Div Biostat & Clin Epidemiol, Toyama 930, Japan. [Yamazaki, Tsutomu] Univ Tokyo, Grad Sch Med, Dept Pharmacoepidemiol, Tokyo, Japan. [Shigematsu, Hiroshi] Tokyo Med Univ, Dept Vasc Surg, Tokyo, Japan. [Shimada, Kazuyuki] Jichi Med Univ, Dept Cardiol, Shimotsuke, Tochigi, Japan. [Yamada, Nobuhiro] Univ Tsukuba, Dept Endocrinol & Metab, Ibaraki, Japan. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Steg, P. Gabriel] Univ Paris 07, INSERM, U698, Paris, France. [Steg, P. Gabriel] AP HP, Paris, France. [Ikeda, Yasuo] Keio Univ, Sch Med, Dept Med, Tokyo 160, Japan. RP Uchiyama, S (reprint author), Tokyo Womens Med Univ, Sch Med, Dept Neurol, Shinjuku Ku, 8-1 Kawada Cho, Tokyo 1628666, Japan. EM suchiyam@nij.twmu.ac.jp RI Kuzuya, Masafumi/I-1583-2012 NR 24 TC 22 Z9 22 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD DEC 15 PY 2009 VL 287 IS 1-2 BP 45 EP 51 DI 10.1016/j.jns.2009.09.011 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529MK UT WOS:000272521200008 PM 19815240 ER PT J AU York, MK Wilde, EA Simpson, R Jankovic, J AF York, Michele K. Wilde, Elisabeth A. Simpson, Richard Jankovic, Joseph TI Relationship between neuropsychological outcome and DBS surgical trajectory and electrode location SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Parkinson's disease; Deep brain stimulation; Neuropsychology; Cognition; Neuroimagmg; Magnetic resonance imaging ID DEEP BRAIN-STIMULATION; ADVANCED PARKINSONS-DISEASE; SUBTHALAMIC NUCLEUS; PALLIDAL STIMULATION; POSTEROVENTRAL PALLIDOTOMY; FOLLOW-UP; CIRCUITS; STN; MRI; GPI AB Background: The outcome literature of subthalamic nuclei (STN) deep brain stimulation (DBS) suggests that cognitive declines are commonly reported following surgery. We hypothesized that differences in electrode position and surgical trajectory may lead to a differential neuropsychological outcome. Methods: We conducted a standardized evaluation of the location of the DBS electrode tip and the active electrodes, the surgical trajectory through which they were placed, and their relation to neuropsychological change scores (mental status, verbal memory, verbal fluency, and psychological measures) in 17 bilateral STN DBS patients using 6 month post-surgical magnetic resonance imaging data. Results: Declines in mental status scores were related to electrodes that were more posterior-laterally placed within the frontal quadrant in either hemisphere or those located superiorally in the left hemisphere. Electrodes that were closer to the approximated STN and more superiorally located in the left hemisphere were associated with verbal learning declines at 6 months following surgery. In the right hemisphere, the electrodes that were located more in the lateral direction were related to verbal short-term memory declines; while for verbal long-term memory declines were found for electrodes located more posterior-laterally in the left hemisphere. Declines in verbal fluency scores were more variable with associations found between change scores and electrodes in the lateral and superior directions in the left hemisphere and those electrodes closer to the approximated STN and more superiorally and posteriorally located in the right hemisphere. In contrast, semantic fluency declines were only related to right hemisphere electrodes located more superiorally. Declines in mood were related to those electrodes located further away from the approximated STN, particularly those located more inferiorally and laterally in the left hemisphere. Anxiety change scores were not associated with the location of the electrodes. Conclusions: The results provide preliminary evidence that 6 months following bilateral STN DBS cognitive and emotional changes may be related to the surgical trajectory and electrode placement. Published by Elsevier B.V. C1 [York, Michele K.; Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Parkinsons Dis & Movement Disorders Clin, Michael E Debakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Wilde, Elisabeth A.] Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [York, Michele K.] Michael E DeBakey Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Houston, TX USA. [Simpson, Richard] Methodist Hosp, Neurol Inst, Houston, TX 77030 USA. RP York, MK (reprint author), 1 Baylor Plaza,NB302, Houston, TX 77030 USA. EM myork@bcm.edu FU Medtronic, Inc.; NIH [NINDS-5K23NS041254]; Department of Veterans Affairs, Office of Research and Development FX Research supported by Medtronic, Inc., NIH / NINDS-5K23NS041254, and the Department of Veterans Affairs, Office of Research and Development. We gratefully acknowledge the assistance of Stephen McCauley, Ph.D. NR 29 TC 38 Z9 39 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD DEC 15 PY 2009 VL 287 IS 1-2 BP 159 EP 171 DI 10.1016/j.jns.2009.08.003 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529MK UT WOS:000272521200029 PM 19767016 ER PT J AU Bhagwat, N Olsen, AL Wang, AT Hanada, K Stuckert, P Kanaar, R D'Andrea, A Niedernhofer, LJ McHugh, PJ AF Bhagwat, Nikhil Olsen, Anna L. Wang, Anderson T. Hanada, Katsuhiro Stuckert, Patricia Kanaar, Roland D'Andrea, Alan Niedernhofer, Laura J. McHugh, Peter J. TI XPF-ERCC1 Participates in the Fanconi Anemia Pathway of Cross-Link Repair SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; DNA-DAMAGE RESPONSE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; MONOUBIQUITINATED FANCD2; ENDONUCLEASE ERCC1-XPF; ESCHERICHIA-COLI; NITROGEN MUSTARD; UBIQUITIN LIGASE; FOCUS FORMATION AB Interstrand cross-links (ICLs) prevent DNA strand separation and, therefore, transcription and replication, making them extremely cytotoxic. The precise mechanism by which ICLs are removed from mammalian genomes largely remains elusive. Genetic evidence implicates ATR, the Fanconi anemia proteins, proteins required for homologous recombination, translesion synthesis, and at least two endonucleases, MUS81-EME1 and XPF-ERCC1. ICLs cause replication-dependent DNA double-strand breaks (DSBs), and MUS81-EME1 facilitates DSB formation. The subsequent repair of these DSBs occurs via homologous recombination after the ICL is unhooked by XPF-ERCC1. Here, we examined the effect of the loss of either nuclease on FANCD2 monoubiquitination to determine if the nucleolytic processing of ICLs is required for the activation of the Fanconi anemia pathway. FANCD2 was monoubiquitinated in Mus81(-/-), Ercc1(-/-), and XPF-deficient human, mouse, and hamster cells exposed to cross-linking agents. However, the monoubiquitinated form of FANCD2 persisted longer in XPF-ERCC1-deficient cells than in wild-type cells. Moreover, the levels of chromatin-bound FANCD2 were dramatically reduced and the number of ICL-induced FANCD2 foci significantly lower in XPF-ERCC1-deficient cells. These data demonstrate that the unhooking of an ICL by XPF-ERCC1 is necessary for the stable localization of FANCD2 to the chromatin and subsequent homologous recombination-mediated DSB repair. C1 [Bhagwat, Nikhil; Niedernhofer, Laura J.] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. [Bhagwat, Nikhil] Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Olsen, Anna L.; Wang, Anderson T.; McHugh, Peter J.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Hanada, Katsuhiro; Kanaar, Roland] Erasmus MC, Dept Cell Biol & Genet, Canc Genom Ctr, NL-3000 CA Rotterdam, Netherlands. [Stuckert, Patricia; D'Andrea, Alan] Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kanaar, Roland] Erasmus MC, Dept Radiat Oncol, NL-3000 CA Rotterdam, Netherlands. [Niedernhofer, Laura J.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Sch Med, Pittsburgh, PA 15261 USA. RP Niedernhofer, LJ (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Res Pavil 2-6,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM niedernhoferl@upmc.edu; peter.mchugh@imm.ox.ac.uk FU Ellison Medical Foundation [AG-NS-0303-05]; NCI [CA111525-03]; ECMC; New Zealand Top Achiever Scholarship; Cancer Research UK; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO); European Commission [512113] FX L.J.N. and N.R.B. were supported by The Ellison Medical Foundation (AG-NS-0303-05) and NCI (CA111525-03). A.O. was supported by ECMC, and A. T. W. was supported by a New Zealand Top Achiever Scholarship. Research in P. M.'s laboratory is funded by Cancer Research UK. Work in the R. K. laboratory was supported by The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and the European Commission (Integrated Project 512113). NR 82 TC 72 Z9 75 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 15 PY 2009 VL 29 IS 24 BP 6427 EP 6437 DI 10.1128/MCB.00086-09 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522QI UT WOS:000272013000009 PM 19805513 ER PT J AU Kaufer, D Gandy, S AF Kaufer, Dan Gandy, Sam TI APOE epsilon 4 and bapineuzumab Infusing pharmacogenomics into Alzheimer disease therapeutics SO NEUROLOGY LA English DT Editorial Material ID APOLIPOPROTEIN E4; IMMUNIZATION; PATHOLOGY C1 [Kaufer, Dan] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Gandy, Sam] Mt Sinai Sch Med, Dept Neurol & Psychiat, New York, NY USA. [Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Kaufer, D (reprint author), Univ N Carolina, Dept Neurol, CB 7025,3129 POB,170 Manning Dr, Chapel Hill, NC 27599 USA. EM kauferd@neurology.unc.edu FU NCIPC CDC HHS [R49CE001495]; NIA NIH HHS [P50 AG005138, R21 AG033387, P01 AG010491, P01 AG10491, R21AG033387, R01 AG022462]; NIBIB NIH HHS [K01 EB009724] NR 10 TC 14 Z9 15 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 15 PY 2009 VL 73 IS 24 BP 2052 EP 2053 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 531YM UT WOS:000272709500001 PM 19923549 ER PT J AU Milad, MR Igoe, SA Lebron-Milad, K Novales, JE AF Milad, M. R. Igoe, S. A. Lebron-Milad, K. Novales, J. E. TI ESTROUS CYCLE PHASE AND GONADAL HORMONES INFLUENCE CONDITIONED FEAR EXTINCTION SO NEUROSCIENCE LA English DT Article DE estrous cycle; conditioned fear; anxiety; estrogen; progesterone ID POSTTRAUMATIC-STRESS-DISORDER; MEDIAL PREFRONTAL CORTEX; DENDRITIC SPINE DENSITY; LONG-TERM POTENTIATION; EMOTIONALLY INFLUENCED MEMORY; SEX-DIFFERENCES; ANXIETY DISORDERS; ORBITOFRONTAL CORTEX; HIPPOCAMPAL-NEURONS; OVARIAN-STEROIDS AB Gonadal hormones modulate fear acquisition, but less is known about the influence of gonadal hormones on fear extinction. We assessed sex differences and the influence of gonadal hormone fluctuations and exogenous manipulations of estrogen and progesterone on acquisition, extinction learning and extinction recall in a 3 day auditory fear conditioning and extinction protocol. Experiments were conducted on males and naturally cycling female rats. Regarding female rats, significant differences in fear extinction were observed between subgroups of females, depending on their phase of the estrous cycle. Extinction that took place during the proestrus (high estrogen/progesterone) phase was more fully consolidated, as evidenced by low freezing during a recall test. This suggests that estrogen and/or progesterone facilitate extinction. In support of this, injection of both estrogen and progesterone prior to extinction learning in female rats during the metestrus phase of the cycle (low estrogen/progesterone) facilitated extinction consolidation, and blockade of estrogen and progesterone receptors during the proestrus phase impaired extinction consolidation. When comparing male to female rats without consideration of the estrous cycle phase, no significant sex differences were observed. When accounting for cycle phase in females, sex differences were observed only during extinction recall. Female rats that underwent extinction during the metestrus phase showed significantly higher freezing during the recall test relative to males. Collectively, these data suggest that gonadal hormones influence extinction behavior possibly by influencing the function of brain regions involved in the consolidation of fear extinction. Moreover, the elevated fear observed in female relative to male rats during extinction recall suggests that gonadal hormones may in part play a role in the higher prevalence of anxiety disorders in women. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Milad, M. R.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Milad, MR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM milad@nmr.mgh.harvard.edu FU National Institute of Mental Health [K01 MH080346]; Rapapport Fellowship FX The work was supported by a grant from the National Institute of Mental Health (K01 MH080346) and a Rapapport Fellowship to M.R.M. The authors would like to thank Dr. David Rubinow and Dr. Gregory J. Quirk for helpful comments on the manuscript. NR 62 TC 103 Z9 106 U1 5 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD DEC 15 PY 2009 VL 164 IS 3 BP 887 EP 895 DI 10.1016/j.neuroscience.2009.09.011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 520NM UT WOS:000271852000001 PM 19761818 ER PT J AU Chung, E Yamashita, H Au, P Tannous, BA Fukumura, D Jain, RK AF Chung, Euiheon Yamashita, Hiroshi Au, Patrick Tannous, Bakhos A. Fukumura, Dai Jain, Rakesh K. TI Secreted Gaussia Luciferase as a Biomarker for Monitoring Tumor Progression and Treatment Response of Systemic Metastases SO PLOS ONE LA English DT Article ID BREAST-CANCER CELLS; IN-VIVO; GENE-EXPRESSION; GROWTH; BRAIN; OUTGROWTH; CULTURE; VITRO AB Background: Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc), and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses. Methodology/Principal Findings: We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI). Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R(2) = 0.84) and urine (R(2) = 0.55) in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2. Conclusion/Significance: We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments. C1 [Chung, Euiheon; Yamashita, Hiroshi; Au, Patrick; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab,Dept Radiat Oncol, Boston, MA 02115 USA. [Tannous, Bakhos A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit,Dept Neurol, Boston, MA USA. [Tannous, Bakhos A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Ctr Mol Imaging Res, Boston, MA USA. RP Chung, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab,Dept Radiat Oncol, Boston, MA 02115 USA. EM btannous@hms.harvard.edu; dai@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu OI Chung, Euiheon/0000-0002-3326-6927 FU National Cancer Institute [R01-CA96915, R01-CA85140, R01-CA115767, R01-CA126642, P01-CA80124]; Federal Share/National Cancer Institute Proton Beam Program Income; [R00CA126839]; [P50CA86355-07] FX This study was supported in part by R00CA126839 and P50CA86355-07 (BAT), National Cancer Institute grants R01-CA96915 (DF), and R01-CA85140, R01-CA115767, R01-CA126642, P01-CA80124, and Federal Share/National Cancer Institute Proton Beam Program Income grant (RKJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 42 Z9 46 U1 3 U2 11 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 DEC 15 PY 2009 VL 4 IS 12 AR e8316 DI 10.1371/journal.pone.0008316 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533ON UT WOS:000272833800012 PM 20016816 ER PT J AU Chinsomboon, J Ruas, J Gupta, RK Thom, R Shoag, J Rowe, GC Sawada, N Raghuram, S Arany, Z AF Chinsomboon, Jessica Ruas, Jorge Gupta, Rana K. Thom, Robyn Shoag, Jonathan Rowe, Glenn C. Sawada, Naoki Raghuram, Srilatha Arany, Zoltan TI The transcriptional coactivator PGC-1 alpha mediates exercise-induced angiogenesis in skeletal muscle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE VEGF; ERR alpha; b-adrenergic ID PERIPHERAL ARTERIAL-DISEASE; PPAR-GAMMA COACTIVATOR-1; MITOCHONDRIAL BIOGENESIS; MESSENGER-RNA; RECEPTOR ACTIVATION; ENERGY-METABOLISM; EXPRESSION; ADAPTATIONS; PROTEIN; GROWTH AB Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPAR gamma coactivator (PGC)-1 alpha is a potent transcriptional coactivator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1 alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1 alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1 alpha from an alternate promoter. The induction of PGC-1 alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1 alpha. The orphan nuclear receptor ERR alpha mediated the induction of VEGF by PGC-1 alpha, and mice lacking ERR alpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1 alpha/ERR alpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle. C1 [Chinsomboon, Jessica; Thom, Robyn; Shoag, Jonathan; Rowe, Glenn C.; Sawada, Naoki; Raghuram, Srilatha; Arany, Zoltan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Inst, Boston, MA 02215 USA. [Ruas, Jorge; Gupta, Rana K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ruas, Jorge; Gupta, Rana K.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Sawada, Naoki] Tokyo Med & Dent Univ, Int Res Ctr Mol Sci Tooth & Bone Dis, Global Ctr Excellence Program, Tokyo 1138510, Japan. RP Arany, Z (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Inst, 330 Brookline Ave, Boston, MA 02215 USA. EM zarany@bidmc.harvard.edu OI Ruas, Jorge/0000-0002-1110-2606 FU National Heart, Lung, and Blood Institute; Smith Family Foundation FX We thank Dr. Sharmina Rangwala (Novartis) for reagents and mice, and Dr. Stewart Lecker for reading of the manuscript. This work was supported by the National Heart, Lung, and Blood Institute (Z.A.) and the Smith Family Foundation (Z.A.). NR 54 TC 155 Z9 163 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 15 PY 2009 VL 106 IS 50 BP 21401 EP 21406 DI 10.1073/pnas.0909131106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533AW UT WOS:000272795300070 PM 19966219 ER PT J AU Guo, DL Prins, RM Dang, J Kuga, D Iwanami, A Soto, H Lin, KY Huang, TT Akhavan, D Hock, MB Zhu, SJ Kofman, AA Bensinger, SJ Yong, WH Vinters, HV Horvath, S Watson, AD Kuhn, JG Robins, HI Mehta, MP Wen, PY DeAngelis, LM Prados, MD Mellinghoff, IK Cloughesy, TF Mischel, PS AF Guo, Deliang Prins, Robert M. Dang, Julie Kuga, Daisuke Iwanami, Akio Soto, Horacio Lin, Kelly Y. Huang, Tiffany T. Akhavan, David Hock, M. Benjamin Zhu, Shaojun Kofman, Ava A. Bensinger, Steve J. Yong, William H. Vinters, Harry V. Horvath, Steve Watson, Andrew D. Kuhn, John G. Robins, H. Ian Mehta, Minesh P. Wen, Patrick Y. DeAngelis, Lisa M. Prados, Michael D. Mellinghoff, Ingo K. Cloughesy, Timothy F. Mischel, Paul S. TI EGFR Signaling Through an Akt-SREBP-1-Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy SO SCIENCE SIGNALING LA English DT Article ID TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; CANCER-CELLS; ACQUIRED-RESISTANCE; PROTEIN-KINASE; METABOLISM; RECURRENT; TUMOR; PROLIFERATION; CHOLESTEROL AB Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor ( EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas. C1 [Guo, Deliang; Dang, Julie; Kuga, Daisuke; Iwanami, Akio; Lin, Kelly Y.; Huang, Tiffany T.; Akhavan, David; Hock, M. Benjamin; Zhu, Shaojun; Kofman, Ava A.; Bensinger, Steve J.; Yong, William H.; Vinters, Harry V.; Mischel, Paul S.] David Geffen UCLA Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Prins, Robert M.; Soto, Horacio] David Geffen UCLA Sch Med, Dept Surg, Div Neurosurg, Los Angeles, CA 90095 USA. [Yong, William H.; Cloughesy, Timothy F.; Mischel, Paul S.] David Geffen UCLA Sch Med, Henry Singleton Brain Tumor Program, Los Angeles, CA 90095 USA. [Yong, William H.; Cloughesy, Timothy F.; Mischel, Paul S.] David Geffen UCLA Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Vinters, Harry V.; Cloughesy, Timothy F.] David Geffen UCLA Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Horvath, Steve] David Geffen UCLA Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Horvath, Steve] David Geffen UCLA Sch Med, Dept Biostat, Los Angeles, CA 90095 USA. [Watson, Andrew D.] David Geffen UCLA Sch Med, Div Cardiol, Dept Med, Los Angeles, CA 90095 USA. [Kuhn, John G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Robins, H. Ian; Mehta, Minesh P.] Univ Wisconsin, Madison, WI 53711 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [DeAngelis, Lisa M.; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Mischel, PS (reprint author), David Geffen UCLA Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. EM pmischel@mednet.ucla.edu RI Guo, Deliang/I-3735-2014; OI Guo, Deliang/0000-0002-8359-390X; Prins, Robert/0000-0002-6282-6583; mehta, minesh/0000-0002-4812-5713 FU National Institute for Neurological Disorders and Stroke [NS050151]; National Cancer Institute [CA119347, CA108633]; Brain Tumor Funders' Collaborative; Harry Allgauer Foundation; Ziering Family Foundation; Accelerate Brain Cancer Cure; NABTC [04-01]; University of Texas Health Science Center (San Antonio, TX) [UO1CA62426, P30CA54174]; University of California at San Francisco [U01CA62422, M01-RR00079]; Dana-Farber Cancer Center [U01CA62407]; UCLA [U01CA62339]; GCRC [M01-RR0865]; University of Wisconsin Hospital [U01CA62421, M01-RR03186]; Memorial Sloan-Kettering Cancer Center [U01CA62399]; University of Texas M. D. Anderson Cancer Center [CA62412, CA16672]; University of Pittsburgh NABTC [CA 62404, M01-RR00056] FX We thank G. Thomas, C. Radu, J. Czernin, O. Witte, and P. Edwards for helpful discussions. This work was supported by the National Institute for Neurological Disorders and Stroke (NS050151), the National Cancer Institute (CA119347 and CA108633), and the Brain Tumor Funders' Collaborative. This work was also supported by the Harry Allgauer Foundation through the Doris R. Ullman Fund for Brain Tumor Research Technologies, the Henry E. Singleton Brain Tumor Program, and generous donations from the Ziering Family Foundation in memory of Sigi Ziering and Timothy and Mary Hahneman and a grant from Accelerate Brain Cancer Cure. We acknowledge institutional investigators from NABTC 04-01 "A biomarker and phase II study of GW 572016 in recurrent malignant glioma": H. Fine, S. Chang, F. Lieberman, D. Reardon, L. Abrey, A. Lassman, K. Aldape, W. K. A. Yung, J. Dancey, and K. Lamborn. Grant support (for the lapatinib trial): University of Texas Health Science Center (San Antonio, TX) grants UO1CA62426 and P30CA54174, University of California at San Francisco grants U01CA62422 and GCRC# M01-RR00079, Dana-Farber Cancer Center grant U01CA62407, UCLA grants U01CA62339 and GCRC# M01-RR0865, University of Wisconsin Hospital grants U01CA62421 and GCRC# M01-RR03186, and Memorial Sloan-Kettering Cancer Center grant U01CA62399, University of Texas M. D. Anderson Cancer Center grants CA62412 and CA16672, University of Pittsburgh NABTC grant CA 62404, and GCRC grant M01-RR00056. NR 37 TC 92 Z9 94 U1 1 U2 5 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 DEC 15 PY 2009 VL 2 IS 101 AR ra82 DI 10.1126/scisignal.2000446 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570BM UT WOS:000275646600002 PM 20009104 ER PT J AU DiPaola, CP Conrad, BP Horodyski, M DiPaola, MJ Sawers, A Rechtine, GR AF DiPaola, Christian P. Conrad, Bryan P. Horodyski, MaryBeth DiPaola, Matthew J. Sawers, Andrew Rechtine, Glenn R., II TI Cervical Spine Motion Generated With Manual Versus Jackson Table Turning Methods in a Cadaveric C1-C2 Global Instability Model SO SPINE LA English DT Article DE patient transfer; Jackson table; prone position; neurologic deterioration; patient safety; atlantoaxial instability; spinal cord injury ID CHIARI-I MALFORMATION; NEUROLOGIC DETERIORATION; EVOKED-POTENTIALS; CORD INJURY; IMMOBILIZATION; PATIENT; MYELOPATHY AB Study Design. Cadaveric biomechanical study. Objective. To quantify spinal motion created by transfer methods from supine to prone position in a cadaveric C1-C2 global instability model. Summary of Background Data. Patients who have sustained a spinal cord injury remain at high risk for further secondary injury until their spine is adequately stabilized. To date, no study has evaluated the effect of patient transfer methods from supine to prone position in the operating room, on atlantoaxial cervical spine motion. Methods. A global instability was surgically created at the C1-C2 level in 4 fresh cadavers. Two transfer protocols were tested on each cadaver. The log-roll technique entailed performing a standard 180 log-roll rotation of the supine patient from a stretcher to the prone position onto the operating room Jackson table (OSI, Union City, CA). The "Jackson technique" involved sliding the supine patient to the Jackson table, securing them to the table, and then rotating them into a prone position. An electromagnetic tracking device registered motion between the C1 and C2 vertebral segments. Three different head holding devices (Mayfield, Prone view, and blue foam pillow) were also compared for their ability to restrict C1-C2 motion. Six motion parameters were tracked. Repeated measures statistical analysis was performed to evaluate angular and translational motion. Results. For 6 of 6 measures of angulation and translation, manual log-roll prone positioning generated significantly more C1-C2 motion than the Jackson table turning technique. Out of 6 motion parameters, 5 were statistically significant (P < 0.001-0.005). There was minimal difference in C1-C2 motion generated when comparing all 3 head holding devices. Conclusion. The data demonstrate that manual log-roll technique generated significantly more C1-C2 motion compared to the Jackson table technique. Choice of headrest has a minimal effect on the amount of motion generated during patient transfer, except that the Mayfield device demonstrates a slight trend toward increased C1-C2 motion. C1 [Rechtine, Glenn R., II] Univ Rochester, Med Ctr, Dept Orthopaed Surg, Spine Div, Rochester, NY 14624 USA. [DiPaola, Christian P.] Univ Massachusetts, Med Ctr, Dept Orthopaed, Worcester, MA USA. [Conrad, Bryan P.] Univ Florida, Dept Orthopaed Res, Gainesville, FL USA. [Horodyski, MaryBeth] Univ Florida, Dept Orthopaed & Rehabil, Gainesville, FL USA. [DiPaola, Matthew J.] Wright State Univ, Dept Orthopaed, Dayton, OH 45435 USA. [Sawers, Andrew] Univ Washington, Ctr Excellence Limb Loss Prevent & Prosthet Engn, VA Puget Sound, Seattle, WA 98195 USA. [Sawers, Andrew] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Rechtine, GR (reprint author), Univ Rochester, Med Ctr, Dept Orthopaed Surg, Spine Div, 601 Elmwood Ave, Rochester, NY 14624 USA. EM cpd62@yahoo.com RI conrad, bryan/I-1299-2012 OI conrad, bryan/0000-0002-7304-3648 NR 28 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD DEC 15 PY 2009 VL 34 IS 26 BP 2912 EP 2918 DI 10.1097/BRS.0b013e3181b7eddb PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 533AK UT WOS:000272794000016 PM 20010399 ER PT J AU Meeran, SM Singh, T Nagy, TR Katiyar, SK AF Meeran, Syed M. Singh, Tripti Nagy, Tim R. Katiyar, Santosh K. TI High-fat diet exacerbates inflammation and cell survival signals in the skin of ultraviolet B-irradiated C57BL/6 mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE High-fat diet; Inflammation; Cyclooxygenase-2; Ultraviolet radiation; Skin; Interleukin ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; CYCLOOXYGENASE-2 OVEREXPRESSION; TUMOR-DEVELOPMENT; OXIDATIVE STRESS; US CHILDREN; MOUSE SKIN; CANCER; OBESITY; ACTIVATION AB Inflammation induced by chronic exposure to ultraviolet (UV) radiation has been implicated in various skin diseases. We formulated the hypothesis that a high-fat diet may influence the UV-induced inflammatory responses in the skin. C57BL/6 mice were fed a high-fat diet or control diet and exposed to UVB radiation (120 mJ/cm(2)) three times/week for 10 weeks. The mice were then sacrificed and skin and plasma samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. We found that the levels of inflammatory biomarkers were increased in the UVB-exposed skin of the mice fed the high-fat diet than the UVB-exposed skin of the mice fed the control diet. The levels of inflammatory biomarkers of early responses to UVB exposure (e.g., myeloperoxidase, cyclooxygenase-2, prostaglandin-E(2)), proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser(473)) were higher in high-fat-diet-fed mouse skin than control-diet-fed mouse skin. The plasma levels of insulin growth factor-1 were greater in the UVB-irradiated mice fed the high-fat diet than the UVB-irradiated mice fed the control diet, whereas the levels of plasma adiponectin were significantly lower. This pronounced exacerbation of the UVB-induced inflammatory responses in the skin of mice fed a high-fat diet suggests that high-fat diet may increase susceptibility to inflammation-associated skin diseases, including the risk of skin cancer. (C) 2009 Elsevier Inc. All rights reserved. C1 [Meeran, Syed M.; Singh, Tripti; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Katiyar, SK (reprint author), Univ Alabama, Dept Dermatol, 1670 Univ Blvd,Volker Hall 557,POB 202, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration Merit Review Award FX This work was financially supported by the Veterans Administration Merit Review Award (S.K.K.). NR 45 TC 16 Z9 17 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 15 PY 2009 VL 241 IS 3 BP 303 EP 310 DI 10.1016/j.taap.2009.09.003 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 520JX UT WOS:000271841400007 PM 19747500 ER PT J AU Meyerhardt, JA Giovannucci, EL Ogino, S Kirkner, GJ Chan, AT Willett, W Fuchs, CS AF Meyerhardt, Jeffrey A. Giovannucci, Edward L. Ogino, Shuji Kirkner, Gregory J. Chan, Andrew T. Willett, Walter Fuchs, Charles S. TI Physical Activity and Male Colorectal Cancer Survival SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID GROWTH-FACTOR (IGF)-I; IGF-BINDING-PROTEINS; COLON-CANCER; ACTIVITY QUESTIONNAIRE; NORTHERN SWEDEN; BODY-SIZE; FACTOR-I; RISK; INSULIN; MEN AB Background: Although physically active individuals have a lower risk of developing colorectal cancer, few studies have examined whether exercise benefits colorectal cancer survivors. Methods: Derived from the Health Professionals Follow-up Study, we studied colorectal cancer-specific and overall mortality in a cohort of 668 men with a history of stage I to stage III colorectal cancer according to pre-defined physical activity categories after diagnosis. To minimize bias by occult recurrences, we excluded men who died within 6 months of their post diagnosis physical activity assessment. Results: In a cohort of men with colorectal cancer and no apparent metastases at diagnosis, 50.4% exercised at least 18 metabolic equivalent task (MET) hours per week. Increased physical activity was significantly associated with improved colorectal cancer-specific mortality (P = .002 for trend) and overall mortality (P < .001 for trend). Men who engaged in more than 27 MET hours per week of physical activity had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.47 (95% confidence interval, 0.24-0.92) compared with men who engaged in 3 or less MET hours per week of physical activity. The apparent benefit of physical activity was seen regardless of age, disease stage, body mass index, diagnosis year, tumor location, and pre-diagnosis physical activity. Conclusion: In a large cohort of men with a history of nonmetastatic colorectal cancer, more physical activity was associated with a lower risk of colorectal cancer-specific and overall mortality. C1 [Meyerhardt, Jeffrey A.; Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Ogino, Shuji; Kirkner, Gregory J.; Chan, Andrew T.; Willett, Walter; Fuchs, Charles S.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Willett, Walter] Harvard Univ, Sch Publ Hlth, Harvard Med Sch, Dept Nutr, Cambridge, MA 02138 USA. [Giovannucci, Edward L.; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [P01 CA055075, P01 CA055075-15, P01 CA55075, P50 CA127003, P50 CA127003-020004, R01 CA137178] NR 33 TC 115 Z9 116 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 14 PY 2009 VL 169 IS 22 BP 2102 EP 2108 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800010 PM 20008694 ER PT J AU Robinson-Cohen, C Katz, R Mozaffarian, D Dalrymple, LS de Boer, I Sarnak, M Shlipak, M Siscovick, D Kestenbaum, B AF Robinson-Cohen, Cassianne Katz, Ronit Mozaffarian, Dariush Dalrymple, Lorien S. de Boer, Ian Sarnak, Mark Shlipak, Mike Siscovick, David Kestenbaum, Bryan TI Physical Activity and Rapid Decline in Kidney Function Among Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; CYSTATIN-C; CARDIOVASCULAR-HEALTH; METABOLIC SYNDROME; LIFE-STYLE; INSULIN SENSITIVITY; DIABETES-MELLITUS; BLOOD-PRESSURE; RENAL-FUNCTION; HEART-DISEASE AB Background: Habitual physical activity (PA) has both physiologic and metabolic effects that may moderate the risk of kidney function decline. We tested the hypothesis that higher levels of PA are associated with a lower risk of kidney function decline using longitudinal data from a large cohort of older adults. Methods: We studied 4011 ambulatory participants aged 65 or older from the Cardiovascular Health Study (CHS) who completed at least 2 measurements of kidney function over 7 years. We calculated a PA score (range, 2-8) by summing kilocalories expended per week (ordinal score of 1-5 from quintiles of kilocalories per week) and walking pace (ordinal score for categories of <2, 2-3, and >3 mph). Rapid decline in kidney function decline (RDKF) was defined by loss of more than 3.0 mL/min/1.73 m(3) per year in glomerular filtration rate, which we estimated by using longitudinal measurements of cystatin C levels. Results: A total of 958 participants had RDKF (23.9%; 4.1 events per 100 person-years). The estimated risk of RDKF was 16% in the highest PA group (score of 8) and 30% in the lowest PA group (score of 2). After multivariate adjustment, we found that the 2 highest PA groups (scores of 7-8) were associated with a 28% lower risk of RDKF (95% confidence interval, 21%-41% lower risk) than the 2 lowest PA groups (score of 2-3). Greater kilocalories of leisure-time PA and walking pace were also each associated with a lower incidence of RDKF. Conclusion: Higher levels of PA are associated with a lower risk of RDKF among older adults. C1 [Robinson-Cohen, Cassianne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Katz, Ronit] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Dept Biostat, Seattle, WA 98195 USA. [de Boer, Ian; Kestenbaum, Bryan] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA. [Mozaffarian, Dariush] Harvard Univ, Sch Med, Boston, MA USA. [Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Dalrymple, Lorien S.] Univ Calif Davis, Dept Internal Med, Div Nephrol, Sacramento, CA 95817 USA. [Sarnak, Mark] Tufts Univ New England Med Ctr, Dept Med, Boston, MA USA. [Shlipak, Mike] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Robinson-Cohen, C (reprint author), Univ Washington, Dept Epidemiol, Box 357236, Seattle, WA 98195 USA. EM cassyrc@u.washington.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU National Institutes of Health Research Project [R01 AG 027002]; CHS [N01-HC-35129, N01-HC-45133, N01-HC-751.50, N01-HC-85079]; National Heart, Lung, and Blood Institute [N01-HC-85086, N01-HC-15103, N01-HC-55222, U01 HL080295]; National Institute of Neurological Disorders and Stroke; National Institutes on Aging [R01AG027002] FX This research was supported by National Institutes of Health Research Project Grant R01 AG 027002. The CHS was supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-751.50, N01-HC-85079 through N01-HC-85086, N01-HC-15103, N01-HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute; by the National Institute of Neurological Disorders and Stroke; and by grant R01AG027002 from the National Institutes on Aging. NR 46 TC 43 Z9 43 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 DEC 14 PY 2009 VL 169 IS 22 BP 2116 EP 2123 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800013 PM 20008696 ER PT J AU Smoller, JW Allison, M Cochrane, BB Curb, JD Perlis, RH Robinson, JG Rosal, MC Wenger, NK Wassertheil-Smoller, S AF Smoller, Jordan W. Allison, Matthew Cochrane, Barbara B. Curb, J. David Perlis, Roy H. Robinson, Jennifer G. Rosal, Milagros C. Wenger, Nanette K. Wassertheil-Smoller, Sylvia TI Antidepressant Use and Risk of Incident Cardiovascular Morbidity and Mortality Among Postmenopausal Women in the Women's Health Initiative Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; BASE-LINE CHARACTERISTICS; ACUTE MYOCARDIAL-INFARCTION; SELECTIVE SEROTONIN; DEPRESSIVE SYMPTOMS; PLATELET INHIBITION; CORONARY EVENTS; HEART-DISEASE; POPULATION; STROKE AB Background: Antidepressants are commonly prescribed medications, but their effect on cardiovascular morbidity and mortality remains unclear. Methods: Prospective cohort study of 136 293 community-dwelling postmenopausal women in the Women's Health Initiative (WHI). Women taking no antidepressants at study entry and who had at least 1 follow-up visit were included. Cardiovascular morbidity and all-cause mortality for women with new antidepressant use at follow-up (n = 5496) were compared with those characteristics for women taking no antidepressants at follow-up (mean follow-up, 5.9 years). Results: Antidepressant use was not associated with coronary heart disease (CHD). Selective serotonin reuptake inhibitor (SSRI) use was associated with increased stroke risk (hazard ratio [HR], 1.45, [95% CI, 1.08-1.97]) and all-cause mortality (HR,1.32 [95% Cl, 1.10-1.59]). Annualized rates per 1000 person-years of stroke with no antidepressant use and SSRI use were 2.99 and 4.16, respectively, and death rates were 7.79 and 12.77. Tricyclic antidepressant (TCA) use was associated with increased risk of all-cause mortality (HR, 1.67 [95% CI, 1.33-2.09]; annualized rate, 14.14 deaths per 1000 person-years). There were no significant differences between SSRI and TCA use in risk of any outcomes. In analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke (HR, 2.12 [95% Cl, 1.10-4.07]) and fatal stroke (HR, 2.10 [95% CI, 1.15-3.81]). Conclusions: In postmenopausal women, there were no significant differences between SSRI and TCA use in risk of CHD, stroke, or mortality. Antidepressants were not associated with risk of CHD. Tricyclic antidepressants and SSRIs may be associated with increased risk of mortality, and SSRIs with increased risk of hemorrhagic and fatal stroke, although absolute event risks are low. These findings must be weighed against quality of life and established risks of cardiovascular disease and mortality associated with untreated depression. C1 [Smoller, Jordan W.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Allison, Matthew] Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, La Jolla, CA 92093 USA. [Cochrane, Barbara B.] Univ Washington, Dept Family & Child Nursing, Seattle, WA 98195 USA. [Curb, J. David] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Rosal, Milagros C.] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA USA. [Wenger, Nanette K.] Emory Univ, Sch Med, Div Cardiol, Dept Med, Atlanta, GA 30322 USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Smoller, JW (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Simches Res Bldg,185 Cambridge St,Ste 2200, Boston, MA 02114 USA. EM jsmoller@hms.harvard.edu OI Allison, Matthew/0000-0003-0777-8272 FU PHS HHS [32108-9, 24152, 32100-2, 32105-6, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; WHI NIH HHS [N01WH22110] NR 50 TC 116 Z9 118 U1 3 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 14 PY 2009 VL 169 IS 22 BP 2128 EP 2139 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800015 PM 20008698 ER PT J AU Ayalon, L Covinsky, KE AF Ayalon, Liat Covinsky, Kenneth E. TI Spouse-Rated vs Self-rated Health as Predictors of Mortality SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID QUALITY-OF-LIFE; FUNCTIONAL STATUS; PROXY AGREEMENT; OLDER; PERSPECTIVE; EXPECTANCY; PATIENT; IMPACT AB Background: The Health and Retirement Study is a national sample of Americans older than 50 years and their spouses. The present study evaluated cross-sectional and longitudinal data from January 2000 through December 2006. The objective of the study was to evaluate the roles of spouse-rated vs self-rated health as predictors of all-cause mortality among adults older than 50 years. Methods: A total of 673 dyads of married couples were randomly selected to participate in a Health and Retirement Study module examining spouse-rated health. For each couple, one member was asked to rate his or her overall health status, and his or her spouse was asked to report the partner's overall health status. Mortality data were available through 2006. Results: our findings demonstrate that spouse-rated health (area under the curve, 0.75) is as strong a predictor of mortality as self-rated health (area under the curve, 0.73) (chi(2)(1) = 0.36, P = .54). Combining spouse-rated and self-rated health predicts mortality better than using self-rated health alone (area under the curve, 0.77) (chi(2)(1) = 6.72, P = .009). Conclusions: Spouse ratings of health are at least as strongly predictive of mortality as self-rated health. This suggests that, when self-rated health is elicited as a prognostic indicator, spouse ratings can be used when self-ratings are unavailable. Both measures together may be more informative than either measure alone. C1 [Ayalon, Liat] Bar Ilan Univ, Louis & Gabi Weisfeld Sch Social Work, IL-52900 Ramat Gan, Israel. [Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Covinsky, Kenneth E.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. RP Ayalon, L (reprint author), Bar Ilan Univ, Louis & Gabi Weisfeld Sch Social Work, IL-52900 Ramat Gan, Israel. EM ayalonl@mail.biu.ac.il FU National Institute on Aging [5K24 AG029812, 5R01 AG023626] FX This study was supported by grants 5K24 AG029812 and 5R01 AG023626 from the National Institute on Aging (Dr Covinsky). NR 31 TC 7 Z9 7 U1 1 U2 5 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 DEC 14 PY 2009 VL 169 IS 22 BP 2156 EP 2161 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800019 PM 20008702 ER PT J AU Benes, C Settleman, J AF Benes, Cyril Settleman, Jeff TI Integrating complex genomic datasets and tumour cell sensitivity profiles to address a 'simple' question: which patients should get this drug? SO BMC MEDICINE LA English DT Editorial Material ID GENOTYPE-CORRELATED SENSITIVITY; GROWTH-FACTOR RECEPTOR; LUNG-CANCER; BREAST-CANCER; KINASE INHIBITORS; MUTATIONS; RESISTANCE; CHEMOTHERAPY; TRASTUZUMAB; PREDICTORS AB It is becoming increasingly apparent that cancer drug therapies can only reach their full potential through appropriate patient selection. Matching drugs and cancer patients has proven to be a complex challenge, due in large part to the substantial molecular heterogeneity inherent to human cancers. This is not only a major hurdle to the improvement of the use of current treatments but also for the development of novel therapies and the ability to steer them to the relevant clinical indications. In this commentary we discuss recent studies from Kuo et al., published this month in BMC Medicine, in which they used a panel of cancer cell lines as a model for capturing patient heterogeneity at the genomic and proteomic level in order to identify potential biomarkers for predicting the clinical activity of a novel candidate chemotherapeutic across a patient population. The findings highlight the ability of a 'systems approach' to develop a better understanding of the properties of novel candidate therapeutics and to guide clinical testing and application. C1 [Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, 149 13th St, Charlestown, MA 02129 USA. EM cbenes@bidmc.harvard.edu; settleman@helix.mgh.harvard.edu NR 30 TC 2 Z9 2 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD DEC 14 PY 2009 VL 7 AR 78 DI 10.1186/1741-7015-7-78 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 537OL UT WOS:000273122500001 PM 20003409 ER PT J AU Elrefaei, M Burke, CM Baker, CAR Jones, NG Bousheri, S Bangsberg, DR Cao, HY AF Elrefaei, Mohamed Burke, Candace M. Baker, Chris A. R. Jones, Norman G. Bousheri, Stephanie Bangsberg, David R. Cao, Huyen TI TGF-beta and IL-10 Production by HIV-Specific CD8+T Cells Is Regulated by CTLA-4 Signaling on CD4+T Cells SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; CD8(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; SUPPRESSOR LYMPHOCYTES; CYTOKINE PRODUCTION; UP-REGULATION; CUTTING EDGE; INFECTION; EXPRESSION; PROLIFERATION AB Immune dysregulation in HIV-1 infection is associated with increased expression of inhibitory molecules such as CTLA-4, TGF-beta, and IL-10. In this study we examined one potential mechanism for regulating TGF-beta and IL-10 expression by HIV-specific suppressor CD8+ T cells. No overlap between TGF-beta, IL-10, and IFN-gamma cytokine production by HIV-specific CD8+ T cells was observed. TGF-beta positive and IL-10 positive cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. TGF-beta and IL-10 positive CD8+ T cells did not express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-beta positive and IL-10 positive CD8+ T cell responses, and a concomitant increase in HIV-specific IFN-gamma positive CD8+ T cell responses. Depletion of CD4+ T cells abrogated the impact of CTLA-4 on HIV-specific TGF-beta positive and IL-10 positive CD8+ T cells. Our study suggests that CTLA-4 Signaling on CD4+ T cells regulates the inhibitory functions of the HIV-specific suppressor CD8+ T cells. C1 [Elrefaei, Mohamed; Burke, Candace M.; Baker, Chris A. R.; Jones, Norman G.; Bousheri, Stephanie; Cao, Huyen] Calif Dept Publ Hlth, Richmond, CA USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Harvard Initiat Global Hlth, Cambridge, MA USA. RP Elrefaei, M (reprint author), Calif Dept Publ Hlth, Richmond, CA USA. EM hcao@dhs.ca.gov FU NIH [AI43885, MH54907, AI71772]; California Research Center for the Biology of HIV in Minorities FX Work was supported by NIH grants AI43885, MH54907, AI71772, and California Research Center for the Biology of HIV in Minorities grant, UC Davis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 14 Z9 17 U1 0 U2 0 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 DEC 14 PY 2009 VL 4 IS 12 AR e8194 DI 10.1371/journal.pone.0008194 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533NI UT WOS:000272830300003 PM 20016783 ER PT J AU Nelissen, K Joly, O Durand, JB Todd, JT Vanduffel, W Orban, GA AF Nelissen, Koen Joly, Olivier Durand, Jean-Baptiste Todd, James T. Vanduffel, Wim Orban, Guy A. TI The Extraction of Depth Structure from Shading and Texture in the Macaque Brain SO PLOS ONE LA English DT Article ID LATERAL OCCIPITAL COMPLEX; INFERIOR TEMPORAL CORTEX; VISUAL 3D SHAPE; SURFACE ORIENTATION; INFEROTEMPORAL CORTEX; 3-DIMENSIONAL SHAPE; CONTRAST AGENT; OBJECT SHAPE; PERCEPTION; DISPARITY AB We used contrast-agent enhanced functional magnetic resonance imaging (fMRI) in the alert monkey to map the cortical regions involved in the extraction of 3D shape from the monocular static cues, texture and shading. As in the parallel human imaging study [1], we contrasted the 3D condition to several 2D control conditions. The extraction of 3D shape from texture (3D SfT) involves both ventral and parietal regions, in addition to early visual areas. Strongest activation was observed in CIP, with decreasing strength towards the anterior part of the intraparietal sulcus (IPS). In the ventral stream 3D SfT sensitivity was observed in a ventral portion of TEO. The extraction of 3D shape from shading (3D SfS) involved predominantly ventral regions, such as V4 and a dorsal potion of TEO. These results are similar to those obtained earlier in human subjects and indicate that the extraction of 3D shape from texture is performed in both ventral and dorsal regions for both species, as are the motion and disparity cues, whereas shading is mainly processed in the ventral stream. C1 [Nelissen, Koen; Joly, Olivier; Durand, Jean-Baptiste; Vanduffel, Wim; Orban, Guy A.] Katholieke Univ Leuven, Sch Med, Neuro & Psychofysiol Lab, Leuven, Belgium. [Todd, James T.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Nelissen, Koen; Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02114 USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Nelissen, K (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02114 USA. EM koen.nelissen@med.kuleuven.be RI DURAND, Jean-Baptiste/E-9252-2011; OI DURAND, Jean-Baptiste/0000-0003-4780-8691; Joly, Olivier/0000-0002-5818-6552 FU EU [GOA 2005/18] FX This work was supported by EU project Insight 2+ and Neurobotics and GOA 2005/18. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 20 Z9 20 U1 0 U2 6 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 DEC 14 PY 2009 VL 4 IS 12 AR e8306 DI 10.1371/journal.pone.0008306 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533NI UT WOS:000272830300051 PM 20011540 ER PT J AU Sebastiani, P Montano, M Puca, A Solovieff, N Kojima, T Wang, MC Melista, E Meltzer, M Fischer, SEJ Andersen, S Hartley, SH Sedgewick, A Arai, Y Bergman, A Barzilai, N Terry, DF Riva, A Anselmi, CV Malovini, A Kitamoto, A Sawabe, M Arai, T Gondo, Y Steinberg, MH Hirose, N Atzmon, G Ruvkun, G Baldwin, CT Perls, TT AF Sebastiani, Paola Montano, Monty Puca, Annibale Solovieff, Nadia Kojima, Toshio Wang, Meng C. Melista, Efthymia Meltzer, Micah Fischer, Sylvia E. J. Andersen, Stacy Hartley, Stephen H. Sedgewick, Amanda Arai, Yasumichi Bergman, Aviv Barzilai, Nir Terry, Dellara F. Riva, Alberto Anselmi, Chiara Viviani Malovini, Alberto Kitamoto, Aya Sawabe, Motoji Arai, Tomio Gondo, Yasuyuki Steinberg, Martin H. Hirose, Nobuyoshi Atzmon, Gil Ruvkun, Gary Baldwin, Clinton T. Perls, Thomas T. TI RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C-elegans SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN LONGEVITY; CAENORHABDITIS-ELEGANS; EXCEPTIONAL LONGEVITY; MESSENGER-RNA; CENTENARIANS; INSULIN; GENOTYPE; POPULATION; DROSOPHILA AB Background: The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered. Methodology/Principal Findings: Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U. S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function. Conclusions/Significance: Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan. C1 [Sebastiani, Paola; Solovieff, Nadia; Hartley, Stephen H.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Montano, Monty; Meltzer, Micah] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Puca, Annibale; Anselmi, Chiara Viviani; Malovini, Alberto] IRCCS Multimed, Dept Genet, Milan, Italy. [Kojima, Toshio; Kitamoto, Aya] RIKEN, Adv Sci Inst, Computat Syst Biol Res Grp, Kanagawa, Japan. [Wang, Meng C.; Fischer, Sylvia E. J.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02114 USA. [Wang, Meng C.; Fischer, Sylvia E. J.; Ruvkun, Gary] Harvard Univ, Sch Med, Boston, MA USA. [Melista, Efthymia; Steinberg, Martin H.; Baldwin, Clinton T.] Boston Univ, Sch Med, Ctr Human Genet, Boston, MA 02118 USA. [Andersen, Stacy; Terry, Dellara F.; Perls, Thomas T.] Boston Univ, Sch Med, Dept Med, Geriatr Sect, Boston, MA 02118 USA. [Sedgewick, Amanda] Boston Univ, Sch Engn, Dept Bioengn, Boston, MA 02215 USA. [Arai, Yasumichi; Hirose, Nobuyoshi] Keio Univ, Sch Med, Dept Internal Med, Div Geriatr Med, Tokyo, Japan. [Bergman, Aviv] Albert Einstein Coll Med, Dept Syst & Computat Biol, Bronx, NY 10467 USA. [Barzilai, Nir; Atzmon, Gil] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA. [Barzilai, Nir; Atzmon, Gil] Albert Einstein Coll Med, Dept Genet, Diabet Res Ctr, Bronx, NY 10467 USA. [Barzilai, Nir; Atzmon, Gil] Albert Einstein Coll Med, Dept Med, Diabet Res Ctr, Bronx, NY 10467 USA. [Riva, Alberto] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Sawabe, Motoji; Arai, Tomio] Tokyo Metropolitan Geriatr Hosp, Dept Pathol, Tokyo 173, Japan. [Gondo, Yasuyuki] Osaka Univ, Grad Sch Human Sci, Osaka, Japan. RP Sebastiani, P (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM sebas@bu.edu; mmontano@bu.edu OI Andersen, Stacy/0000-0002-2442-6386; Perls, Thomas/0000-0002-2492-4334; Steinberg, Martin/0000-0001-8800-8020; sebastiani, paola/0000-0001-6419-1545; Riva, Alberto/0000-0001-9150-8333 FU National Institutes of Health [R01 HL087681, K24 AG025727, R01 AR055115, RO1 AG027216]; Italian Ministry of Research and University; Glenn Foundation [AG-027734, AG-18728, RR-12248, DK-20541, M01-RR12248]; Life Sciences Research Foundation; MGH ECOR Fund FX This work was supported by National Institutes of Health grants: R01 HL087681 (to M. H. S), K24 AG025727 (to T. T. P), R01 AR055115 (to M. M.), RO1 AG027216 (to C. B.), the Italian Ministry of Research and University (to A. P. and A. M), and the following grants to G. A, A. B. and N. B.: AG-027734, AG-18728, RR-12248, DK-20541, and M01-RR12248 and a grant from the Glenn Foundation. M. C. W. is supported by a Life Sciences Research Foundation fellowship. S. E. J. F. is supported by the MGH ECOR Fund for Medical Discovery. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 40 Z9 44 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 DEC 14 PY 2009 VL 4 IS 12 AR e8210 DI 10.1371/journal.pone.0008210 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533NI UT WOS:000272830300005 PM 20011587 ER PT J AU Knebelmann, B Kurschat, C Thadhani, R AF Knebelmann, Bertrand Kurschat, Christine Thadhani, Ravi TI Enzyme therapy for Fabry's disease: registered for success? SO LANCET LA English DT Editorial Material ID REPLACEMENT THERAPY; AGALSIDASE-BETA; NEPHROPATHY; ALPHA C1 [Thadhani, Ravi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit, Boston, MA 02144 USA. [Knebelmann, Bertrand] Paris Descartes Univ, Necker Hosp, AP HP, Paris, France. [Kurschat, Christine] Univ Hosp Cologne, Dept Nephrol, Cologne, Germany. RP Thadhani, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit, Boston, MA 02144 USA. EM thadhani.r@mgh.harvard.edu NR 14 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD DEC 12 PY 2009 VL 374 IS 9706 BP 1950 EP 1951 DI 10.1016/S0140-6736(09)61838-9 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 532EA UT WOS:000272727000006 PM 19959220 ER PT J AU de Gelder, B AF de Gelder, Beatrice TI Why bodies? Twelve reasons for including bodily expressions in affective neuroscience SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Meeting on Computation of Emotions in Man and Machines CY APR, 2009 CL Royal Soc London, London, ENGLAND HO Royal Soc London ID DYNAMIC BODY EXPRESSIONS; NON-CONSCIOUS RECOGNITION; AUTISM SPECTRUM DISORDER; FACIAL EXPRESSIONS; ASPERGERS-SYNDROME; AMYGDALA THEORY; AFFECTIVE BLINDSIGHT; EMOTION PERCEPTION; BIOLOGICAL MOTION; FACE PERCEPTION AB Why bodies? It is rather puzzling that given the massive interest in affective neuroscience in the last decade, it still seems to make sense to raise the question 'Why bodies' and to try to provide an answer to it, as is the goal of this article. There are now hundreds of articles on human emotion perception ranging from behavioural studies to brain imaging experiments. These experimental studies complement decades of reports on affective disorders in neurological patients and clinical studies of psychiatric populations. The most cursory glance at the literature on emotion in humans, now referred to by the umbrella term of social and affective neuroscience, shows that over 95 per cent of them have used faces as stimuli. Of the remaining 5 per cent, a few have used scenes or auditory information including human voices, music or environmental sounds. But by far the smallest number has looked into whole-body expressions. As a rough estimate, a search on PubMed today, 1 May 2009, yields 3521 hits for emotion x faces, 1003 hits for emotion x music and 339 hits for emotion x bodies. When looking in more detail, the body x emotion category in fact yields a majority of papers on well-being, nursing, sexual violence or organ donation. But the number of cognitive and affective neuroscience studies of emotional body perception as of today is lower than 20. Why then have whole bodies and bodily expressions not attracted the attention of researchers so far? The goal of this article is to contribute some elements for an answer to this question. I believe that there is something to learn from the historical neglect of bodies and bodily expressions. I will next address some historical misconceptions about whole-body perception, and in the process I intend not only to provide an impetus for this kind of work but also to contribute to a better understanding of the significance of the affective dimension of behaviour, mind and brain as seen from the vantage point of bodily communication. Subsequent sections discuss available evidence for the neurofunctional basis of facial and bodily expressions as well as neuropsychological and clinical studies of bodily expressions. C1 [de Gelder, Beatrice] Tilburg Univ, Lab Cognit & Affect Neurosci, Tilburg, Netherlands. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [de Gelder, Beatrice] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP de Gelder, B (reprint author), Tilburg Univ, Lab Cognit & Affect Neurosci, Tilburg, Netherlands. EM degelder@uvt.nl NR 88 TC 102 Z9 102 U1 1 U2 22 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD DEC 12 PY 2009 VL 364 IS 1535 BP 3475 EP 3484 DI 10.1098/rstb.2009.0190 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 513PB UT WOS:000271333900005 PM 19884142 ER PT J AU Mochida, GH Mahajnah, M Hill, AD Basel-Vanagaite, L Gleason, D Hill, RS Bodell, A Crosier, M Straussberg, R Walsh, CA AF Mochida, Ganeshwaran H. Mahajnah, Muhammad Hill, Anthony D. Basel-Vanagaite, Lina Gleason, Danielle Hill, R. Sean Bodell, Adria Crosier, Moira Straussberg, Rachel Walsh, Christopher A. TI A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NONSYNDROMIC MENTAL-RETARDATION; NF-KAPPA-B; X-CHROMOSOME; GENE; NEUROGENESIS; DEFECT AB Although autosomal genes are increasingly recognized as important causes of intellectual disability, very few of them are known. We identified a genetic locus for autosomal-recessive nonsyndromic intellectual disability associated with variable postnatal microcephaly through homozygosity mapping of a consanguineous Israeli Arab family. Sequence analysis of genes in the candidate interval identified a nonsense nucleotide change in the gene that encodes TRAPPC9 (trafficking protein particle complex 9, also known as NIBP), which has been implicated in NF-kappa B activation and possibly in intracellular protein trafficking. TRAPPC9 is highly expressed in the postmitotic neurons of the cerebral cortex, and MRI analysis of affected patients shows defects in axonal connectivity. This suggests essential roles of TRAPPC9 in human brain development, possibly through its effect on NF-kappa B activation and protein trafficking in the postmitotic neurons of the cerebral cortex. C1 [Mochida, Ganeshwaran H.; Hill, Anthony D.; Hill, R. Sean; Bodell, Adria; Walsh, Christopher A.] Harvard Univ, Sch Med, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Hill, Anthony D.; Hill, R. Sean; Bodell, Adria; Walsh, Christopher A.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Gleason, Danielle; Walsh, Christopher A.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Gleason, Danielle; Walsh, Christopher A.] Childrens Hosp, Manton Ctr Orphan Dis Res, Dept Med, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.] Massachusetts Gen Hosp, Dept Neurol, Pediat Neurol Unit, Boston, MA 02114 USA. [Mahajnah, Muhammad] Hillel Yaffe Med Ctr, Pediat Neurol & Child Dev Ctr, IL-38100 Hadera, Israel. [Mahajnah, Muhammad] Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel. [Basel-Vanagaite, Lina] Schneider Childrens Med Ctr Israel, Dept Med Genet, IL-49202 Petah Tiqwa, Israel. [Straussberg, Rachel] Schneider Childrens Med Ctr Israel, Neurogenet Clin, IL-49202 Petah Tiqwa, Israel. [Basel-Vanagaite, Lina] Rabin Med Ctr, Raphael Recanati Genet Inst, IL-49202 Petah Tiqwa, Israel. [Basel-Vanagaite, Lina; Straussberg, Rachel] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Crosier, Moira] Newcastle Univ, MRC Wellcome Trust Human Dev Biol Resource Newcas, Inst Human Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. RP Walsh, CA (reprint author), Harvard Univ, Sch Med, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM christopher.walsh@childrens.harvard.edu FU National Institutes of Health to The Johns Hopkins University [FIHSN268200782096C]; NINDS [2R01NS035129-12]; Nancy Lurie Marks Family Foundation; Dubai Harvard Foundation for Medical Research; Simons Foundation; Manton Center for Orphan Disease Research; Young Investigator Award of NARSAD as a NARSAD Lieber Investigator; Investigator of the Howard Hughes Medical Institute FX We would like to thank the patients and family for their participation in this research. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number FIHSN268200782096C. We thank Jennifer Partlow and Brenda Barry for coordinating patient studies, James Barkovich for help in interpretation of brain MRI of Patient 2, Jillian Felie and Dan Rakiec for technical assistance in DNA sequencing, the Partners HealthCare Center for Personalized Genetic Medicine for establishing the lymphoblast cell lines, and Urs Berger for help with in situ hybridization using the mouse brain. The authors would like to thank Jacques Michaud for sharing DNA samples. The human embryonic and fetal material was provided by, the joint MRC-Wellcome Trust Human Developmental Biology Resource at the Institute of Human Genetics, Newcastle-upon-Tyne, UK. We thank the consenting women who made this study possible and A. Farnworth, who gained consent on our behalf. This research was supported by grants from the NINDS (2R01NS035129-12) to C.A.W. and by the Nancy Lurie Marks Family Foundation, the Dubai Harvard Foundation for Medical Research, the Simons Foundation, and the Manton Center for Orphan Disease Research. G.H.M. was supported by the Young Investigator Award of NARSAD as a NARSAD Lieber Investigator. C.A.W. is an Investigator of the Howard Hughes Medical Institute. NR 22 TC 53 Z9 55 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 11 PY 2009 VL 85 IS 6 BP 897 EP 902 DI 10.1016/j.ajhg.2009.10.027 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 533BN UT WOS:000272797100013 PM 20004763 ER PT J AU Rha, GB Wu, G Shoelson, SE Chi, YI AF Rha, Geun Bae Wu, Guangteng Shoelson, Steven E. Chi, Young-In TI Multiple Binding Modes between HNF4 alpha and the LXXLL Motifs of PGC-1 alpha Lead to Full Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR-GAMMA COACTIVATOR-1-ALPHA; NUCLEAR FACTOR 4-ALPHA; ALPHA ERR-ALPHA; TRANSCRIPTIONAL COACTIVATOR; ESTROGEN-RECEPTOR; GENE-EXPRESSION; LIGAND-BINDING; STRUCTURAL BASIS; INSULIN-SECRETION; ANDROGEN RECEPTOR AB Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4 alpha interacts, peroxisome proliferation-activated receptor gamma(PPAR gamma) coactivator 1 alpha(PGC-1 alpha) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1 alpha recruitment, we have determined the crystal structure of HNF4 alpha in complex with a fragment of PGC-1 alpha containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4 alpha toward the LXXLL motifs of PGC-1 alpha could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators. C1 [Rha, Geun Bae; Wu, Guangteng; Chi, Young-In] Univ Kentucky, Dept Mol & Cellular Biochem, Struct Biol Ctr, Lexington, KY 40536 USA. [Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Shoelson, Steven E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Chi, YI (reprint author), Univ Kentucky, Dept Mol & Cellular Biochem, Struct Biol Ctr, 741 S Limestone Ave, Lexington, KY 40536 USA. EM ychi@uky.edu FU National Institutes of Health [P20RR20171]; American Diabetes Association [7-08-CD-03] FX This work was supported, in whole or in part, by National Institutes of Health Grant P20RR20171 from the COBRE Program of the NCRR. This work was also supported by American Diabetes Association Grant 7-08-CD-03 (to Y.I.C.). NR 75 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 11 PY 2009 VL 284 IS 50 BP 35165 EP 35176 DI 10.1074/jbc.M109.052506 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528JG UT WOS:000272439600070 PM 19846556 ER PT J AU Zou, L AF Zou, Lee TI Checkpoint Mec-tivation Comes in Many Flavors SO MOLECULAR CELL LA English DT Editorial Material ID DNA-DAMAGE CHECKPOINT; DPB11; COMPLEX; TOPBP1; REPLICATION; PROTEIN; KINASE; ATRIP AB In this issue of Molecular Cell, Navadgi-Patil and Burgers show that the budding yeast Mec1 kinase is activated by DNA damage through two distinct Ddc1-mediated mechanisms during G1 and G2 phases of the cell cycle. C1 [Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 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 NR 10 TC 3 Z9 3 U1 0 U2 0 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 DEC 11 PY 2009 VL 36 IS 5 BP 734 EP 735 DI 10.1016/j.molcel.2009.11.026 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 535JV UT WOS:000272965400007 PM 20005837 ER PT J AU Voytas, DF Joung, JK AF Voytas, Daniel F. Joung, J. Keith TI DNA Binding Made Easy SO SCIENCE LA English DT Editorial Material ID GENE; RICE C1 [Voytas, Daniel F.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Voytas, Daniel F.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Voytas, DF (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. EM voytas@umn.edu FU NIH HHS [DP1 OD006862] NR 10 TC 13 Z9 14 U1 2 U2 6 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 DEC 11 PY 2009 VL 326 IS 5959 BP 1491 EP 1492 DI 10.1126/science.1183604 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 530WS UT WOS:000272623600044 PM 20007890 ER PT J AU Verduzco, LA Nathan, DG AF Verduzco, Luis A. Nathan, David G. TI Sickle cell disease and stroke SO BLOOD LA English DT Review ID IRON-CHELATION-THERAPY; TRANSCRANIAL DOPPLER; TRANSFUSION THERAPY; FETAL-HEMOGLOBIN; CORD BLOOD; POLYCYTHEMIA-VERA; THALASSEMIA MAJOR; RECURRENT STROKE; CEREBROVASCULAR-DISEASE; HYDROXYUREA TREATMENT AB Twenty-four percent of sickle cell disease (SCD) patients have a stroke by the age of 45 years. Blood transfusions decrease stroke risk in patients deemed high risk by transcranial Doppler. However, transcranial Doppler has poor specificity, and transfusions are limited by alloimmunization and iron overload. Transfusion withdrawal may be associated with an increased rebound stroke risk. Extended blood typing decreases alloimmunization in SCD but is not universally adopted. Transfusions for thalassemia begun in early childhood are associated with lower rates of alloimmunization than are seen in SCD, suggesting immune tolerance. Optimal oxygen transport efficiency occurs at a relatively low hematocrit for SCD patients because of hyperviscosity. Consequently, exchange rather than simple transfusions are more effective in improving oxygen transport efficiency, but the former are technically more demanding and require more blood units. Although viscosity is of importance in the noncerebral manifestations of SCD, inflammation may play a larger role than viscosity in the development of large-vessel stroke. The future of SCD stroke management lies in the avoidance of transfusion. Hydroxyurea and anti-inflammatory measures may reduce the need for transfusion. Recent genome-wide association studies may provide methods for modulating fetal hemoglobin production enough to attenuate stroke risk and other complications of SCD. (Blood. 2009; 114: 5117-5125) C1 [Nathan, David G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nathan, David G.] Childrens Hosp, Boston, MA 02115 USA. [Verduzco, Luis A.; Nathan, David G.] Harvard Univ, Sch Med, Boston, MA USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM david_nathan@dfci.harvard.edu NR 115 TC 54 Z9 55 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 DEC 10 PY 2009 VL 114 IS 25 BP 5117 EP 5125 DI 10.1182/blood-2009-05-220921 PG 9 WC Hematology SC Hematology GA 530SH UT WOS:000272612100003 PM 19797523 ER PT J AU Aryee, MJ Gutierrez-Pabello, JA Kramnik, I Maiti, T Quackenbush, J AF Aryee, Martin J. Gutierrez-Pabello, Jose A. Kramnik, Igor Maiti, Tapabrata Quackenbush, John TI An improved empirical bayes approach to estimating differential gene expression in microarray time-course data: BETR (Bayesian Estimation of Temporal Regulation) SO BMC BIOINFORMATICS LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS INFECTION; GRANULOMA-FORMATION; UP-REGULATION; MICE; PROFILES; IMMUNITY; MODEL AB Background: Microarray gene expression time-course experiments provide the opportunity to observe the evolution of transcriptional programs that cells use to respond to internal and external stimuli. Most commonly used methods for identifying differentially expressed genes treat each time point as independent and ignore important correlations, including those within samples and between sampling times. Therefore they do not make full use of the information intrinsic to the data, leading to a loss of power. Results: We present a flexible random-effects model that takes such correlations into account, improving our ability to detect genes that have sustained differential expression over more than one time point. By modeling the joint distribution of the samples that have been profiled across all time points, we gain sensitivity compared to a marginal analysis that examines each time point in isolation. We assign each gene a probability of differential expression using an empirical Bayes approach that reduces the effective number of parameters to be estimated. Conclusions: Based on results from theory, simulated data, and application to the genomic data presented here, we show that BETR has increased power to detect subtle differential expression in time-series data. The open-source R package betr is available through Bioconductor. BETR has also been incorporated in the freely-available, open-source MeV software tool available from http:/www.tm4.org/mev.html. C1 [Aryee, Martin J.; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gutierrez-Pabello, Jose A.; Kramnik, Igor] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Maiti, Tapabrata] Michigan State Univ, Dept Stat & Probabil, E Lansing, MI 48824 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Quackenbush, J (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM aryee@jhu.edu; jagp@servidor.unam.mx; ikramnik@hsph.harvard.edu; maiti@stt.msu.edu; johnq@jimmy.harvard.edu OI Kramnik, Igor/0000-0001-6511-9246 FU US National Institutes of Health [HL059836, 1P50 HG004233] FX We thank Thomas Hoffmann for assistance with microarray data preprocessing, Louise Ryan for helpful discussions about statistical methodology, and James Sissons and Alexander Pichugin for valuable insights into tuberculosis pathogenesis. This work was supported in part by the US National Institutes of Health [IK by HL059836; MA and JQ by 1P50 HG004233]. NR 28 TC 49 Z9 49 U1 1 U2 4 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 DEC 10 PY 2009 VL 10 AR 409 DI 10.1186/1471-2105-10-409 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 540LD UT WOS:000273332200001 PM 20003283 ER PT J AU Cohen, AB Bianchi, MT AF Cohen, Adam B. Bianchi, Matt T. TI Commentary: Neurological perspective SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material C1 [Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, SL Div, Boston, MA 02114 USA. [Cohen, Adam B.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Bianchi, MT (reprint author), Massachusetts Gen Hosp, Dept Neurol, SL Div, Boston, MA 02114 USA. EM mtbianchi@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD DEC 10 PY 2009 VL 339 AR b5250 DI 10.1136/bmj.b5250 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 531VH UT WOS:000272697600009 PM 20007661 ER PT J AU Garber, JE Golshan, M AF Garber, Judy E. Golshan, Mehra TI Contralateral Breast Cancer in BRCA1/BRCA2 Mutation Carriers: The Story of the Other Side SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PROPHYLACTIC MASTECTOMY; RISK ASSESSMENT C1 [Garber, Judy E.] Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Garber, JE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 16 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 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2009 VL 27 IS 35 BP 5862 EP 5864 DI 10.1200/JCO.2009.25.1652 PG 4 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700002 PM 19858367 ER PT J AU Bertagnolli, MM AF Bertagnolli, Monica M. TI The Forest and the Trees: Pathways and Proteins As Colorectal Cancer Biomarkers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID HUMAN BREAST; TUMORIGENESIS C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 8 TC 7 Z9 8 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2009 VL 27 IS 35 BP 5866 EP 5867 DI 10.1200/JCO.2009.24.8013 PG 3 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700004 PM 19884524 ER PT J AU Bhattacharya, S Fyfe, G Gray, RJ Sargent, DJ AF Bhattacharya, Suman Fyfe, Gwen Gray, Robert J. Sargent, Daniel J. TI Role of Sensitivity Analyses in Assessing Progression-Free Survival in Late-Stage Oncology Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MATTERS AB Sensitivity analysis is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. Until recently, sensitivity analyses were rarely included in phase III trials, and they remain poorly understood by many oncologists. Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis of a late-stage clinical trial. They examine the influence of protocol design errors, unintended biases, deviations from assumptions underlying statistical models, and any unanticipated treatment delivery or practice patterns on trial results. In trials with complex or subjective end points, they also allow an understanding of the extent to which a positive outcome is driven by a single, possibly subjective, and therefore biased, element of an end point. The purposes of this article are to explain how sensitivity analyses are performed, to discuss areas of a clinical trial where sensitivity analyses should focus, and to illuminate the importance of this technique in the rigorous evaluation of late-stage clinical trial data, using specific examples. This article focuses on late-stage trials that use progression-free survival or time to progression as their primary end point, because sensitivity analyses are particularly important in these cases for which the end point is potentially subject to bias. Three sources of potential bias are explored: assessment time, symptomatic (ie, nonradiologic) disease progression, and missing data. For each source of potential bias, case studies are presented to highlight the role that sensitivity analyses play in determining whether the trial's conclusions are robust. C1 Genentech Inc, San Francisco, CA 94080 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. RP Bhattacharya, S (reprint author), 1 DNA Way,MS 242B, San Francisco, CA 94080 USA. EM sumanb@gene.com OI Sargent, Daniel/0000-0002-2684-4741 NR 16 TC 19 Z9 19 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 DEC 10 PY 2009 VL 27 IS 35 BP 5958 EP 5964 DI 10.1200/JCO.2009.22.4329 PG 7 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700019 PM 19826121 ER PT J AU Wo, JY Chen, MH Nguyen, PL Renshaw, AA Loffredo, MJ Kantoff, PW D'Amico, AV AF Wo, Jennifer Y. Chen, Ming-Hui Nguyen, Paul L. Renshaw, Andrew A. Loffredo, Marian J. Kantoff, Philip W. D'Amico, Anthony V. TI Evaluating the Combined Effect of Comorbidity and Prostate-Specific Antigen Kinetics on the Risk of Death in Men After Prostate-Specific Antigen Recurrence SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER-SPECIFIC MORTALITY; RADICAL PROSTATECTOMY; ANDROGEN SUPPRESSION; RADIATION-THERAPY; RANDOMIZED-TRIAL AB Purpose We examined whether time-dependent continuous prostate-specific antigen (PSA) velocity at recurrence was associated with all cause mortality (ACM) adjusting for comorbidity levels among men treated with definitive radiation therapy (RT) alone with or without androgen suppression therapy (AST) in the setting of a randomized controlled trial. Patients and Methods From 1995 to 2001, 206 men with localized, unfavorable prostate cancer were randomly assigned to receive RT alone or RT and AST combined. Cox multivariate regression analysis was performed to evaluate the relationship between PSA velocity at recurrence and ACM, adjusting for known prostate cancer prognostic factors, including Adult Comorbidity Evaluation 27 comorbidity level. Results With a median follow-up of 8.4 years, 89 biochemical recurrences and 74 ACM deaths occurred. Among all patients, higher PSA velocity was associated with increased ACM (hazard ratio [HR], 1.47; 95% CI, 1.07 to 1.44; P < .001) after adjusting for age, treatment arm, comorbidity score, and salvage AST. For 89 patients with biochemical recurrence, increasing PSA velocity at recurrence (HR, 1.60; 95% CI, 1.23 to 2.09; P <= .001) and moderate to severe comorbidity score (HR, 7.94; 95% CI, 1.55 to 40.52; P = .01) were associated with increased ACM. PSA velocity at recurrence was associated with significantly higher risk of ACM among patients with no or minimal comorbidity (P < .001), but not moderate to severe comorbidity (P = .12). Conclusion Rapid PSA velocity at recurrence is significantly associated with an increased risk of ACM among patients with no or minimal comorbidity but not moderate to severe comorbidity. These findings support judicious use of salvage AST, particularly in men with moderate to severe comorbidities, where prospective surveillance protocols are needed. C1 [Wo, Jennifer Y.] Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. RP Wo, JY (reprint author), Brigham & Womens Hosp, 75 Francis St,ASB1 L2, Boston, MA 02115 USA. EM jwo@partners.org NR 18 TC 7 Z9 7 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 DEC 10 PY 2009 VL 27 IS 35 BP 6000 EP 6005 DI 10.1200/JCO.2009.23.6067 PG 6 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700025 PM 19858385 ER PT J AU Horn, L Dahlberg, SE Sandler, AB Dowlati, A Moore, DF Murren, JR Schiller, JH AF Horn, Leora Dahlberg, Suzanne E. Sandler, Alan B. Dowlati, Afshin Moore, Dennis F. Murren, John R. Schiller, Joan H. TI Phase II Study of Cisplatin Plus Etoposide and Bevacizumab for Previously Untreated, Extensive-Stage Small-Cell Lung Cancer: Eastern Cooperative Oncology Group Study E3501 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; ENDOTHELIAL GROWTH-FACTOR; E-SELECTIN; CLINICOPATHOLOGICAL FEATURES; COLORECTAL-CANCER; RANDOMIZED TRIAL; SERUM-LEVELS; CARBOPLATIN; PACLITAXEL; CYCLOPHOSPHAMIDE AB Purpose To investigate the efficacy and safety of bevacizumab plus cisplatin and etoposide in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Patients and Methods In this phase II trial, 63 patients were treated with bevacizumab 15 mg/kg plus cisplatin 60 mg/m(2) and etoposide 120 mg/m(2), which was followed by bevacizumab alone until death or disease progression occurred. The primary end point was the proportion of patients alive at 6 months without disease progression (ie, progression-free survival [PFS]). Secondary end points included overall survival (OS), objective response rate, and toxicity. Correlative studies were performed to explore the relationship between baseline and changes in plasma vascular endothelial growth factor (VEGF), soluble cell adhesion molecules (ie, vascular cell adhesion molecule [VCAM], intercellular cell adhesion molecule [ICAM], and E-selectin) and basic fibroblast growth factor and outcome. Results The 6-month PFS was 30.2%, the median PFS was 4.7 months, and OS was 10.9 months. The response rate was 63.5%. The most common adverse event was neutropenia (57.8%). Only one patient had grade 3 pulmonary hemorrhage. Patients who had high baseline VCAM had a higher risk of progression or death compared with those who had low baseline VCAM levels. No relationships between outcome and any other biomarkers were seen. Conclusion The addition of bevacizumab to cisplatin and etoposide in patients with ED-SCLC results in improved PFS and OS relative to historical controls who received this chemotherapy regimen without bevacizumab. This regimen appears to be well tolerated and has minimal increase in toxicities compared with chemotherapy alone. Baseline VCAM levels predicted survival, but no other relationships among treatment, biomarkers, and outcome were identified. C1 Vanderbilt Univ, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Oregon Hlth & Sci Univ, Portland, OR USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Wichita Community Clin Oncol Practice, Wichita, KS USA. Yale Univ, Sch Med, New Haven, CT USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Schiller, JH (reprint author), Univ Texas SW, Dept Med, Div Hematol Oncol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM joan.schiller@utsouthwestern.edu FU National Cancer Institute, National Institutes of Health and the Department of Health and Human Services [CA23318, CA66636, CA21115, CA49957, CA07190, CA14548] FX Supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA49957, CA07190, and CA14548 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. NR 24 TC 70 Z9 76 U1 1 U2 4 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 DEC 10 PY 2009 VL 27 IS 35 BP 6006 EP 6011 DI 10.1200/JCO.2009.23.7545 PG 6 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700026 PM 19826110 ER PT J AU Qi, Y Spong, MC Nam, K Banerjee, A Jiralerspong, S Karplus, M Verdine, GL AF Qi, Yan Spong, Marie C. Nam, Kwangho Banerjee, Anirban Jiralerspong, Sao Karplus, Martin Verdine, Gregory L. TI Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme SO NATURE LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; EMPIRICAL FORCE-FIELD; ESCHERICHIA-COLI; FREE-ENERGY; STRUCTURAL BASIS; NUCLEIC-ACIDS; FPG PROTEIN; DAMAGED DNA; DUPLEX DNA; RECOGNITION AB How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein-DNA interfaces in the matched complexes differ by only two atoms-those that distinguish oxoG from G-their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway. C1 [Spong, Marie C.; Nam, Kwangho; Banerjee, Anirban; Jiralerspong, Sao; Karplus, Martin; Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Qi, Yan; Verdine, Gregory L.] Harvard Univ, Sch Med, Grad Program Biophys, Boston, MA 02115 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Chem Biol Initiat, Boston, MA 02115 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Karplus, Martin] Univ Strasbourg, ISIS, F-67000 Strasbourg, France. RP Karplus, M (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM marci@tammy.harvard.edu; gregory_verdine@harvard.edu FU NIH [GM044853, GM047467, CA100742, GM030804]; the National Science Foundation; Howard Hughes Medical Institute; National Cancer Center FX This work was supported by grants from the NIH: GM044853, GM047467, CA100742 ( G. L. V.) and GM030804 ( M. K.). Y. Q. is supported by a predoctoral fellowship from the National Science Foundation; M. C. S. by a predoctoral fellowship from the Howard Hughes Medical Institute; K. N. by a postdoctoral fellowship from National Cancer Center. We thank the staff of the NSLS, APS and CHESS synchrotron facilities. These experiments made use of the computing facilities at NERSC and Harvard FAS. We are grateful to J. Jin for experimental assistance and J. Pu, V. Ovchinnikov and other members of the Karplus and Verdine groups for helpful advice. NR 47 TC 74 Z9 74 U1 1 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 10 PY 2009 VL 462 IS 7274 BP 762 EP U79 DI 10.1038/nature08561 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529ZZ UT WOS:000272559900032 PM 20010681 ER PT J AU Gostissa, M Yan, CT Bianco, JM Cogne, M Pinaud, E Alt, FW AF Gostissa, Monica Yan, Catherine T. Bianco, Julia M. Cogne, Michel Pinaud, Eric Alt, Frederick W. TI Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3 ' regulatory region SO NATURE LA English DT Article ID HEAVY-CHAIN LOCUS; CLASS-SWITCH RECOMBINATION; B-CELL DEVELOPMENT; CHROMOSOMAL TRANSLOCATIONS; V(D)J RECOMBINATION; GENE AMPLIFICATION; TRANSGENIC MICE; DNA BREAKS; END; MECHANISM AB B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh)(1). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR)(2-4). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (C mu) exons, which are the first of several sets of CH exons ('C(H) genes') within a CH locus that span several hundred kilobases (kb)(5,6). In mature B cells, CSR deletes C mu and replaces it with a downstream C(H) gene(6). An intronic enhancer (iE mu) between the variable region exons and C mu promotes V(D)J recombination in developing B cells(7). Furthermore, the Igh 3' regulatory region (Igh3' RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes(8-10). Transgenic mice bearing iE mu or Igh3' RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression(11-16). However, in many B-cell lymphomas, Igh-c-myc translocations delete iE mu and place c-myc up to 200 kb upstream of the Igh3' RR(1). Here we address the oncogenic role of the Igh3' RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3' RR is dispensable for pro-B-cell lymphomas with V( D) J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3' RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes. C1 [Gostissa, Monica; Yan, Catherine T.; Bianco, Julia M.; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Gostissa, Monica; Yan, Catherine T.; Bianco, Julia M.; Alt, Frederick W.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Gostissa, Monica; Yan, Catherine T.; Bianco, Julia M.; Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Gostissa, Monica; Yan, Catherine T.; Bianco, Julia M.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Cogne, Michel; Pinaud, Eric] Univ Limoges, CNRS, Fac Med, UMR 6101, Limoges, France. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI PINAUD, Eric/O-8443-2016; cogne, michel/D-7370-2015 OI PINAUD, Eric/0000-0001-7405-9273; cogne, michel/0000-0002-8519-4427 FU National Institutes of Health (NIH) [CA92625]; Leukemia and Lymphoma Society of America (LLS) SCORE; NCI; de Villiers International Achievement Award; Fondation pour la Recherche Medicale; Howard Hughes Medical Institute FX We thank L. G. Jiang for help with cloning translocation breakpoints. This work was supported by National Institutes of Health (NIH) grant CA92625 and the Leukemia and Lymphoma Society of America (LLS) SCORE grant to F. W. A. M. G. was a Special Fellow of the LLS and C.T.Y. was supported by an NCI training grant. M. G. and C. T. Y. were also supported by the de Villiers International Achievement Award of the LLS to F. W. A. E. P. was a Fellow of the Fondation pour la Recherche Medicale. F. W. A. is an Investigator of the Howard Hughes Medical Institute. NR 30 TC 48 Z9 49 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 10 PY 2009 VL 462 IS 7274 BP 803 EP U128 DI 10.1038/nature08633 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529ZZ UT WOS:000272559900042 PM 20010689 ER PT J AU Harrington, RA Stone, GW McNulty, S White, HD Lincoff, AM Gibson, CM Pollack, CV Montalescot, G Mahaffey, KW Kleiman, NS Goodman, SG Amine, M Angiolillo, DJ Becker, RC Chew, DP French, WJ Leisch, F Parikh, KH Skerjanec, S Bhatt, DL AF Harrington, Robert A. Stone, Gregg W. McNulty, Steven White, Harvey D. Lincoff, A. Michael Gibson, C. Michael Pollack, Charles V., Jr. Montalescot, Gilles Mahaffey, Kenneth W. Kleiman, Neal S. Goodman, Shaun G. Amine, Maged Angiolillo, Dominick J. Becker, Richard C. Chew, Derek P. French, William J. Leisch, Franz Parikh, Keyur H. Skerjanec, Simona Bhatt, Deepak L. TI Platelet Inhibition with Cangrelor in Patients Undergoing PCI. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE CORONARY SYNDROMES; PLACEBO-CONTROLLED TRIAL; ST-SEGMENT ELEVATION; ACUTE MYOCARDIAL-INFARCTION; PROCOAGULANT ACTIVITY; RECEPTOR ANTAGONISTS; RANDOMIZED-TRIAL; STENT THROMBOSIS; END-POINTS; CLOPIDOGREL AB Background: Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(sub 12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition. Methods: We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. Results: We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14). Conclusions: Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.) N Engl J Med 2009;361:2318-29. C1 [Harrington, Robert A.; McNulty, Steven; Mahaffey, Kenneth W.; Becker, Richard C.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Stone, Gregg W.] Columbia Univ, Med Ctr, New York, NY USA. [Stone, Gregg W.] Cardiovasc Res Fdn, New York, NY USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Lincoff, A. Michael] Cleveland Clin, Cleveland, OH USA. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pollack, Charles V., Jr.] Univ Penn, Penn Hosp, Philadelphia, PA 19104 USA. [Montalescot, Gilles] Hop La Pitie Salpetriere, Inst Cardiol, Paris, France. [Kleiman, Neal S.] Methodist Hosp, Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Amine, Maged] NW Heart Ctr, Tomball, TX USA. [Goodman, Shaun G.] St Michaels Hosp, Terrence Donnelly Heart Ctr, Div Cardiol, Toronto, ON M5B 1W8, Canada. [Goodman, Shaun G.] Canadian Heart Res Ctr, Toronto, ON, Canada. [Angiolillo, Dominick J.] Univ Florida, Coll Med, Jacksonville, FL USA. [Chew, Derek P.] Flinders Univ S Australia, Adelaide, SA 5001, Australia. [Chew, Derek P.] Flinders Med Ctr, Adelaide, SA, Australia. [French, William J.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Leisch, Franz] City Hosp Linz, Div Cardiovasc, Linz, Austria. [Parikh, Keyur H.] Heart Care Clin, Ahmadabad, Gujarat, India. [Skerjanec, Simona] Medicines Co, Parsippany, NJ USA. RP Harrington, RA (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM robert.harrington@duke.edu RI bashzar, salman/R-5748-2016 NR 35 TC 280 Z9 300 U1 0 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 10 PY 2009 VL 361 IS 24 BP 2318 EP 2329 DI 10.1056/NEJMoa0908628 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 529VS UT WOS:000272547600006 PM 19915221 ER PT J AU Bhatt, DL Lincoff, AM Gibson, CM Stone, GW McNulty, S Montalescot, G Kleiman, NS Goodman, SG White, HD Mahaffey, KW Pollack, CV Manoukian, SV Widimsky, P Chew, DP Cura, F Manukov, I Tousek, F Jafar, MZ Arneja, J Skerjanec, S Harrington, RA AF Bhatt, Deepak L. Lincoff, A. Michael Gibson, C. Michael Stone, Gregg W. McNulty, Steven Montalescot, Gilles Kleiman, Neal S. Goodman, Shaun G. White, Harvey D. Mahaffey, Kenneth W. Pollack, Charles V., Jr. Manoukian, Steven V. Widimsky, Petr Chew, Derek P. Cura, Fernando Manukov, Ivan Tousek, Frantisek Jafar, M. Zubair Arneja, Jaspal Skerjanec, Simona Harrington, Robert A. CA CHAMPION PLATFORM Investigators TI Intravenous Platelet Blockade with Cangrelor during PCI. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; ANTIPLATELET-THERAPY; ELUTING STENTS; CLOPIDOGREL; TRIAL; ASPIRIN; PRETREATMENT; PRASUGREL AB Background: Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI). Methods: In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point. Results: The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas. Conclusions: The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.) N Engl J Med 2009;361:2330-41. C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA 02132 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Lincoff, A. Michael] Cleveland Clin, Cleveland, OH USA. [Stone, Gregg W.] Columbia Univ, Med Ctr, New York, NY USA. [Stone, Gregg W.] Cardiovasc Res Fdn, New York, NY USA. [Jafar, M. Zubair] Hudson Valley Heart Ctr, Poughkeepsie, NY USA. [McNulty, Steven; Mahaffey, Kenneth W.; Harrington, Robert A.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Montalescot, Gilles] Hop La Pitie Salpetriere, Inst Cardiol, Paris, France. [Kleiman, Neal S.] Methodist Hosp, Methodist DeBakey Heart Ctr, Houston, TX 77030 USA. [Goodman, Shaun G.] St Michaels Hosp, Div Cardiol, Terrence Donnelly Heart Ctr, Toronto, ON M5B 1W8, Canada. [Goodman, Shaun G.] Canadian Heart Res Ctr, Toronto, ON, Canada. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Pollack, Charles V., Jr.] Univ Penn, Penn Hosp, Philadelphia, PA 19104 USA. [Manoukian, Steven V.] Sarah Cannon Res Inst, Nashville, TN USA. [Manoukian, Steven V.] Hosp Corp Amer, Nashville, TN USA. [Widimsky, Petr] Charles Univ Prague, Fac Med 3, Prague, Czech Republic. [Chew, Derek P.] Flinders Univ S Australia, Flinders Med Ctr, Adelaide, SA 5001, Australia. [Cura, Fernando] Inst Cardiovasc Buenos Aires, Dept Intervent Cardiol, Buenos Aires, DF, Argentina. [Manukov, Ivan] St Georges Univ Hosp, Clin Invas Cardiol, Plovdiv, Bulgaria. [Tousek, Frantisek] Reg Hosp, Ceske Budejovice, Czech Republic. [Arneja, Jaspal] Arneja Heart Inst, Nagpur, Maharashtra, India. [Skerjanec, Simona] Medicines Co, Parsippany, NJ USA. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, Boston, MA 02132 USA. EM dlbhattmd@post.harvard.edu RI Vasilieva, Elena/B-2137-2016; Cortese, Bernardo/M-4374-2016; Widimsky, Petr/P-8088-2016; OI Cortese, Bernardo/0000-0002-5808-7810; Widimsky, Petr/0000-0001-5686-7752; Leonardi, Sergio/0000-0002-4800-6132; Brilakis, Emmanouil/0000-0001-9416-9701 FU Medicines Company FX Supported by the Medicines Company. NR 24 TC 292 Z9 314 U1 1 U2 22 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 10 PY 2009 VL 361 IS 24 BP 2330 EP 2341 DI 10.1056/NEJMoa0908629 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 529VS UT WOS:000272547600007 PM 19915222 ER PT J AU Brass, SD Dinkin, MJ Williams, Z Krishnamoorthy, KS Copen, WA Freeman, SH AF Brass, Steven D. Dinkin, Marc J. Williams, Ziv Krishnamoorthy, Kalpathy S. Copen, William A. Freeman, Stefanie H. TI A 16-Year-Old Boy with Paroxysmal Headaches and Visual Changes Spinal arachnoid cyst. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC INTRACRANIAL HYPERTENSION; CEREBRAL VENOUS THROMBOSIS; OPTIC DISK EDEMA; PSEUDOTUMOR CEREBRI; MAGNETIC-RESONANCE; PEDIATRIC-PATIENTS; MENINGEAL CYSTS; BIFIDA OCCULTA; CAUDA-EQUINA; BRAIN-TUMOR C1 [Brass, Steven D.; Krishnamoorthy, Kalpathy S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dinkin, Marc J.] Massachusetts Gen Hosp, Dept Neuroophthalmol, Boston, MA 02114 USA. [Williams, Ziv] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Copen, William A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Freeman, Stefanie H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Brass, Steven D.; Dinkin, Marc J.; Krishnamoorthy, Kalpathy S.] Harvard Univ, Dept Neurol, Sch Med, Cambridge, MA 02138 USA. [Williams, Ziv] Harvard Univ, Dept Surg, Sch Med, Cambridge, MA 02138 USA. [Copen, William A.] Harvard Univ, Dept Radiol, Sch Med, Cambridge, MA 02138 USA. [Freeman, Stefanie H.] Harvard Univ, Dept Pathol, Sch Med, Cambridge, MA 02138 USA. RP Brass, SD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 46 TC 2 Z9 2 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 10 PY 2009 VL 361 IS 24 BP 2367 EP 2378 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 529VS UT WOS:000272547600012 PM 20007563 ER PT J AU Singh, H Wilson, L Petersen, LA Sawhney, MK Reis, B Espadas, D Sittig, DF AF Singh, Hardeep Wilson, Lindsey Petersen, Laura A. Sawhney, Mona K. Reis, Brian Espadas, Donna Sittig, Dean F. TI Improving follow-up of abnormal cancer screens using electronic health records: trust but verify test result communication SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID FECAL OCCULT-BLOOD; COMPLETE DIAGNOSTIC EVALUATION; COLORECTAL-CANCER; MALPRACTICE CLAIMS; UNITED-STATES; QUALITY; REASONS; ERRORS; CARE AB Background: Early detection of colorectal cancer through timely follow-up of positive Fecal Occult Blood Tests (FOBTs) remains a challenge. In our previous work, we found 40% of positive FOBT results eligible for colonoscopy had no documented response by a treating clinician at two weeks despite procedures for electronic result notification. We determined if technical and/or workflow-related aspects of automated communication in the electronic health record could lead to the lack of response. Methods: Using both qualitative and quantitative methods, we evaluated positive FOBT communication in the electronic health record of a large, urban facility between May 2008 and March 2009. We identified the source of test result communication breakdown, and developed an intervention to fix the problem. Explicit medical record reviews measured timely follow-up (defined as response within 30 days of positive FOBT) pre- and post-intervention. Results: Data from 11 interviews and tracking information from 490 FOBT alerts revealed that the software intended to alert primary care practitioners (PCPs) of positive FOBT results was not configured correctly and over a third of positive FOBTs were not transmitted to PCPs. Upon correction of the technical problem, lack of timely follow-up decreased immediately from 29.9% to 5.4% (p < 0.01) and was sustained at month 4 following the intervention. Conclusion: Electronic communication of positive FOBT results should be monitored to avoid limiting colorectal cancer screening benefits. Robust quality assurance and oversight systems are needed to achieve this. Our methods may be useful for others seeking to improve follow-up of FOBTs in their systems. C1 [Singh, Hardeep; Wilson, Lindsey; Petersen, Laura A.; Sawhney, Mona K.; Reis, Brian; Espadas, Donna] VA Med Ctr, Ctr Inquiry Improve Outpatient Safety Effect Elec, Houston, TX 77030 USA. [Singh, Hardeep; Wilson, Lindsey; Petersen, Laura A.; Sawhney, Mona K.; Reis, Brian; Espadas, Donna] VA Med Ctr, Houston VA HSR&D Ctr Excellence Michael E DeBakey, Houston, TX 77030 USA. [Singh, Hardeep; Petersen, Laura A.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, MEDVAMC,HSR&D Ctr Excellence, Houston, TX 77030 USA. [Sittig, Dean F.] Univ Texas Houston, Sch Hlth Informat Sci, Ctr Inquiry Improve Outpatient Safety Effect Elec, Houston, TX 77030 USA. [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX 77030 USA. RP Singh, H (reprint author), VA Med Ctr, Ctr Inquiry Improve Outpatient Safety Effect Elec, 152 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu; lawilson@bcm.tmc.edu; laurap@bcm.tmc.edu; sawhney@bcm.tmc.edu; bareis@bcm.tmc.edu; despadas@bcm.tmc.edu; Dean.F.Sittig@uth.tmc.edu FU NCI NIH HHS [K23CA125585] NR 28 TC 23 Z9 23 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD DEC 9 PY 2009 VL 9 AR 49 DI 10.1186/1472-6947-9-49 PG 7 WC Medical Informatics SC Medical Informatics GA 535YJ UT WOS:000273007600001 PM 20003236 ER PT J AU Tsai, TT Maddox, TM Roe, MT Dai, D Alexander, KP Ho, PM Messenger, JC Nallamothu, BK Peterson, ED Rumsfeld, JS AF Tsai, Thomas T. Maddox, Thomas M. Roe, Matthew T. Dai, David Alexander, Karen P. Ho, P. Michael Messenger, John C. Nallamothu, Brahmajee K. Peterson, Eric D. Rumsfeld, John S. CA Natl Cardiovasc Data Registry TI Contraindicated Medication Use in Dialysis Patients Undergoing Percutaneous Coronary Intervention SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CHRONIC-HEMODIALYSIS PATIENTS; DRUG-RELATED PROBLEMS; RENAL-INSUFFICIENCY; ENOXAPARIN; ANTICOAGULATION; REGISTRY AB Context The US Food and Drug Administration guides clinicians through drug labeling of medications that are contraindicated or not recommended for use in specific patient groups. Little is known about the use of such medications and their effects on outcomes in clinical practice. Objective To investigate the use of the contraindicated/not-recommended agents enoxaparin and eptifibatide among dialysis patients undergoing percutaneous coronary intervention (PCI) and their association with outcomes. Design, Setting, and Participants Data from 829 US hospitals on 22 778 dialysis patients who underwent PCI between January 1, 2004, and August 31, 2008. Main Outcome Measures In-hospital bleeding and death. Results Five thousand eighty-four patients (22.3%) received a contraindicated antithrombotic; of these patients, 2375 (46.7%) received enoxaparin, 3261 (64.1%) received eptifibatide, and 552 (10.9%) received both. Compared with patients who did not receive a contraindicated antithrombotic, patients who did had higher rates of in-hospital bleeding (5.6% vs 2.9%; odds ratio [OR], 1.93; 95% confidence interval [CI], 1.66-2.23) and death (6.5% vs 3.9%; OR, 1.68; 95% CI, 1.46-1.95). After multivariable adjustment, patients receiving contraindicated antithrombotics had significantly higher risks of in-hospital bleeding (OR, 1.66; 95% CI, 1.43-1.92) and death (OR, 1.24; 95% CI, 1.04-1.48). In 10 158 patients matched by propensity scores, receipt of contraindicated antithrombotics remained significantly associated with in-hospital bleeding (OR, 1.63; 95% CI, 1.35-1.98) but not in-hospital death (OR, 1.15; 95% CI, 0.97-1.36). Conclusions In a sample of dialysis patients undergoing PCI, 22.3% received a contraindicated antithrombotic medication. In propensity-matched analysis, receipt of these medications was significantly associated with an increased risk of in-hospital major bleeding. JAMA. 2009; 302(22): 2458-2464 C1 [Tsai, Thomas T.] Denver VA Med Ctr, Cardiol Sect 111B, Denver, CO 80220 USA. [Tsai, Thomas T.; Maddox, Thomas M.; Ho, P. Michael; Messenger, John C.; Rumsfeld, John S.] Univ Colorado, Denver, CO USA. [Tsai, Thomas T.; Maddox, Thomas M.; Ho, P. Michael; Rumsfeld, John S.] Colorado Cardiovasc Outcomes Res Grp, Denver, CO USA. [Roe, Matthew T.; Dai, David; Alexander, Karen P.; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Nallamothu, Brahmajee K.] Univ Michigan Hosp, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. RP Tsai, TT (reprint author), Denver VA Med Ctr, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. EM thomas.tsai@va.gov FU NCDR CathPCI Registry; VA Health Services Research and Development Service (HSR&D) Career Development Award FX This analysis was funded by the NCDR CathPCI Registry, which oversees the collection and management of data in the registry. Dr Ho is supported by a VA Health Services Research and Development Service (HSR&D) Career Development Award. NR 18 TC 46 Z9 46 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 9 PY 2009 VL 302 IS 22 BP 2458 EP 2464 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 529MD UT WOS:000272520500025 PM 19996401 ER PT J AU Hammitt, LL Bartlett, JP Li, SB Rahkola, J Lang, N Janoff, EN Levin, MJ Weinberg, A AF Hammitt, Laura L. Bartlett, Julie Patterson Li, Shaobing Rahkola, Jeremy Lang, Nancy Janoff, Edward N. Levin, Myron J. Weinberg, Adriana TI Kinetics of viral shedding and immune responses in adults following administration of cold-adapted influenza vaccine SO VACCINE LA English DT Article DE Cold-adapted influenza vaccine; Immunogenicity; Vaccine virus shedding ID CULTURE-CONFIRMED INFLUENZA; IMMUNIZATION PRACTICES ACIP; CD8(+) T-CELLS; VIRUS-VACCINE; YOUNG-CHILDREN; ADVISORY-COMMITTEE; LIVE; TRIVALENT; INFECTION; PROTECTION AB The optimal type and timing of specimens to study the immune responses to cold-adapted influenza vaccine (CAIV) and shedding of vaccine virus are not well established. Healthy adults were vaccinated with CAIV (n = 10) or trivalent influenza vaccine (TIV) (n = 5). Shedding of vaccine strain influenza B was detected by culture in 6 of 10 CAN recipients; influenza A was also detected in one of these subjects. Viral shedding by quantitative RT-PCR was detected in 9 of 10 subjects. We detected a >= 2-fold increase in influenza-specific IgA in nasal wash in 80-100% of CAIV recipients following vaccination, but specific IgG increased in neither nasal wash nor saliva. Recipients of TIV had significant increases in specific serum IgG antibodies. Recipients of both CAIV and TIV had significant increases in IFN gamma-secreting peripheral blood mononuclear cells (PBMCs). PBMCs from subjects receiving CAN showed a higher proportion of functional, tissue-tropic T-cells (CD4+CD69+CD18+MIP1 alpha+) specific for homotypic and heterosubtypic strains of influenza by flow cytometry. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Rahkola, Jeremy; Janoff, Edward N.] Univ Colorado Denver, Mucosal & Vaccine Res Ctr Colorado, Div Infect Dis, Dept Med,Denver Vet Affairs Med Ctr, Denver, CO USA. [Hammitt, Laura L.; Bartlett, Julie Patterson; Li, Shaobing; Lang, Nancy; Levin, Myron J.; Weinberg, Adriana] Univ Colorado Denver, Dept Pediat, Infect Dis Sect, Denver, CO USA. RP Hammitt, LL (reprint author), KEMRI Wellcome Trust, Ctr Geog Med Res Coast, POB 230, Kilifi 80108, Kenya. EM lhammitt@kilifi.kemri-wellcome.org FU MedImmune; NIH [R21 A1077069]; Veterans Affairs Research Service FX The authors give special thanks to Kelly Richardson and Adriana Tovar Salazar for assistance with specimen processing and T-cell assays; to Karen Helm at the UCHSC Cancer Center Flow Cytometry Core; to Alicia Huber for assistance with viral culture; to Tingting Yi for statistical advice; and George Kemble at Medimmune for providing attenuated influenza virus. Funding for the study was provided by MedImmune. Laura L. Hammitt was supported by a Pediatric Fellowship Program grant from MedImmune. Myron J. Levin and Adriana Weinberg are paid consultants for MedIMMUne. Edward N. Janoff was supported in part by NIH R21 A1077069 and the Veterans Affairs Research Service. Influenza strain-specific PCR primers were provided by CDC under a materials transfer agreement. NR 47 TC 21 Z9 22 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 9 PY 2009 VL 27 IS 52 BP 7359 EP 7366 DI 10.1016/j.vaccine.2009.09.041 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 541KP UT WOS:000273414900020 PM 19800447 ER PT J AU Schiffer, F Johnston, AL Ravichandran, C Polcari, A Teicher, MH Webb, RH Hamblin, MR AF Schiffer, Fredric Johnston, Andrea L. Ravichandran, Caitlin Polcari, Ann Teicher, Martin H. Webb, Robert H. Hamblin, Michael R. TI Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety SO BEHAVIORAL AND BRAIN FUNCTIONS LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; LEVEL LASER THERAPY; VISUAL-FIELD STIMULATION; CONTROLLED-TRIAL; DOUBLE-BLIND; ELECTROCONVULSIVE-THERAPY; RAYNAUDS-PHENOMENON; RAT-BRAIN; IRRADIATION; EFFICACY AB Background: Many studies have reported beneficial effects from the application of near-infrared (NIR) light photobiomodulation (PBM) to the body, and one group has reported beneficial effects applying it to the brain in stroke patients. We have reported that the measurement of a patient's left and right hemispheric emotional valence (HEV) may clarify data and guide lateralized treatments. We sought to test whether a NIR treatment could 1. improve the psychological status of patients, 2. show a relationship between immediate psychological improvements when HEV was taken into account, and 3. show an increase in frontal pole regional cerebral blood flow (rCBF), and 4. be applied without side effects. Methods: We gave 10 patients, (5 M/5 F) with major depression, including 9 with anxiety, 7 with a past history of substance abuse (6 with an opiate abuse and 1 with an alcohol abuse history), and 3 with post traumatic stress disorder, a baseline standard diagnostic interview, a Hamilton Depression Rating Scale (HAM-D), a Hamilton Anxiety Rating Scale (HAM-A), and a Positive and Negative Affect Scale (PANAS). We then gave four 4-minute treatments in a random order: NIR to left forehead at F3, to right forehead at F4, and placebo treatments (light off) at the same sites. Immediately following each treatment we repeated the PANAS, and at 2-weeks and at 4-weeks post treatment we repeated all 3 rating scales. During all treatments we recorded total hemoglobin (cHb), as a measure of rCBF with a commercial NIR spectroscopy device over the left and the right frontal poles of the brain. Results: At 2-weeks post treatment 6 of 10 patients had a remission (a score <= 10) on the HAMD and 7 of 10 achieved this on the HAM-A. Patients experienced highly significant reductions in both HAM-D and HAM-A scores following treatment, with the greatest reductions occurring at 2 weeks. Mean rCBF across hemispheres increased from 0.011 units in the off condition to 0.043 units in the on condition, for a difference of 0.032 (95% CI: -0.016, 0.080) units, though this result did not reach statistical significance. Immediately after treatment the PANAS improved to a significantly greater extent with NIR "on" relative to NIR "off" when a hemisphere with more positive HEV was treated than when one with more negative HEV was treated. We observed no side effects. Conclusion: This small feasibility study suggests that NIR-PBM may have utility for the treatment of depression and other psychiatric disorders and that double blind randomized placebo-controlled trials are indicated. C1 [Schiffer, Fredric; Ravichandran, Caitlin; Polcari, Ann; Teicher, Martin H.] Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. [Schiffer, Fredric; Polcari, Ann; Teicher, Martin H.] McLean Hosp, Dev Biopsychiat Res Program, Belmont, MA 02478 USA. [Ravichandran, Caitlin] McLean Hosp, Lab Psychiat Biostat, Belmont, MA 02478 USA. [Johnston, Andrea L.; Webb, Robert H.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Webb, Robert H.; 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 Schiffer, F (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 115 Mill St, Belmont, MA 02478 USA. EM fschiffer@mclean.harvard.edu; ajohnston2@partners.org; cravichandran@mclean.harvard.edu; apolcari@mclean.harvard.edu; martin_teicher@hms.harvard.edu; webb@eri.harvard.edu; hamblin@helix.mgh.harvard.edu FU Andre Danesh through the Combined Jewish Philanthropies FX The study was funded entirely by unrestricted contributions over the past 11 years by Andre Danesh through the Combined Jewish Philanthropies to McLean Hospital for the research of FS. Andre Danesh had no 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 55 TC 56 Z9 56 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-9081 J9 BEHAV BRAIN FUNCT JI Behav. Brain Funct. PD DEC 8 PY 2009 VL 5 AR 46 DI 10.1186/1744-9081-5-46 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 535OG UT WOS:000272979500001 PM 19995444 ER PT J AU Tokhtaeva, E Sachs, G Vagin, O AF Tokhtaeva, Elmira Sachs, George Vagin, Olga TI Assembly with the Na,K-ATPase alpha(1) Subunit Is Required for Export of beta(1) and beta(2) Subunits from the Endoplasmic Reticulum SO BIOCHEMISTRY LA English DT Article ID NA+-K+-ATPASE; ACTIVATED ADENOSINE-TRIPHOSPHATASE; SODIUM-POTASSIUM PUMP; INTRACELLULAR-TRANSPORT; PLASMA-MEMBRANE; FUNCTIONAL EXPRESSION; CRYSTAL-STRUCTURE; MOLECULAR-WEIGHT; N-GLYCOSYLATION; XENOPUS OOCYTES AB The level of the heterodimeric Na,K-ATPase is tightly controlled in epithelia to maintain appropriate transport function. The catalytic Na,K-ATPase alpha subunit is not able to exit the ER or catalyze ion transport unless assembled with the beta subunit. However, requirements for the ER exit of the Na,K-ATPase beta subunit that plays an additional, ion-transport-independent, role in Intercellular adhesion are not clear. Exogenous beta(1) or beta(2) subunits expressed in renal MDCK cells replace endogenous beta(1) subunits in the alpha-beta complexes in the ER, resulting in a decrease in the amount of the alpha(1)-bound endogenous beta(1) subunits by 47-61% with no change in the amount of alpha(1) subunits. Disruption of the alpha(1)-beta association by mutations in defined alpha(1)-interacting regions of either beta(1) or beta(2) subunits results in the ER retention and rapid degradation of unassembled mutants. Hence, the ER quality control system allows export only of assembled alpha-beta complexes to the Golgi, thereby maintaining an equimolar ratio of alpha and beta subunits in the plasma membrane, whereas the number of alpha(1) subunits in the ER determines the amount of the alpha-beta complexes. C1 [Vagin, Olga] Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. Vet Adm Greater Los Angeles Hlth Care Syst, VAGLAHS W LA, Los Angeles, CA 90073 USA. RP Vagin, O (reprint author), Univ Calif Los Angeles, Sch Med, Dept Physiol, Bldg 113,Room 324,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM olgav@ucla.edu FU NIH [DK077149, DK058333] FX Supported by NIH Grants DK077149 and DK058333. NR 44 TC 20 Z9 20 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 8 PY 2009 VL 48 IS 48 BP 11421 EP 11431 DI 10.1021/bi901438z PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523OP UT WOS:000272083900011 PM 19764716 ER PT J AU Zhong, W Celli, JP Rizvi, I Mai, Z Spring, BQ Yun, SH Hasan, T AF Zhong, W. Celli, J. P. Rizvi, I. Mai, Z. Spring, B. Q. Yun, S. H. Hasan, T. TI In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring SO BRITISH JOURNAL OF CANCER LA English DT Article DE imaging; optical fibre; photodynamic therapy (PDT); benzoporphyrin-derivative monoacid ring A (BPD-MA) ID INTRAPERITONEAL PHOTODYNAMIC THERAPY; MONOACID RING-A; PHASE-II TRIAL; 5-AMINOLEVULINIC ACID; CONFOCAL MICROSCOPY; COMPUTED-TOMOGRAPHY; BARRETTS-ESOPHAGUS; EPITHELIAL ACINI; MODEL; CARCINOMATOSIS AB BACKGROUND: In patients with advanced ovarian cancer (OvCa), microscopic residual tumour nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resolution fibre-optic fluorescence imaging of the clinically approved photodynamic therapy (PDT) agent benzoporphyin-derivative monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. METHODS: Our fluorescence microendoscope consists of a flexible imaging fibre coupled to a custom epi-fluorescence system optimised for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterisation in an in vitro OvCa 3D model, we used the flexible imaging fibre to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered intraperitoneally (i.p.). To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. RESULTS: By comparison with histopathology, we report an 86% sensitivity for tumour detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an average decrease of 58.8% in tumour volumes compared with an increase of 59.3% in untreated controls (P<0.05). CONCLUSIONS: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa. British Journal of Cancer (2009) 101, 2015-2022. doi: 10.1038/sj.bjc.6605436 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK C1 [Zhong, W.; Celli, J. P.; Rizvi, I.; Mai, Z.; Spring, B. Q.; Yun, S. H.; Hasan, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Rizvi, I.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. RP Hasan, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM thasan@partners.org OI Rizvi, Imran/0000-0001-9673-4700 FU National Institute of Health [5R01CA119388-03, P01 CA084203-06] FX We thank QLT Inc. (Vancouver, BC, Canada), for providing BPDMA. We also thank Pilhan Kim, Conor Evans, Prakash Rai, and Adnan Abu-Yousif of the Wellman Center for Photomedicine, and Esther Oliva of the Department of Pathology at the Massachusetts General Hospital for their many valuable insights resulting from discussions of this work. We also gratefully acknowledge funding from the National Institute of Health, 5R01CA119388-03 and P01 CA084203-06. NR 39 TC 59 Z9 60 U1 1 U2 18 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 DEC 8 PY 2009 VL 101 IS 12 BP 2015 EP 2022 DI 10.1038/sj.bjc.6605436 PG 8 WC Oncology SC Oncology GA 529ZH UT WOS:000272557800010 PM 19920823 ER PT J AU Osorio, A Milne, RL Pita, G Peterlongo, P Heikkinen, T Simard, J Chenevix-Trench, G Spurdle, AB Beesley, J Chen, X Healey, S Neuhausen, SL Ding, YC Couch, FJ Wang, X Lindor, N Manoukian, S Barile, M Viel, A Tizzoni, L Szabo, CI Foretova, L Zikan, M Claes, K Greene, MH Mai, P Rennert, G Lejbkowicz, F Barnett-Griness, O Andrulis, IL Ozcelik, H Weerasooriya, N Gerdes, AM Thomassen, M Cruger, DG Caligo, MA Friedman, E Kaufman, B Laitman, Y Cohen, S Kontorovich, T Gershoni-Baruch, R Dagan, E Jernstrom, H Askmalm, MS Arver, B Malmer, B Domchek, SM Nathanson, KL Brunet, J Cajal, TRY Yannoukakos, D Hamann, U Hogervorst, FBL Verhoef, S Garcia, EBG Wijnen, JT van den Ouweland, A Easton, DF Peock, S Cook, M Oliver, CT Frost, D Luccarini, C Evans, DG Lalloo, F Eeles, R Pichert, G Cook, J Hodgson, S Morrison, PJ Douglas, F Godwin, AK Sinilnikova, OM Barjhoux, L Stoppa-Lyonnet, D Moncoutier, V Giraud, S Cassini, C Olivier-Faivre, L Revillion, F Peyrat, JP Muller, D Fricker, JP Lynch, HT John, EM Buys, S Daly, M Hopper, JL Terry, MB Miron, A Yassin, Y Goldgar, D Singer, CF Gschwantler-Kaulich, D Pfeiler, G Spiess, AC Hansen, TV Johannsson, OT Kirchhoff, T Offit, K Kosarin, K Piedmonte, M Rodriguez, GC Wakeley, K Boggess, JF Basil, J Schwartz, PE Blank, SV Toland, AE Montagna, M Casella, C Imyanitov, EN Allavena, A Schmutzler, RK Versmold, B Engel, C Meindl, A Ditsch, N Arnold, N Niederacher, D Deissler, H Fiebig, B Varon-Mateeva, R Schaefer, D Froster, UG Caldes, T de la Hoya, M McGuffog, L Antoniou, AC Nevanlinna, H Radice, P Benitez, J AF Osorio, A. Milne, R. L. Pita, G. Peterlongo, P. Heikkinen, T. Simard, J. Chenevix-Trench, G. Spurdle, A. B. Beesley, J. Chen, X. Healey, S. Neuhausen, S. L. Ding, Y. C. Couch, F. J. Wang, X. Lindor, N. Manoukian, S. Barile, M. Viel, A. Tizzoni, L. Szabo, C. I. Foretova, L. Zikan, M. Claes, K. Greene, M. H. Mai, P. Rennert, G. Lejbkowicz, F. Barnett-Griness, O. Andrulis, I. L. Ozcelik, H. Weerasooriya, N. Gerdes, A-M Thomassen, M. Cruger, D. G. Caligo, M. A. Friedman, E. Kaufman, B. Laitman, Y. Cohen, S. Kontorovich, T. Gershoni-Baruch, R. Dagan, E. Jernstrom, H. Askmalm, M. S. Arver, B. Malmer, B. Domchek, S. M. Nathanson, K. L. Brunet, J. Ramon y Cajal, T. Yannoukakos, D. Hamann, U. Hogervorst, F. B. L. Verhoef, S. Gomez Garcia, E. B. Wijnen, J. T. van den Ouweland, A. Easton, D. F. Peock, S. Cook, M. Oliver, C. T. Frost, D. Luccarini, C. Evans, D. G. Lalloo, F. Eeles, R. Pichert, G. Cook, J. Hodgson, S. Morrison, P. J. Douglas, F. Godwin, A. K. Sinilnikova, O. M. Barjhoux, L. Stoppa-Lyonnet, D. Moncoutier, V. Giraud, S. Cassini, C. Olivier-Faivre, L. Revillion, F. Peyrat, J-P Muller, D. Fricker, J-P Lynch, H. T. John, E. M. Buys, S. Daly, M. Hopper, J. L. Terry, M. B. Miron, A. Yassin, Y. Goldgar, D. Singer, C. F. Gschwantler-Kaulich, D. Pfeiler, G. Spiess, A-C Hansen, Thomas v. O. Johannsson, O. T. Kirchhoff, T. Offit, K. Kosarin, K. Piedmonte, M. Rodriguez, G. C. Wakeley, K. Boggess, J. F. Basil, J. Schwartz, P. E. Blank, S. V. Toland, A. E. Montagna, M. Casella, C. Imyanitov, E. N. Allavena, A. Schmutzler, R. K. Versmold, B. Engel, C. Meindl, A. Ditsch, N. Arnold, N. Niederacher, D. Deissler, H. Fiebig, B. Varon-Mateeva, R. Schaefer, D. Froster, U. G. Caldes, T. de la Hoya, M. McGuffog, L. Antoniou, A. C. Nevanlinna, H. Radice, P. Benitez, J. CA KConFab OCGN SWE-BRCA HEBON EMBRACE GEMO Breast Cancer Family Registry CIMBA TI Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) SO BRITISH JOURNAL OF CANCER LA English DT Article DE BRCA1; BRCA2; ERCC4; breast cancer ID EXCISION-REPAIR; OVARIAN-CANCER; POLYMORPHISMS; GENES; NUCLEOTIDE AB BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. British Journal of Cancer (2009) 101, 2048-2054. doi: 10.1038/sj.bjc.6605416 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK C1 [Osorio, A.; Benitez, J.] Spanish Natl Canc Res Ctr, Human Genet Grp, Madrid, Spain. [Milne, R. L.] Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain. [Pita, G.; Benitez, J.] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain. [Peterlongo, P.; Manoukian, S.; Radice, P.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Peterlongo, P.; Tizzoni, L.; Radice, P.] Fdn Ist FIRC Oncol Mol, Milan, Italy. [Heikkinen, T.; Nevanlinna, H.] Helsinki Univ Cent Hosp, Dept Obstet & Gynaecol, Helsvinki, Finland. [Simard, J.] Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada. [Simard, J.] Univ Laval, Quebec City, PQ, Canada. [Chenevix-Trench, G.; Spurdle, A. B.; Beesley, J.; Chen, X.; Healey, S.] Queensland Inst Med Res, Div Genet & Populat Hlth, Brisbane, Qld 4006, Australia. [KConFab] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic, Australia. [Neuhausen, S. L.; Ding, Y. C.] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Couch, F. J.; Wang, X.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, F. J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lindor, N.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Barile, M.] Ist Europeo Oncol, Milan, Italy. [Viel, A.] IRCCS, Ctr Riferimento Oncol, Aviano, PN, Italy. [Tizzoni, L.] Consortium Genom Technol, Milan, Italy. [Szabo, C. I.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Foretova, L.] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Zikan, M.] Charles Univ Prague, Fac Med 1, Dept Biochem & Expt Oncol, Prague, Czech Republic. [Claes, K.] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Greene, M. H.; Mai, P.] NCI, Clin Genet Branch, Rockville, MD USA. [Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.] Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.] Technion Israel Inst Technol, Fac Med, Haifa, Israel. [Andrulis, I. L.; Weerasooriya, N.; OCGN] Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, I. L.; Ozcelik, H.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Gerdes, A-M; Thomassen, M.] Odense Univ Hosp, Clin Genet BFG, DK-5000 Odense, Denmark. [Cruger, D. G.] Vejle Hosp, Dept Clin Genet, Vijle, Denmark. [Caligo, M. A.] Univ Pisa, Dept Oncol, Div Pathol, Pisa, Italy. [Caligo, M. A.] Univ Hosp Pisa, Pisa, Italy. [Friedman, E.; Kaufman, B.; Laitman, Y.; Cohen, S.; Kontorovich, T.] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Friedman, E.; Kaufman, B.] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Gershoni-Baruch, R.] Rambam Med Ctr, Haifa, Israel. [Dagan, E.] Univ Haifa, Fac Social Welf & Hlth Sci, Dept Nursing, IL-31999 Haifa, Israel. [Dagan, E.] Inst Human Genet, Haifa, Israel. [Jernstrom, H.] Lund Univ, Dept Oncol, Lund, Sweden. [Askmalm, M. S.] Linkoping Univ Hosp, Dept Oncol, S-58185 Linkoping, Sweden. [Arver, B.] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Malmer, B.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Domchek, S. M.; Nathanson, K. L.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Brunet, J.] Hosp Dr Josep Trueta IdiBGi, Inst Catalan Oncol, Programa Consejo Genet Canc, Girona, Spain. [Ramon y Cajal, T.] Hosp Santa Creu & Sant Pau, Med Oncol Serv, Barcelona, Spain. [Yannoukakos, D.] Demokritos Natl Ctr Sci Res, IRRP, Mol Diagnost Lab, GR-15310 Athens, Greece. [Hamann, U.] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Hogervorst, F. B. L.; Verhoef, S.] Netherlands Canc Inst, Family Canc Clin, Dept Clin Mol Genet, Amsterdam, Netherlands. [Gomez Garcia, E. B.] Univ Med Ctr, Dept Genet & Cell Biol, Maastricht, Netherlands. [Gomez Garcia, E. B.] Res Inst Growth & Dev, Maastricht, Netherlands. [Wijnen, J. T.] Leiden Univ, Med Ctr, Dept Clin Mol Genet, Leiden, Netherlands. [Wijnen, J. T.] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [van den Ouweland, A.] Erasmus Univ, Med Ctr, Dept Mol Genet, Rotterdam, Netherlands. [Easton, D. F.; Peock, S.; Cook, M.; Oliver, C. T.; Frost, D.; McGuffog, L.; Antoniou, A. C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. [Luccarini, C.] Univ Cambridge, Dept Oncol, Cambridge, England. [Evans, D. G.; Lalloo, F.] St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England. [Evans, D. G.; Lalloo, F.] St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. [Eeles, R.] Inst Canc Res, Translat Canc Genet Team, London SW3 6JB, England. [Eeles, R.] Royal Marsden NHS Fdn Trust, London, England. [Pichert, G.] Guys Hosp, London SE1 9RT, England. [Cook, J.] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Hodgson, S.] Univ London, St Georges Hosp, Dept Canc Genet, London, England. [Morrison, P. J.] Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Douglas, F.] Newcastle Upon Tyne Hosp NHS Trust, Inst Human Genet, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England. [Godwin, A. K.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Sinilnikova, O. M.; Barjhoux, L.; Giraud, S.] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, O. M.; Barjhoux, L.] Univ Lyon, Lab Genet Mol Signalisat & Canc, CNRS, UMR5201, Lyon, France. [Stoppa-Lyonnet, D.; Moncoutier, V.; GEMO] Univ Paris 05, Inst Curie, Serv Gent Oncol, INSERM,U509, Paris, France. [Cassini, C.; Olivier-Faivre, L.] Ctr Genet, Dijon, France. [Cassini, C.; Olivier-Faivre, L.] CLCC Georges Francois Leclerc, Dijon, France. [Revillion, F.; Peyrat, J-P] Ctr Oscar Lambret, Human Mol Oncol Lab, F-59020 Lille, France. [Muller, D.; Fricker, J-P] CLCC Paul Strauss, Unite Oncogenet, Strasbourg, France. [Lynch, H. T.] Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA. [John, E. M.] No Calif Canc Ctr, Fremont, CA USA. [Buys, S.] Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Hopper, J. L.] Univ Melbourne, Melbourne, Vic, Australia. [Terry, M. B.] Columbia Univ, New York, NY USA. [Miron, A.; Yassin, Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldgar, D.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Singer, C. F.; Gschwantler-Kaulich, D.; Pfeiler, G.; Spiess, A-C] Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria. [Hansen, Thomas v. O.] Odense Univ Hosp, Dept Biochem Pharmacol & Genet, DK-5000 Odense, Denmark. [Johannsson, O. T.] Landspitali Univ Hosp, Dept Oncol, Reykjavik, Iceland. [Kirchhoff, T.; Offit, K.; Kosarin, K.] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, M.] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rodriguez, G. C.] Evanston NW Healthcare, NorthShore Univ Hlth Syst, Evanston, IL USA. [Wakeley, K.] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. [Boggess, J. F.] Univ N Carolina, Chapel Hill, NC USA. [Basil, J.] St Elizabeth Hosp, Edgewood, KY USA. [Schwartz, P. E.] Yale Univ, Sch Med, New Haven, CT USA. [Blank, S. V.] NYU, Sch Med, New York, NY USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Internal Med & Mol Virol, Columbus, OH 43210 USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Immunol, Columbus, OH 43210 USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Med Genet, Columbus, OH 43210 USA. [Montagna, M.] IRCCS, Inst Oncol Veneto, Padua, Italy. [Casella, C.] Dept Oncol & Surg Sci, Padua, Italy. [Imyanitov, E. N.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Allavena, A.] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Schmutzler, R. K.; Versmold, B.] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaecooncol, Cologne, Germany. [Engel, C.] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, A.] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Ditsch, N.] Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Arnold, N.] Univ Schleswig Holstein, Dept Obstet & Gynaecol, Lubeck, Germany. [Niederacher, D.] Univ Dusseldorf, Dept Obstet & Gynaecol, Mol Genet Lab, Dusseldorf, Germany. [Deissler, H.] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Fiebig, B.] Univ Regensburg, Inst Human Genet, Regensburg, Germany. [Varon-Mateeva, R.] Humboldt Univ, Inst Human Genet, Charite, Berlin, Germany. [Schaefer, D.] Goethe Univ Frankfurt, Inst Human Genet, Frankfurt, Germany. [Froster, U. G.] Univ Leipzig, Inst Human Genet, Leipzig, Germany. [Caldes, T.; de la Hoya, M.] Hosp Clin San Carlos, Madrid, Spain. RP Osorio, A (reprint author), Spanish Natl Canc Ctr CNIO, Human Genet Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM aosorio@cnio.es RI Spurdle, Amanda/A-4978-2011; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Andrulis, Irene/E-7267-2013; Ligtenberg, Marjolijn/N-9666-2013; manoukian, siranoush/E-7132-2017; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Ditsch, Nina/F-6267-2014; Osorio, Ana/I-4324-2014; Ehrencrona, Hans/M-5619-2014; GLADIEFF, Laurence/O-5129-2014 OI Evans, Gareth/0000-0002-8482-5784; Nordling, Margareta/0000-0002-4047-4994; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Brunet, Joan/0000-0003-1945-3512; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Yannoukakos, Drakoulis/0000-0001-7509-3510; Spurdle, Amanda/0000-0003-1337-7897; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719 FU Canadian Institutes of Health Research; Cancer Research UK [10118, C1287/A10118, C1287/A8874, C5047/A8385, C8197/A10123]; Intramural NIH HHS [NIH0014262027]; NCI NIH HHS [P50 CA116201, CA 27469, CA 37517, CA116167, CA122340, CA128978, CA74415, N02-CP-11019-50, N02CP11019, N02CP65504, P50CA116201, R01 CA074415, R01 CA116167, R01 CA122340, R01 CA128978, RFA-CA-06-503, U01 CA069398, U01 CA069417, U01 CA069446, U01 CA069467, U01 CA069631, U01 CA069638, U01 CA116167, U01 CA69398, U01 CA69417, U01 CA69446, U01 CA69467, U01 CA69631, U01 CA69638, U10 CA027469, U10 CA037517]; Associazione Italiana per la Ricerca sul Cancro NR 19 TC 11 Z9 11 U1 0 U2 8 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 DEC 8 PY 2009 VL 101 IS 12 BP 2048 EP 2054 DI 10.1038/sj.bjc.6605416 PG 7 WC Oncology SC Oncology GA 529ZH UT WOS:000272557800015 PM 19920816 ER PT J AU Mok, SC Bonome, T Vathipadiekal, V Bell, A Johnson, ME Wong, KK Park, DC Hao, K Yip, DKP Donninger, H Ozbun, L Samimi, G Brady, J Randonovich, M Pise-Masison, CA Barrett, JC Wong, WH Welch, WR Berkowitz, RS Birrer, MJ AF Mok, Samuel C. Bonome, Tomas Vathipadiekal, Vinod Bell, Aaron Johnson, Michael E. Wong, Kwong-kwok Park, Dong-Choon Hao, Ke Yip, Daniel K. P. Donninger, Howard Ozbun, Laurent Samimi, Goli Brady, John Randonovich, Mike Pise-Masison, Cindy A. Barrett, J. Carl Wong, Wing H. Welch, William R. Berkowitz, Ross S. Birrer, Michael J. TI A Gene Signature Predictive for Outcome in Advanced Ovarian Cancer Identifies a Survival Factor: Microfibril-Associated Glycoprotein 2 SO CANCER CELL LA English DT Article ID EXPRESSION PATTERNS; ENDOTHELIAL-CELLS; ADHESION; STATISTICS; CENTROSOME; INTEGRINS; INTERACTS; MAGP-2; TUMORS AB Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. Here, we identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Independent evaluation confirmed the association of a prognostic gene microfibril-associated glycoprotein 2 (MAGP2) with poor prognosis, whereas in vitro mechanistic analyses demonstrated its ability to prolong tumor cell survival and stimulate endothelial cell motility and survival via the alpha(V)beta(3) integrin receptor. Increased MAGP2 expression correlated with microvessel density suggesting a proangiogenic role in vivo. Thus, MAGP2 may serve as a survival-associated target. C1 [Bonome, Tomas; Vathipadiekal, Vinod; Bell, Aaron; Donninger, Howard; Ozbun, Laurent; Samimi, Goli; Barrett, J. Carl; Birrer, Michael J.] NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20892 USA. [Mok, Samuel C.; Wong, Kwong-kwok] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Samimi, Goli] NCI, Canc Prevent Fellowship Program, NIH, Rockville, MD 20892 USA. [Brady, John; Randonovich, Mike; Pise-Masison, Cindy A.] NCI, Cellular Oncol Lab, NIH, Rockville, MD 20892 USA. [Johnson, Michael E.; Park, Dong-Choon; Berkowitz, Ross S.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Brigham & Womens Hosp,Div Gynecol Oncol, Boston, MA 02115 USA. [Welch, William R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Park, Dong-Choon] Catholic Univ Korea, St Vincent Hosp, Dept Obstet & Gynecol, Suwon 442723, Gyeonggi Do, South Korea. [Hao, Ke; Wong, Wing H.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yip, Daniel K. P.] Univ S Florida, Dept Physiol & Biophys, Tampa, FL 33612 USA. [Berkowitz, Ross S.] Dana Farber Harvard Canc Ctr, Gillette Ctr Womens Canc, Boston, MA 02115 USA. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20892 USA. EM mbirrer@partners.org RI Yip, Kay-Pong/H-4639-2012; OI Yip, Kay-Pong/0000-0003-4364-6701; Vathipadiekal, Vinod/0000-0002-8181-6890; Wong, Kwong-Kwok/0000-0002-0375-6669 FU National Institutes of Health, Department of Health and Human Services [P50CA105009, R33CA103595, RO1CA133057]; Ovarian Cancer Research Fund, Inc.; National Institutes of Health, National Cancer Institute FX This study was supported in part by Dana-Farber Ovarian Cancer SPORE grant P50CA105009, R33CA103595, and RO1CA133057 from the National Institutes of Health, Department of Health and Human Services, the Ovarian Cancer Research Fund, Inc., and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 31 TC 82 Z9 84 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD DEC 8 PY 2009 VL 16 IS 6 BP 521 EP 532 DI 10.1016/j.ccr.2009.10.018 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 531UD UT WOS:000272693700011 PM 19962670 ER PT J AU Berger, JS Bhatt, DL Steinhubl, SR Shao, MY Steg, PG Montalescot, G Hacke, W Fox, KA Lincoff, AM Topol, EJ Berger, PB AF Berger, Jeffrey S. Bhatt, Deepak L. Steinhubl, Steven R. Shao, Mingyuan Steg, P. Gabriel Montalescot, Gilles Hacke, Werner Fox, Keith A. Lincoff, A. Michael Topol, Eric J. Berger, Peter B. CA CHARISMA Investigators TI Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease SO CIRCULATION LA English DT Article DE smoking; clopidogrel; mortality; cardiovascular disease ID ACUTE MYOCARDIAL-INFARCTION; CIGARETTE-SMOKING; ATHEROTHROMBOTIC EVENTS; THROMBOLYTIC THERAPY; SECONDARY PREVENTION; CORONARY; RISK; CESSATION; WOMEN; TRIAL AB Background-Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown. Methods and Results-We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause ( adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15). Conclusions-Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility. (Circulation. 2009; 120:2337-2344.) C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Berger, Jeffrey S.] NYU, Sch Med, New York, NY USA. [Berger, Jeffrey S.] Univ Penn, Philadelphia, PA 19104 USA. [Steinhubl, Steven R.] Weis Ctr Res, Geisinger Clin, Danville, PA 17822 USA. [Steinhubl, Steven R.] Medicines Co, Zurich, Switzerland. [Shao, Mingyuan; Lincoff, A. Michael] Cleveland Clin, Cleveland, OH 44106 USA. [Steg, P. Gabriel] Univ Paris 07, INSERM, U698, Paris, France. AP HP, Paris, France. [Montalescot, Gilles] CHU Pitie Salpetriere, Inst Cardiol, Paris, France. [Hacke, Werner] Univ Heidelberg, Heidelberg, Germany. [Fox, Keith A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Topol, Eric J.] Scripps Clin, La Jolla, CA 92037 USA. [Berger, Peter B.] Geisinger Med Ctr, Danville, PA 17822 USA. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, 75 Francis St,PBB-146, Boston, MA 02115 USA. EM dlbhattmd@post.harvard.edu RI Walker, Philip/F-3034-2010; OI Topol, Eric/0000-0002-1478-4729 FU Sanofi-Aventis; Bristol-Myers Squibb; National Heart, Lung, and Blood Institute [5K12HL83772-2]; American Heart Association Fellow to Faculty Award [0775074N] FX The CHARISMA trial was funded by Sanofi-Aventis and Bristol-Myers Squibb. Dr Jeffrey Berger was funded in part by a Research Career Development Award (5K12HL83772-2) from the National Heart, Lung, and Blood Institute and by an American Heart Association Fellow to Faculty Award (0775074N). NR 33 TC 78 Z9 79 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 8 PY 2009 VL 120 IS 23 BP 2337 EP 2344 DI 10.1161/CIRCULATIONAHA.109.866533 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 528TA UT WOS:000272468600006 PM 19933933 ER PT J AU Gibson, CM Pride, YB Hochberg, CP Sloan, S Sabatine, MS Cannon, CP AF Gibson, C. Michael Pride, Yuri B. Hochberg, Claudia P. Sloan, Sarah Sabatine, Marc S. Cannon, Christopher P. CA TIMI Study Grp TI Effect of Intensive Statin Therapy on Clinical Outcomes Among Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Substudy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome; percutaneous coronary intervention; pleiotropic; statin ID RANDOMIZED CONTROLLED-TRIAL; ATHEROSCLEROSIS; EVENTS; ROSUVASTATIN; PROGRESSION; TARGETS AB Objectives The goal of this analysis was to determine whether intensive statin therapy, compared with moderate-dose statin therapy, leads to a reduction in major adverse cardiovascular events (MACE) among patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Background When compared with moderate-dose statins, intensive statin therapy reduces MACE among patients with ACS. The role of intensive statin therapy specifically among patients who undergo PCI for ACS is unknown. Methods Outcomes were compared in 2,868 patients who underwent PCI for ACS just prior to enrollment in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial, which randomized patients to either atorvastatin 80 mg or pravastatin 40 mg daily. The incidence of the primary composite end point of all-cause mortality, myocardial infarction, unstable angina leading to hospitalization, and revascularization after 30 days and stroke was evaluated, as was the incidence of target vessel revascularization (TVR) and non-TVR during follow-up. Results Treatment with 80 mg atorvastatin reduced the incidence of the composite end point (21.5% vs. 26.5%, hazard ratio: 0.78, 95% confidence interval: 0.67 to 0.91, p = 0.002) and lowered the incidence of both TVR (11.4% vs. 15.4%, p = 0.001) and non-TVR (8.0% vs. 10.5%, p = 0.017) compared with 40 mg pravastatin. After adjusting for on-treatment serum low-density lipoprotein cholesterol and C-reactive protein concentrations, the odds of TVR with high-dose statin therapy remained significant (odds ratio: 0.74, p = 0.015) while the odds of non-TVR did not (odds ratio: 0.92, p = 0.55). Conclusions Among patients with ACS who undergo PCI, intensive statin therapy reduces MACE compared with moderate-dose statin therapy. The reduction in the incidence of TVR was independent of low-density lipoprotein cholesterol and C-reactive protein lowering and may therefore be due, at least in part, to a pleiotropic effect of high-dose statin therapy. (PROVE IT-TIMI 22; NCT00382460) (J Am Coll Cardiol 2009;54:2290-5) (C) 2009 by the American College of Cardiology Foundation C1 [Gibson, C. Michael; Pride, Yuri B.; Hochberg, Claudia P.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02215 USA. [Sloan, Sarah; Sabatine, Marc S.; Cannon, Christopher P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. RP Gibson, CM (reprint author), TIMI Data Coordinating Ctr, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM mgibson@perfuse.org FU Bristol-Myers Squibb; Daiichi Sankyo; Schering-Plough; AstraZeneca; Accumetrics; Bristol-Myers Squibb/Sanofi; GlaxoSmithKline; Intekrin Therapeutics; Merck; Merck/Schering-Plough; Novartis; Takeda FX Supported, in part, by a grant from Bristol-Myers Squibb and Daiichi Sankyo. Dr. Sabatine has received research grant support from Schering-Plough and AstraZeneca, has served on the Scientific Advisory Board of AstraZeneca, and has received honoraria from Bristol-Myers Squibb. Dr. Cannon has received research grants/support from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering-Plough Partnership, Novartis, and Takeda; and has equity in and served as clinical advisor for Automedics Medical Systems. NR 23 TC 49 Z9 54 U1 0 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 DEC 8 PY 2009 VL 54 IS 24 BP 2290 EP 2295 DI 10.1016/j.jacc.2009.09.010 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526LG UT WOS:000272289600005 PM 19958964 ER PT J AU Rost, NS Masrur, S Pervez, MA Viswanathan, A Schwamm, LH AF Rost, N. S. Masrur, S. Pervez, M. A. Viswanathan, A. Schwamm, L. H. TI Unsuspected coagulopathy rarely prevents IV thrombolysis in acute ischemic stroke SO NEUROLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; RT-PA STROKE; SAFE IMPLEMENTATION; PATIENT ELIGIBILITY; TPA THERAPY; SITS-MOST; ALTEPLASE; REASONS; ASSOCIATION; GUIDELINES AB Background: American Heart Association/American Stroke Association guidelines recommend initiating treatment with IV tissue plasminogen activator (tPA) in acute ischemic stroke patients without suspected coagulopathy prior to availability of clotting results; however, little or no data support this practice. We sought to identify how often blood clotting abnormalities were responsible for withholding IV tPA at our institution. Methods: We conducted a retrospective review of our prospectively acquired Get With the Guidelines Stroke database from January 2003 to April 2008. All patients underwent clinical evaluation by a neurologist, diagnostic neuroimaging, and laboratory testing on admission. We classified patients with absolute contraindications to IV tPA as ineligible, and those with warnings/relative contraindications or potentially treatable factors as potentially eligible. Results: Of 2,335 considered for analysis, 470 (20.1%) patients presented to our emergency department (ED) within 3 hours. Among these, 147 (31.3%) received IV tPA in our ED, 102 (21.7%) had an absolute contraindication, and 221 (47%) had a reason to consider withholding tPA. Only 30/470 (6.4%) of potential thrombolysis patients were discovered to have international normalized ratio >= 1.7 or platelets <= 100,000/mu L, and of these, 28 were suspected a priori due to known coagulopathy from medication or illness. Only 2/470 (0.4%) patients had an unsuspected coagulopathy that ultimately prevented thrombolysis. Conclusions: Based on the experience of a large thrombolysis referral center, stroke patients without suspected clotting abnormality can safely begin thrombolytic therapy before clotting results are available. These data support the current practice guidelines, and may reassure clinicians that the benefits of early administration greatly outweigh the risks due to an unsuspected bleeding diathesis. Neurology (R) 2009; 73: 1957-1962 C1 [Rost, N. S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Rost, NS (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM nrost@partners.org OI Schwamm, Lee/0000-0003-0592-9145 FU Bugher Foundation/American Stroke Association; NIH [NIA 2P50AG005134-268382, NINDS P50 NS051343-01, NINDS U01 NS052220 IMS-3, NCRR 1 UL 1 RR025758-01]; Forest Laboratories, Inc.; Department of Health and Human Services [CDC 5 U13 DP001176-02] FX Dr. Rost receives research support from the Bugher Foundation/American Stroke Association (training fellowship grant). Dr. Masrur and Dr. Pervez report no disclosures. Dr. Viswanathan receives research support from the NIH [NIA 2P50AG005134-268382 (Co-I)]. Dr. Schwamm serves as vice chair of the American Heart Association GWTG Steering Committee; serves on scientific advisory boards for CoAxia, Inc., Phreesia, and Lundbeck Inc.; serves on the editorial board of Neurocritical Care; may accrue revenue on US Patent 6,542,769, Issued: 1 Apr 2003: Imaging system for obtaining quantitative perfusion indices; his wife receives royalties from publishing Obstetric Anesthesia (Cambridge Pocket Clinicians, 2007); has received honoraria for lectures or educational activities not funded by industry; serves/has served as a consultant to CryoCath r Technologies Inc., Research Triangle Inc., Massachusetts Department of Public Health, and the Canadian Stroke Network; receives research support from Forest Laboratories, Inc., the NIH [NINDS P50 NS051343-01 (Co-I), NINDS U01 NS052220 IMS-3 (Site PI), NCRR 1 UL 1 RR025758-01 (CRC Staff)], and the Department of Health and Human Services [CDC 5 U13 DP001176-02 (PI)]; and has provided expert medical opinions in malpractice lawsuits [RE: stroke treatment and prevention]. NR 29 TC 18 Z9 19 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 8 PY 2009 VL 73 IS 23 BP 1957 EP 1962 DI 10.1212/WNL.0b013e3181c5b46d PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 528SJ UT WOS:000272466800007 PM 19940272 ER PT J AU Apidianakis, Y Pitsouli, C Perrimon, N Rahme, L AF Apidianakis, Yiorgos Pitsouli, Chrysoula Perrimon, Norbert Rahme, Laurence TI Synergy between bacterial infection and genetic predisposition in intestinal dysplasia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; cell polarity; cytokines; tumor; virulence factors ID STEM-CELLS; DROSOPHILA MIDGUT; HUMAN COLON; DISEASE; CANCER; NOTCH; HOMEOSTASIS; TOLL; JNK AB Accumulating evidence suggests that hyperproliferating intestinal stem cells (SCs) and progenitors drive cancer initiation, maintenance, and metastasis. In addition, chronic inflammation and infection have been increasingly recognized for their roles in cancer. Nevertheless, the mechanisms by which bacterial infections can initiate SC-mediated tumorigenesis remain elusive. Using a Drosophila model of gut pathogenesis, we show that intestinal infection with Pseudomonas aeruginosa, a human opportunistic bacterial pathogen, activates the c-Jun N-terminal kinase (JNK) pathway, a hallmark of the host stress response. This, in turn, causes apoptosis of enterocytes, the largest class of differentiated intestinal cells, and promotes a dramatic proliferation of SCs and progenitors that serves as a homeostatic compensatory mechanism to replenish the apoptotic enterocytes. However, we find that this homeostatic mechanism can lead to massive over-proliferation of intestinal cells when infection occurs in animals with a latent oncogenic form of the Ras1 oncogene. The affected intestines develop excess layers of cells with altered apicobasal polarity reminiscent of dysplasia, suggesting that infection can directly synergize with the genetic background in predisposed individuals to initiate SC-mediated tumorigenesis. Our results provide a framework for the study of intestinal bacterial infections and their effects on undifferentiated and mature enteric epithelial cells in the initial stages of intestinal cancer. Assessment of progenitor cell responses to pathogenic intestinal bacteria could provide a measure of predisposition for apoptotic enterocyte-assisted intestinal dysplasias in humans. C1 [Pitsouli, Chrysoula; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Boston, MA 02115 USA. [Apidianakis, Yiorgos; Rahme, Laurence] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Apidianakis, Yiorgos; Rahme, Laurence] Shriners Burns Inst, Boston, MA 02114 USA. [Rahme, Laurence] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Perrimon, N (reprint author), Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Boston, MA 02115 USA. EM perrimon@genetics.med.harvard.edu; rahme@molbio.mgh.harvard.edu OI Apidianakis, Yiorgos/0000-0002-7465-3560 FU National Institutes of Health (NIH) [AI063433]; Shriners [8892] FX We thank Nikolaos Giagtzoglou, Michele Markstein, and Richard Binari for critical reading of the manuscript.This work was partially supported by National Institutes of Health (NIH) Grant AI063433 and Shriners Grant no.8892 (to L.G.R.). N.P.was supported by the NIH and is an Investigator of the Howard Hughes Medical Institute, and Y.A.received a Shriners Fellowship. NR 31 TC 87 Z9 87 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 8 PY 2009 VL 106 IS 49 BP 20883 EP 20888 DI 10.1073/pnas.0911797106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000060 PM 19934041 ER PT J AU Chiu, IM Phatnani, H Kuligowski, M Tapia, JC Carrasco, MA Zhang, M Maniatis, T Carroll, MC AF Chiu, Isaac M. Phatnani, Hemali Kuligowski, Michael Tapia, Juan C. Carrasco, Monica A. Zhang, Ming Maniatis, Tom Carroll, Michael C. TI Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE innate immunity; macrophage; peripheral nervous system; neuroimmunology; amyotrophic lateral sclerosis ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOUSE MODEL; WALLERIAN DEGENERATION; DISEASE PROGRESSION; INHERITED ALS; MOTOR-NEURONS; FAMILIAL ALS; COMPLEMENT; INJURY; CELLS AB During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice. C1 [Chiu, Isaac M.; Kuligowski, Michael; Carroll, Michael C.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Immune Dis Inst,Childrens Hosp, Boston, MA 02115 USA. [Phatnani, Hemali; Tapia, Juan C.; Carrasco, Monica A.; Maniatis, Tom] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Zhang, Ming] Suny Downstate Med Ctr, Dept Anesthesiol, Brooklyn, NY 11203 USA. RP Maniatis, T (reprint author), Harvard Univ, Sch Med, Program Cellular & Mol Med, Immune Dis Inst,Childrens Hosp, Boston, MA 02115 USA. EM maniatis@mcb.harvard.edu; carroll@idi.harvard.edu FU National Institutes of Health; ALS Association FX We thank Lisa Pitcher, Bela Kosaras, Hilary Bowden, and Ryan Conway for technical help. Wethank Robert Brown, Jr, Vijay Kuchroo, Beth Stevens, Jack Strominger, and Ben Barres for helpful advice. This work was supported by the National Institutes of Health and the ALS Association. NR 32 TC 69 Z9 69 U1 1 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 DEC 8 PY 2009 VL 106 IS 49 BP 20960 EP 20965 DI 10.1073/pnas.0911405106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000073 PM 19933335 ER PT J AU Vinegoni, C Fexon, L Feruglio, PF Pivovarov, M Figueiredo, JL Nahrendorf, M Pozzo, A Sbarbati, A Weissleder, R AF Vinegoni, Claudio Fexon, Lyuba Feruglio, Paolo Fumene Pivovarov, Misha Figueiredo, Jose-Luiz Nahrendorf, Matthias Pozzo, Antonio Sbarbati, Andrea Weissleder, Ralph TI High throughput transmission optical projection tomography using low cost graphics processing unit SO OPTICS EXPRESS LA English DT Article ID FILTERED BACKPROJECTION; IMAGE-RECONSTRUCTION; FOURIER INVERSION; MICROSCOPY; TRANSFORM; ALGORITHM AB We implement the use of a graphics processing unit (GPU) in order to achieve real time data processing for high-throughput transmission optical projection tomography imaging. By implementing the GPU we have obtained a 300 fold performance enhancement in comparison to a CPU workstation implementation. This enables to obtain on-the-fly reconstructions enabling for high throughput imaging. (C) 2009 Optical Society of America C1 [Vinegoni, Claudio; Fexon, Lyuba; Pivovarov, Misha; Figueiredo, Jose-Luiz; Nahrendorf, Matthias; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Feruglio, Paolo Fumene; Sbarbati, Andrea] Univ Verona, Dept Morphol & Biomed Sci, Anat & Histol Sect, I-37134 Verona, Italy. RP Vinegoni, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM cvinegoni@mgh.harvard.edu FU National Institutes of Health (NIH) [1-RO1-EB006432]; Regione Veneto; CARIVERONA Foundation (Italy) FX We acknowledge support from National Institutes of Health (NIH) grant 1-RO1-EB006432. We also acknowledge support from Regione Veneto and CARIVERONA Foundation (Italy). NR 28 TC 17 Z9 18 U1 1 U2 5 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 7 PY 2009 VL 17 IS 25 BP 22320 EP 22332 DI 10.1364/OE.17.022320 PG 13 WC Optics SC Optics GA 532PG UT WOS:000272761300006 PM 20052155 ER PT J AU Yaseen, MA Srinivasan, VJ Sakadzic, S Wu, W Ruvinskaya, S Vinogradov, SA Boas, DA AF Yaseen, Mohammad A. Srinivasan, Vivek J. Sakadzic, Sava Wu, Weicheng Ruvinskaya, Svetlana Vinogradov, Sergei A. Boas, David A. TI Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy SO OPTICS EXPRESS LA English DT Article ID CEREBRAL-CORTEX; RAT MESENTERY; IN-VIVO; PHOSPHORESCENCE; TISSUE; VESSELS AB Evaluating cerebral oxygenation is of critical importance for the understanding of brain function and several neuropathologies. Although several techniques exist for measuring cerebral oxygenation in vivo, the most widely accepted techniques offer limited spatial resolution. We have developed a confocal imaging system for minimally invasive measurement of oxygen tension (pO(2)) in cerebral microvessels with high spatial and temporal resolution. The system relies on the phosphorescence quenching method using exogenous porphyrin-based dendritic oxygen probes. Here we present high-resolution phosphorescence images of cortical microvasculature and temporal pO(2) profiles from multiple locations in response to varied fraction of inspired oxygen and functional activation. (C) 2009 Optical Society of America C1 [Yaseen, Mohammad A.; Srinivasan, Vivek J.; Sakadzic, Sava; Wu, Weicheng; Ruvinskaya, Svetlana; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Photon Migrat Imaging Lab, MGH MIT HMS Athinuola A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. RP Yaseen, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Photon Migrat Imaging Lab, MGH MIT HMS Athinuola A Martinos Ctr Biomed Imagi, Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM dboas@nmr.mgh.harvard.edu FU NIH [R01-NS057476, P50-NS010828, K99NS067050, P01NS055104] FX This work was supported by NIH R01-NS057476, P50-NS010828, K99NS067050, and P01NS055104. NR 32 TC 31 Z9 31 U1 2 U2 5 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 7 PY 2009 VL 17 IS 25 BP 22341 EP 22350 DI 10.1364/OE.17.022341 PG 10 WC Optics SC Optics GA 532PG UT WOS:000272761300008 PM 20052157 ER PT J AU Figlewicz, DP Ioannou, G Jay, JB Kittleson, S Savard, C Roth, CL AF Figlewicz, D. P. Ioannou, G. Jay, J. Bennett Kittleson, S. Savard, C. Roth, C. L. TI Effect of moderate intake of sweeteners on metabolic health in the rat SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE High fructose corn syrup; Agave; Stevia; Hoodia; Liver ID DIETARY FRUCTOSE; APPETITE-SUPPRESSANT; STEVIA-REBAUDIANA; INSULIN; STEVIOSIDE; OBESITY; SUGAR; DYSREGULATION; ACTIVATION; MECHANISM AB The rise in prevalence of obesity, diabetes. metabolic syndrome, and fatty liver disease has been linked to increased consumption of fructose-containing foods or beverages. Our aim was to compare the effects of moderate consumption of fructose-containing and non-caloric sweetened beverages on feeding behavior, metabolic and serum lipid profiles. and hepatic histology and serum liver enzymes, in rats. Behavioral tests determined preferred ( 12.5-15%) concentrations of solutions of agave, fructose, high fructose corn syrup (HFCS), a combination of HFC5 and Hoodia (a putative appetite suppressant), or the non-caloric sweetener Stevia (n = 5/gp). HFCS intake was highest, in preference and self-administration tests. Groups (n = 10/gp) were then assigned to one of the sweetened beverages or water as the sole source of liquid at night (3 nights/wk, 10 wks). Although within the normal range, serum cholesterol was higher in the fructose and HFCS groups, and serum triglycerides were higher in the Agave, HFCS, and HFCS/Hoodia groups (vs. water-controls, p < 0.05). Liver histology was normal in all groups with no evidence of steatosis, inflammation, or fibrosis; however serum alanine aminotransferase was higher in the fructose and HFCS groups (vs. water-controls, p < 0.05). Serum inflammatory marker levels were comparable among Stevia, agave. fructose, HFCS. and water-consuming groups, however levels of IL-6 were significantly lower in association with the ingestion of Hoodia. There were no differences in terminal body weights, or glucose tolerance assessed by 120-min IVGTTs performed at the end of the 10-week regimen. We conclude that even moderate consumption of fructose-containing liquids may lead to the onset of unfavorable changes in the plasma lipid profile and one marker of liver health. independent of significant effects of sweetener consumption on body weight. Published by Elsevier Inc. C1 [Figlewicz, D. P.; Jay, J. Bennett; Kittleson, S.] VA Puget Sound Hlth Care Syst 151, R&D, Seattle, WA 98108 USA. [Figlewicz, D. P.; Jay, J. Bennett] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Ioannou, G.; Savard, C.] VA Puget Sound Hlth Care Syst, Dept Med, Div Gastroenterol, Seattle, WA USA. [Roth, C. L.] Seattle Childrens Res Inst, Seattle, WA 98101 USA. RP Figlewicz, DP (reprint author), VA Puget Sound Hlth Care Syst 151, R&D, 1660 So Columbian Way, Seattle, WA 98108 USA. EM latte@u.washington.edu FU NIH [RO1 DK40963]; Seattle Children's Hospital Research Institute; Seattle Children's Hospital FX This work was carried out at the VA Puget Sound Health Care System, Seattle Division, and was supported by the Merit Review (DFL), Career Scientist (DFL) and Research Enhancement Award Program (REAP) (GI and DFL) Programs of the Dept of Veterans Affairs; NIH RO1 DK40963 (DFL); and by the CUMG Seed Funds of Seattle Children's Hospital Research Institute and Seattle Children's Hospital (CR). George Ioannou is supported by the Jan Albrecht Award from the American Liver Foundation and American Association for the Study of Liver Diseases. Christian Roth is supported by Seattle Children's Hospital. The authors gratefully acknowledge the outstanding support and technical expertise of Connie Holmes West, Guochi Zhang, and Melissa Ralston. The generous and able assistance of Dr. Nicole Sanders, and student aides Marissa Haberlach, Kimberly Brennan, and Nick Shalygin, is acknowledged with grateful appreciation. The drug Hoodia was generously provided by Trade Avail Company, USA. We thank Dr. Tami Wolden-Hanson for the advice on fat pad dissection, and Dr. Alfred J. Sipols for assistance with the statistical analysis. The helpful discussion of Alan Bernstein, Dr. Janis Wignall, and Dr. Cindy Pekow is gratefully acknowledged. NR 38 TC 20 Z9 22 U1 3 U2 37 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD DEC 7 PY 2009 VL 98 IS 5 BP 618 EP 624 DI 10.1016/j.physbeh.2009.09.016 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 529LN UT WOS:000272518200016 PM 19815021 ER PT J AU Hong, W Chen, LF Liu, YD Gao, WZ AF Hong, Wei Chen, Linfeng Liu, Yunde Gao, Weizhen TI ATP hydrolysis is essential for Bag-1M-mediated inhibition of the DNA binding by the glucocorticoid receptor SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ATP; Bag-1; Nuclear hormone receptor; Chaperone; Heat shock protein ID CHAPERONE ACTIVITY; MOLECULAR CHAPERONES; NUCLEOTIDE EXCHANGE; IN-VIVO; SUBSTRATE-BINDING; STRUCTURAL BASIS; CANCER-CELLS; HSP70; PROTEIN; BAG-1 AB The 70-kDa heat shock protein (Hsp70) is involved in providing the appropriate conformation of various nuclear hormone receptors, including the glucocorticoid receptor (GR). The Bcl-2 associated athanogene 1M (Bag-1M) is known to downregulate the DNA binding by the GR. Also, Bag-1M interacts with the ATPase domain of Hsp70 to modulate the release of the Substrate from Hsp70. In this study, we demonstrate that ATP hydrolysis enhances Bag-1M-n-tediated inhibition of the DNA binding by the GR. However, the inhibitory effect of Bag-1M was abolished when the intracellular ATP was depleted. In addition, a Bag-1M mutant lacking the interaction with Hsp70 did not influence the GR to bind DNA, suggesting the interaction of Bag-1M with Hsp70 in needed for its negative effect. These results indicate that ATP hydrolysis is essential for Bag-1M-mediated inhibition of the DNA binding by the GR and Hsp70 is a mediator for this process. (C) 2009 Elsevier Inc. All rights reserved. C1 [Hong, Wei; Liu, Yunde; Gao, Weizhen] Tianjin Med Univ, Dept Lab Med, Tianjin 300203, Peoples R China. [Chen, Linfeng] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hong, W (reprint author), Tianjin Med Univ, Dept Lab Med, Tianjin 300203, Peoples R China. EM hongwei@tijmu.edu.cn FU Tianjin Medical University FX We thank Dr. Aria Baniahmad (University of Jena, Germany) for his constant help and David Fisher for critically reading the manuscript. This work was supported by a grant for the "11-5" New Century Outstanding Scientist from Tianjin Medical University (W.H.). NR 38 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 4 PY 2009 VL 390 IS 1 BP 77 EP 81 DI 10.1016/j.bbrc.2009.09.069 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 513AZ UT WOS:000271295500015 PM 19778524 ER PT J AU Firth, PG Zheng, H Biller, JA AF Firth, P. G. Zheng, H. Biller, J. A. TI CHRISTMAS: YEARS LIKE THIS Ingested foreign bodies and societal wealth: three year observational study of swallowed coins SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID PENNY; EURO AB Objective To examine the relation between coins ingested by children and the Dow Jones Industrial Average. Design Observational study. Main outcome measures Total value of coins ingested and number of incidents of coins versus other objects swallowed, measured before and after the stock market crash of October 2008. Results Eighteen objects, including 11 coins, were ingested (NASDAQ ( numismatic and sundry detritus acquired) composite of 18). The total value of the 11 coins swallowed was $1.03 (FTSE 100 (fraction of the US$ or 100 cents) index of 103). The pecuniary extraction ratio ( PE ratio) was 0.57 (9/16). Comparing values for a period before and after October 2008, the mean monthly NASDAQ composite (0.41 (SD 0.67) v 0.5 (0.85), P=0.75), FTSE 100 index in cents (2.3 (6.8) v 3.1 (7.8), P=0.77), and PE ratio (0.54 (0.52) v 0.66 (0.29), P=0.50) did not change. The mean end-of-month closing value of the Dow Jones, however, decreased significantly (12537 (841.4) v 8388 (699.8), P<0.001) Conclusion There was no detectable difference in the total value of coins ingested, or ratio of coins to other objects swallowed, before or after a massive stock market crash. C1 [Firth, P. G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Zheng, H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA 02114 USA. [Biller, J. A.] Harvard Univ, Sch Med, Dept Gastroenterol, Waltham, MA 02451 USA. RP Firth, PG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM pfirth@partners.org NR 12 TC 0 Z9 0 U1 2 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD DEC 4 PY 2009 VL 339 AR b5066 DI 10.1136/bmj.b5066 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 528NU UT WOS:000272453700004 PM 19965938 ER PT J AU Alam, MN Kumar, S Rai, S Methippara, M Szymusiak, R McGinty, D AF Alam, Md Noor Kumar, Sunil Rai, Seema Methippara, Melvi Szymusiak, Ronald McGinty, Dennis TI Role of adenosine A(1) receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats SO BRAIN RESEARCH LA English DT Article DE Orexin; Hypocretin; Adenosine; Posterior-lateral hypothalamus; Sleep ID EYE-MOVEMENT SLEEP; BASAL FOREBRAIN; OREXIN NEURONS; HYPOCRETIN OREXIN; A1 RECEPTOR; NERVOUS-SYSTEM; ACTIVE NEURONS; PREOPTIC AREA; WAKEFULNESS; WAKING AB The perifornical-lateral hypothalamic area (PF-LHA) has been implicated in the regulation of arousal. The PF-LHA contains wake-active neurons that are quiescent during non-REM sleep and in the case of neurons expressing the peptide hypocretin (HCRT), quiescent during both non-REM and REM sleep. Adenosine is an endogenous sleep factor and recent evidence suggests that adenosine via A(1) receptors may act on PF-LHA neurons to promote sleep. We examined the effects of bilateral activation as well as blockade of A(1) receptors in the PF-LHA on sleep wakefulness in freely behaving rats. The sleep-wake profiles of male Wistar rats were recorded during reverse microdialysis perfusion of artificial cerebrospinal fluid (aCSF) and two doses of adenosine A(1) receptor antagonist, 1,3-dipropyl-8-phenylxanthine (CPDX; 5 mu M and 50 mu M) or A(1) receptor agonist, N-6-cyclopentyladenosine (CPA; 5 mu M and 50 mu M) into the PF-LHA for 2 h followed by 4 h of aCSF perfusion. CPDX perfused into the PF-LHA during lights-on phase produced arousal (F=7.035, p<0.001) and concomitantly decreased both non-REM (F=7.295, p<0.001) and REM sleep (F=3.456, p<0.004). In contrast, CPA perfused into the PF-LHA during lights-off phase significantly suppressed arousal (F=7.891,p<0.001) and increased non-REM (F = 8.18, p <0.001) and REM sleep (F = 30.036, p < 0.001). These results suggest that PF-LHA is one of the sites where adenosine, acting via A(1) receptors, inhibits PF-LHA neurons to promote sleep. Published by Elsevier B.V. C1 [Alam, Md Noor; Kumar, Sunil; Rai, Seema; Methippara, Melvi; Szymusiak, Ronald; McGinty, Dennis] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Sepulveda, CA 91343 USA. [Alam, Md Noor; Methippara, Melvi; McGinty, Dennis] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Kumar, Sunil; Szymusiak, Ronald] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Szymusiak, Ronald] Univ Calif Los Angeles, Sch Med, Dept Neurobiol, Los Angeles, CA USA. RP Alam, MN (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv 151A3, 16111 Plummer St, Sepulveda, CA 91343 USA. EM noor@ucla.edu FU US Department of Veterans Affairs Medical Research Service; US National Institutes of Health [NS-050939, MH47480, HL60296, MH63323] FX This work was supported by the US Department of Veterans Affairs Medical Research Service and US National Institutes of Health grants NS-050939 (Alam), MH47480 and HL60296 (McGinty), and MH63323 (Szymusiak). NR 56 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 4 PY 2009 VL 1304 BP 96 EP 104 DI 10.1016/j.brainres.2009.09.066 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 531HE UT WOS:000272654400010 PM 19781535 ER PT J AU Teh, J Berendt, T Lipsky, BA AF Teh, James Berendt, Tony Lipsky, Benjamin A. TI Rational Imaging Investigating suspected bone infection in the diabetic foot SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID DIAGNOSTIC-ACCURACY; COST-EFFECTIVENESS; OSTEOMYELITIS; METAANALYSIS C1 [Teh, James] Nuffield Orthopaed Ctr, Dept Radiol, Oxford OX3 7LD, England. [Berendt, Tony] Nuffield Orthopaed Ctr, Bone Infect Unit, Oxford OX3 7LD, England. [Lipsky, Benjamin A.] VA Puget Sound Hlth Care Syst, Seattle, WA 98416 USA. [Lipsky, Benjamin A.] Univ Washington, Seattle, WA 98416 USA. RP Teh, J (reprint author), Nuffield Orthopaed Ctr, Dept Radiol, Oxford OX3 7LD, England. EM james.teh@tiscali.co.uk OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 17 TC 12 Z9 12 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD DEC 4 PY 2009 VL 339 AR b4690 DI 10.1136/bmj.b4690 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 528NU UT WOS:000272453700001 PM 19965936 ER PT J AU Dai, J Matsui, T Abel, ED Seidman, CE Seidman, JG Rosenzweig, A AF Dai, Jing Matsui, Takashi Abel, E. Dale Seidman, Christine E. Seidman, J. G. Rosenzweig, Anthony TI DSAGE Identifies the Orphan Nuclear Receptor, Nur77, as a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK Knockout Mice SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL, 2009 CL Las Vegas, NV C1 [Dai, Jing; Matsui, Takashi; Rosenzweig, Anthony] BIDMC, Boston, MA USA. [Abel, E. Dale] Univ Utah, Salt Lake City, UT USA. [Seidman, Christine E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Seidman, Christine E.; Seidman, J. G.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 4 PY 2009 VL 105 IS 12 MA 5287 BP E56 EP E56 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 527PO UT WOS:000272379200016 ER PT J AU Hjortnaes, J Butcher, J Figueiredo, JL Riccio, ML Kohler, RH Weissleder, R Aikawa, E AF Hjortnaes, Jesper Butcher, Jonathan Figueiredo, Jose-Luiz Riccio, Mark L. Kohler, Rainer H. Weissleder, Ralph Aikawa, Elena TI Inverse Correlation of Arterial and Aortic Valve Calcification With Bone Mineral Density Evaluated by Molecular Imaging SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL, 2009 CL Las Vegas, NV C1 [Hjortnaes, Jesper; Figueiredo, Jose-Luiz; Kohler, Rainer H.; Weissleder, Ralph] Ctr Mol Imaging Rsch, Charlestown, MA USA. [Butcher, Jonathan; Riccio, Mark L.] Cornell Univ, Ithaca, NY USA. [Aikawa, Elena] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 4 PY 2009 VL 105 IS 12 MA 5179 BP E59 EP E60 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 527PO UT WOS:000272379200030 ER PT J AU Lu, L Wang, SY Zheng, L Li, XL Suswam, EA Zhang, XW Wheeler, CG Nabors, LB Filippova, N King, PH AF Lu, Liang Wang, Shuying Zheng, Lei Li, Xuelin Suswam, Esther A. Zhang, Xiaowen Wheeler, Crystal G. Nabors, L. B. Filippova, Natalia King, Peter H. TI Amyotrophic Lateral Sclerosis-linked Mutant SOD1 Sequesters Hu Antigen R (HuR) and TIA-1-related Protein (TIAR) IMPLICATIONS FOR IMPAIRED POST-TRANSCRIPTIONAL REGULATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA STABILITY; 3' UNTRANSLATED REGION; AU-RICH ELEMENTS; GROWTH-FACTOR; OXIDATIVE STRESS; BINDING PROTEINS; STABILIZATION; APOPTOSIS; BCL-2; GENE AB Down-regulation of vascular endothelial growth factor (VEGF) in the mouse leads to progressive and selective degeneration of motor neurons similar to amyotrophic lateral sclerosis (ALS). In mice expressing ALS-associated mutant superoxide dismutase 1 (SOD1), VEGF mRNA expression in the spinal cord declines significantly prior to the onset of clinical manifestations. In vitro models suggest that dysregulation of VEGF mRNA stability contributes to that decline. Here, we show that the major RNA stabilizer, Hu Antigen R (HuR), and TIA-1-related protein (TIAR) colocalize with mutant SOD1 in mouse spinal cord extracts and cultured glioma cells. The colocalization was markedly reduced or abolished by RNase treatment. Immunoanalysis of transfected cells indicated that colocalization occurred in insoluble aggregates and inclusions. RNA immunoprecipitation showed a significant loss of VEGF mRNA binding to HuR and TIAR in mutant SOD1 cells, and there was marked depletion of HuR from polysomes. Ectopic expression of HuR in mutant SOD1 cells more than doubled the mRNA half-life of VEGF and significantly increased expression to that of wild-type SOD1 control. Cellular effects produced by mutant SOD1, including impaired mitochondrial function and oxidative stress-induced apoptosis, were reversed by HuR in a gene dose-dependent pattern. In summary, our findings indicate that mutant SOD1 impairs post-transcriptional regulation by sequestering key regulatory RNA-binding proteins. The rescue effect of HuR suggests that this impairment, whether related to VEGF or other potential mRNA targets, contributes to cytotoxicity in ALS. C1 [Lu, Liang; Wang, Shuying; Zheng, Lei; Li, Xuelin; Suswam, Esther A.; Zhang, Xiaowen; Nabors, L. B.; Filippova, Natalia; King, Peter H.] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. [King, Peter H.] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA. [Wheeler, Crystal G.] Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. [King, Peter H.] Univ Alabama, Dept Physiol & Biophys, Birmingham, AL 35294 USA. [Lu, Liang; Zheng, Lei; Li, Xuelin; King, Peter H.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP King, PH (reprint author), Sparks Ctr, Suite 260,1720-7th Ave S, Birmingham, AL 35233 USA. EM pking@uab.edu FU National Institutes of Health [NS058538, NS064133, NS057664]; NINDS [R01 CA112397]; NCI; Dept. of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health Grants NS058538, NS064133 (to P. H. K.), NS057664 (to L. L.) from the NINDS, R01 CA112397 (to L. B. N.) from the NCI, and a Merit Review award from the Dept. of Veterans Affairs (to P. H. K.). NR 44 TC 24 Z9 24 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 DEC 4 PY 2009 VL 284 IS 49 BP 33989 EP 33998 DI 10.1074/jbc.M109.067918 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524TE UT WOS:000272165200031 PM 19805546 ER PT J AU Isselbacher, KJ AF Isselbacher, Kurt J. TI Paul C. Zamecnik (1912-2009) RETROSPECTIVE SO SCIENCE LA English DT Biographical-Item C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. RP Isselbacher, KJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM kisselbacher@partners.org NR 1 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 4 PY 2009 VL 326 IS 5958 BP 1359 EP 1359 DI 10.1126/science.1184725 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 527EX UT WOS:000272351100029 PM 19965748 ER PT J AU Yoshimoto, G Miyamoto, T Jabbarzadeh-Tabrizi, S Iino, T Rocnik, JL Kikushige, Y Mori, Y Shima, T Iwasaki, H Takenaka, K Nagafuji, K Mizuno, SI Niiro, H Gilliland, GD Akashi, K AF Yoshimoto, Goichi Miyamoto, Toshihiro Jabbarzadeh-Tabrizi, Siamak Iino, Tadafumi Rocnik, Jennifer L. Kikushige, Yoshikane Mori, Yasuo Shima, Takahiro Iwasaki, Hiromi Takenaka, Katsuto Nagafuji, Koji Mizuno, Shin-ichi Niiro, Hiroaki Gilliland, Gary D. Akashi, Koichi TI FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation SO BLOOD LA English DT Article ID INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; CONSTITUTIVE ACTIVATION; PERIPHERAL-BLOOD; POOR-PROGNOSIS; BCL-2 FAMILY; BLAST CELLS; B-CELLS; MUTATIONS AB Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34(+)CD38-LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wildtype FLT3 signaling. (Blood. 2009; 114: 5034-5043) C1 [Akashi, Koichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Biosyst Sci, Higashi Ku, Fukuoka 8128582, Japan. [Yoshimoto, Goichi; Kikushige, Yoshikane; Iwasaki, Hiromi; Akashi, Koichi] Kyushu Univ, Grad Sch Med Sci, Ctr Cellular & Mol Med, Fukuoka 8128582, Japan. [Iino, Tadafumi; Mizuno, Shin-ichi; Akashi, Koichi] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Rocnik, Jennifer L.; Gilliland, Gary D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Akashi, K (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Biosyst Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM akashi@med.kyushu-u.ac.jp RI U-ID, Kyushu/C-5291-2016 FU Ministry of Education, Culture, Sports, Science and Technology in Japan [19659248, 20390272, 17109010, 17047029]; Takeda Science Foundation FX This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology in Japan (19659248 and 20390272 [T. M.], 17109010 and 17047029 [K. A.]) and the Takeda Science Foundation (T. M.). NR 61 TC 81 Z9 84 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 3 PY 2009 VL 114 IS 24 BP 5034 EP 5043 DI 10.1182/blood-2008-12-196055 PG 10 WC Hematology SC Hematology GA 527WX UT WOS:000272403000021 PM 19808698 ER PT J AU Fujii, H Chinnusamy, V Rodrigues, A Rubio, S Antoni, R Park, SY Cutler, SR Sheen, J Rodriguez, PL Zhu, JK AF Fujii, Hiroaki Chinnusamy, Viswanathan Rodrigues, Americo Rubio, Silvia Antoni, Regina Park, Sang-Youl Cutler, Sean R. Sheen, Jen Rodriguez, Pedro L. Zhu, Jian-Kang TI In vitro reconstitution of an abscisic acid signalling pathway SO NATURE LA English DT Article ID PROTEIN PHOSPHATASES; GENE-EXPRESSION; ARABIDOPSIS; STRESS; KINASE; ABA; IDENTIFICATION; TRANSDUCTION; GERMINATION; RECEPTORS AB The phytohormone abscisic acid (ABA) regulates the expression of many genes in plants; it has critical functions in stress resistance and in growth and development(1-7). Several proteins have been reported to function as ABA receptors(8-13), and many more are known to be involved in ABA signalling(3,4,14). However, the identities of ABA receptors remain controversial and the mechanism of signalling from perception to downstream gene expression is unclear(15,16). Here we show that by combining the recently identified ABA receptor PYR1 with the type 2C protein phosphatase (PP2C) ABI1, the serine/threonine protein kinase SnRK2.6/OST1 and the transcription factor ABF2/AREB1, we can reconstitute ABA-triggered phosphorylation of the transcription factor in vitro. Introduction of these four components into plant protoplasts results in ABA-responsive gene expression. Protoplast and test-tube reconstitution assays were used to test the function of various members of the receptor, protein phosphatase and kinase families. Our results suggest that the default state of the SnRK2 kinases is an autophosphorylated, active state and that the SnRK2 kinases are kept inactive by the PP2Cs through physical interaction and dephosphorylation. We found that in the presence of ABA, the PYR/PYL (pyrabactin resistance 1/PYR1-like) receptor proteins can disrupt the interaction between the SnRK2s and PP2Cs, thus preventing the PP2C-mediated dephosphorylation of the SnRK2s and resulting in the activation of the SnRK2 kinases. Our results reveal new insights into ABA signalling mechanisms and define a minimal set of core components of a complete major ABA signalling pathway. C1 [Fujii, Hiroaki; Chinnusamy, Viswanathan; Park, Sang-Youl; Cutler, Sean R.; Zhu, Jian-Kang] Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA. [Fujii, Hiroaki; Chinnusamy, Viswanathan; Zhu, Jian-Kang] 4700 King Abdullah Univ Sci & Technol, Ctr Plant Stress Genom & Technol, Thuwal 239556900, Saudi Arabia. [Rodrigues, Americo; Rubio, Silvia; Antoni, Regina; Rodriguez, Pedro L.] Univ Politecn Valencia, CSIC, Inst Biol Mol & Celular Plantas, ES-46022 Valencia, Spain. [Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Zhu, JK (reprint author), Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA. EM jian-kang.zhu@ucr.edu RI Chinnusamy, Viswanathan/B-9079-2009; Rodrigues, Americo/F-9573-2010; Cutler, Sean/D-6617-2011; Rodriguez, Pedro L./K-4605-2014; Zhu, Jian-Kang/F-7658-2011; OI Chinnusamy, Viswanathan/0000-0003-2174-9064; Rodrigues, Americo/0000-0002-5293-5583; Rodriguez, Pedro L./0000-0002-5886-9425; Zhu, Jian-Kang/0000-0001-5134-731X; Fujii, Hiroaki/0000-0002-0013-5891 FU National Institutes of Health; MICIIN; CSIC FX We thank R. Bressan for helpful discussions and for editing of the manuscript. This work was supported by National Institutes of Health grants ( J.- K. Z.) and MICIIN and CSIC fellowships ( S. R. and R. A.). NR 30 TC 378 Z9 415 U1 16 U2 162 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 3 PY 2009 VL 462 IS 7273 BP 660 EP U138 DI 10.1038/nature08599 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 526HH UT WOS:000272277900043 PM 19924127 ER PT J AU Sax, PE Tierney, C Collier, AC Fischl, MA Mollan, K Peeples, L Godfrey, C Jahed, NC Myers, L Katzenstein, D Farajallah, A Rooney, JF Ha, B Woodward, WC Koletar, SL Johnson, VA Geiseler, PJ Daar, ES AF Sax, Paul E. Tierney, Camlin Collier, Ann C. Fischl, Margaret A. Mollan, Katie Peeples, Lynne Godfrey, Catherine Jahed, Nasreen C. Myers, Laurie Katzenstein, David Farajallah, Awny Rooney, James F. Ha, Belinda Woodward, William C. Koletar, Susan L. Johnson, Victoria A. Geiseler, P. Jan Daar, Eric S. CA AIDS Clinical Trials Grp Study TI Abacavir-Lamivudine versus Tenofovir-Emtricitabine for Initial HIV-1 Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED-TRIAL; INFECTED ADULTS; NAIVE PATIENTS; LOPINAVIR/RITONAVIR; ZIDOVUDINE; DF; EFAVIRENZ; EFFICACY; SAFETY AB BACKGROUND The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known. METHODS In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily anti-retroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level >= 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or = 200 copies per milliliter at or after 24 weeks). RESULTS A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48. CONCLUSIONS In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.) C1 [Sax, Paul E.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Sax, Paul E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Sax, Paul E.] Harvard Univ, Sch Med, Boston, MA USA. [Tierney, Camlin; Mollan, Katie; Peeples, Lynne] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Collier, Ann C.] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Fischl, Margaret A.] Univ Miami, Sch Med, Miami, FL USA. [Godfrey, Catherine] NIAID, Div Aids, Bethesda, MD 20892 USA. [Jahed, Nasreen C.] Social & Sci Syst, Silver Spring, MD USA. [Myers, Laurie] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Katzenstein, David] Stanford Univ, Palo Alto, CA 94304 USA. [Rooney, James F.] Gilead Sci Inc, Foster City, CA 94404 USA. [Geiseler, P. Jan] Univ So Calif, Los Angeles, CA USA. [Daar, Eric S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Daar, Eric S.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Farajallah, Awny] Bristol Myers Squibb Co, Plainsboro, NJ USA. [Ha, Belinda] GlaxoSmithKline, Res Triangle Pk, NC USA. [Woodward, William C.] Abbott Labs, Abbott Pk, IL 60064 USA. [Koletar, Susan L.] Ohio State Univ, Columbus, OH 43210 USA. [Johnson, Victoria A.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Sax, PE (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM psax@partners.org FU GlaxoSmithKline; Pfizer; Merck Laboratories; Abbott Laboratories; Bristol-Myers Squibb; Gilead Sciences; Tibotec; Johnson Johnson; Koronis; Schering-Plough; Bionor Immuno AS; Cytheris; Siemens Medical Solutions Diagnostics and Roche Diagnostics; Boehringer Ingelheim; Panacos Pharmaceuticals; National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI38858, AI68636, AI68634]; National Center for Research Resources FX Dr. Sax reports receiving grant support from GlaxoSmithKline, Pfizer, and Merck Laboratories and consulting fees from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Laboratories, and Tibotec and serving as a member of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents; Dr. Tierney, serving on a data and safety monitoring board for Tibotec; Dr. Collier, receiving grant support from Johnson & Johnson (Tibotec), Koronis, Merck Laboratories, Schering-Plough, and Gilead Sciences and consulting fees from GlaxoSmithKline, Pfizer, Merck Laboratories; Dr. Fischl, receiving grant support from Abbott Laboratories, Bionor Immuno AS, Bristol-Myers Squibb, Cytheris, GlaxoSmithKline, and Tibotec and grant support and lecture and consulting fees from Merck Laboratories; Dr. Katzenstein, receiving grant support from Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Gilead Sciences; Dr. Farajallah, being an employee of Bristol-Myers Squibb; Dr. Rooney, being an employee of Gilead Sciences; Dr. Ha, being an employee of GlaxoSmithKline; Dr. Woodward, being an employee of Abbott Laboratories; Dr. Johnson, receiving grant support from Siemens Medical Solutions Diagnostics and Roche Diagnostics; Dr. Geiseler, receiving lecture fees from Cubist Pharmaceuticals; Dr. Daar, receiving grant support from Abbott Laboratories, Merck Laboratories, GlaxoSmithKline, and Gilead Sciences and consulting fees from Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, Pfizer, Merck Laboratories, Tibotec, Boehringer Ingelheim, and Schering-Plough, and serving as a member of the data and safety monitoring board for Ardea Biosciences and of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents; and Dr. Koletar, receiving grant support from Panacos Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. Supported by grants (AI38858, to the AIDS Clinical Trials Group [ACTG] Central Group; AI68636, to the ACTG Network; and AI68634 and AI38855, to the ACTG Statistical and Data Analysis Center) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, with additional support from the General Clinical Research Center units funded by the National Center for Research Resources. NR 16 TC 171 Z9 171 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 3 PY 2009 VL 361 IS 23 BP 2230 EP 2240 DI 10.1056/NEJMoa0906768 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 525ZM UT WOS:000272257100006 PM 19952143 ER PT J AU Desai, AS Chutkow, WA Edelman, E Economy, KE Dec, GW AF Desai, Akshay S. Chutkow, William A. Edelman, Elazer Economy, Katherine E. Dec, G. William, Jr. TI A Crisis in Late Pregnancy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHEOCHROMOCYTOMA; CARDIOMYOPATHY; MYOCARDITIS; PREVALENCE C1 [Desai, Akshay S.; Chutkow, William A.; Edelman, Elazer] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Economy, Katherine E.] Brigham & Womens Hosp, Ctr Maternal Fetal Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Dec, G. William, Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Desai, AS (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, PBB-A3,AB370,75 Francis St, Boston, MA 02115 USA. EM adesai@partners.org NR 15 TC 10 Z9 13 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 3 PY 2009 VL 361 IS 23 BP 2271 EP 2277 DI 10.1056/NEJMcps0708258 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 525ZM UT WOS:000272257100012 PM 19955528 ER PT J AU Jaskelioff, M Song, W Xia, J Liu, C Kramer, J Koido, S Gendler, SJ Calderwood, SK Gong, J AF Jaskelioff, M. Song, W. Xia, J. Liu, C. Kramer, J. Koido, S. Gendler, S. J. Calderwood, S. K. Gong, J. TI Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene SO ONCOGENE LA English DT Article DE telomerase; telomeres; PyMT; MUC1; mammary carcinoma ID NORMAL HUMAN-CELLS; LIFE-SPAN; REVERSE-TRANSCRIPTASE; TRANSGENIC MICE; IMMORTAL CELLS; CANCER; TUMORIGENESIS; MOUSE; CARCINOGENESIS; CARCINOMA AB Mice transgenic for MUC1 (mucin 1) and polyomavirus middle T (PyMT) develop mammary carcinomas within 15 weeks with 100% penetrance. PyMT-induced mammary tumorigenesis is closely correlated with robust telomerase expression and activity. To assess the role of telomerase activation and telomere maintenance in mammary carcinoma tumorigenesis, we generated mice expressing MUC1 and PyMT (MMT mice) but deficient in the telomerase RNA component, mTerc, on the C57BL/6 background. Successive generational intercrosses of mTerc(-/-)MMT mice produced cohorts with progressively shorter telomeres that were audited for mammary tumor formation. Relative to MMT (N=14) and G0 mTerc(+/-) female controls (G0=14), mTerc(-/-)MMT females (G1=11, G2=15, G3=15 and G4=5) showed decreased tumor volumes and increased tumor latency-MMT=95.6 days; G0 mTerc(+/-) MMT=98.6 days versus G1, G2, G3 and G4 mTerc(-/-)MMT mice with latencies of 122.6, 138.9, 140.7 and 220.9 days, respectively (controls versus G1-G4, P<0.005). The progressive impairment of lung metastasis was also observed with each successive mTerc(-/-)MMT generation. The impairment of tumorigenesis was associated with decreased proliferation of mammary epithelial and tumor cells and increased apoptosis of tumor cells. Together, these results indicate that, in the setting of viral oncoprotein mammary tumorigenesis, telomerase-dependent telomere maintenance facilitates the formation and metastatic progression of mammary tumors. Oncogene (2009) 28, 4225-4236; doi: 10.1038/onc.2009.268; published online 7 September 2009 C1 [Gong, J.] Boston Univ, Sch Med, Dept Med, Med Ctr, Boston, MA 02215 USA. [Jaskelioff, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Koido, S.] Jikei Univ, Sch Med, Dept Internal Med, Tokyo, Japan. [Gendler, S. J.] Mayo Clin, Dept Biochem & Mol Biol, Scottsdale, AZ USA. [Calderwood, S. K.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Gong, J (reprint author), Boston Univ, Sch Med, Dept Med, Med Ctr, 650 Albany St,Room 309, Boston, MA 02215 USA. EM jgong@bu.edu FU Susan G Komen Breast Cancer Foundation [BCTR0503792, PDF060881]; US Department of Defense Breast Cancer Research FX This work was supported by the Susan G Komen Breast Cancer Foundation (BCTR0503792 to JG and PDF060881 to MJ) and the US Department of Defense Breast Cancer Research programs (JG). We thank Dr Ronald A DePinho for providing mTerc-/- mice, advice and comments on the paper. NR 54 TC 13 Z9 13 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 3 PY 2009 VL 28 IS 48 BP 4225 EP 4236 DI 10.1038/onc.2009.268 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 534DS UT WOS:000272876300001 PM 19734944 ER PT J AU April, C Klotzle, B Royce, T Wickham-Garcia, E Boyaniwsky, T Izzo, J Cox, D Jones, W Rubio, R Holton, K Matulonis, U Quackenbush, J Fan, JB AF April, Craig Klotzle, Brandy Royce, Thomas Wickham-Garcia, Eliza Boyaniwsky, Tanya Izzo, John Cox, Donald Jones, Wendell Rubio, Renee Holton, Kristina Matulonis, Ursula Quackenbush, John Fan, Jian-Bing TI Whole-Genome Gene Expression Profiling of Formalin-Fixed, Paraffin-Embedded Tissue Samples SO PLOS ONE LA English DT Article ID PROSTATE-CANCER; BREAST-CANCER; MICROARRAY ANALYSIS; RNA EXTRACTION; FROZEN TISSUE; SIGNATURES; ASSAY; OLIGONUCLEOTIDE; AMPLIFICATION; OPTIMIZATION AB Background: We have developed a gene expression assay (Whole-Genome DASLH), capable of generating whole-genome gene expression profiles from degraded samples such as formalin-fixed, paraffin-embedded (FFPE) specimens. Methodology/Principal Findings: We demonstrated a similar level of sensitivity in gene detection between matched fresh-frozen (FF) and FFPE samples, with the number and overlap of probes detected in the FFPE samples being approximately 88% and 95% of that in the corresponding FF samples, respectively; 74% of the differentially expressed probes overlapped between the FF and FFPE pairs. The WG-DASL assay is also able to detect 1.3-1.5 and 1.5-2-fold changes in intact and FFPE samples, respectively. The dynamic range for the assay is,3 logs. Comparing the WG-DASL assay with an in vitro transcription-based labeling method yielded fold-change correlations of R 2,0.83, while fold-change comparisons with quantitative RT-PCR assays yielded R(2)similar to 0.86 and R(2)similar to 0.55 for intact and FFPE samples, respectively. Additionally, the WG-DASL assay yielded high self-correlations (R(2)> 0.98) with low intact RNA inputs ranging from 1 ng to 100 ng; reproducible expression profiles were also obtained with 250 pg total RNA (R(2)> 0.92), with,71% of the probes detected in 100 ng total RNA also detected at the 250 pg level. When FFPE samples were assayed, 1 ng total RNA yielded self-correlations of R(2)similar to 0.80, while still maintaining a correlation of R(2)similar to 0.75 with standard FFPE inputs (200 ng). Conclusions/Significance: Taken together, these results show that WG-DASL assay provides a reliable platform for genome-wide expression profiling in archived materials. It also possesses utility within clinical settings where only limited quantities of samples may be available (e.g. microdissected material) or when minimally invasive procedures are performed (e.g. biopsied specimens). C1 [April, Craig; Klotzle, Brandy; Royce, Thomas; Wickham-Garcia, Eliza; Boyaniwsky, Tanya; Izzo, John; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Cox, Donald; Jones, Wendell] Express Anal Inc, Durham, NC USA. [Rubio, Renee; Holton, Kristina; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Matulonis, Ursula] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP April, C (reprint author), Illumina Inc, San Diego, CA USA. EM jfan@illumina.com FU Madeline Franchi Ovarian Cancer Research Fund; Claudia Adams Barr Program; US National Cancer Institute [P50 CA105009] FX This work was supported in part by grants from the Madeline Franchi Ovarian Cancer Research Fund, the Claudia Adams Barr Program, and a grant from the US National Cancer Institute (P50 CA105009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 77 Z9 78 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 DEC 3 PY 2009 VL 4 IS 12 AR e8162 DI 10.1371/journal.pone.0008162 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MW UT WOS:000272829000013 PM 19997620 ER PT J AU Oleastro, M Cordeiro, R Menard, A Yamaoka, Y Queiroz, D Megraud, F Monteiro, L AF Oleastro, Monica Cordeiro, Rita Menard, Armelle Yamaoka, Yoshio Queiroz, Dulciene Megraud, Francis Monteiro, Lurdes TI Allelic diversity and phylogeny of homB, a novel co-virulence marker of Helicobacter pylori SO BMC MICROBIOLOGY LA English DT Article ID PEPTIC-ULCER DISEASE; RESTRICTION-MODIFICATION SYSTEM; COMPLETE GENOME SEQUENCE; CONCERTED EVOLUTION; PHASE VARIATION; HOPQ ALLELES; STRAINS; INFECTION; VACA; CAGA AB Background: The homB gene is a Helicobacter pylori disease-marker candidate, strongly associated with peptic ulcer disease, while homA, its paralogue gene with 90% sequence identity, is correlated with non-ulcer dyspepsia. The HomB encoded outer membrane protein was shown to contribute to the proinflammatory properties of H. pylori and also to be involved in bacterial adherence. This study investigated the distribution of homB and homA genes in 455 H. pylori strains from East Asian and Western countries, and carried out sequence comparison and phylogenetic analyses. Results: Both homB and homA genes were heterogeneously distributed worldwide, with a marked difference between East Asian and Western strains. Analysis of homB and homA sequences revealed diversity regarding the number of copies and their genomic localization, with East Asian and Western strains presenting different genotypes. Moreover, homB and homA sequence analysis suggests regulation by phase variation. It also indicates possible recombination events, leading to gene duplication or homB/homA conversion which may as well be implicated in the regulation of these genes. Phylogenetic reconstruction of homB and homA revealed clustering according to the geographic origin of strains. Allelic diversity in the middle region of the genes was observed for both homB and homA, although there was no correlation between any allele and disease. For each gene, a dominant worldwide allele was detected, suggesting that homB/homA allelic variants were independent of the geographical origin of the strain. Moreover, all alleles were demonstrated to be expressed in vivo. Conclusion: Overall, these results suggest that homB and homA genes are good candidates to be part of the pool of H. pylori OMPs implicated in host-bacteria interface and also contributing to the generation of antigenic variability, and thus involved in H. pylori persistence. C1 [Oleastro, Monica; Menard, Armelle; Megraud, Francis] INSERM, U853, F-33076 Bordeaux, France. [Oleastro, Monica; Cordeiro, Rita; Monteiro, Lurdes] Inst Nacl Saude Dr Ricardo Jorge, Dept Doencas Infecc, P-1649016 Lisbon, Portugal. [Menard, Armelle; Megraud, Francis] Univ Bordeaux 2, Bacteriol Lab, F-33076 Bordeaux, France. [Yamaoka, Yoshio] Baylor Coll Med, Houston, TX 77030 USA. [Yamaoka, Yoshio] Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Houston, TX 77030 USA. [Queiroz, Dulciene] Univ Fed Minas Gerais, Fac Med, Lab Pesquisa Bacteriol, BR-30130100 Belo Horizonte, MG, Brazil. RP Megraud, F (reprint author), INSERM, U853, F-33076 Bordeaux, France. EM monica.oleastro@insa.min-saude.pt; rita.cordeiro@insa.min-saude.pt; armelle.menard@labhel.u-bordeaux2.fr; yyamaoka@bcm.tmc.edu; dqueiroz@medicina.ufmg.br; francis.megraud@chu-bordeaux.fr; m.lurdes.monteiro@insa.min-saude.pt OI menard, armelle/0000-0002-6130-736X; Oleastro, Monica/0000-0001-6360-2576; Monteiro, Maria de Lurdes/0000-0002-5064-5718 FU Fundacao para a Ciencia e Tecnologia [PPCDT/SAL-IMI/57297/2004] FX The authors thank Markus Gerhard for supplying H. pylori strains from German patients, and Thomas Boren and Lars Engstrand for providing the Swedish strains used in this study. The authors would like to thank also to Sandrine Dupouy and Christina Morate for technical assistance. Finally, we which to thank to the Fundacao para a Ciencia e Tecnologia, project PPCDT/SAL-IMI/57297/2004, for financial support. NR 40 TC 16 Z9 17 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD DEC 2 PY 2009 VL 9 AR 248 DI 10.1186/1471-2180-9-248 PG 12 WC Microbiology SC Microbiology GA 535YK UT WOS:000273007700001 PM 19954539 ER PT J AU Basch, E Jia, XY Heller, G Barz, A Sit, L Fruscione, M Appawu, M Iasonos, A Atkinson, T Goldfarb, S Culkin, A Kris, MG Schrag, D AF Basch, Ethan Jia, Xiaoyu Heller, Glenn Barz, Allison Sit, Laura Fruscione, Michael Appawu, Mark Iasonos, Alexia Atkinson, Thomas Goldfarb, Shari Culkin, Ann Kris, Mark G. Schrag, Deborah TI Adverse Symptom Event Reporting by Patients vs Clinicians: Relationships With Clinical Outcomes SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; REFRACTORY PROSTATE-CANCER; PROGNOSTIC-FACTORS; LUNG-CANCER; SEVERE PAIN; SURVIVAL; COMMUNICATION; QUESTIONNAIRE; CHEMOTHERAPY AB In cancer treatment trials, the standard source of adverse symptom data is clinician reporting by use of items from the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Patient self-reporting has been proposed as an additional data source, but the implications of such a shift are not understood. Patients with lung cancer receiving chemotherapy and their clinicians independently reported six CTCAE symptoms and Karnofsky Performance Status longitudinally at sequential office visits. To compare how patient's vs clinician's reports relate to sentinel clinical events, a time-dependent Cox regression model was used to measure associations between reaching particular CTCAE grade severity thresholds with the risk of death and emergency room visits. To measure concordance of CTCAE reports with indices of daily health status, Kendall tau rank correlation coefficients were calculated for each symptom with EuroQoL EQ-5D questionnaire and global question scores. Statistical tests were two-sided. A total of 163 patients were enrolled for an average of 12 months (range = 1-28 months), with a mean of 11 visits and 67 (41%) deaths. CTCAE reports were submitted by clinicians at 95% of visits and by patients at 80% of visits. Patients generally reported symptoms earlier and more frequently than clinicians. Statistically significant associations with death and emergency room admissions were seen for clinician reports of fatigue (P < .001), nausea (P = .01), constipation (P = .038), and Karnofsky Performance Status (P < .001) but not for patient reports of these items. Higher concordance with EuroQoL EQ-5D questionnaire and global question scores was observed for patient-reported symptoms than for clinician-reported symptoms. Longitudinally collected clinician CTCAE assessments better predict unfavorable clinical events, whereas patient reports better reflect daily health status. These perspectives are complementary, each providing clinically meaningful information. Inclusion of both types of data in treatment trial results and drug labels appears to be warranted. C1 [Basch, Ethan] Mem Sloan Kettering Canc Ctr, Hlth Outcomes Grp, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Basch, Ethan; Jia, Xiaoyu; Heller, Glenn; Barz, Allison; Sit, Laura; Fruscione, Michael; Appawu, Mark; Iasonos, Alexia; Atkinson, Thomas; Goldfarb, Shari; Culkin, Ann; Kris, Mark G.] Mem Sloan Kettering Canc Ctr, Dept Med, Dept Nursing, New York, NY 10065 USA. [Schrag, Deborah] Cent Adm, Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Basch, E (reprint author), Mem Sloan Kettering Canc Ctr, Hlth Outcomes Grp, Dept Epidemiol & Biostat, 307 E 63rd St, New York, NY 10065 USA. EM basche@mskcc.org OI Kris, Mark/0000-0002-7317-5341 FU National Cancer Institute; American Society of Clinical Oncology; Memorial Sloan-Kettering Cancer Center FX Funding to conduct this research was received from the National Cancer Institute, American Society of Clinical Oncology, and the Steps-for-Breath philanthropic fund of Memorial Sloan-Kettering Cancer Center. NR 43 TC 136 Z9 140 U1 3 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 2 PY 2009 VL 101 IS 23 BP 1624 EP 1632 DI 10.1093/jnci/djp386 PG 9 WC Oncology SC Oncology GA 528RT UT WOS:000272465100008 PM 19920223 ER PT J AU Rastogi, A Bose, T Feldman, MD Patel, D Stavchansky, S AF Rastogi, Ashish Bose, Tanushree Feldman, Marc D. Patel, Devang Stavchansky, Salomon TI Characterization of Nanoporous Surfaces as Templates for Drug Delivery Devices SO AAPS JOURNAL LA English DT Review DE cyanoacrylate; drug delivery; methyl orange; nanopores; volume calculation ID GENE DELIVERY; NANO DEVICE; NANOPARTICLES; SYSTEM C1 [Rastogi, Ashish; Bose, Tanushree; Stavchansky, Salomon] Univ Texas Austin, Coll Pharm, Div Pharmaceut, Austin, TX 78712 USA. [Feldman, Marc D.; Patel, Devang] Univ Texas Hlth Sci Ctr San Antonio, Div Cardiol, San Antonio, TX 78229 USA. [Feldman, Marc D.] S Texas Vet Affairs Hlth Care Syst, San Antonio, TX 78229 USA. RP Stavchansky, S (reprint author), Univ Texas Austin, Coll Pharm, Div Pharmaceut, Austin, TX 78712 USA. EM stavchansky@mail.utexas.edu NR 19 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD DEC PY 2009 VL 11 IS 4 BP 758 EP 761 DI 10.1208/s12248-009-9152-x PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 544UZ UT WOS:000273686100012 PM 19876743 ER PT J AU Senecal, EL Thomas, SH Beeson, MS AF Senecal, Emily L. Thomas, Stephen H. Beeson, Michael S. TI A Four-Year Perspective of Society for Academic Emergency Medicine Tests: An Online Testing Tool for Medical Students SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Academic-Emergency-Medicine CY MAY 16-19, 2007 CL Chicago, IL SP Soc Acad Emergency Med DE education; online testing; shelf exam; medical student; emergency medicine ID IMPACT AB Nationwide survey findings that most U.S. emergency medicine clerkship directors were interested in participating in a methodologically rigorous student testing program prompted the development of the Society for Academic Emergency Medicine (SAEM) Medical Student Online Testing Service (SAEM Tests). This article describes the development of SAEM Tests and details usage and progress since the on-line release in June 2005. Specifically, we review the construction of SAEM Tests and present validity and difficulty statistics obtained at the first analysis of test performance 6 months after its release and again 12 months later after revisions aimed at enhancing test performance. We then review the current status of SAEM Tests and summarize future goals and directions. C1 [Senecal, Emily L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. [Thomas, Stephen H.] Univ Oklahoma, Dept Emergency Med, Sch Community Med, Tulsa, OK USA. [Beeson, Michael S.] Northeastern Ohio Univ Coll Med & Pharm, Dept Emergency Med, Chicago, IL USA. RP Senecal, EL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. EM ESenecal@Partners.org NR 7 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2009 VL 16 IS 12 SU 2 BP S42 EP S45 DI 10.1111/j.1553-2712.2009.00594.x PG 4 WC Emergency Medicine SC Emergency Medicine GA 530BX UT WOS:000272565000009 PM 20053210 ER PT J AU Pronovost, PJ Miller, MR Wachter, RM Meyer, GS AF Pronovost, Peter J. Miller, Marlene R. Wachter, Robert M. Meyer, Gregg S. TI Perspective: Physician Leadership in Quality SO ACADEMIC MEDICINE LA English DT Article AB While advances in biomedicine are awesome, progress in patient safety and quality of care has proven slow and arduous. One factor contributing to the labored progress is the paucity of physician-leaders who can help advance the science and practice of quality and safety. This limited talent pool, which has particularly serious consequences in academic medical centers (AMCs), stems from insufficient training in quality and safety, which in turn owes to our collective failure to view the delivery of health care as a science. Even when AMCs have trained and skilled quality and safety leaders, the infrastructure to support their work is deficient, with poorly defined job descriptions, competing responsibilities, and limited formal roles in the medical school compared with the hospital. Though there is limited empiric evidence to guide recommendations, the authors support four initiatives to accelerate national progress on quality and safety: (1) invest in quality and safety science, (2) revise quality and safety governance in AMCs, and (3) integrate roles within the hospital and medical school. Many of these shortcomings can be addressed by creating a newly integrated role: the vice dean for quality and hospital director of quality and safety. For AMCs to achieve significant improvements in quality and safety, they must invest in physician-leaders and in the support these leaders need to carry out their educational and operational roles. C1 [Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Qual & Safety Res Grp, Baltimore, MD 21231 USA. [Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21231 USA. [Pronovost, Peter J.; Miller, Marlene R.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Miller, Marlene R.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21231 USA. [Miller, Marlene R.] Natl Assoc Childrens Hosp & Related Inst, Alexandria, VA USA. [Wachter, Robert M.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. [Wachter, Robert M.] Univ Calif San Francisco, Sch Med, Div Hosp Med, San Francisco, CA USA. [Meyer, Gregg S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meyer, Gregg S.] Massachusetts Gen Phys Org, Boston, MA USA. RP Pronovost, PJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Qual & Safety Res Grp, 1909 Thames St,2nd Floor, Baltimore, MD 21231 USA. EM ppronovo@jhmi.edu NR 30 TC 37 Z9 37 U1 1 U2 12 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 DEC PY 2009 VL 84 IS 12 BP 1651 EP 1656 DI 10.1097/ACM.0b013e3181bce0ee PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA V15EW UT WOS:000207786300009 PM 19940567 ER PT J AU Bohmer, RMJ Bloom, JD Mort, EA Demehin, AA Meyer, GS AF Bohmer, Richard M. J. Bloom, Jonathan D. Mort, Elizabeth A. Demehin, Akinluwa A. Meyer, Gregg S. TI Restructuring Within an Academic Health Center to Support Quality and Safety: The Development of the Center for Quality and Safety at the Massachusetts General Hospital SO ACADEMIC MEDICINE LA English DT Article AB Recent focus on the need to improve the quality and safety of health care has created new challenges for academic health centers (AHCs). Whereas previously quality was largely assumed, today it is increasingly quantifiable and requires organized systems for improvement. Traditional structures and cultures within AHCs, although well suited to the tripartite missions of teaching, research, and clinical care, are not easily adaptable to the tasks of measuring, reporting, and improving quality. Here, the authors use a case study of Massachusetts General Hospital's efforts to restructure quality and safety to illustrate the value of beginning with a focus on organizational culture, using a systematic process of engaging clinical leadership, developing an organizational framework dependent on proven business principles, leveraging focus events, and maintaining executive dedication to execution of the initiative. The case provides a generalizable example for AHCs of how applying explicit management design can foster robust organizational change with relatively modest incremental financial resources. C1 [Bohmer, Richard M. J.] Harvard Univ, Sch Business, Boston, MA 02163 USA. [Bloom, Jonathan D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Demehin, Akinluwa A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Qual & Safety, Boston, MA USA. RP Meyer, GS (reprint author), Bulfinch 250,55 Fruit St, Boston, MA 02114 USA. EM gmeyer@partners.org NR 21 TC 9 Z9 9 U1 2 U2 4 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 DEC PY 2009 VL 84 IS 12 BP 1663 EP 1671 DI 10.1097/ACM.0b013e3181bfd09b PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA V15EW UT WOS:000207786300012 PM 19940570 ER PT J AU Splaine, ME Ogrinc, G Gilman, SC Aron, DC Estrada, CA Rosenthal, GE Lee, S Dittus, RS Batalden, PB AF Splaine, Mark E. Ogrinc, Greg Gilman, Stuart C. Aron, David C. Estrada, Carlos A. Rosenthal, Gary E. Lee, Sei Dittus, Robert S. Batalden, Paul B. TI The Department of Veterans Affairs National Quality Scholars Fellowship Program: Experience From 10 Years of Training Quality Scholars SO ACADEMIC MEDICINE LA English DT Article AB The Department of Veterans Affairs (VA) National Quality Scholars Fellowship Program (VAQS) was established in 1998 as a postgraduate medical education fellowship to train physicians in new methods of improving the quality and safety of health care for veterans and the nation. The VAQS curriculum is based on adult learning theory, with a national core curriculum of face-to-face components, technologically mediated distance learning components, and a unique local curriculum that draws from the strengths of regional resources. VAQS has established strong ties with other VA programs. Fellows' research and quality improvement projects are integrated with local and regional VA leaders' priorities, enhancing the relevance and visibility of the fellows' efforts and promoting recruitment of fellows to VA positions. VAQS has enrolled 98 fellows since 1999; 75 have completed the program and 24 are currently enrolled. Fellowship graduates have pursued a variety of career paths: 17% are continuing training (most in VA), 31% hold a VA faculty/staff position, 66% are academic faculty, and 80% conduct clinical or research work related to health care improvement. Graduates have held leadership positions in VA, Department of Defense, academic medicine, and public health agencies. Combining knowledge about the improvement of health care with adult learning strategies, distance learning technologies, face-to-face meetings, local mentorship, and experiential projects has been successful in improving care in VA and preparing physicians to participate in, study, and lead the improvement of health care quality and safety. C1 [Splaine, Mark E.] Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Ctr Leadership & Improvement, VA Natl Qual Scholars Fellowship Program, Lebanon, NH 03756 USA. [Ogrinc, Greg] Dept Vet Affairs Med Ctr, Dept Vet Affairs Natl Qual Scholars Fellowship Pr, White River Jct, VT USA. [Gilman, Stuart C.] VA Off Acad Affiliat, Washington, DC USA. [Aron, David C.] Vet Affairs Med Ctr, Dept Vet Affairs Natl Qual Scholars Fellowship Pr, Cleveland, OH USA. [Aron, David C.] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, VA HSR&D QUERI Ctr Implementat Practice & Res Sup, Cleveland, OH USA. [Aron, David C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Estrada, Carlos A.] Birmingham Vet Affairs Med Ctr, Vet Affairs Natl Qual Scholars Fellowship Program, Birmingham, AL USA. [Estrada, Carlos A.] Univ Alabama, Birmingham, AL USA. [Rosenthal, Gary E.] Univ Iowa, Sch Med, Vet Affairs Med Ctr, Dept Vet Affairs Natl Qual Scholars Fellowship Pr, Iowa City, IA 52242 USA. [Rosenthal, Gary E.] Univ Iowa, Sch Med, Vet Affairs Med Ctr, Iowa City Dept,Dept Med,Div Gen Internal Med, Iowa City, IA 52242 USA. [Lee, Sei] Vet Affairs Med Ctr, San Francisco Dept, Dept Vet Affairs Natl Qual Scholars Fellowship Pr, Div Geriatr, La Jolla, CA 92161 USA. [Lee, Sei] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dittus, Robert S.] Vanderbilt Univ, Sch Med, Dept Vet Affairs Natl Qual Scholars Fellowship Pr, Nashville, TN 37212 USA. [Dittus, Robert S.] Vanderbilt Univ, Sch Med, Nashville Dept, Dept Med,Div Gen Internal Med, Nashville, TN 37212 USA. RP Splaine, ME (reprint author), Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Ctr Leadership & Improvement, VA Natl Qual Scholars Fellowship Program, 30 Lafayette St,3rd Floor Novell, Lebanon, NH 03756 USA. EM mark.e.splaine@hitchcock.org FU Department of Veterans Affairs FX The authors are deeply grateful to Leslie K. Walker, Department of Veterans Affairs National Quality Scholars Fellowship (VAQS) national program coordinator, for her assistance in the preparation of this manuscript and her ongoing support of VAQS. Information about the VAQS can be obtained at www.vaqs.org. NR 35 TC 16 Z9 16 U1 0 U2 3 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 DEC PY 2009 VL 84 IS 12 BP 1741 EP 1748 DI 10.1097/ACM.0b013e3181bfdcef PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA V15EW UT WOS:000207786300022 PM 19940583 ER PT J AU Hauer, KE Ciccone, A Henzel, TR Katsufrakis, P Miller, SH Norcross, WA Papadakis, MA Irby, DM AF Hauer, Karen E. Ciccone, Andrea Henzel, Thomas R. Katsufrakis, Peter Miller, Stephen H. Norcross, William A. Papadakis, Maxine A. Irby, David M. TI Remediation of the Deficiencies of Physicians Across the Continuum From Medical School to Practice: A Thematic Review of the Literature SO ACADEMIC MEDICINE LA English DT Review AB Despite widespread endorsement of competency-based assessment of medical trainees and practicing physicians, methods for identifying those who are not competent and strategies for remediation of their deficits are not standardized. This literature review describes the published studies of deficit remediation at the undergraduate, graduate, and continuing medical education levels. Thirteen studies primarily describe small, single-institution efforts to remediate deficient knowledge or clinical skills of trainees or below-standard-practice performance of practicing physicians. Working from these studies and research from the learning sciences, the authors propose a model that includes multiple assessment tools for identifying deficiencies, individualized instruction, deliberate practice followed by feedback and reflection, and reassessment. The findings of the study reveal a paucity of evidence to guide best practices of remediation in medical education at all levels. There is an urgent need for multiinstitutional, outcomes-based research on strategies for remediation of less than fully competent trainees and physicians with the use of long-term follow-up to determine the impact on future performance. C1 [Hauer, Karen E.] Univ Calif San Francisco, Dept Med, Sch Med, San Francisco, CA 94143 USA. [Ciccone, Andrea; Henzel, Thomas R.] Natl Board Med Examiners, Post Licensure Assessment Serv, Philadelphia, PA USA. [Katsufrakis, Peter] Natl Board Med Examiners, Assessment Programs, Philadelphia, PA USA. [Miller, Stephen H.] Univ Calif San Diego, Sch Med, Dept Family Med, San Diego, CA 92103 USA. [Miller, Stephen H.] Univ Calif San Diego, Dept Surg, Sch Med, San Diego, CA 92103 USA. [Norcross, William A.] Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, San Diego, CA 92103 USA. [Papadakis, Maxine A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Papadakis, Maxine A.; Irby, David M.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. RP Hauer, KE (reprint author), Univ Calif San Francisco, Dept Med, Sch Med, 533 Parnassus Ave,U137,Box 0131, San Francisco, CA 94143 USA. EM karen.hauer@ucsf.edu OI Irby, David/0000-0001-5753-8918 NR 55 TC 61 Z9 62 U1 0 U2 11 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 DEC PY 2009 VL 84 IS 12 BP 1822 EP 1832 DI 10.1097/ACM.0b013e3181bf3170 PG 11 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA V15EW UT WOS:000207786300035 PM 19940595 ER PT J AU Park, ER Chang, Y Quinn, VP Ross, K Rigotti, NA AF Park, Elyse R. Chang, Yuchiao Quinn, Virginia P. Ross, Kaile Rigotti, Nancy A. TI Perceived support to stay quit: What happens after delivery? SO ADDICTIVE BEHAVIORS LA English DT Article DE Postpartum; Relapse prevention; Smoking cessation ID SMOKING-CESSATION; POSTPARTUM RELAPSE; PREGNANCY OUTCOMES; PARTNER SMOKING; SOCIAL SUPPORT; PREDICTORS; WOMEN; INTERVENTION; ABSTINENCE; MOTHERS AB Objective: To assess whether perceived changes in postpartum support were associated with postpartum return to smoking. Study design: This is a prospective repeated measures, mixed methods observational study. Sixty-five women who smoked prior to pregnancy were recruited at delivery and surveyed at 2, 6, 12, and 24 weeks postpartum; in-depth interviews were conducted when participants reported smoking. Results: Fifty-two percent self identified as White, non-Hispanic. Forty-seven percent resumed smoking by 24 weeks postpartum. Women who had returned to smoking by 24 weeks had a significantly larger decrease in perceived smoking-specific support than women who remained abstinent (p<0.001). By 24-week postpartum follow-up, only 24% of women reported that an obstetric clinician had discussed how to quit/stay quit. When qualitatively interviewed, more than half of women reported having no one to support them to stay quit or quit smoking. Conclusion: Following delivery, women lack needed smoking-specific support. Decline in perceived smoking-specific support from family and friends is associated with postpartum smoking resumption. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Park, Elyse R.; Chang, Yuchiao; Ross, Kaile; Rigotti, Nancy A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Quinn, Virginia P.] Kaiser Permanente So Calif, Pasadena, CA 91188 USA. RP Park, ER (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM epark@partners.org; ychang@partners.org; Virginia.P.Quinn@kp.org; kailemaureen@gmail.com; nrigotti@partners.org FU Robert Wood Johnson Foundation; American Cancer Society FX We want to acknowledge the hard work of Kristin Perry and Jennifer Kelley, MSW In addition, we would like to thank Laura Solomon, Ph.D. and Jennifer Haas, M.D., MPH for their support of this work. We acknowledge funding from the Robert Wood Johnson Foundation and the American Cancer Society. NR 30 TC 10 Z9 10 U1 2 U2 5 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 DEC PY 2009 VL 34 IS 12 BP 1000 EP 1004 DI 10.1016/j.addbeh.2009.06.005 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 502PN UT WOS:000270472500002 PM 19560280 ER PT J AU Pasquale, LR Walt, JG Stern, LS Wiederkehr, D Malangone, E Dolgitser, M AF Pasquale, Louis R. Walt, John G. Stern, Lee S. Wiederkehr, Daniel Malangone, Elisabetta Dolgitser, Margarita TI Healthcare charges in patients with glaucoma who undergo laser trabeculoplasty SO ADVANCES IN THERAPY LA English DT Article DE case-control analysis; healthcare charges; laser trabeculoplasty; ophthalmology; primary open-angle glaucoma ID OPEN-ANGLE GLAUCOMA; OCULAR HYPERTENSION; INTRAOCULAR-PRESSURE; ECONOMIC-EVALUATION; INSURANCE PLAN; CLAIMS DATA; MANAGEMENT; TRIAL; COST; MEDICATION AB The objective of this study was to assess the impact of laser trabeculoplasty (LTP) on healthcare charges in patients with primary open-angle glaucoma (POAG). Using a managed care database (PharMetrics; Watertown, MA, USA), we formed a case-control group nested within a POAG cohort (n=72,412) formed using International Classification of Disease, Ninth Edition (ICD-9) coding data. Cases (n=1145) had LTP (Current Procedural Terminology code: 65855) with a parts per thousand yen1 year of continuous enrollment both prior to, and following LTP index date in PharMetrics from 1998-2005. Using the date of LTP as the index date, controls (n=2290) without LTP were matched to cases on gender, age, and index year in a 2:1 ratio. Cases and controls had a parts per thousand yen6 months of continuous enrollment in PharMetrics prior to receiving a diagnosis of POAG (ICD-9 code: 365.11). One-year total and ophthalmology healthcare charges were calculated in the year pre- and post-index date (excluding charges for LTP at the index date). Conditional logistic regression models and multiple linear regression models determined the impact of LTP on healthcare charges, while controlling for glaucoma duration and other key covariates. While the mean age of cases (60.1 +/- 13.1 years) and controls (60.3 +/- 13.6 years) was similar (P=0.5589), cases had more comorbid systemic conditions (P < 0.05) and underwent more cataract surgery in the year after index date (4.4% vs. 2.1%; P=0.002). In the year after index date, ophthalmology-related charges increased by $1364 for cases vs. $30 for controls (P=0.0003). Total healthcare charges increased by $5084 for cases and $1594 for controls in the year after index date (P=0.0085). Cases and controls experienced similar increases in ophthalmology-related pharmacy charges from the year pre- to the year post-index date ($26 vs. $43, P=0.385). In both logistic regression and linear regression models, which adjusted for several covariates, performing LTP was associated with increased total healthcare and ophthalmologyrelated charges. Among patients with POAG in this study, performing LTP was associated with increased total and ophthalmologyrelated healthcare charges, while ophthalmology pharmacy charges did not decline. C1 [Stern, Lee S.; Wiederkehr, Daniel; Malangone, Elisabetta; Dolgitser, Margarita] Analyt Int, New York, NY 10018 USA. [Pasquale, Louis R.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Glaucoma Serv, Boston, MA USA. [Walt, John G.] Allergan Pharmaceut Inc, Irvine, CA 92715 USA. RP Stern, LS (reprint author), Analyt Int, 24 W 40th St,8th Floor, New York, NY 10018 USA. EM lstern@analyticaintl.com NR 27 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0741-238X J9 ADV THER JI Adv. Ther. PD DEC PY 2009 VL 26 IS 12 BP 1084 EP 1096 DI 10.1007/s12325-009-0085-7 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 557FN UT WOS:000274655100004 PM 20077051 ER PT J AU Niikura, Y Niikura, T Tilly, JL AF Niikura, Yuichi Niikura, Teruko Tilly, Jonathan L. TI Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment SO AGING-US LA English DT Article DE aging; germ cell; meiosis; Stra8; oogenesis; oocyte; ovary; stem cell ID ADULT MAMMALIAN OVARIES; STEM-CELLS; BONE-MARROW; MICE; EXPRESSION; MEIOSIS; FAILURE; FERTILITY; RENEWAL; PROTEIN AB Of all the major organ systems in the body, the ovaries of females are the first to exhibit impaired function with advancing age. Until recently, traditional thinking was that female mammals are provided with a non-renewable pool of oocyte-containing follicles at birth that are depleted during postnatal life to exhaustion, driving ovarian failure. However, a growing body of evidence, including the isolation of germline stem cells (GSC) from adult mouse ovaries that produce developmentally-competent oocytes, has challenged this belief. In addition, rare germline stem-like cells capable of generating oocytes in vitro that undergo parthenogenesis to form blastocyst-like structures have recently been identified in postmenopausal human ovaries. Here we show that the germline-specific meiosis-commitment genes, Stimulated by retinoic acid gene 8 (Stra8) and Deleted in azoospermia-like ( Dazl), are highly expressed in aged mouse ovaries. However, histological and marker analyses fail to demonstrate the presence of oocytes, supporting that Stra8 and Dazl are expressed in premeiotic germ cells that do not undergo further differentiation. Through the use of aged germline-specific GFP expressing transgenic mice, we further show that these germ cells can generate GFP-positive oocytes that co-express the primordial oocyte marker NOBOX and form follicles when grafted into young adult wild-type female hosts. Thus, aged mouse ovaries possess a rare population of premeiotic germ cells that retain the capacity to form oocytes if exposed to a young host environment. C1 [Niikura, Yuichi; Niikura, Teruko; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA 02114 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, THR 901B,55 Fruit St, Boston, MA 02114 USA. EM jtilly@partners.org FU NIH MERIT [R37-AG012279]; Rubin Shulsky Philanthropic Fund; Henry and Vivian Rosenberg Philanthropic Fund; Sea Breeze Foundation; Vincent Memorial Research Funds FX We thank D. C. Page for testes from Stra8 gene knockout mice, J. R. Mann and K. J. MacLaughlin for TgOG2 transgenic mice, and A. Wagers for teaching us how to perform parabiosis in mice. This work was supported by NIH MERIT Award R37-AG012279, the Rubin Shulsky Philanthropic Fund, the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation, and Vincent Memorial Research Funds. NR 32 TC 63 Z9 72 U1 0 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD DEC PY 2009 VL 1 IS 12 BP 971 EP 978 PG 8 WC Cell Biology SC Cell Biology GA 579VA UT WOS:000276403100002 PM 20157580 ER PT J AU Hendriksen, ES Hlubinka, D Chariyalertsak, S Chingono, A Gray, G Mbwambo, J Richter, L Kulich, M Coates, TJ AF Hendriksen, Ellen Setsuko Hlubinka, Daniel Chariyalertsak, Suwat Chingono, Alfred Gray, Glenda Mbwambo, Jessie Richter, Linda Kulich, Michal Coates, Thomas J. TI Keep Talking About It: HIV/AIDS-Related Communication and Prior HIV Testing in Tanzania, Zimbabwe, South Africa, and Thailand SO AIDS AND BEHAVIOR LA English DT Article DE HIV; AIDS; Communication; VCT; Public opinion ID SEXUAL RISK BEHAVIOR; NORTHERN THAILAND; SOCIAL NETWORKS; PUBLIC-OPINION; MASS-MEDIA; STIGMA; SILENCE; UGANDA; WOMEN; PROVINCE AB Informal, interpersonal communication within a community about HIV and AIDS, or lack of such communication, may influence community members' uptake of voluntary counseling and testing. Drawing from Noelle-Neumann's spiral of silence theory, this study examined the association between communication about HIV/AIDS and prior HIV testing in communities in Tanzania, Zimbabwe, South Africa, and Thailand. Participants (N = 14,818) in 48 communities across five sites throughout the four countries completed a behavioral survey assessing communication, prior voluntary counseling and testing (VCT) uptake, social norms, stigma, and sexual risk. Site-specific logistic regression models demonstrated that frequent conversations about HIV were significantly associated with prior HIV testing at every site. Odds ratios for each site ranged from 1.885 to 3.085, indicating a roughly doubled or tripled chance of past VCT uptake. Results indicate that verbal communication may be an important mechanism for increasing health behaviors and inclusion in future interventions should be considered. C1 [Hendriksen, Ellen Setsuko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Hlubinka, Daniel; Kulich, Michal] Charles Univ Prague, Fac Math & Phys, Dept Probabil & Stat, Prague, Czech Republic. [Chariyalertsak, Suwat] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Chingono, Alfred] Univ Zimbabwe, Sch Med, Dept Psychiat, Harare, Zimbabwe. [Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Chris Hani Baragwanath Hosp, Johannesburg, South Africa. [Mbwambo, Jessie] Muhimbili Univ, Coll Hlth Sci, Dept Psychiat, Dar Es Salaam, Tanzania. [Richter, Linda] Human Sci Res Council, Durban, South Africa. [Coates, Thomas J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. RP Hendriksen, ES (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ehendriksen@partners.org RI Kulich, Michal/B-1483-2013; Hlubinka, Daniel/C-6385-2017 OI Kulich, Michal/0000-0002-2812-8968; Hlubinka, Daniel/0000-0003-4016-3632 FU NIMH NIH HHS [U01 MH066701-07, 5U01MH066687, 5U01MH066688, 5U01MH066701, 5U01MH066702, U01 MH066687, U01 MH066687-01A1, U01 MH066687-02, U01 MH066687-03, U01 MH066687-04, U01 MH066687-05, U01 MH066687-06, U01 MH066687-07, U01 MH066688, U01 MH066688-01A1, U01 MH066688-02, U01 MH066688-03, U01 MH066688-04, U01 MH066688-05, U01 MH066688-06, U01 MH066688-06S1, U01 MH066688-07, U01 MH066688-07S1, U01 MH066688-08, U01 MH066701, U01 MH066701-01A1, U01 MH066701-02, U01 MH066701-02S1, U01 MH066701-03, U01 MH066701-04, U01 MH066701-05, U01 MH066701-06, U01 MH066701-07S1, U01 MH066701-08, U01 MH066702, U01 MH066702-01A1, U01 MH066702-02, U01 MH066702-03, U01 MH066702-04, U01 MH066702-05, U01 MH066702-06, U01 MH066702-07] NR 26 TC 18 Z9 18 U1 2 U2 14 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD DEC PY 2009 VL 13 IS 6 BP 1213 EP 1221 DI 10.1007/s10461-009-9608-0 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 526NX UT WOS:000272298900020 PM 19760154 ER PT J AU Palin, FL Armistead, L Clayton, A Ketchen, B Lindner, G Kokot-Louw, P Pauw, A AF Palin, Frances L. Armistead, Lisa Clayton, Alana Ketchen, Bethany Lindner, Gretchen Kokot-Louw, Penny Pauw, Analie TI Disclosure of Maternal HIV-Infection in South Africa: Description and Relationship to Child Functioning SO AIDS AND BEHAVIOR LA English DT Article DE HIV disclosure; South African mothers ID PSYCHOLOGICAL DISTRESS; PSYCHOSOCIAL ADJUSTMENT; ADOLESCENT DYADS; MOTHERS; AIDS; HIV/AIDS; FAMILIES; DIFFICULTIES; CHALLENGES; SEROSTATUS AB South Africa has one of the highest HIV-infection rates in the world, yet few studies have examined disclosure of maternal HIV status and its influence on children. This study provides descriptive information about HIV disclosure among South African mothers and explores whether family context variables interact with maternal HIV disclosure to affect children's functioning. A total of 103 mothers, who self-identified as living with HIV and who were the primary caregivers of a child between the ages of 11 and 16, were interviewed. A total of 44% of mothers had disclosed, and those who had most typically perceived children's reactions to disclosure to be sadness and worry. Widows and married mothers were more likely than single mothers to disclose their HIV status. Disclosure to children significantly predicted externalizing, but not internalizing, behaviors. Family variables had direct but not interactive effects on child functioning. This study highlights the complexity of disclosure-related decisions and the importance of addressing the family context. C1 [Palin, Frances L.] Cherokee Hlth Syst, Ctr City, Knoxville, TN 37921 USA. [Armistead, Lisa; Clayton, Alana] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. [Lindner, Gretchen] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Kokot-Louw, Penny; Pauw, Analie] Univ Pretoria, Dept Psychol, ZA-0002 Pretoria, South Africa. [Ketchen, Bethany] San Francisco VA Med Ctr, San Francisco, CA USA. RP Palin, FL (reprint author), Cherokee Hlth Syst, Ctr City, 2018 Western Ave, Knoxville, TN 37921 USA. EM frances.palin@cherokeehealth.com; lparmistead@gsu.edu FU NICHD NIH HHS [R03HD046371, R03 HD046371] NR 59 TC 26 Z9 26 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD DEC PY 2009 VL 13 IS 6 BP 1241 EP 1252 DI 10.1007/s10461-008-9447-4 PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 526NX UT WOS:000272298900023 PM 18770026 ER PT J AU Boodram, B Plankey, MW Cox, C Tien, PC Cohen, MH Anastos, K Karim, R Hyman, C Hershow, RC AF Boodram, Basmattee Plankey, Michael W. Cox, Christopher Tien, Phyllis C. Cohen, Mardge H. Anastos, Kathryn Karim, Roksana Hyman, Charles Hershow, Ronald C. TI Prevalence and Correlates of Elevated Body Mass Index among HIV-Positive and HIV-Negative Women in the Women's Interagency HIV Study SO AIDS PATIENT CARE AND STDS LA English DT Article; Proceedings Paper CT 4th International-AIDS-Society Conference on HIV Pathogenesis, Treatment and Prevention CY JUL 22-25, 2007 CL Sydney, AUSTRALIA SP Int AIDS Soc ID UNITED-STATES; ANTIRETROVIRAL THERAPY; SMOKING-CESSATION; NATIONAL-HEALTH; INFECTED WOMEN; DIETARY-INTAKE; DRUG-ABUSERS; RISK-FACTORS; US ADULTS; OBESITY AB Since the introduction of highly active antiretroviral therapy (HAART) and the subsequent increased life expectancy in HIV-infected persons, non-HIV-related diseases have become an important cause of morbidity and mortality. This cross-sectional study reports the prevalence of overweight and obesity, and sociodemographic, psychological, and substance use-related risk factors for elevated body mass index (BMI) among 2157 HIV-seropositive (HIV+) in comparison to 730 HIV-seronegative (HIV-) participants in the Women's Interagency HIV Study (WIHS). Separate univariable and multivariate linear regression analyses were completed for HIV+ and HIV- women. Our study revealed a similar proportion of obesity (body mass index [BMI] >= 30) among HIV+ (33%) and HIV+ women (29%) (p = 0.12), as well as comparable median BMI (HIV+: 26.1 versus HIV-: 26.7, p = 0.16). HIV+ compared to HIV- women, respectively, were significantly (p < 0.01) older (median 35.6 versus. 32.5), but similar (p = 0.97) by race/ethnicity (57% African American, 28% Hispanic, and 15% white for both). In multivariate models for both HIV+ and HIV- women, African American race/ethnicity was significantly (p < 0.05) associated with higher BMI, while higher quality of life score and illicit hard drug use were associated with lower BMI. Additionally, smoking, alcohol use, markers of advanced HIV infection (AIDS diagnosis, elevated HIV viral load, low CD4 count), and a history of antiretroviral therapy use (ART) were also associated with lower BMI among HIV+ women. In conclusion, risk factors for elevated BMI were similar for HIV+ and HIV- women in the WIHS. For HIV+ women, all markers of advanced HIV infection and ART use were additionally associated with lower BMI. C1 [Boodram, Basmattee; Hershow, Ronald C.] Univ Illinois, Div Epidemiol & Biostat, Sch Publ Hlth, Chicago, IL 60612 USA. [Plankey, Michael W.] Georgetown Univ, Med Ctr, Dept Med, Div Infect Dis, Washington, DC 20007 USA. [Cox, Christopher] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cohen, Mardge H.] Rush Univ, Dept Med, Chicago, IL 60612 USA. [Cohen, Mardge H.] Stroger Hosp, Cook Cty Bur Hlth Serv, Chicago, IL USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Epidemiol, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Populat Hlth, Bronx, NY 10467 USA. [Karim, Roksana] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Hyman, Charles] SUNY Hlth Sci Ctr, Dept Med, Brooklyn, NY 11203 USA. RP Boodram, B (reprint author), Univ Illinois, Div Epidemiol & Biostat, Sch Publ Hlth, 1603 W Taylor St,M-C 923, Chicago, IL 60612 USA. EM bboodram@uic.edu FU NCRR NIH HHS [UL1 RR024131]; NIAID NIH HHS [UO1-AI-42590, UO1-AI-34994, UO1-AI-34993, UO1-AI-35004, UO1-AI-31834, UO1-AI-34989]; NICHD NIH HHS [UO1-HD-32632] NR 48 TC 22 Z9 22 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD DEC PY 2009 VL 23 IS 12 BP 1009 EP 1016 DI 10.1089/apc.2009.0175 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 535GR UT WOS:000272955800003 PM 19909168 ER PT J AU Ancha, HR Spungen, AM Bauman, WA Rosman, AS Shaw, S Hunt, KK Post, JB Galea, M Korsten, MA AF Ancha, H. R. Spungen, A. M. Bauman, W. A. Rosman, A. S. Shaw, S. Hunt, K. K. Post, J. B. Galea, M. Korsten, M. A. TI Clinical trial: the efficacy and safety of routine bowel cleansing agents for elective colonoscopy in persons with spinal cord injury - a randomized prospective single-blind study SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ORAL SODIUM-PHOSPHATE; COLORECTAL-CANCER; POLYETHYLENE-GLYCOL; RENAL-FUNCTION; CT COLONOGRAPHY; KIDNEY INJURY; FAILURE; NEPHROPATHY; EVACUATION; GUIDELINES AB P>Background As difficulty with evacuation is a common occurrence in individuals with spinal cord injury, preparation prior to colonoscopy may be suboptimal and, perhaps, more hazardous. Aim To assess the safety and efficacy of bowel cleansing regimens in persons with spinal cord injury. Methods Randomized, prospective, single blind study comparing polyethylene glycol (PEG), oral sodium phosphosoda (OSPS) and combination of both for colonic preparation prior to colonoscopy in subjects with spinal cord injury. Results Thirty six subjects with eGFR >= 60 mL/min/1.73 m2 were randomized to PEG or OSPS or PEG+OSPS. Regardless of bowel preparation employed, > 73% of subjects had unacceptable colonic cleansing. No subject in the OSPS preparation group demonstrated a decrease in eGFR or an increase in serum creatinine concentration from the baseline. OSPS and PEG+OSPS preparations caused a transient change in serum potassium, phosphate and calcium concentrations, but no change in electrolytes was noted in the PEG group. Conclusions Neither OSPS alone, PEG alone nor their combination was sufficient to prepare adequately the bowel for colonoscopy in most patients with spinal cord injury. However, administration of OSPS and/or PEG appears to be safe in the spinal cord injury population, provided adequate hydration is provided. C1 [Ancha, H. R.; Spungen, A. M.; Bauman, W. A.; Rosman, A. S.; Hunt, K. K.; Post, J. B.; Korsten, M. A.] James J Peters VA Med Ctr, RR&D Ctr Excellence Med Consequences Spinal Cord, Bronx, NY 10468 USA. [Spungen, A. M.; Bauman, W. A.; Rosman, A. S.; Shaw, S.; Post, J. B.; Korsten, M. A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Spungen, A. M.; Bauman, W. A.; Post, J. B.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Galea, M.] James J Peters VA Med Ctr, SCI Serv, Bronx, NY 10468 USA. RP Korsten, MA (reprint author), James J Peters VA Med Ctr, RR&D Ctr Excellence Med Consequences Spinal Cord, 7A-11,130 Kingsbridge Rd, Bronx, NY 10468 USA. EM mark.korsten@va.gov FU Center of Excellence VA Grant [B4162C]; VA Merit Review [A6428R] FX Center of Excellence VA Grant #B4162C, VA Merit Review A6428R. NR 33 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD DEC 1 PY 2009 VL 30 IS 11-12 BP 1110 EP 1117 DI 10.1111/j.1365-2036.2009.04147.x PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 515JF UT WOS:000271465300003 PM 19769634 ER PT J AU Spiegel, B Bolus, R Harris, LA Lucak, S Naliboff, B Esrailian, E Chey, WD Lembo, A Karsan, H Tillisch, K Talley, J Mayer, E Chang, L AF Spiegel, B. Bolus, R. Harris, L. A. Lucak, S. Naliboff, B. Esrailian, E. Chey, W. D. Lembo, A. Karsan, H. Tillisch, K. Talley, J. Mayer, E. Chang, L. TI Measuring irritable bowel syndrome patient-reported outcomes with an abdominal pain numeric rating scale SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID QUALITY-OF-LIFE; VISCERAL SENSITIVITY INDEX; CLINICAL IMPORTANCE; ILLNESS SEVERITY; HEALTH-STATUS; IBS; VALIDATION; DISORDERS; VALIDITY; ANXIETY AB P>Background Controversy exists on how to measure patient-reported outcomes in irritable bowel syndrome (IBS) clinical trials effectively. Pain numeric rating scales (NRS) are widely used in the non-IBS pain literature. The Food and Drug Administration has proposed using the NRS in IBS. Aim To test the psychometrics of an abdominal pain NRS in IBS. Methods We analysed data from a longitudinal cohort of Rome III IBS subjects. At entry, subjects completed a 10-point NRS, bowel symptoms, IBS severity measurements (IBS-SSS, FBDSI), health-related quality of life indices (IBS-QOL, EQ5D), and the Worker Productivity Activity Index (WPAI). We repeated assessments at 3 months along with a response scale to calculate the minimal clinically important difference. Results There were 277 subjects (82% women; age = 42 +/- 15) at baseline and 90 at 3 months. The NRS correlated cross-sectionally with IBS-SSS (r = 0.60; P < 0.0011), FBDSI (r = 0.49; P < 0.0001), IBS-QOL (r = 0.43; P < 0.0001), EQ5D (r = 0.48; P < 0.0001), presenteeism (r = 0.39; P < 0.0001), absenteeism (r = 0.17; P = 0.04) and distension (r = 0.46; P < 0.0001), but not stool frequency or form. The minimal clinically important difference was 2.2 points, correlating with a 29.5% reduction over time. Conclusions An abdominal pain NRS exhibits excellent validity and can be readily interpreted with a minimal clinically important difference in patients with IBS. These data support the use of the NRS in IBS clinical trials. C1 [Spiegel, B.; Naliboff, B.; Talley, J.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Spiegel, B.; Bolus, R.; Naliboff, B.; Esrailian, E.; Tillisch, K.; Mayer, E.; Chang, L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Spiegel, B.; Bolus, R.; Naliboff, B.; Tillisch, K.; Mayer, E.; Chang, L.] Univ Calif Los Angeles, Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. [Spiegel, B.; Bolus, R.; Esrailian, E.; Talley, J.; Chang, L.] Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ, Los Angeles, CA 90024 USA. [Harris, L. A.] Mayo Clin Scottsdale, Scottsdale, AZ USA. [Lucak, S.] Columbia Univ, New York, NY 10027 USA. [Chey, W. D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Lembo, A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Cambridge, MA 02138 USA. [Karsan, H.] Atlanta Gastroenterol Associates, Los Angeles, CA USA. RP Spiegel, B (reprint author), 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu FU Takeda; AstraZeneca; Rose Pharmaceuticals; UCLA Center for Neurobiology of Stress [NIH P50 DK64539, 1 R24 AT002681-NCCAM]; Veteran's Affairs Health Services Research and Development (HSRD) [RCD 03-179-2]; CURE Digestive Disease Research Center [NIH 2P30 DK 041301-17]; NIH [1 R24 AT002681-NCCAM, P50 DK64539] FX Dr Spiegel has received grant support from Takeda, AstraZeneca, and Rose Pharmaceuticals. Partial support was provided from the UCLA Center for Neurobiology of Stress (NIH P50 DK64539 and 1 R24 AT002681-NCCAM). Dr Spiegel is supported by a Veteran's Affairs Health Services Research and Development (HSR&D) Career Development Award (RCD 03-179-2), and the CURE Digestive Disease Research Center (NIH 2P30 DK 041301-17). Dr Chang, Naliboff and Mayer are supported by NIH Grant No. P50 DK64539, and Dr Spiegel, Mayer and Naliboff are supported by NIH Center Grant 1 R24 AT002681-NCCAM. Study supported by an investigator-initiated research grant from Takeda Pharmaceuticals. NR 37 TC 39 Z9 39 U1 2 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD DEC 1 PY 2009 VL 30 IS 11-12 BP 1159 EP 1170 DI 10.1111/j.1365-2036.2009.04144.x PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 515JF UT WOS:000271465300008 PM 19751360 ER PT J AU Berger, JS Roe, MT Gibson, CM Kilaru, R Green, CL Melton, L Blankenship, JD Metzger, DC Granger, CB Gretler, DD Grines, CL Huber, K Zeymer, U Buszman, P Harrington, RA Armstrong, PW AF Berger, Jeffrey S. Roe, Matthew T. Gibson, C. Michael Kilaru, Rakhi Green, Cynthia L. Melton, Laura Blankenship, James D. Metzger, D. Christopher Granger, Christopher B. Gretler, Daniel D. Grines, Cindy L. Huber, Kurt Zeymer, Uwe Buszman, Pawel Harrington, Robert A. Armstrong, Paul W. TI Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial SO AMERICAN HEART JOURNAL LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CORONARY INTERVENTION; SEGMENT ELEVATION; FIBRINOLYTIC THERAPY; TASK-FORCE; CLOPIDOGREL; GUIDELINES; ASPIRIN; TIME AB Background Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI. Methods The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated. Results Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo. Conclusions With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI. (Am Heart J 2009; 158: 998-1004. e1.) C1 [Berger, Jeffrey S.; Roe, Matthew T.; Kilaru, Rakhi; Green, Cynthia L.; Melton, Laura; Granger, Christopher B.; Harrington, Robert A.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Gibson, C. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp, Boston, MA USA. [Blankenship, James D.] Weis Ctr Res, Geisinger Clin, Danville, PA 17822 USA. [Metzger, D. Christopher] Holston Valley Med Ctr, Kingsport, TN USA. [Gretler, Daniel D.] Portola Pharmaceut Inc, San Francisco, CA USA. [Grines, Cindy L.] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Huber, Kurt] Wilhelminenhosp, Dept Cardiol & Emergency Med, Vienna, Austria. [Zeymer, Uwe] Herzzentrum Ludwigshafen, Ludwigshafen, Germany. [Zeymer, Uwe] Inst Herzinfarktforsch, Ludwigshafen, Germany. [Buszman, Pawel] Med Univ Silesia, Katowice, Poland. [Armstrong, Paul W.] Univ Alberta, Edmonton, AB, Canada. RP Roe, MT (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM roe00001@mc.duke.edu RI Granger, Christopher/D-3458-2014 OI Granger, Christopher/0000-0002-0045-3291 FU Portola Pharmaceuticals, South San Francisco, CA FX This study was funded by Portola Pharmaceuticals, South San Francisco, CA. NR 17 TC 65 Z9 72 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2009 VL 158 IS 6 BP 998 EP U145 DI 10.1016/j.ahj.2009.10.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 536NM UT WOS:000273051100016 PM 19958867 ER PT J AU Meadows, TA Bhatt, DL Hirsch, AT Creager, MA Califf, RM Ohman, EM Cannon, CP Eagle, KA Alberts, MJ Goto, S Smith, SC Wilson, PWF Watson, KE Steg, PG AF Meadows, Telly A. Bhatt, Deepak L. Hirsch, Alan T. Creager, Mark A. Califf, Robert M. Ohman, E. Magnus Cannon, Christopher P. Eagle, Kim A. Alberts, Mark J. Goto, Shinya Smith, Sidney C., Jr. Wilson, Peter W. F. Watson, Karol E. Steg, P. Gabriel CA REACH Registry Investigators TI Ethnic differences in the prevalence and treatment of cardiovascular risk factors in US outpatients with peripheral arterial disease: Insights from the Reduction of Atherothrombosis for Continued Health (REACH) Registry SO AMERICAN HEART JOURNAL LA English DT Article ID VASCULAR-DISEASE; DISPARITIES; CORONARY; OUTCOMES; POPULATION; GUIDELINES; CARE AB Background Prior investigations to define ethnic-related differences in the risks, medical treatment, and outcomes of patients with peripheral arterial disease (PAD) have been limited. Methods The impact of ethnicity on the risk factor profiles, use of evidence-based medical therapies, and 2-year cardiovascular outcomes were investigated in 2,168 individuals (blacks n = 237, Hispanics n = 115, whites n = 1,816) from the United States with PAD from the international Reduction of Atherothrombosis for Continued Health Registry. Results Blacks and Hispanics were more likely to have diabetes mellitus and hypertension, whereas whites had a higher rate of diagnosed hypercholesterolemia. Control of blood pressure and cholesterol levels differed significantly in the groups at baseline: elevated blood pressure was present in 55% of blacks versus 48% of Hispanics versus 38% of whites (P < .01), whereas 41% of blacks versus 31% of Hispanics versus 25% of whites had elevated total cholesterol (P < .01). Aspirin use (62% of blacks vs 68% of Hispanics vs 72% of whites, P < .01) and statin use (72% of blacks vs 68% of Hispanics vs 77% of whites, P = .03) also varied significantly. In this context, rates by ethnicity for cardiovascular death, myocardial infarction, or stroke seemed to be no different at 2 years, at 8.8% for the total population: 11.6% for blacks, 8.5% for whites, and 5.0% for Hispanics (P = .32). Fewer blacks (0.6%) had undergone peripheral arterial bypass surgery compared with whites (3.4%) and Hispanics (5.2%) (P = .02). Conclusions Ethnic-related differences have been documented in the prevalence and treatment of several atherosclerotic risk factors known to be associated with PAD, including a variation in the use of surgical revascularization procedures. (Am Heart J 2009; 158: 1038-45.) C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA 02115 USA. [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA 02115 USA. [Meadows, Telly A.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Hirsch, Alan T.] Univ Minnesota, Sch Publ Hlth, Minnesota Heart Inst Fdn, Minneapolis, MN USA. [Hirsch, Alan T.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Hirsch, Alan T.; Cannon, Christopher P.] Harvard Univ, Sch Med, Boston, MA USA. [Califf, Robert M.; Ohman, E. Magnus] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Eagle, Kim A.] Univ Michigan, Ctr Cardiovasc, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Alberts, Mark J.] Northwestern Univ, Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Goto, Shinya] Tokai Univ, Sch Med, Dept Med Cardiol, Kanagawa 2591100, Japan. [Smith, Sidney C., Jr.] Univ N Carolina, Sch Med, Ctr Cardiovasc Med & Sci, Chapel Hill, NC USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Watson, Karol E.] Univ Calif Los Angeles, Ctr Cholesterol & Lipid Management, Los Angeles, CA USA. [Steg, P. Gabriel] Univ Paris 07, INSERM, U698, Paris, France. [Steg, P. Gabriel] AP HP, Paris, France. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, 75 Francis St, Boston, MA 02115 USA. EM dlbhattmd@alum.mit.edu FU sanofi-aventis; Bristol-Myers Squibb FX We thank sanofi-aventis and Bristol-Myers Squibb for their support of the REACH registry. NR 17 TC 15 Z9 15 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2009 VL 158 IS 6 BP 1038 EP 1045 DI 10.1016/j.ahj.2009.09.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 536NM UT WOS:000273051100022 PM 19958873 ER PT J AU McManus, DD Corteville, DCM Shlipak, MG Whooley, MA Ix, JH AF McManus, David D. Corteville, David C. M. Shlipak, Michael G. Whooley, Mary A. Ix, Joachim H. TI Relation of Kidney Function and Albuminuria With Atrial Fibrillation (from the Heart and Soul Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CYSTATIN-C; RENAL-DISEASE; HEMODIALYSIS; ASSOCIATION; PREVALENCE; SYSTEM AB Atrial fibrillation (AF) is common in end-stage renal disease, but the relation between more modest decrements in kidney function or albuminuria with AF is uncertain. Among 956 outpatients with coronary artery disease, kidney function was assessed using 3 methods (cystatin C-based estimated glomerular filtration rate [eGFR(cys)], creatinine-based eGFR [eGFR(Cr)], and the urinary albumin/creatinine ratio [ACR]) and prevalent AF using surface electrocardiography. Multivariate logistic regression was used to evaluated the association of 2 each measure of kidney function with AF. The mean eGFR(cys) was 71 +/- 23 ml/min/1.73 m(2), and the median ACR was 10 mg/g (interquartile range 6 to 19). Forty subjects (4%) had prevalent AF. Compared to participants with eGFR(cys) in the highest tertile (eGFR(cys) >79), those with eGFRcys in the lowest tertile (eGFR(cys) <62) had more than threefold greater odds of AF (odds ratio [OR] 3.43, 95% confidence interval [CI] 1.18 to 9.97) after multivariate adjustment for traditional cardiovascular disease risk factors. This association remained significant with further adjustment for ACR (OR 3.37, 95% 1.02 to 11.14). Results were similar for eGFR(Cr) but did not reach statistical significance (OR 1.59, 95% CI 0.57 to 4.40). Participants with ACRs in the highest tertile (ACR > 15 mg/g) had more than fourfold greater odds of AF compared to participants in the lowest ACR tertile (ACR <7 mg/g); an association that remained significant after adjustment for eGFR(cys) (OR 4.36, 95% CI 1.45 to 13.05) or eGFRCr (OR 4.61, 95% CI 1.56 to 13.66). In conclusion, among outpatients with coronary artery disease, lower eGFR(cys) and higher ACR were associated with prevalent AF, independent of each other. Published by Elsevier Inc. (Am J Cardiol 2009;104:1551-1555) C1 [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. [McManus, David D.] Univ Massachusetts, Dept Med, Div Cardiol, Sect Cardiac Electrophysiol, Worcester, MA 01605 USA. [Corteville, David C. M.] Univ Michigan, Dept Med, Div Cardiol, Ann Arbor, MI 48109 USA. [Corteville, David C. M.; Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. EM joeix@ucsd.edu FU United States Department of Veterans Affairs, Washington; Robert Wood Johnson Foundation; American Federation for Aging Research; Ischemia Research and Education Foundation; National Institutes of Health [R01 HL079235]; American Heart Association Fellow to Faculty Transition Award [0575021N] FX This study was supported by grants from the United States Department of Veterans Affairs, Washington. District of Columbia; the Robert Wood Johnson Foundation (Faculty Scholars Program), Princeton, New Jersey; the American Federation for Aging Research (Paul Beeson Scholars Progoram), New York. New York: the Ischemia Research and Education Foundation. South San Francisco, California: and the National Institutes of Health (R01 HL079235). Bethesda, Maryland. Dr. Ix was Supported by American Heart Association Fellow to Faculty Transition Award 0575021N, Dallas, Texas. Dade Behring, Deerfield, Illinois, supported the cystatin C measurements in the Heart and Soul cohort. NR 16 TC 31 Z9 38 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2009 VL 104 IS 11 BP 1551 EP 1555 DI 10.1016/j.amjcard.2009.07.026 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 531BK UT WOS:000272637500017 PM 19932791 ER PT J AU Rumawas, ME Meigs, JB Dwyer, JT McKeown, NM Jacques, PF AF Rumawas, Marcella E. Meigs, James B. Dwyer, Johanna T. McKeown, Nicola M. Jacques, Paul F. TI Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham Offspring Cohort SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; ENERGY-INTAKE; HEALTH; REPRODUCIBILITY; HOMEOSTASIS; PREVALENCE; MANAGEMENT AB Background: The benefit of the Mediterranean-style dietary pattern in mitigating metabolic risk factors for type 2 diabetes and cardiovascular disease has not been well investigated among nondiabetic Americans. Objective: The aim of this study was to examine the prospective association between the Mediterranean-style dietary pattern and metabolic syndrome. Design: The Mediterranean-style dietary pattern score (MSDPS) was used to characterize a Mediterranean-style dietary pattern in the Framingham Heart Study Offspring Cohort. We examined the longitudinal association between MSDPS and metabolic syndrome traits (including homeostasis model assessment-insulin resistance, fasting glucose, waist circumference, triglyceride, HDL cholesterol, and systolic and diastolic blood pressure) among 2730 participants of the Framingham Heart Study Offspring Cohort without type 2 diabetes (baseline median age: 54 y; 55% women), who were followed from the fifth (baseline) to the seventh study examinations (mean follow-up time: 7 y), and metabolic syndrome incidence (according to the National Cholesterol Education Program Adult Treatment Panel III definition) in 1918 participants free of the condition at baseline. Results: A higher MSDPS was associated with lower homeostasis model assessment-insulin resistance (P = 0.02), waist circumference (P < 0.001), fasting plasma glucose (P = 0.03), and triglycerides (P < 0.001) and higher HDL cholesterol (P = 0.02) after adjustment for the corresponding baseline values and for several confounding factors associated with type 2 diabetes risk. Participants in the highest quintile category of the MSDPS had a lower incidence of metabolic syndrome than those in the lowest quintile category (38.5% compared with 30.1%; P = 0.01). Conclusion: Our study suggests that the consumption of a diet consistent with the principles of the Mediterranean-style diet may protect against metabolic syndrome in Americans. Am J Clin Nutr 2009;90:1608-14. C1 [Rumawas, Marcella E.; Dwyer, Johanna T.; McKeown, Nicola M.; Jacques, Paul F.] Tufts Univ, JM USDA HNRCA, Nutr Epidemiol Program, Boston, MA 02111 USA. [Rumawas, Marcella E.; Dwyer, Johanna T.; McKeown, Nicola M.; Jacques, Paul F.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Med Ctr Hosp, Boston, MA USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. RP Jacques, PF (reprint author), Tufts Univ, JM USDA HNRCA, Nutr Epidemiol Program, 711 Washington St, Boston, MA 02111 USA. EM paul.jacques@tufts.edu OI Dwyer, Johanna/0000-0002-0783-1769 FU USDA [58-1950-7-707]; Framingham Heart Study of the National Heart Lung and Blood Institute of the NIH [NO1-HC-25195]; Helen Smith Brownstein Memorial Scholarship; American Diabetes Association's Career Development Award; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140]; General Mills Bell Institute of Health FX Supported by the USDA (agreement 58-1950-7-707) and the Framingham Heart Study of the National Heart Lung and Blood Institute of the NIH (contract NO1-HC-25195). MER was a recipient of the Helen Smith Brownstein Memorial Scholarship. JBM was supported in part by the American Diabetes Association's Career Development Award and the National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK080140. NMM was supported in part by the General Mills Bell Institute of Health. NR 30 TC 99 Z9 101 U1 4 U2 14 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2009 VL 90 IS 6 BP 1608 EP 1614 DI 10.3945/ajcn.2009.27908 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 522XZ UT WOS:000272034900023 PM 19828705 ER PT J AU Wu, K Platz, EA Willett, WC Fuchs, CS Selhub, J Rosner, BA Hunter, DJ Giovannucci, E AF Wu, Kana Platz, Elizabeth A. Willett, Walter C. Fuchs, Charles S. Selhub, Jacob Rosner, Bernard A. Hunter, David J. Giovannucci, Edward TI A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOLATE; PREVENTION; CANCER; SAFETY AB Background: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. Objective: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conducted a cost-efficient, double-blind, randomized trial among participants of 2 large prospective cohorts, the Health Professionals Follow-Up Study and the Nurses' Health Study. Design: Participants were randomly assigned to receive folic acid (1 mg/d) (n = 338) or placebo (n = 334) for 3-6.5 y. The primary endpoint was any new diagnosis of adenoma during the study period (May 1996-March 2004). Secondary outcomes were adenoma by site and stage and number of recurrent adenomas. Associations were also examined by plasma folate concentrations at baseline. Results: Incidence of at least one recurrent adenoma was not significantly associated with folic acid supplementation [relative risk (RR): 0.82; 95% CI: 0.59,1.13; P = 0.22]. Among participants with low plasma folate concentrations at baseline (<= 7.5 ng/mL), those randomly assigned to receive folic acid experienced a significant decrease in adenoma recurrence (RR: 0.61; 95% CI: 0.42, 0.90; P = 0.01), whereas for subjects with high folate concentrations at baseline (>7.5 ng/mL), supplemental folic acid had no significant effect (RR: 1.28; 95% CI: 0.82, 1.99; P = 0.27, P(interaction) = 0.01). Contrary to findings from another clinical trial, there was no evidence for an increased risk of advanced or multiple adenomas. Conclusions: Our results do not support an overall protective effect of folic acid supplementation on adenoma recurrence. Folic acid supplementation may be beneficial among those with lower folate concentrations at baseline. This trial was registered at clinical trials. gov as NCT00512850. Am J Clin Nutr 2009;90:1623-31. C1 [Wu, Kana; Willett, Walter C.; Hunter, David J.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, Walter C.; Hunter, David J.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosner, Bernard A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Willett, Walter C.; Fuchs, Charles S.; Rosner, Bernard A.; Hunter, David J.; Giovannucci, Edward] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. RP Wu, K (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2, Boston, MA 02115 USA. EM kana.wu@channing.harvard.edu FU National Cancer Institute [CA 55075, CA 95589]; NIH [U54 100971, R01 CA 67883] FX Supported by the National Cancer Institute grants CA 55075 and CA 95589 and NIH grants U54 100971 and R01 CA 67883. Folic acid and placebo pills were provided by the pharmaceutical company Lederle (now Wyeth Pharmaceuticals, Collegeville, PA). NR 17 TC 70 Z9 75 U1 3 U2 9 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2009 VL 90 IS 6 BP 1623 EP 1631 DI 10.3945/ajcn.2009.28319 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 522XZ UT WOS:000272034900025 PM 19864409 ER PT J AU Vano, M Carvalho, C Sedda, M Gabriele, M Garcia-Godoy, F Ferrari, M AF Vano, Michele Carvalho, Carlos Sedda, Maurizio Gabriele, Mario Garcia-Godoy, Franklin Ferrari, Marco TI The influence of storage condition and duration on the resistance to fracture of different fiber post systems SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID ENDODONTICALLY TREATED TEETH; SILANE COUPLING AGENT; 3-POINT BENDING TEST; WATER SORPTION; REINFORCED COMPOSITES; FLEXURAL PROPERTIES; DENTAL COMPOSITES; SEM EVALUATION; RESIN; STABILITY AB Purpose: To evaluate the effects of storage condition and duration on the resistance to fracture of different fiber post systems (and to morphologically assess the post structure before and after storage. Methods: Three types of fiber posts (DT Light Post, GC Post, FRC Postect Plus) were divided in different groups (n=12) according to the storage condition (dry at 37 degrees C; saline water at 37 degrees C; mineral oil at 37 degrees C and storage inside the roots of extracted human teeth immersed in saline water at 37 degrees C and duration (6, 12 months). A universal testing machine loading at a 90 degrees angle was employed for the three-point bending test. The test was carried out until fracture of the post. A 3-way ANOVA and Tukey's test (alpha= 0.05) were used to compare the effect of the experimental factors on the fracture strength. Two posts of each group were observed before and after the storage using a scanning electron microscope. Results: Storage condition and post type had a significant effect on post fracture strength (P< 0.05). The interaction between these factors was significant (P< 0.05). Water storage significantly decreased the fracture strength, regardless of the post type and the storage duration. Storage inside roots, in oil, and at dry conditions did not significantly affect post fracture strength. SEM micrographs revealed voids between fibers and resin matrix for posts stored in water. Posts stored under the other conditions showed a compact matrix without porosities. (Am J Dent 2009;22:366-370). C1 [Sedda, Maurizio; Ferrari, Marco] Univ Siena, Dept Fixed Prosthodont & Dent Mat, I-53100 Siena, Italy. [Vano, Michele; Carvalho, Carlos] Univ Siena, Dept Fixed Prosthodont, Dept Dent Mat, I-53100 Siena, Italy. [Vano, Michele; Gabriele, Mario] Univ Pisa, Dept Oral Surg, Pisa, Italy. [Carvalho, Carlos] Univ Sao Paulo, Bauru Sch Dent, Dept Operat Dent, Bauru, Brazil. [Garcia-Godoy, Franklin] Univ Tennessee, Coll Dent, Biosci Res Ctr, Memphis, TN USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Ferrari, M (reprint author), Univ Siena, Policlin Le Scotte, Dept Restorat Dent & Dent Mat, Viale Bracci, I-53100 Siena, Italy. EM ferrarimar@unisi.it NR 30 TC 4 Z9 4 U1 0 U2 1 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD DEC PY 2009 VL 22 IS 6 BP 366 EP 370 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 548JP UT WOS:000273958200008 PM 20178214 ER PT J AU Ragland, M Hutter, C Zabetian, C Edwards, K AF Ragland, Margaret Hutter, Carolyn Zabetian, Cyrus Edwards, Karen TI Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE case-control studies; epidemiology; genes; genetics; meta-analysis; Parkinson disease; review; UCHL1 ID SINGLE-NUCLEOTIDE POLYMORPHISMS; WHOLE-GENOME ASSOCIATION; HYDROLASE L1; NEURODEGENERATIVE DISEASES; SUSCEPTIBILITY GENE; CLINICAL-DIAGNOSIS; ALPHA-SYNUCLEIN; UCH-L1 GENE; PESTICIDE EXPOSURE; MUTATION ANALYSIS AB The ubiquitin carboxyl-terminal esterase L1 gene, UCHL1, located on chromosome 4p14, has been studied as a potential candidate gene for Parkinson's disease risk. The authors conducted a Human Genome Epidemiology review and meta-analysis of published case-control studies of the UCHL1 S18Y variant and Parkinson's disease in Asian and Caucasian samples. The meta-analysis of studies in populations of Asian ancestry showed a statistically significant association between the Y allele and reduced risk of Parkinson's disease under a recessive model (odds ratio (OR) for YY vs. SY + SS = 0.79, 95% confidence interval (CI): 0.67, 0.94; P = 0.006). For a dominant model, the association was not significant in Asian populations (OR for YY + SY vs. SS = 0.88, 95% CI: 0.68, 1.14; P = 0.33). For populations of European ancestry, the meta-analysis showed a significant association between the Y allele and decreased risk of Parkinson's disease under a dominant model (OR = 0.89, 95% CI: 0.81, 0.98; P = 0.02) but not under a recessive model (OR = 0.92, 95% CI: 0.66, 1.30; P = 0.65). Using the Venice criteria, developed by the Human Genome Epidemiology Network Working Group on the assessment of cumulative evidence, the authors concluded that moderate evidence exists for an association between the S18Y variant and Parkinson's disease. C1 [Edwards, Karen] Univ Washington, Ctr Genom & Publ Hlth, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98115 USA. [Ragland, Margaret; Edwards, Karen] Univ Washington, Inst Publ Hlth Genet, Sch Publ Hlth, Seattle, WA 98115 USA. [Zabetian, Cyrus] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. [Zabetian, Cyrus] Univ Washington, Dept Neurol, Sch Med, Seattle, WA 98115 USA. RP Edwards, K (reprint author), Univ Washington, Ctr Genom & Publ Hlth, Dept Epidemiol, Sch Publ Hlth, Box 354921,6200 NE 74th St,Bldg 29,Suite 250, Seattle, WA 98115 USA. EM keddy@u.washington.edu OI Zabetian, Cyrus/0000-0002-7739-4306 FU Centers for Disease Control and Prevention through the Association of Schools of Public Health [U36/CCU300430-23, U10/CCU025038] FX This project was financially supported under a cooperative agreement from the Centers for Disease Control and Prevention through the Association of Schools of Public Health, grant U36/CCU300430-23 and U10/CCU025038 (Karen L. Edwards, Principal Investigator). NR 111 TC 30 Z9 31 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2009 VL 170 IS 11 BP 1344 EP 1357 DI 10.1093/aje/kwp288 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 523JR UT WOS:000272069900003 PM 19864305 ER PT J AU Williams, EV Unutzer, J Lee, S Noel, PH AF Williams, Emily Van Leeuwen Unuetzer, Juergen Lee, Shuko Noel, Polly Hitchcock TI Collaborative Depression Care for the Old-Old: Findings From the IMPACT Trial SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Depression; old-old; collaborative care; late life ID RANDOMIZED CONTROLLED-TRIAL; NURSING-HOME RESIDENTS; LATE-LIFE; MAJOR DEPRESSION; CLINICAL-TRIAL; DISORDERS; PREVALENCE; MANAGEMENT; VALIDITY; RISK AB Objectives: To compare the clinical outcomes of young-old patients (aged 60-74 years) and old-old patients (aged 75 years and older) who received collaborative care management for depression. Design: Multisite randomized clinical trial. Setting: Eighteen primary care clinics from eight healthcare organizations. Participants: Nine hundred six patients (N = 606 young-old; N = 300 old-old) with major depression and/or dysthymia who were randomized to receive collaborative care in the Improving Mood: Promoting Access to Collaborative Treatment trial. Intervention: Patients had access for 12 months to a depression clinical specialist who coordinated depression care with their primary care physician. Measurements: Young-old and old-old patients were compared on process of care and outcome variables. Process of care was determined by the type of treatment and level of care received. Clinical outcomes included Symptom Checklist (SCL)-20 depression scores, treatment response (defined as a >= 50% decrease in the SCL-20 score from baseline), and complete remission (defined as a SCL-20 score <0.5) at 3-, 6-, 12-, 18-, and 24-month follow-up. Results: The process of care variables did not significantly differ between the two age groups. Young-old patients had similar treatment responses at initial follow-up (3 months) but were significantly more likely to respond to treatment and meet complete remission criteria than old-old patients at 6-, 12-, 18-, and 24-months. Conclusions: Young-old and old-old patients who receive collaborative depression care have a similar initial clinical response, but old-old patients may have a lower rate of long-term treatment response and complete remission in the long run. (Am J Geriatr Psychiatry 2009;17:1040-1049) C1 [Williams, Emily Van Leeuwen] Duke Univ, Sch Med, Durham, NC USA. [Williams, Emily Van Leeuwen] Univ Texas Hlth Sci Ctr, Houston Sch Publ Hlth, San Antonio, TX USA. [Unuetzer, Juergen] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lee, Shuko; Noel, Polly Hitchcock] S Texas Vet Hlth Care Syst, Houston, TX USA. [Noel, Polly Hitchcock] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Williams, EV (reprint author), 15 Med Pk Suite 141, Columbia, SC 29203 USA. EM emily.williams@palmettohealth.org FU John A. Hartford Foundation; California HealthCare Foundation; Hogg Foundation for Mental Health; Kirschstein National Research Service Award FX This work was supported by the John A. Hartford Foundation, the California HealthCare Foundation, the Hogg Foundation for Mental Health, and the Kirschstein National Research Service Award ( to E. V. L. W.). NR 38 TC 9 Z9 9 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2009 VL 17 IS 12 BP 1040 EP 1049 DI 10.1097/JGP.0b013e3181b4bf08 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 528PV UT WOS:000272459700006 ER PT J AU de Boer, IH Katz, R Fried, LF Ix, JH Luchsinger, J Sarnak, MJ Shlipak, MG Siscovick, DS Kestenbaum, B AF de Boer, Ian H. Katz, Ronit Fried, Linda F. Ix, Joachim H. Luchsinger, Jose Sarnak, Mark J. Shlipak, Michael G. Siscovick, David S. Kestenbaum, Bryan TI Obesity and Change in Estimated GFR Among Older Adults SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Obesity; chronic kidney disease; glomerular filtration rate; cohort study ID BODY-MASS INDEX; GLOMERULAR-FILTRATION-RATE; SERUM CYSTATIN-C; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; FAT-FREE MASS; CARDIOVASCULAR HEALTH; BIOELECTRICAL IMPEDANCE; POOLED ANALYSIS; RISK-FACTOR AB Background: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease. Study Design: Cohort study. Setting & Participants: 4,295 participants in the community-based Cardiovascular Health Study, aged >= 65 years. Predictors: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance. Outcome: Change in glomerular filtration rate (GFR) during 7 years of follow-up. Measurements: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Results: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16% ). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95% Cl, 1.09-1.30) per5 kg/m(2),1.25 (95% Cl, 1.16-1.36) per 12 cm, and 1.14 (95%CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level. Limitations: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements. Conclusion: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults. Am J Kidney Dis 54:1043-1051. (C) 2009 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [de Boer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Ix, Joachim H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Luchsinger, Jose] Columbia Univ, New York, NY USA. [Sarnak, Mark J.] Tufts Med Ctr, Boston, MA USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP de Boer, IH (reprint author), Univ Washington, Div Nephrol, Box 356521,1959 NE Pacific St, Seattle, WA 98195 USA. EM deboer@u.washington.edu FU National Heart, Lung, and Blood Institute [N01-HC-85079 to N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [1KL2RR025015-01] FX The research reported in this article was supported by contract numbers N01-HC-85079 to N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and grant number U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support came from grant 1KL2RR025015-01 from the National Center for Research Resources. NR 37 TC 39 Z9 40 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2009 VL 54 IS 6 BP 1043 EP 1051 DI 10.1053/j.ajkd.2009.07.018 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 524LF UT WOS:000272144100012 PM 19782454 ER PT J AU Steinman, MA Yang, KY Byron, SC Maselli, JH Gonzales, R AF Steinman, Michael A. Yang, Katherine Y. Byron, Sepheen C. Maselli, Judith H. Gonzales, Ralph TI Variation in Outpatient Antibiotic Prescribing in the United States SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID ANTIMICROBIAL CONSUMPTION ESAC; UPPER RESPIRATORY-INFECTIONS; EUROPEAN SURVEILLANCE; GEOGRAPHIC-VARIATION; SORE THROAT; CARE; RESISTANCE; TRENDS; PHYSICIANS; DATABASE AB Objective: To evaluate variation in outpatient antibiotic utilization among US commercial health plans and the implications of this variation for cost and quality. Study Design and Methods: We measured antibiotic utilization rates among 229 US commercial health plans that participated in the 2005 Healthcare Effectiveness Data and Information Set. Rates were adjusted to account for health plan age and sex distribution. To estimate antibiotic costs, we multiplied utilization data for each drug class by national estimates of intraclass distribution of drugs, duration of therapy, and median average wholesale price. Results: Antibiotic utilization rates varied markedly among plans, ranging from 0.64 antibiotic fills per member per year (PMPY) at the 5th percentile of plans to 1.08 fills PMPY at the 95th percentile, with a mean of 0.88 (SD +/- 0.15) antibiotic fills PMPY. US census region was the strongest predictor of antibiotic utilization. Antibiotic costs averaged $49 PMPY and ranged from $34 to $63 PMPY among plans at the 5th and 95th percentiles of cost, respectively. If a health plan with 250,000 members at the 90th percentile of antibiotic costs reduced its costs to the 25th percentile, annual drug cost savings would be approximately $4.1 million. Conclusions: Antibiotic utilization varies substantially among commercial health plans and is not accounted for by differences in the age and sex distribution of plan members. Because reducing rates of antibiotic utilization is likely to lower costs and improve quality, high-utilizing plans may reap considerable rewards from investing in programs to reduce the overuse of antibiotics. (Am J Manag Care. 2009; 15(12): 861-868) C1 [Steinman, Michael A.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA 94121 USA. [Yang, Katherine Y.] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA. [Steinman, Michael A.; Maselli, Judith H.; Gonzales, Ralph] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Byron, Sepheen C.] Natl Comm Qual Assurance, Washington, DC USA. RP Steinman, MA (reprint author), San Francisco VA Med Ctr, Div Geriatr, 4150 Clement St,Box 181-G, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu FU VA Health Services Research and Development Service [01-013]; National Institute on AginG [K23-AG030999]; American Federation for Aging Research; Agency for Healthcare Research and Quality (NCQA) [R01 HS13915]; National Center for Research Resources [KL2 RR024130] FX This work was supported by Career Development Transition Award 01-013 from the VA Health Services Research and Development Service (Dr Steinman), by grant K23-AG030999 from the National Institute on Aging and the American Federation for Aging Research (Dr Steinman), by the Agency for Healthcare Research and Quality (NCQA) Translating Research into Practice Program (R01 HS13915; Dr Gonzales and Ms Maselli) and by grant KL2 RR024130 from the National Center for Research Resources (Dr Yang). We submitted an advance copy of this paper to NCQA for review and comments, but that institution had no control over the analyses and interpretation of data or over the decision to publish this work. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official view of the Department of Veterans Affairs, the National Center for Research Resources, or the National Institutes of Health. NR 30 TC 21 Z9 21 U1 1 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD DEC PY 2009 VL 15 IS 12 BP 861 EP 868 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 538AA UT WOS:000273154800003 PM 20001167 ER PT J AU Siegel, LC Sesso, HD Bowman, TS Lee, IM Manson, JE Gaziano, JM AF Siegel, Lydia C. Sesso, Howard D. Bowman, Thomas S. Lee, I-Min Manson, JoAnn E. Gaziano, J. Michael TI Physical Activity, Body Mass Index, and Diabetes Risk in Men: A Prospective Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Body mass index; Diabetes; Obesity; Physical activity ID UNITED-STATES; WEIGHT-GAIN; WOMEN; MELLITUS; EXERCISE; OBESITY; HEALTH; PREVENTION; OVERWEIGHT; ADIPOSITY AB OBJECTIVE: Physical activity has been associated with lower diabetes risk, but several prospective studies among women found that activity only slightly attenuated the diabetes risk associated with high body mass index (BMI). We investigated the independent and joint associations between vigorous activity and BMI on diabetes risk in men. METHODS: This was a prospective cohort design within the Physicians' Health Study, using Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident diabetes in 20,757 men without diabetes at baseline. Models were based on self-reported BMI and exercise frequency at baseline, first separately and then with a 6-category joint variable combining World Health Organization BMI category (normal/overweight/obese) with activity status (active/inactive) using weekly vigorous activity as the threshold. RESULTS: After a median follow-up of 23.1 years, there were 1836 cases of incident diabetes. Compared with active participants with normal BMIs, active but overweight and obese men had multivariable-adjusted HRs of 2.39 (95% CI, 2.11-2.71) and 6.22 (95% CI, 5.12-7.56). Inactive men with normal, overweight, or obese BMIs had multivariable-adjusted HRs of 1.41 (95% CI, 1.19-1.67), 3.14 (95% CI, 2.73-3.62), and 6.57 (95% CI, 5.25-8.21). CONCLUSION: Active men with normal and overweight BMIs had lower diabetes hazards than their inactive counterparts, but no difference by weekly activity was seen in obese men. Elevated BMI is a key driver of diabetes risk, with relatively modest attenuation by activity. Published by Elsevier Inc. The American Journal of Medicine (2009) 122, 1115-1121 C1 [Siegel, Lydia C.; Sesso, Howard D.; Bowman, Thomas S.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Siegel, Lydia C.; Bowman, Thomas S.; Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Sesso, Howard D.; Lee, I-Min; Manson, JoAnn E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Sesso, Howard D.; Lee, I-Min; Manson, JoAnn E.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. RP Siegel, LC (reprint author), Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. EM Lcsiegel@partners.org FU National Cancer Institute [CA-34944, CA-40360, CA-097193]; National Heart, Lung, and Blood Institute, Bethesda, Maryland [HL-26490, HL-34595]; Office of Research and Development, Cooperative Studies Program, Department of Veterans Affairs FX The Physicians' Health Study is supported by grants CA-34944 and CA-40360 and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr Siegel received support from the Office of Research and Development, Cooperative Studies Program, Department of Veterans Affairs. NR 30 TC 19 Z9 20 U1 2 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 DEC PY 2009 VL 122 IS 12 BP 1115 EP 1121 DI 10.1016/j.amjmed.2009.02.008 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 526YW UT WOS:000272333700018 PM 19958889 ER PT J AU Allen, JD Mohllajee, AP Shelton, RC Drake, BF Mars, DR AF Allen, Jennifer D. Mohllajee, Anshu P. Shelton, Rachel C. Drake, Bettina F. Mars, Dana R. TI A Computer-Tailored Intervention to Promote Informed Decision Making for Prostate Cancer Screening Among African American Men SO AMERICAN JOURNAL OF MENS HEALTH LA English DT Article DE health screening; digital rectal exam; PSA testing; prostate cancer; oncology/cancer ID RANDOMIZED CONTROLLED-TRIAL; RACIAL-DIFFERENCES; EDUCATIONAL INTERVENTIONS; ENTERTAINMENT EDUCATION; HEALTH DISPARITIES; LITERATE WOMEN; ANTIGEN TEST; KNOWLEDGE; AID; INFORMATION AB African American men experience a disproportionate burden of prostate cancer (CaP) morbidity and mortality. National screening guidelines advise men to make individualized screening decisions through a process termed informed decision making (IDM). In this pilot study, a computer-tailored decision-aid designed to promote IDM was evaluated using a pre-/posttest design. African American men aged 40 years and older were recruited from a variety of community settings (n = 108). At pretest, 43% of men reported having made a screening decision; at posttest 47% reported this to be the case (p = .39). Significant improvements were observed between pre- and posttest on scores of knowledge, decision self-efficacy, and decisional conflict. Men were also more likely to want an active role in decision making after using the tool. These results suggest that use of a computer-tailored decision aid is a promising strategy to promote IDM for CaP screening among African American men. C1 [Allen, Jennifer D.; Mohllajee, Anshu P.; Shelton, Rachel C.; Drake, Bettina F.; Mars, Dana R.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Allen, Jennifer D.] Boston Coll, William Connell Sch Nursing, Chestnut Hill, MA 02167 USA. [Allen, Jennifer D.; Shelton, Rachel C.; Drake, Bettina F.] Harvard Univ, Sch Publ Hlth, Dept Social Human dev & Hlth, Boston, MA 02115 USA. [Mohllajee, Anshu P.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Allen, JD (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM jennifer_allen@dfci.harvard.edu RI Allen, Jennifer/M-2113-2015; OI Drake, Bettina/0000-0001-9340-5848 FU NCI NIH HHS [P50 CA090381, P50 CA090381-06] NR 76 TC 13 Z9 13 U1 4 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1557-9883 J9 AM J MENS HEALTH JI Am. J. Mens Health PD DEC PY 2009 VL 3 IS 4 BP 340 EP 351 DI 10.1177/1557988308325460 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 522JD UT WOS:000271992800008 PM 19477736 ER PT J AU Witter, FR Zimmerman, AW Reichmann, JP Connors, SL AF Witter, Frank R. Zimmerman, Andrew W. Reichmann, James P. Connors, Susan L. TI In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE asthma; autism spectrum disorder; beta 2 adrenergic agonist; preterm labor; ritodrine; terbutaline ID BETA-ADRENERGIC-RECEPTOR; PRETERM LABOR; BETA(2)-ADRENERGIC RECEPTOR; DOUBLE-BLIND; TERBUTALINE PUMP; HEART-FAILURE; GLUCOSE-INTOLERANCE; SINGLE INJECTION; PREMATURE LABOR; NERVOUS-SYSTEM AB Beta 2 adrenergic receptor overstimulation during critical periods of prenatal development can induce a permanent shift in the balance of sympathetic-to-parasympathetic tone. This is a biologically plausible mechanism whereby beta 2 adrenergic agonists can induce functional and behavioral teratogenesis, which explains their association with increases in autism spectrum disorders, psychiatric disorders, poor cognitive, motor function and school performance, and changes in blood pressure in the offspring. The use of beta 2 adrenergic agonists should be limited to proven indications when alternate drugs are ineffective or unavailable; the risks of untreated disease to the mother and fetus are greater than the risk of the beta 2 adrenergic agonist. C1 [Witter, Frank R.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Div Maternal Fetal Med, Baltimore, MD 21205 USA. [Zimmerman, Andrew W.; Connors, Susan L.] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. [Zimmerman, Andrew W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Zimmerman, Andrew W.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Zimmerman, Andrew W.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Zimmerman, Andrew W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Reichmann, James P.] Amer Home Patient, Brentwood, TN USA. [Connors, Susan L.] Mass Gen Hosp, LADDERS Clin, Boston, MA USA. [Connors, Susan L.] Harvard Univ, Sch Med, Boston, MA USA. RP Witter, FR (reprint author), Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Div Maternal Fetal Med, Baltimore, MD 21205 USA. NR 87 TC 32 Z9 34 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 BP 553 EP 559 DI 10.1016/j.ajog.2009.07.010 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 527AH UT WOS:000272337600011 PM 19961985 ER PT J AU Kaimal, A Janakiraman, V Caughey, A AF Kaimal, Anjali Janakiraman, Vanitha Caughey, Aaron TI Weekly membrane stripping at 39 weeks: is it cost-effective? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Kaimal, Anjali; Janakiraman, Vanitha] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Caughey, Aaron] Univ Calif San Francisco, San Francisco, CA 94143 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 132 BP S63 EP S64 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500132 ER PT J AU Katz, D Wylie, B AF Katz, Daniel Wylie, Blair TI The Chinese birth calendar for prediction of gender - fact or fiction? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Katz, Daniel; Wylie, Blair] 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 568 BP S211 EP S211 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500563 ER PT J AU Little, S Janakiraman, V Kaimal, A Musci, T Ecker, J Caughey, A AF Little, Sarah Janakiraman, Vanitha Kaimal, Anjali Musci, Thomas Ecker, Jeffrey Caughey, Aaron TI The cost-effectiveness of prenatal screening for spinal muscular atrophy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Little, Sarah; Janakiraman, Vanitha; Kaimal, Anjali; Ecker, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Musci, Thomas] Calif Pacific Med Ctr, San Francisco, CA USA. [Caughey, Aaron] Univ Calif San Francisco, San Francisco, CA 94143 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 65 BP S37 EP S37 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500066 ER PT J AU Panda, B Stiller, R Panda, A AF Panda, Britta Stiller, Robert Panda, Alexander TI Influenza vaccination in pregnancy: compliance with current CDC guidelines and means to increase vaccination rates SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Panda, Britta] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stiller, Robert] Bridgeport Hosp, Bridgeport, CT USA. [Panda, Alexander] Yale Univ, Infect Dis Sect, New Haven, CT 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 636 BP S232 EP S232 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500630 ER PT J AU Andreoli, MT Morrison, MA Kim, BJ Chen, L Adams, SM Miller, JW Deangelis, MM Kim, IK AF Andreoli, Michael T. Morrison, Margaux A. Kim, Ben J. Chen, Ling Adams, Scott M. Miller, Joan W. Deangelis, Margaret M. Kim, Ivana K. TI Comprehensive Analysis of Complement Factor H and LOC387715/ARMS2/HTRA1 Variants With Respect to Phenotype in Advanced Age-Related Macular Degeneration SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CHOROIDAL NEOVASCULARIZATION; LOC387715 GENOTYPES; STRONG ASSOCIATION; Y402H VARIANT; POLYMORPHISM; RISK; HTRA1; CFH; POPULATION; EYE AB PURPOSE: To examine the interaction of genotypic variation of 16 single-nucleotide polymorphisms (SNP) in the complement factor H (CFH) and LOC387715/ARMS2/HTRA1 loci with clinical characteristics of age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. METHODS: Eighty,four patients with neovascular AMD were genotyped using direct sequencing or Sequenom iPLEX technology. The Fisher exact test, Cochran-Mantel-Haenszel statistics, and Mann-Whitney U test were used to assess the effect of each SNP with respect to the following phenotypic manifestations: age at diagnosis, gender, affected eye, study and fellow eye visual acuity at diagnosis and at last follow-up, study eye best acuity during follow-up, presence of large drusen and retinal pigment epithelium (RPE) hyperpigmentation in study and fellow eye, choroidal neovascularization (CNV) angiographic subtype (classic vs occult), CNV size, presence of wet AMD in fellow eye, presence of dry AMD in fellow eye, and smoking history. RESULTS: Only SNPs in the LOC387715/ARMS2/HTRA1 (10q26) region were associated with disease phenotypes. The polymorphisms rs10664316 and rs1049331 were associated with a decreased risk of poor visual acuity during follow-up and at diagnosis; rs2672598 and rs2293870 were associated with a decreased risk of RPE hyperpigmentation; rs10664316 was associated with a de, creased risk of RPE hyperpigmentation with large drusen in the study eye, but an increased risk of large drusen in the fellow eye; rs11200638 was associated with an increased risk of larger CNV; rs10490924 and rs11200638 were associated with younger age of diagnosis. CONCLUSIONS: Several polymorphisms examined in the LOC387715/ARMS2/HTRA1 locus, but none in the CFH region, correlated with specific phenotypic attributes of AMD. (Am J Ophthalmol 2009; 148: 869-874. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Kim, Ben J.; Chen, Ling; Miller, Joan W.; Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. [Andreoli, Michael T.; Morrison, Margaux A.; Adams, Scott M.; Deangelis, Margaret M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. RP Kim, IK (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. EM ivana_kim@meei.harvard.edu RI DeAngelis, e/J-7863-2015 FU LINCY FOUNDATION, BEVERLY HILLS, CALIFORNIA; MASSACHUSETTS LIONS, NEW BEDFORD, Massachusetts; Eannelli for Macular Degeneration Fund, MEEI, Boston, Massachusetts; Genetics of Age-Related Macular Degeneration Fund, MEEI, Boston, Massachusetts; Research to Prevent Blindness Inc, New York, New York; Marion W. and Edward F. Knight Age-Related Macular Degeneration Fund, Boston, Massachusetts; National Institutes of Health, Bethesda, Maryland [EY014458]; Fight For Sight, New York, New York FX THIS STUDY WAS SUPPORTED BY THE LINCY FOUNDATION, BEVERLY HILLS, CALIFORNIA; MASSACHUSETTS LIONS, NEW BEDFORD, Massachusetts; Eannelli for Macular Degeneration Fund, MEEI, Boston, Massachusetts; Genetics of Age-Related Macular Degeneration Fund, MEEI, Boston, Massachusetts; Research to Prevent Blindness Inc, New York, New York; Marion W. and Edward F. Knight Age-Related Macular Degeneration Fund, Boston, Massachusetts; Grant No. EY014458 from the National Institutes of Health, Bethesda, Maryland; and Fight For Sight, New York, New York. Dr Ivana Kim is a consultant for Genentech Inc. Dr DeAngelis serves on the scientific advisory board for ArcticD.x and is a consultant for Observant LLC and Genentech Inc. Involved in design and conduct of study (BJ.K., M.M.D., I.K.K., J.W.M.); collection and management of data (B.J.K., SAM.A., M.M.D., I.K.K., J.W.M.); analysis and interpretation of data (M.T.A., M.A.M., L.C., B.J.K., M.M.D., I.K.K.);and preparation (M.T.A., M.A.M., L.C., M.M.D., I.K.K.) and review and approval of the manuscript (M.T.A., M.A.M., B.J.K., L.C., S.M.A., M.M.D., I.K.K., J.W.M.). The study protocol was approved by the Massachusetts Eye and Ear Infirmary Institutional Review Board. The study is in accordance with Health Insurance Portability and Accountability Act regulations and conforms to the tenets of the Declaration of Helsinki. NR 26 TC 34 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 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2009 VL 148 IS 6 BP 869 EP 874 DI 10.1016/j.ajo.2009.07.002 PG 6 WC Ophthalmology SC Ophthalmology GA 530BP UT WOS:000272564200010 PM 19796758 ER PT J AU Lara-Castillo, N Zandi, S Nakao, S Ito, Y Noda, K She, HC Ahmed, M Frimmel, S Ablonczy, Z Hafezi-Moghadam, A AF Lara-Castillo, Nuria Zandi, Souska Nakao, Shintaro Ito, Yasuhiro Noda, Kousuke She, Haicheng Ahmed, Muna Frimmel, Sonja Ablonczy, Zsolt Hafezi-Moghadam, Ali TI Atrial Natriuretic Peptide Reduces Vascular Leakage and Choroidal Neovascularization SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RETINAL BARRIER BREAKDOWN; MACULAR DEGENERATION; PERMEABILITY FACTOR; GROWTH-FACTOR; VEGF; ANGIOGENESIS; RECEPTOR; CELLS AB Atrial natriuretic peptide (ANP) is a hormone with diuretic, natriuretic, and vasodilatory properties. ANP blocks vascular endothelial growth factor (VEGF) production and signaling in vitro; however, its role in vascular leakage and angiogenesis is unknown. In vitro, retinal barrier permeability (transepithelial electrical resistance (TEER)) was measured in cultured retinal endothelial (HuREC) and retinal epithelial (ARPE-19) cells with VEGF (10 ng/ml), ANP (1 pM to I mu mol/L), and/or isatin, an ANP receptor antagonist. In vivo, blood-retinal barrier (BRB) leakage was studied using the Evans Blue dye technique in rats treated with intravitreal injections of ANP, VEGF, or vehicle. Choroidal neovascularization was generated by laser injury, and 7 days later, lesion size and leakage was quantitated. ANP significantly reversed VEGF-induced BRB TEER reduction in both HuREC and ARPE-19 cells, modeling the inner and the outer BRB, respectively. Isatin, a specific ANP receptor antagonist, reversed ANP's effect. ANP reduced the response of ARPE-19 cells to VEGF apically but not basolaterally, suggesting polarized expression of the ANP receptors in these cells. ANP's TEER response was concentration but not time dependent. lit vivo, ANP significantly reduced VFGF-induced BRB leakage and the size of laser-induced choroidal neovascularization lesions. In sum, ANP is an effective inhibitor of VEGF-induced vascular leakage and angiogenesis in vivo. These results may lead to new treatments for ocular diseases where VEGF plays a central role, such as age-related macular degeneration or diabetic retinopathy. (Am J Pathol 2009, 175:2343-2350; DOI: 10.2353/ajpath.2009.090439) C1 [Lara-Castillo, Nuria; Zandi, Souska; Nakao, Shintaro; Ito, Yasuhiro; Noda, Kousuke; She, Haicheng; Ahmed, Muna; Frimmel, Sonja; Hafezi-Moghadam, Ali] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab, Boston, MA USA. [Lara-Castillo, Nuria; Zandi, Souska; Nakao, Shintaro; Ito, Yasuhiro; Noda, Kousuke; She, Haicheng; Ahmed, Muna; Frimmel, Sonja; Hafezi-Moghadam, Ali] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Ablonczy, Zsolt] Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. RP Hafezi-Moghadam, A (reprint author), 325 Cambridge St,3rd Floor, Boston, MA 02114 USA. EM AHM@meei.harvard.edu OI Hafezi-Moghadam, Ali/0000-0002-5336-0697 FU NEI NIH HHS [P30 EY014104, EY14104, EY14793, R24 EY014793]; NIAID NIH HHS [AI050775, K08 AI050775] NR 25 TC 22 Z9 23 U1 0 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2009 VL 175 IS 6 BP 2343 EP 2350 DI 10.2353/ajpath.2009.090439 PG 8 WC Pathology SC Pathology GA 530NW UT WOS:000272600600011 PM 19910509 ER PT J AU Dicianno, BE Bellin, MH Zabel, AT AF Dicianno, Brad E. Bellin, Melissa H. Zabel, Andrew T. TI Spina Bifida and Mobility in the Transition Years SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Mobility Limitation; Psychological Stress; Quality of Life; Rehabilitation; Self-Care; Spinal Dysraphism ID ASSISTIVE TECHNOLOGY USE; QUALITY-OF-LIFE; YOUNG-ADULTS; ADOLESCENTS; HEALTH; ILLNESS AB Objective: Adolescents with spina bifida experience decreased mobility (Johnson KL, Dudgeon B, Kuehn C, et al: Am J Public Health 2007;9 7:330-6), especially during the time of transition from pediatric to adult care, but little research has been done on the relationships between mobility and self-management skills, psychological health, or quality of life. Design: In this multicenter, interdisciplinary study, a convenience sample of 61 participants with spina bifida from regional spina bifida clinics (mean age = 21.0 +/- 2.1 yrs) participated in a structured clinical interview on self-management and completed standardized self-report measures of psychological distress, quality of life, and mobility status. Participants were divided into three mobility groups: ambulators, part-time wheelchair users, and full-time wheelchair users and were compared with respect to outcome measures. Results: We found that full-time wheelchair use is associated with reduced quality of life but that psychological distress and problems with self-management are prevalent, regardless of mobility status. Conclusion: Research should be aimed at assessing life satisfaction as it relates to assistive technology use to delineate further how technological advancements in wheelchair design and universal design of homes and communities can have the greatest impact on mobility and quality of life. C1 [Dicianno, Brad E.] Univ Pittsburgh, Human Engn Res Labs, Pittsburgh, PA USA. [Dicianno, Brad E.] Univ Pittsburgh, Dept Phys Med & Rehabil, Adult Spina Bifida Clin, Pittsburgh, PA USA. [Dicianno, Brad E.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Dicianno, Brad E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Dicianno, Brad E.] Ctr Excellence Wheelchairs & Associated Rehabil E, VA Pittsburgh HealthCare Syst, Pittsburgh, PA USA. [Bellin, Melissa H.] Univ Maryland, Sch Social Work, Baltimore, MD 21201 USA. [Zabel, Andrew T.] Kennedy Krieger Inst, Baltimore, MD USA. RP Dicianno, BE (reprint author), Suite 202,Kaufmann Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. OI Dicianno, Brad/0000-0003-0738-0192 FU Spina Bifida Association Young Investigator Award; University of Maryland FX Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. This study was funded, in part, by the Spina Bifida Association Young Investigator Award and the University of Maryland Designated Research Initiative Funds (PI: M. Bellin). Portions of the results were presented at the Spina Bifida World Congress Meeting, 2009. NR 18 TC 9 Z9 9 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2009 VL 88 IS 12 BP 1002 EP 1006 DI 10.1097/PHM.0b013e3181c1ede3 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 527XV UT WOS:000272405400006 PM 19935183 ER PT J AU Yang, J Boninger, ML Leath, JD Fitzgerald, SG Dyson-Hudson, TA Chang, MW AF Yang, Jennifer Boninger, Michael L. Leath, Janet D. Fitzgerald, Shirley G. Dyson-Hudson, Trevor A. Chang, Michael W. TI Carpal Tunnel Syndrome in Manual Wheelchair Users with Spinal Cord Injury A Cross-Sectional Multicenter Study SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Spinal Cord Injuries; Paraplegia; Carpal Tunnel Syndrome; Median Nerve; Neuropathy; Cumulative Trauma Disorders; Wheelchairs ID BEARING UPPER EXTREMITY; ULNAR NERVE-CONDUCTION; NEUROPHYSIOLOGICAL DIAGNOSIS; ELECTRODIAGNOSTIC FINDINGS; PUSHRIM BIOMECHANICS; PARAPLEGIC PATIENTS; GENERAL-POPULATION; SYMPTOMS; MOTOR; TEMPERATURE AB Objective: To investigate relationships between carpal tunnel syndrome, functional status, subject demographics, physical examination findings, and median nerve conduction study findings in manual wheelchair users with paraplegia. Design: Multicenter cross-sectional study. One hundred twenty-six manual wheelchair-using individuals with chronic paraplegia answered self-administered questionnaires on demographics, symptoms, and functional status. They underwent physical examination specific for carpal tunnel syndrome and upper-limb nerve conduction studies. Results: Fifty-seven percent of subjects had symptoms (72.2% bilateral); hand numbness was most common. Sixty percent of subjects had carpal tunnel syndrome physical examination findings (59.2% bilateral). Those with physical examination findings were more likely to have longer duration of injury (P = 0.003). Seventy-eight percent of subjects had electrophysiologic evidence of median mononeuropathy. Symptomatic subjects had significantly greater median-ulnar motor latency difference in the dominant hand (P = 0.02) and smaller compound muscle action potential amplitudes bilaterally (dominant hand, P = 0.01; nondominant hand, P = 0.04). Persons with carpal tunnel syndrome symptoms and physical examination findings had significantly worse functional status (symptoms, P < 0.001; physical examination, P = 0.02) and symptom severity scores (symptoms, P < 0.001; physical examination, P = 0.01), but a similar difference between subjects with and without median mononeuropathy was not seen. Logistic regression analysis revealed that the presence of symptoms was predicted by median-ulnar motor latency difference in the dominant hand (odds ratio, 4.38; 95% confidence interval 1.72-11.14) and sensory nerve action potential amplitude in the nondominant hand (odds ratio, 0.97; 95% confidence interval, 0.94-0.99). Conclusions: The interaction among symptoms, physical examination, and nerve conduction study findings is complex. Carpal tunnel syndrome and median mononeuropathy are highly prevalent and functionally significant. This study highlights the need for primary prevention and patient education for preserving upper-limb function. C1 [Boninger, Michael L.] Univ Pittsburgh, Human Engn Res Labs, VA Pittsburgh Healthcare Syst, Dept Phys Med & Rehabil,Sch Med, Pittsburgh, PA 15206 USA. [Yang, Jennifer; Boninger, Michael L.; Fitzgerald, Shirley G.] Ctr Excellence Wheelchairs & Related Technol, VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Boninger, Michael L.; Fitzgerald, Shirley G.] Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Rehabil Sci & Technol, Pittsburgh, PA 15206 USA. [Boninger, Michael L.] Univ Pittsburgh, Sch Engn, Dept Bioengn, Pittsburgh, PA 15206 USA. [Dyson-Hudson, Trevor A.] Univ Med & Dent New Jersey, New Jersey Med Sch, Kessler Med Rehabil Res & Educ Corp, W Orange, NJ 07052 USA. [Dyson-Hudson, Trevor A.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Phys Med & Rehabil, W Orange, NJ 07052 USA. [Chang, Michael W.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Boninger, ML (reprint author), Univ Pittsburgh, Human Engn Res Labs, VA Pittsburgh Healthcare Syst, Dept Phys Med & Rehabil,Sch Med, 7180 Highland Dr,Bldg 4,2nd Floor E,151R-1, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 55 TC 17 Z9 17 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2009 VL 88 IS 12 BP 1007 EP 1016 DI 10.1097/PHM.0b013e3181bbddc9 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 527XV UT WOS:000272405400007 PM 19789435 ER PT J AU Hasler, WL Saad, RJ Rao, SS Wilding, GE Parkman, HP Koch, KL McCallum, RW Kuo, B Sarosiek, I Sitrin, MD Semler, JR Chey, WD AF Hasler, William L. Saad, Richard J. Rao, Satish S. Wilding, Gregory E. Parkman, Henry P. Koch, Kenneth L. McCallum, Richard W. Kuo, Braden Sarosiek, Irene Sitrin, Michael D. Semler, John R. Chey, William D. TI Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE gastrointestinal motility; irritable bowel syndrome; functional outlet obstruction ID IRRITABLE-BOWEL-SYNDROME; SLOW-TRANSIT; INTRACTABLE CONSTIPATION; IDIOPATHIC CONSTIPATION; MANOMETRY; CHILDREN; MOTILITY; DISORDERS; ABNORMALITIES AB Hasler WL, Saad RJ, Rao SS, Wilding GE, Parkman HP, Koch KL, McCallum RW, Kuo B, Sarosiek I, Sitrin MD, Semler JR, Chey WD. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol 297: G1107-G1114, 2009. First published October 1, 2009; doi: 10.1152/ajpgi.00136.2009.-Relationships of regional colonic motility to transit in health, constipation, and constipation-predominant irritable bowel syndrome (C-IBS) are poorly characterized. This study aimed to 1) characterize regional differences in colon pressure, 2) relate motor differences in constipation to colon transit, and 3) quantify the role of IBS in altered contractility with constipation. Colon pH and pressure were measured by wireless capsules in 53 healthy and 36 constipated subjects. Numbers of contractions > 25 mmHg and areas under curves (AUC) were calculated for colon transit quartiles by time. Constipation was classified as normal transit (< 59 h), moderate slow transit (STC) (59-100 h), and severe STC (> 100 h). Twelve out of 36 constipated subjects had C-IBS; 24 had functional constipation. Numbers of contractions and AUCs increased from the first to the fourth quartile in health (P < 0.0001). Mean numbers of contractions in constipated subjects were similar to controls. Mean AUCs with normal transit (P = 0.01) and moderate STC (P = 0.004) but not severe STC (P = NS) were higher than healthy subjects. IBS was associated with greater mean numbers of contractions (P = 0.05) and AUCs (P = 0.0006) vs. controls independent of transit. Numbers of contractions increased from the first to fourth quartiles in moderate STC, C-IBS, and functional constipation; AUCs increased from the first to fourth quartiles in all groups (all P < 0.05). In conclusion, colon pressure activity is greater distally than proximally in health. Constipated patients with normal or moderately delayed transit show increased motor activity that is partly explained by IBS. These findings emphasize differential effects on transit and motility in different constipation subtypes. C1 [Hasler, William L.; Saad, Richard J.; Chey, William D.] Univ Michigan Hlth Syst, Div Gastroenterol, Ann Arbor, MI USA. [Rao, Satish S.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Wilding, Gregory E.] SUNY Buffalo, Buffalo, NY 14260 USA. [Parkman, Henry P.] Temple Univ, Med Ctr, Philadelphia, PA 19122 USA. [Koch, Kenneth L.] Wake Forest Baptist Med Ctr, Winston Salem, NC USA. [McCallum, Richard W.; Sarosiek, Irene] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Kuo, Braden] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sitrin, Michael D.] Buffalo Vet Adm Hosp, Buffalo, NY USA. [Semler, John R.] SmartPill Corp, Buffalo, NY USA. RP Hasler, WL (reprint author), 3912 Taubman Ctr,5362, Ann Arbor, MI 48109 USA. EM whasler@umich.edu FU SmartPill Corporation FX This work was supported by a grant from the SmartPill Corporation. NR 32 TC 24 Z9 26 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD DEC PY 2009 VL 297 IS 6 BP G1107 EP G1114 DI 10.1152/ajpgi.00136.2009 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 524OF UT WOS:000272151900008 PM 19808653 ER PT J AU Bian, Y Sun, MY Silver, M Ho, KKL Marchionni, MA Caggiano, AO Stone, JR Amende, I Hampton, TG Morgan, JP Yan, XH AF Bian, Yun Sun, Maoyun Silver, Marcy Ho, Kalon K. L. Marchionni, Mark A. Caggiano, Anthony O. Stone, James R. Amende, Ivo Hampton, Thomas G. Morgan, James P. Yan, Xinhua TI Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE ErbB2; troponin proteins; signaling ID MITOCHONDRIAL DYSFUNCTION; INDUCED CARDIOTOXICITY; VENTRICULAR MYOCYTES; ENDOTHELIAL-CELLS; APOPTOSIS; ACTIVATION; INHIBITION; GROWTH; CARDIOMYOPATHY; EXPRESSION AB Bian Y, Sun M, Silver M, Ho KK, Marchionni MA, Caggiano AO, Stone JR, Amende I, Hampton TG, Morgan JP, Yan X. Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins. Am J Physiol Heart Circ Physiol 297: H1974-H1983, 2009. First published October 2, 2009; doi: 10.1152/ajpheart.01010.2008. Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin (Dox)-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is, therefore, important to understand how NRG1, via erbB2, protects the heart against Dox cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins [cardiac troponin I (cTnI) and cardiac troponin T (cTnT)] and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT, and cardiac troponin C (cTnC) and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2, phosphoinositide 3-kinase (PI3K), Akt, and mTOR blocked the protective effects of NRG1 on cTnI and cTnT in NRVM. NRG1 significantly reduced Dox-induced caspase activation, which degraded troponins, in NRVM. NRG1 reduced Dox-induced proteasome degradation of cTnI. NRG1 attenuates Dox-induced decrease in cardiac troponins by increasing transcription and translation and by inhibiting caspase activation and proteasome degradation of troponin proteins. NRG1 maintains cardiac troponins by the erbB2-PI3K pathway, which may lessen Dox-induced cardiac dysfunction. C1 [Bian, Yun; Sun, Maoyun; Silver, Marcy; Amende, Ivo; Morgan, James P.; Yan, Xinhua] Caritas St Elizabeths Med Ctr, Boston, MA 02135 USA. [Bian, Yun; Sun, Maoyun; Silver, Marcy; Amende, Ivo; Morgan, James P.; Yan, Xinhua] Tufts Univ, Boston, MA 02111 USA. [Ho, Kalon K. L.; Hampton, Thomas G.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Ho, Kalon K. L.; Stone, James R.; Hampton, Thomas G.] Harvard Univ, Sch Med, Boston, MA USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Marchionni, Mark A.] Alzcor Therapeut, Arlington, MA USA. [Caggiano, Anthony O.] Acorda Therapeut, Hawthorne, NY USA. RP Yan, XH (reprint author), Caritas St Elizabeths Med Ctr, 736 Cambridge St CBR3, Boston, MA 02135 USA. EM xinhua.yan@tufts.edu RI Sun, Maoyun/I-6622-2012 FU American Heart Association [0120155T, 0635549T]; National Heart, Lung, and Blood Institute [HL-52864] FX This research is funded by American Heart Association Postdoctoral Fellowship Award 0120155T (to X. Yan), American Heart Association Scientist Development Grant 0635549T (to X. Yan), and National Heart, Lung, and Blood Institute Grant HL-52864 (to J. P. Morgan). NR 39 TC 30 Z9 31 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2009 VL 297 IS 6 BP H1974 EP H1983 DI 10.1152/ajpheart.01010.2008 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 523LQ UT WOS:000272075300005 PM 19801490 ER PT J AU Li, YH Xiang, M Yuan, YZ Xiao, GZ Zhang, J Jiang, Y Vodovotz, Y Billiar, TR Wilson, MA Fan, J AF Li, Yuehua Xiang, Meng Yuan, Youzhong Xiao, Guozhi Zhang, Jian Jiang, Yong Vodovotz, Yoram Billiar, Timothy R. Wilson, Mark A. Fan, Jie TI Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2 SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE acute lung injury; neutrophil; Toll-like receptors ID TOLL-LIKE RECEPTOR-4; NF-KAPPA-B; INTERCELLULAR-ADHESION MOLECULE-1; MOBILITY GROUP BOX-1; NEUTROPHIL NADPH OXIDASE; MEDIATES HEPATIC-INJURY; TUMOR-NECROSIS-FACTOR; NAD(P)H OXIDASE; UP-REGULATION; TRANSENDOTHELIAL MIGRATION AB Li Y, Xiang M, Yuan Y, Xiao G, Zhang J, Jiang Y, Vodovotz Y, Billiar TR, Wilson MA, Fan J. Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. Am J Physiol Regul Integr Comp Physiol 297: R1670-R1680, 2009. First published October 14, 2009; doi:10.1152/ajpregu.00445.2009.-Hemorrhagic shock (HS) due to major trauma predisposes the host to the development of acute lung inflammation and injury. The lung vascular endothelium is an active organ that plays a central role in the development of acute lung injury through generating reactive oxygen species and synthesizing and releasing of a number of inflammatory mediators, including leukocyte adhesion molecules that regulate neutrophils emigration. Previous study from our laboratory has demonstrated that in a setting of sepsis, Toll-like receptor-4 (TLR4) signaling can induce TLR2 expression in endothelial cells (ECs), thereby increasing the cells' response to TLR2 ligands. The present study tested the hypothesis that TLR4 activation by HS and the resultant increased TLR2 surface expression in ECs might contribute to the mechanism underlying HS-augmented activation of lung ECs. The results show that high-mobility group box 1 (HMGB1) through TLR4 signaling mediates HS-induced surface expression of TLR2 in the lung and mouse lung vascular endothelial cells (MLVECs). Furthermore, the results demonstrate that HMGB1 induces activation of NAD(P)H oxidase and expression of ICAM-1 in the lung, and MLVECs sequentially depend on TLR4 in the early phase and on TLR2 in the late phase following HS. Finally, the data indicate an important role of the increased TLR2 surface expression in enhancing the activation of MLVECs and augmenting pulmonary neutrophil infiltration in response to TLR2 agonist peptidoglycan. Thus, induction of TLR2 surface expression in lung ECs, induced by HS and mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for endothelial cell-mediated inflammation and organ injury following trauma and hemorrhage. C1 [Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Dept Surg, Res & Dev, Pittsburgh, PA 15240 USA. [Li, Yuehua; Xiang, Meng; Yuan, Youzhong; Vodovotz, Yoram; Billiar, Timothy R.; Wilson, Mark A.; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Jiang, Yong] So Med Univ, Dept Pathophysiol, Guangzhou, Guangdong, Peoples R China. [Xiao, Guozhi; Zhang, Jian] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. RP Fan, J (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Dept Surg, Res & Dev, Bldg 1 2W109 151L-U,Univ Dr, Pittsburgh, PA 15240 USA. EM jif7@pitt.edu FU National Heart, Lung, and Blood Institute [R01-HL-079669]; National Institute of General Medical Sciences [P50-GM-53789]; Veterans Affairs Merit Award; National Key Basic Research Program [2010CB529704, PCSIRT-IRT0731]; National Natural Science Foundation of China (NSFC) [30670828]; Joint Fund of NSFC with the Guangdong Province [U0632004] FX This work was supported by the National Heart, Lung, and Blood Institute Grant R01-HL-079669 ( to J. Fan and M. A. Wilson), National Institute of General Medical Sciences Grant P50-GM-53789 ( T. R. Billiar and Y. Vodovotz), a Veterans Affairs Merit Award ( to J. Fan), National Key Basic Research Program Grant 2010CB529704 ( to Y. Jiang, China), Grant PCSIRT-IRT0731 ( to Y. Jiang), National Natural Science Foundation of China (NSFC) Grant 30670828 ( to Y. Jiang), and Joint Fund of NSFC with the Guangdong Province Grant U0632004 ( to Y. Jiang). NR 69 TC 46 Z9 54 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 2009 VL 297 IS 6 BP R1670 EP R1680 DI 10.1152/ajpregu.00445.2009 PG 11 WC Physiology SC Physiology GA 523BD UT WOS:000272044900007 PM 19828841 ER PT J AU Bouley, R Palomino, Z Tang, SS Nunes, P Kobori, H Lu, HA Shum, WW Sabolic, I Brown, D Ingelfinger, JR Jung, FF AF Bouley, Richard Palomino, Zaira Tang, Shiow-Shih Nunes, Paula Kobori, Hiroyuki Lu, Hua A. Shum, Winnie W. Sabolic, Ivan Brown, Dennis Ingelfinger, Julie R. Jung, Flavia F. TI Angiotensin II and hypertonicity modulate proximal tubular aquaporin 1 expression SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE renin angiotensin system; proximal tubule ID WATER CHANNEL; RAT-KIDNEY; MESSENGER-RNA; ION CONDUCTANCE; COLLECTING DUCT; RECEPTOR SUBTYPES; RENAL-FUNCTION; NULL MICE; VASOPRESSIN; TRANSPORT AB Bouley R, Palomino Z, Tang S-S, Nunes P, Kobori H, Lu HA, Shum WW, Sabolic I, Brown D, Ingelfinger JR, Jung FF. Angiotensin II and hypertonicity modulate proximal tubular aquaporin 1 expression. Am J Physiol Renal Physiol 297: F1575-F1586, 2009. First published September 23, 2009; doi:10.1152/ajprenal.90762.2008.-Aquaporin 1 (AQP1) is the major water channel in the renal proximal tubule (PT) and thin descending limb of Henle, but its regulation remains elusive. Here, we investigated the effect of ANG II, a key mediator of body water homeostasis, on AQP1 expression in immortalized rat proximal tubule cells (IRPTC) and rat kidney. Real-time PCR on IRPTC exposed to ANG II for 12 h revealed a biphasic effect AQP1 mRNA increased dose dependently in response to 10(-12) to 10(-8) M ANG II but decreased by 50% with 10(-7) M ANG II. The twofold increase of AQP1 mRNA in the presence of 10(-8) M ANG II was abolished by the AT(1) receptor blocker losartan. Hypertonicity due to either NaCl or mannitol also upregulated AQP1 mRNA by three- and twofold, respectively. Immunocytochemistry and Western blotting revealed a two- to threefold increase in AQP1 protein expression in IRPTC exposed concomitantly to ANG II (10(-8)M) and hypertonic medium (either NaCl or mannitol), indicating that these stimuli were not additive. Three-dimensional reconstruction of confocal images suggested that AQP1 expression was increased by ANG II in both the apical and basolateral poles of IRPTC. In vivo studies showed that short-term ANG II infusion had a diuretic effect, while this effect was attenuated after several days of ANG II infusion. After 10 days, we observed a twofold increase in AQP1 expression in the PT and thin descending limb of Henle of ANG II-infused rats that was abolished when rats were treated with the selective AT(1)-receptor antagonist olmesartan. Thus ANG II increases AQP1 expression in vitro and in vivo via direct interaction with the AT(1) receptor, providing an important regulatory mechanism to link PT water reabsorption to body fluid homeostasis via the renin-angiotensin system. C1 [Bouley, Richard] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Program Membrane Biol,Nephrol Div, Boston, MA 02114 USA. [Palomino, Zaira] Univ Fed Sao Paulo, Escola Paulista Med, Disciplina Nephrol, Sao Paulo, Brazil. [Tang, Shiow-Shih] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02114 USA. [Kobori, Hiroyuki; Jung, Flavia F.] Tulane Univ, Hlth Sci Ctr, Dept Physiol & Hypertens, New Orleans, LA 70118 USA. [Sabolic, Ivan] Inst Med Res & Occupat Hlth, Zagreb 41000, Croatia. [Ingelfinger, Julie R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jung, Flavia F.] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. RP Bouley, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Program Membrane Biol,Nephrol Div, CPZN 8150,185 Cambridge St, Boston, MA 02114 USA. EM Bouley.Richard@mgh.harvard.edu RI Nunes-Hasler, Paula/N-4337-2015; Kobori, Hiroyuki/F-1994-2014 OI Nunes-Hasler, Paula/0000-0002-4598-685X; Kobori, Hiroyuki/0000-0001-5128-5059 FU National Heart, Lung, and Blood Institute [HL-40210, HL-48455]; National Institute of Diabetes and Digestive and Kidney Diseases [PO1-DK-38452, DK-38452]; National Kidney Foundation Investigator Award; National Sciences and Engineering Research Council; Boston Area Diabetes and Endocrinology Research Center [DK-57521]; Center for the Study of Inflammatory Bowel Disease [DK-43351] FX These studies were supported by National Heart, Lung, and Blood Institute Grants HL-40210 and HL-48455 (to J. Ingelfinger) and by National Institute of Diabetes and Digestive and Kidney Diseases Grant PO1-DK-38452 (to D. Brown). R. Bouley received the National Kidney Foundation Investigator Award. P. Nunes is supported by a Doctoral Level Postgraduate Scholarship from National Sciences and Engineering Research Council and by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38452. The Microscopy Core Facility of the Massachusetts General Hospital Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (DK-57521) and the Center for the Study of Inflammatory Bowel Disease (DK-43351). NR 71 TC 20 Z9 22 U1 0 U2 2 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 DEC PY 2009 VL 297 IS 6 BP F1575 EP F1586 DI 10.1152/ajprenal.90762.2008 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 539VY UT WOS:000273288100011 PM 19776169 ER PT J AU Eisenman, DP Glik, D Gonzalez, L Maranon, R Zhou, Q Tseng, CH Asch, SM AF Eisenman, David P. Glik, Deborah Gonzalez, Lupe Maranon, Richard Zhou, Qiong Tseng, Chi-Hong Asch, Steven M. TI Improving Latino Disaster Preparedness Using Social Networks SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PUBLIC-HEALTH EMERGENCIES; HIDDEN POPULATIONS; RISK; INFORMATION AB Background: Culturally targeted, informal social networking approaches to improving disaster preparedness have not been empirically tested. Purpose: In partnership with community health promoters and the Los Angeles County Department of Public Health, this study tested a disaster preparedness program for Latino households. Design: This study had a community-based, randomized, longitudinal cohort design with two groups and was conducted during February-October 2007. Assessments were made at baseline and 3 months. Analyses were carried out January-October 2008. Settings/participants: Community-based study of 231 Latinos living in Los Angeles County. Intervention: Participants were randomly assigned to attending platicas (small-group discussions led by a health promoter/promotora de salud) or receiving "media" (a culturally tailored mailer). A total of 187 (81.0%) completed the 3-month follow-up. Main outcome measure: A self-reported disaster preparedness checklist was used. Results: Among participants who did not have emergency water pre-intervention, 93.3% of those in the platica arm had it at follow-up, compared to 66.7% in the media arm (p=0.003). Among participants who did not have food pre-intervention, 91.7% in the platica arm reported it at follow-up, compared to 60.6% in the media arm (p=0.013). Finally, among participants who did not have a family communication plan pre-intervention, 70.4% in the platica arm reported one at follow-up, compared to 42.3% in the media arm (p=0.002). Conclusions: Although both arms improved in stockpiling water and food and creating a communication plan, the platica arm showed greater improvement than the media group. (Am J Prev Med 2009;37 (6):512-517) (C) 2009 American journal of Preventive Medicine C1 [Eisenman, David P.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Dept Med, Los Angeles, CA 90095 USA. [Glik, Deborah] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Asch, Steven M.] VA Greater Los Angeles Hlth Syst, Dept Med, Los Angeles, CA USA. [Gonzalez, Lupe] Coalit Community Hlth, Los Angeles, CA USA. RP Eisenman, DP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Dept Med, 911 Broxton Plaza, Los Angeles, CA 90095 USA. EM deisenman@mednet.ucla.edu FU CDC [1 K01 CD000049-01] FX The survey was supported by award No. 1 K01 CD000049-01 by the CDC to DPE. The manuscript's content is solely the responsibility of the authors and does not necessarily represent the views of the granting agency. NR 37 TC 21 Z9 21 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2009 VL 37 IS 6 BP 512 EP 517 DI 10.1016/j.amepre.2009.07.022 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SJ UT WOS:000272769700007 PM 19944917 ER PT J AU Pagan, JA Su, DJ Li, LF Armstrong, K Asch, DA AF Pagan, Jose A. Su, Dejun Li, Lifeng Armstrong, Katrina Asch, David A. TI Racial and Ethnic Disparities in Awareness of Genetic Testing for Cancer Risk SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH INTERVIEW SURVEY; ACCULTURATION; BREAST; RACE AB Background: Racial and ethnic disparities in awareness of genetic testing for cancer risk are substantial. Purpose: This study assesses the relative importance of contributing factors to gaps in awareness of genetic testing for cancer risk across racial and ethnic groups. Methods: Data from the 2005 National Health Interview Survey (N=25,364) were analyzed in 2009 to evaluate the contribution of demographic factors, SES, health Status, nativity/length of residency in the U.S., personal/family history of cancer, and perceived cancer risk to racial and ethnic disparities in genetic testing awareness for cancer risk. The contribution of each factor was assessed using the Fairlie decomposition technique. Results: About 48% of non-Hispanic whites reported that they had heard about genetic testing, followed by 31% of blacks, 28% of Asians, and 19% of Hispanics. Education and nativity/length of residency in the U.S. explained 26% and 30% of the gap between whites and Hispanics, respectively. Education accounted for 22% of the white-black gap, with residential region explaining another 11%. Nativity/length of residency in the U.S. explained 51% of the white-Asian gap. Conclusions: The relative importance of Factors contributing to racial and ethnic disparities in genetic testing awareness is specific to the particular groups under comparison. Diverse, culturally competent approaches are needed to improve awareness for different racial and ethnic groups. (Am J Prev Med 2009;37(6):524-530) (C) 2009 American Journal of Preventive Medicine C1 [Pagan, Jose A.] Univ N Texas, Hlth Sci Ctr, Dept Hlth Management & Policy, Sch Publ Hlth, Ft Worth, TX 76107 USA. [Li, Lifeng] Univ Texas Pan Amer, Dept Econ & Finance, Coll Business Adm, Edinburg, TX 78541 USA. [Su, Dejun] Univ Texas Pan Amer, Dept Sociol, Edinburg, TX 78541 USA. [Armstrong, Katrina; Asch, David A.] Univ Penn, Div Gen Internal Med, Sch Med, Philadelphia, PA 19104 USA. [Armstrong, Katrina; Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Pagan, JA (reprint author), Univ N Texas, Hlth Sci Ctr, Dept Hlth Management & Policy, Sch Publ Hlth, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA. EM jpagan@hsc.unt.edu OI Asch, David/0000-0002-7970-286X FU Agency for Healthcare Research and Quality [R24HS017003]; CDC [H75DP00181201]; Department of Defense Breast Cancer Research Program [W81XW11-064-0334] FX Supported by the Agency for Healthcare Research and Quality (Grant R24HS017003); the CDC (Grant H75DP00181201); and the Department of Defense Breast Cancer Research Program (Grant W81XW11-064-0334). Views and opinions of, and endorsements by, the authors do not reflect those of the Agency for Healthcare Research and Quality, the CDC, the U.S. Army, or the Department of Defense. NR 22 TC 30 Z9 30 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2009 VL 37 IS 6 BP 524 EP 530 DI 10.1016/j.amepre.2009.07.021 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SJ UT WOS:000272769700009 PM 19944919 ER PT J AU Shelton, RC Puleo, E Bennett, GG McNeill, LH Goldman, RE Emmons, KM AF Shelton, Rachel C. Puleo, Elaine Bennett, Gary G. McNeill, Lorna H. Goldman, Roberta E. Emmons, Karen M. TI Racial Discrimination and Physical Activity Among Low-Income-Housing Residents SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PERCEIVED DISCRIMINATION; RACIAL/ETHNIC DISCRIMINATION; BLOOD-PRESSURE; MENTAL-HEALTH; UNITED-STATES; ADULTS; COMMUNITY; AMERICAN; PREVALENCE; PEDOMETER AB Background: Although discrimination has been identified as a potential determinant of existing racial/ethnic health disparities, no sutdies have investigated whether racial discrimination contributes to disparities in physical activity. Purpose: The primary aim Of the current study was to examine the association between interpersonal racial discrimination and physical activity. Methods: Baseline data were collected during 2004-2005 among a predominately black and Hispanic sample of adult residents living in 12 low-income-housing sites in Boston MA (n=1055). Residents reported experiences of lifetime racial discrimination during interviewer-administered surveys and wore a pedometer for 5 days to measure physical activity. For analyses, performed in 2009, linear regression models with a cluster design were conducted to predict physical activity, measured as steps per day. Results: Nearly 48% of participants reported ever experiencing racial discrimination, and discrimination was most commonly experienced on the street or in a public setting. No association was found between discrimination and physical activity, when examined in bivariate, multivariable, or race-stratified models. Conclusions: The current results indicate that self-reported racial discrimination is not a key determinant of physical activity among residents living in low-income housing. However, additional research is warranted to address current limitations of this, study. (Am J Prev Med 2009;37(6):541-545) (C) 2009 American Journal of Preventive Medicine C1 [Shelton, Rachel C.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. [Puleo, Elaine] Univ Massachusetts, Dept Publ Hlth, Amherst, MA 01003 USA. [Bennett, Gary G.; Goldman, Roberta E.; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Bennett, Gary G.; Goldman, Roberta E.; Emmons, Karen M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Bennett, Gary G.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. [Goldman, Roberta E.] Brown Univ, Dept Family Med, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Shelton, RC (reprint author), Mt Sinai Sch Med, Dept Oncol Sci, 1425 Madison Ave,Box 1130, New York, NY 10029 USA. EM rshelton@post.harvard.edu FU National Cancer Institute [5R01CA098864-02, 1K22CA126992-01, K05 CA124415, 5 R25-CA057711-14]; Liberty Mutual, National Grid; Patterson Fellowship; Mt. Sinai Program in Cancer Prevention and Control Multidisciplinary Training [5R25-CA081137] FX This research was supported by Grants 5R01CA098864-02, 1K22CA126992-01, and K05 CA124415 from the National Cancer Institute and support to the Dana-Farber Cancer Institute by Liberty Mutual, National Grid, and the Patterson Fellowship. Funding support for the lead author (RS) was also provided through the National Cancer Institute by the Harvard Education Program in Cancer Prevention and Control (5 R25-CA057711-14) and the Mt. Sinai Program in Cancer Prevention and Control: Multidisciplinary Training (5R25-CA081137). NR 43 TC 10 Z9 11 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2009 VL 37 IS 6 BP 541 EP 545 DI 10.1016/j.amepre.2009.07.018 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SJ UT WOS:000272769700012 PM 19944922 ER PT J AU Cordasco, KM Asch, SM Bell, DS Guterman, JJ Gross-Schulman, S Ramer, L Elkayam, U Franco, I Leatherwood, CL Mangione, CM AF Cordasco, Kristina M. Asch, Steven M. Bell, Doug S. Guterman, Jeffrey J. Gross-Schulman, Sandra Ramer, Lois Elkayam, Uri Franco, Idalid Leatherwood, Cianna L. Mangione, Carol M. TI A Low-Literacy Medication Education Tool for Safety-Net Hospital Patients SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Robert Wood Johnson Clinical Scholars CY APR 11, 2008 CL Washington, DC ID CONGESTIVE-HEART-FAILURE; HEALTH LITERACY; ELDERLY PATIENTS; ADHERENCE; KNOWLEDGE; INTERVENTION; PREVENTION; DISCHARGE; REGIMENS; OUTCOMES AB Background: To improve medication adherence in cardiac patients, in partnership with a safety-net provider, this research team developed and evaluated a low-literacy medication education tool. Methods: Using principles of community-based participatory research, the team developed a prototype of a low-literacy hospital discharge medication education tool, customizable for each patient, featuring instruction-specific icons and Pictures of pills. In 2007, a randomized controlled clinical trial was performed, testing the tool's effect on posthospitalization self-reported medication adherence and knowledge, 2 weeks postdischarge in English- and Spanish-speaking safety-net inpatients. To validate the self-report measure, 4 weeks postdischarge, investigators collected self-reports of the number of pills remaining for each medication in a subsample of participants. Nurses rated tool acceptability. Results: Among the 166/210 eligible participants (79%) completing the Week-2 interview, self-reported medication adherence was 70% (95% CI=62%, 79%) in intervention participants and 78% (95% CI=72%, 84%) in controls (p=0.13). Among the 85 participants (31%) completing the Week-4 interview, self-reported pill Counts indicated high adherence (greater than 90%) and did not differ between Study arms. Self-reported adherence was correlated with self-reported pill count in intervention participants (R=0.5, p=0.004) but not in controls (R=0.07, p=0.65). There were no differences by study arm in medication knowledge. The nurses rated the tool as highly acceptable. Conclusions: Although the evaluation did not demonstrate the tool to have any effect on self-reported medication adherence, patients who received the schedule self-reported their medication adherence more accurately, perhaps indicating C1 [Cordasco, Kristina M.; Asch, Steven M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Cordasco, Kristina M.; Asch, Steven M.; Bell, Doug S.; Guterman, Jeffrey J.; Franco, Idalid; Leatherwood, Cianna L.; Mangione, Carol M.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Guterman, Jeffrey J.; Gross-Schulman, Sandra] Los Angeles Cty Dept Hlth Serv, Los Angeles, CA USA. [Ramer, Lois; Elkayam, Uri] Los Angeles Cty Univ So Calif, Med Ctr, Los Angeles, CA USA. [Elkayam, Uri] Univ So Calif, Dept Med, Los Angeles, CA USA. RP Cordasco, KM (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 111G, Los Angeles, CA 90073 USA. EM kcordasco@mednet.ucla.edu RI Bell, Douglas/G-6702-2013 OI Bell, Douglas/0000-0002-5063-8294 FU NIA NIH HHS [P30AG021684, P30AG028748] NR 35 TC 25 Z9 26 U1 3 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2009 VL 37 IS 6 BP S209 EP S216 DI 10.1016/j.amepre.2009.08.018 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SM UT WOS:000272770000005 PM 19896021 ER PT J AU Rosenthal, MS Ross, JS Bilodeau, R Richter, RS Palley, JE Bradley, EH AF Rosenthal, Marjorie S. Ross, Joseph S. Bilodeau, RoseAnne Richter, Rosemary S. Palley, Jane E. Bradley, Elizabeth H. TI Economic Evaluation of a Comprehensive Teenage Pregnancy Prevention Program Pilot Program SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SAFER CHOICES; UNITED-STATES; MATERNAL AGE; OUTCOMES; SCHOOL; ADOLESCENTS; HIV; STD AB Background: Previous research has Suggested that comprehensive teenage pregnancy prevention programs that address sexual education and life skills development and provide academic Support are effective in reducing births among enrolled teenagers. However, there have been limited data on the costs and cost effectiveness Of Such programs. Purpose: The study used a community-based participation, research approach to develop estimates of the cost-benefit of the Pathways/Senderos Center, a comprehensive neighborhood-based program to prevent unintended pregnancies and promote positive development for adolescents. Methods: Using data from 1997-2003, an in-time intervention analysis was conducted to determine program cost-benefit while teenagers were enrolled; an extrapolation analysis was then used to estimate accrued economic benefits and cost-benefit up to age 30 years. Results: The program operating costs totaled $3,228,152.59 and reduced the teenage childbearing rate from 94.10 to 40.00 per 1000 teenage girls, averting $52,297.84 in total societal costs, with an economic benefit to society from program participation of $2,673,153.11. Therefore, total costs to society exceeded economic benefits by $559,677.05, or $1599.08 per adolescent per year. In an extrapolation analysis, benefits to society exceed costs by $10,474.77 per adolescent per year by age 30 years on average, with social benefits outweighing total social costs by age 20.1 years. Conclusions: This comprehensive teenage pregnancy prevention program is estimated to provide societal economic benefits once participants are young adults, suggesting the need to expand beyond pilot demonstrations and evaluate the long-range cost effectiveness of similarly comprehensive programs when they are implemented more widely in high-risk neighborhoods. (Am J Prev Med 2009;37(6S1):S280-S287) (C) 2009 American journal of Preventive Medicine C1 [Rosenthal, Marjorie S.; Bradley, Elizabeth H.] Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06520 USA. [Rosenthal, Marjorie S.] Yale Univ, Sch Med, Div Gen Pediat, New Haven, CT 06520 USA. [Bradley, Elizabeth H.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, Bronx, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Bilodeau, RoseAnne] New Britain Teen Pregnancy Prevent Inc, New Britain, CT USA. [Richter, Rosemary S.; Palley, Jane E.] Univ Connecticut, Sch Med, Dept Obstet & Gynecol, Farmington, CT USA. RP Rosenthal, MS (reprint author), Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, Room IE-61 SHM,POB 208088, New Haven, CT 06520 USA. EM marjorie.rosenthal@yale.edu FU Patrick and Catherine Weldon Donaghue Medical Research Foundation [02-102]; National Institute on Aging [K08 AG032886]; American Federation of Aging Research FX Dr. Bradley is supported by a Patrick and Catherine Weldon Donaghue Medical Research Foundation Donaghue Investigator Award (Grant #02-102). Dr. Ross is currently) Supported by the National Institute on Aging (K08 AG032886) and by the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program. NR 31 TC 5 Z9 5 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2009 VL 37 IS 6 BP S280 EP S287 DI 10.1016/j.amepre.2009.08.014 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SM UT WOS:000272770000014 PM 19896030 ER PT J AU Reichmuth, KJ Dopp, JM Barczi, SR Skatrud, JB Wojdyla, P Hayes, D Morgan, BJ AF Reichmuth, Kevin J. Dopp, John M. Barczi, Steven R. Skatrud, James B. Wojdyla, Piotr Hayes, Don, Jr. Morgan, Barbara J. TI Impaired Vascular Regulation in Patients with Obstructive Sleep Apnea SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE hypoxia; sleep; vasodilation; cerebral vascular circulation; regional blood flow ID POSITIVE AIRWAY PRESSURE; ENDOTHELIAL FUNCTION; CEREBROVASCULAR RESPONSES; CHEMOREFLEX SENSITIVITY; SELECTIVE POTENTIATION; VASODILATOR RESPONSES; VENTILATORY RESPONSE; CEREBRAL-ARTERIES; HYPOXIC DILATION; BLOOD-PRESSURE AB Rationale Impaired endothelium-dependent vasodilation has been documented in patients with sleep apnea. This impairment may result in blood flow dysregulation during apnea-induced fluctuations in arterial blood gases. Objectives: To test the hypothesis that hypoxic and hypercapnic vasodilation in the forearm and cerebral circulation are impaired in patients with sleep apnea. Methods: We exposed 20 patients with moderate to severe sleep apnea and 20 control subjects, to isocapnic hypoxia and hyperoxic hypercapnia. A subset of 14 patients was restudied after treatment with continuous positive airway pressure. Measurements and Main Results: Cerebral flow velocity (transcranial Doppler), forearm blood flow (venous occlusion plethysmography), arterial pressure (automated sphygmomanometry), oxygen saturation (pulse oximetry), ventilation (pneumotachograph), and endtidal oxygen and carbon dioxide tensions (expired gas analysis) were measured during three levels of hypoxia and two levels of hypercapnia. Cerebral vasodilator responses to hypoxia (-0.65 +/- 0.44 vs. -1.02 +/- 0.72 [mean +/- SD] units/% saturation; P = 0.03) and bypercapnia (2.01 +/- 0.88 vs. 2.57 +/- 0.89 units/mm Hg; P = 0.03) were smaller in patients versus control subjects. Hypoxic vasodilation in the forearm was also attenuated (-0.05 +/- 0.09 vs. -0.10 +/- 0.09 unit/% saturation; P = 0.04). Hypercapnia did not elicit forearm vasodilation in either group. Twelve weeks of continuous positive airway pressure treatment enhanced hypoxic vasodilation in the cerebral circulation (-0.83 +/- 0.32 vs. -0.46 +/- 0.29 units/% saturation; P = 0.01) and forearm (-0.19 +/- 0.15 vs. -0.02 +/- 0.08 units/% saturation; P = 0.003), and hypercapnic vasodilation in the brain showed a trend toward improvement (2.24 +/- 0.78 vs. 1.76 +/- 0.64 units/mm Hg; P 0.06). Conclusions: Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with obstructive sleep apnea. Some of these impairments can be improved with continuous positive airway pressure. C1 [Reichmuth, Kevin J.; Barczi, Steven R.; Skatrud, James B.; Wojdyla, Piotr; Hayes, Don, Jr.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Dopp, John M.; Morgan, Barbara J.] Middleton Vet Adm Hosp, Madison, WI USA. [Morgan, Barbara J.] Univ Wisconsin, Dept Orthoped & Rehabil, Sch Med & Publ Hlth, Madison, WI USA. RP Morgan, BJ (reprint author), 1300 Univ Ave,5173 Med Sci Ctr, Madison, WI 53706 USA. EM morgan@ortho.wisc.edu FU NHLBI [RO1 HL074072, T32 HL07654]; UW-Madison Institutional Clinical and Translational Science [K12 RR025012]; Office of Research and Development, Clinical Science R&D Service, Department of Veterans Affairs FX Supported by NHLBI grant RO1 HL074072. K.J.R. was supported by NHLBI training grant T32 HL07654 and J.M.D. was supported by UW-Madison Institutional Clinical and Translational Science award K12 RR025012. This research was also supported by the Office of Research and Development, Clinical Science R&D Service, Department of Veterans Affairs. NR 44 TC 41 Z9 42 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 1 PY 2009 VL 180 IS 11 BP 1143 EP 1150 DI 10.1164/rccm.200903-0393OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 523WA UT WOS:000272104100016 PM 19745203 ER PT J AU Tejera, P Wang, ZX Zhai, RH Su, L Sheu, CC Taylor, DM Chen, F Gong, MN Thompson, BT Christiani, DC AF Tejera, Paula Wang, Zhaoxi Zhai, Rihong Su, Li Sheu, Chau-Chyun Taylor, Deanne M. Chen, Feng Gong, Michelle N. Thompson, B. Taylor Christiani, David C. TI Genetic Polymorphisms of Peptidase Inhibitor 3 (Elafin) Are Associated with Acute Respiratory Distress Syndrome SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE acute respiratory distress syndrome; elafin; genetic susceptibility; haplotypes; tagging SNP ID ELASTASE-SPECIFIC INHIBITOR; ACUTE LUNG INJURY; PROTEINASE-INHIBITOR; NEUTROPHIL ELASTASE; EPITHELIAL-CELLS; HUMAN KERATINOCYTES; EXPRESSION; ARDS; SEQUENCE; SLPI AB Peptidase inhibitor 3 (PI3, elafin) is a protease inhibitor produced locally in the lung, where it plays a central role in controlling excessive activity of neutrophil elastase. Our previous study revealed that PI3 gene expression is down-regulated during the acute stage of acute respiratory distress syndrome (ARDS). We conducted a case-control study to investigate whether genetic variants in PI3 gene are associated with ARDS development. Based on resequencing data from 29 unrelated white subjects, three tagging single-nucleotide polymorphisms were selected and genotyped in a prospective cohort consisting of 449 white patients with ARDS (cases) and 1,031 critically ill patients (at-risk control subjects). We found that the variant allele of rs2664581 (T34P) was significantly associated with increased ARDS risk (odds ratio [OR], 1.35; 95% confidence interval [Cl], 1.09-1.67; P = 0.006; false discovery rate adjusted P = 0.018). Moreover, this association was stronger among subjects with extrapulmonary injury. The common haplotype Hap2 (TTC), containing the variant allele of rs2664581, was also identified as a risk haplotype for ARDS (OR, 1.31; 95% Cl, 1.05-1.64; P = 0.015). Furthermore, the rs2664581 polymorphism was associated with circulating PI3 levels in multivariate analyses. Patients with ARDS homozygous for the wild-type A allele of rs2664581 showed significant lower PI3 plasma level (P = 0.019) at ARDS onset as compared with those homozygous or heterozygous for the variant Callele. Our data suggest that polymorphisms in PI3 gene are significantly associated with ARDS risk and with circulating PI3 levels. C1 [Tejera, Paula; Wang, Zhaoxi; Zhai, Rihong; Su, Li; Sheu, Chau-Chyun; Chen, Feng; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Taylor, Deanne M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gong, Michelle N.] Mt Sinai Sch Med, Div Pulm & Crit Care Med, New York, NY USA. [Thompson, B. Taylor; Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave,Room I-1407, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU National Institutes of Health [HL 060710, ES00002]; Fundacion Ramon Areces (Spain) FX This work was supported by National Institutes of Health grants HL 060710 and ES00002. P.T. was supported by grant from Fundacion Ramon Areces (Spain). NR 38 TC 23 Z9 26 U1 1 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2009 VL 41 IS 6 BP 696 EP 704 DI 10.1165/rcmb.2008-0410OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 523YV UT WOS:000272111900008 PM 19251943 ER PT J AU Boland, GWL AF Boland, Giles W. L. TI From Herding Cats Toward Best Practices: Standardizing the Radiologic Work Process SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Editorial Material DE best practices; information systems; quality outcomes; radiologist; standardization AB OBJECTIVE. Considerable variation in radiologic procedures, protocols, policies, and workflows exists across the nation, sometimes even within departments. This lack of standardization fosters idiosyncratic behavior and outcomes, undermining the effort to implement best practices across institutions. The purpose of this article is to discuss the need for rapidly implementing recognized standards and best practices when they exist. CONCLUSION. The use of information systems to monitor a wide variety of quality metrics offers managers the opportunity to standardize radiology and departmental practices, with the goal of transforming these practices into those that are more efficient and cost-effective and of higher quality. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Boland, GWL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM gboland@partners.org NR 16 TC 9 Z9 9 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2009 VL 193 IS 6 BP 1593 EP 1595 DI 10.2214/AJR.09.2885 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523AT UT WOS:000272043200019 PM 19933652 ER PT J AU Arellano, RS Garcia, RG Gervais, DA Mueller, PR AF Arellano, Ronald S. Garcia, Rodrigo G. Gervais, Debra A. Mueller, Peter R. TI Percutaneous CT-Guided Radiofrequency Ablation of Renal Cell Carcinoma: Efficacy of Organ Displacement by Injection of 5% Dextrose in Water Into the Retroperitoneum SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE radiofrequency ablation; renal cell carcinoma ID 100 TUMORS; INJURY AB OBJECTIVE. The objective of this study was to evaluate the effectiveness of CT-guided injection of 5% dextrose in water solution (D5W) into the retroperitoneum to displace organs adjacent to renal cell carcinoma. MATERIALS AND METHODS. An interventional radiology database was searched to identify the cases of patients who underwent CT-guided percutaneous radiofrequency ablation of biopsy-proven renal cell carcinoma in which D5W was injected into the retroperitoneal space to displace structures away from the targeted renal tumor. The number of organs displaced and the distance between the renal tumor and adjacent organs before and after displacement with D5W were assessed. RESULTS. The cases of 135 patients with 139 biopsy-proven renal cell carcinomas who underwent 154 percutaneous CT-guided radiofrequency ablation procedures were found in the search. Thirty-one patients with 33 renal cell carcinomas underwent 36 ablation procedures after injection of D5W into the retroperitoneal space. Fifty-five organs were displaced away from renal cell carcinoma with this technique. The average distance between adjacent structures and renal cell carcinomas before displacement was 0.36 cm (range, 0.1-1.0 cm). The average distance between structures and adjacent renal cell carcinomas after displacement was 1.94 cm (range, 1.1-4.3 cm) (p < 0.0001). The average volume of D5W used to achieve organ displacement was 273.5 mL. No complications were associated with this technique. CONCLUSION. CT-guided injection of D5W into the retroperitoneum is an effective method for displacing vital structures away from renal cell carcinoma. C1 [Arellano, Ronald S.; Gervais, Debra A.; Mueller, Peter R.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Garcia, Rodrigo G.] Hosp Israelita Albert Einstein, Sao Paulo, Brazil. RP Arellano, RS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM rarellano@partners.org NR 19 TC 15 Z9 16 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2009 VL 193 IS 6 BP 1686 EP 1690 DI 10.2214/AJR.09.2904 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523AT UT WOS:000272043200032 PM 19933665 ER PT J AU Lee, SI Chew, FS AF Lee, Susanna I. Chew, Felix S. TI Use of IV Iodinated and Gadolinium Contrast Media in the Pregnant or Lactating Patient: Self-Assessment Module SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE amniotic fluid; breast feeding; fetus; placenta; thyroid function ID HUMAN-BREAST-MILK; THYROID-FUNCTION; GADOPENTETATE DIMEGLUMINE; EXCRETION AB Objective The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of the safe use of iodinated and gadolinium contrast and to know the standards of practice regarding their use in the pregnant and lactating patient. Conclusion The activities in this article guide the participant to more safely administer intravenous contrast agents to pregnant and lactating patients. C1 [Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Chew, Felix S.] Seattle Univ, Dept Radiol, Seattle, WA 98122 USA. RP Lee, SI (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM slee0@partners.org OI Chew, Felix/0000-0003-2711-2013 NR 16 TC 0 Z9 0 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2009 VL 193 IS 6 BP S70 EP S73 DI 10.2214/AJR.07.7135 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523AU UT WOS:000272043400002 ER PT J AU Seon, JK Park, SJ Lee, KB Gadikota, HR Kozanek, M Oh, LS Hariri, S Song, EK AF Seon, Jong Keun Park, Sang Jin Lee, Keun Bae Gadikota, Hemanth R. Kozanek, Michal Oh, Luke S. Hariri, Sanaz Song, Eun Kyoo TI A Clinical Comparison of Screw and Suture Fixation of Anterior Cruciate Ligament Tibial Avulsion Fractures SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE tibial avulsion fracture; anterior cruciate ligament; suture; screw; fixation ID INTERCONDYLAR EMINENCE FRACTURES; ARTHROSCOPIC REDUCTION; CANNULATED SCREW; SPINE FRACTURES; CHILDREN AB Background: Screw and suture fixations are the most commonly used methods of fixation in treatment of anterior cruciate ligament tibial avulsion fractures. Even though a few biomechanical studies have compared the stability of the 2 fixation techniques, a clinical comparison has not yet been reported. Hypothesis: The authors hypothesized that both fixations would be identical in all studied clinical outcome measures at a minimum 2-year follow-up. Study Design: Cohort study; Level of evidence, 3. Materials and Methods: Thirty-three patients treated with either screw fixation (16 patients) or suture fixation (17 patients) within 1 month of the anterior cruciate ligament tibial avulsion fracture (type II or III) without associated ligamentous injury were included. All patients were evaluated at a minimum 2-year follow-up in terms of Lysholm knee scores and return to preinjury activities. Knee stability was compared based on the Lachman test and stress radiography. Results: No significant differences were found between the 2 groups in terms of average Lysholm knee scores (91.7 in the screw group and 92.7 in the suture group, P = .413) at follow-up. All patients except 2 (1 in each group) returned to preinjury activity levels. However, flexion contractures (5 degrees to 10 degrees) were found in 3 patients in the screw group and 2 patients in the suture group without significant intergroup difference. Stabilities based on the Lachman test and instrumented stress radiography were also similar between the 2 groups at follow-up. However, 2 patients in the screw group and 1 in the suture group showed more than 5 mm laxity compared with the contralateral knee on stress radiographs. Conclusion: Both the screw and suture fixation techniques for the anterior cruciate ligament tibial avulsion fracture produced relatively good results in terms of functional outcomes and stability without any significant differences. However, some patients in both groups showed residual laxity or flexion contractures. C1 [Seon, Jong Keun; Park, Sang Jin; Lee, Keun Bae; Song, Eun Kyoo] Chonnam Natl Univ, Hwasun Hosp, Dept Orthopaed, Jeonnam, South Korea. [Gadikota, Hemanth R.; Kozanek, Michal; Oh, Luke S.; Hariri, Sanaz] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Gadikota, Hemanth R.; Kozanek, Michal; Oh, Luke S.; Hariri, Sanaz] Harvard Univ, Sch Med, Boston, MA USA. RP Song, EK (reprint author), 160 Ilsimri Hwasuneup Hwasungun, Jeonnam 519809, South Korea. EM eksong@chonnam.ac.kr OI Oh, Luke/0000-0002-6610-8204 NR 26 TC 21 Z9 22 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 EI 1552-3365 J9 AM J SPORT MED JI Am. J. Sports Med. PD DEC PY 2009 VL 37 IS 12 BP 2334 EP 2339 DI 10.1177/0363546509341031 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 524YO UT WOS:000272180500006 PM 19737989 ER PT J AU Gill, TJ Van de Velde, SK Wing, DW Oh, LS Hosseini, A Li, GA AF Gill, Thomas J. Van de Velde, Samuel K. Wing, David W. Oh, Luke S. Hosseini, Ali Li, Guoan TI Tibiofemoral and Patellofemoral Kinematics After Reconstruction of an Isolated Posterior Cruciate Ligament Injury In Vivo Analysis During Lunge SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Orthopaedic-Society-for-Sports-Medicine CY JUL 09-12, 2009 CL Keystone, CO SP Amer Orthopaed Soc Sports Med DE isolated posterior cruciate ligament (PCL) injury; posterior cruciate ligament (PCL) reconstruction; tibiofemoral kinematics; patellofemoral kinematics; patellar tracking; dual fluoroscopic imaging ID SIMULATED MUSCLE LOADS; TERM-FOLLOW-UP; DEFICIENT KNEE; SITU FORCES; 2 BUNDLES; JOINT; FLEXION; STABILITY; FEMUR; ROTATION AB Background: The actual in vivo tibiofemoral and patellofemoral kinematics of the posterior cruciate ligament (PCL)-reconstructed knee joint are unknown. Hypothesis: Current single-bundle PCL reconstruction is unable to correct the abnormal tibiofemoral and patellofemoral kinematics caused by rupture of the ligament. Study Design: Controlled laboratory study/case series; Level of evidence, 4. Methods: Seven patients with an isolated PCL injury in 1 knee and the contralateral side intact were included in the study. Magnetic resonance and dual fluoroscopic imaging techniques were used to compare the tibiofemoral and patellofemoral kinematics between the intact contralateral (control group), PCL-deficient, and PCL-reconstructed knee during physiologic loading with a single-legged lunge. Data were collected preoperatively and 2 years after single-bundle reconstruction. Results: The PCL reconstruction reduced the abnormal posterior tibial translation in PCL-deficient knees to levels not significantly different from those of the intact knee. Posterior cruciate ligament deficiency resulted in an increased lateral tibial translation between 75 degrees and 120 degrees of flexion, and reconstruction was unable to restore these values to normal. No differences were detected among the groups in varus-valgus and internal-external rotation. The PCL reconstruction reduced the increased patellar flexion of PCL-deficient knees between 90 degrees and 120 degrees of knee flexion and the lateral shift at 120. The abnormal patellar rotation and tilt seen in PCL deficiency at flexion angles of 75 degrees and greater persisted after reconstruction. Conclusion: Single-bundle PCL reconstruction was successful in restoring normal anteroposterior translation of the tibia, as well as the patellar flexion and shift. However, single-bundle PCL reconstruction was unable to achieve the same success in mediolateral translation of the tibia or in the patellar rotation and tilt. Clinical Relevance: The persistent abnormal mediolateral translation of the tibia, as well as decreased patellar rotation and tilt, provide a possible explanation for the development of cartilage degeneration after reconstruction of an isolated PCL injury. C1 [Gill, Thomas J.; Van de Velde, Samuel K.; Wing, David W.; Oh, Luke S.; Hosseini, Ali; Li, Guoan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. RP Li, GA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org OI Oh, Luke/0000-0002-6610-8204 FU NIAMS NIH HHS [R01 AR052408, R01 AR 052408] NR 45 TC 14 Z9 15 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 J9 AM J SPORT MED JI Am. J. Sports Med. PD DEC PY 2009 VL 37 IS 12 BP 2377 EP 2385 DI 10.1177/0363546509341829 PG 9 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 524YO UT WOS:000272180500012 PM 19726621 ER PT J AU Mandal, RV Murali, R Lundquist, KF Ragsdale, BD Heenan, P McCarthy, SW Mihm, MC Scolyer, RA Zembowicz, A AF Mandal, Rajni V. Murali, Rajmohan Lundquist, Kurt F. Ragsdale, Bruce D. Heenan, Peter McCarthy, Stanlely W. Mihm, Martin C., Jr. Scolyer, Richard A. Zembowicz, Artur TI Pigmented Epithelioid Melanocytoma: Favorable Outcome After 5-year Follow-up SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE pigmented epithelioid melanocytoma; nevus; melanoma; equine melanotic disease; epithelioid blue nevus; Carney complex; protein kinase A regulatory subunit 1 alpha; pathology; diagnosis ID LYMPH-NODE BIOPSY; ANIMAL-TYPE MELANOMA; BLUE NEVUS; MALIGNANT-MELANOMA; SPITZOID FEATURES; CARNEY COMPLEX; LESIONS; TUMORS AB Pigmented epithelioid melanocytoma (PEM) is a recently described entity encompassing epithelioid blue nevus (of Carney complex) and most tumors earlier considered as so-called "animal-type melanoma". Loss of expression of a Carney complex gene, cyclic adenosine 3',5' monophosphate-dependent protein kinase regulatory subunit 1 alpha, is observed in the majority of PEMs. Initial reports with short-term follow-up have suggested that although PEMs frequently metastasize to lymph nodes. they have a more favorable outcome than conventional Melanomas. In this report, we present the results of long-term Follow-up in 26 patients with PEMs from North America and Australia. There were 9 males and 17 females, with a median age of 20 years. The tumors involved the trunk (6 cases), extremities (12 cases), genitalia (1 case), and the head and neck region (7 cases) had a median Breslow thickness of 2.2 mm (range 0.80 to 10.0 mm) and a median Clark level of 4. Eight of the patients developed lymph node metastases. After a median follow-up period of 67 months (range 39 to 216mo), all patients are alive and free of disease. These findings provide further evidence that PEM is a unique low-grade melanocytic tumor with limited metastatic potential (to lymph nodes), but a favorable long-term clinical course. C1 [Zembowicz, Artur] Dermatopathol Consultat, Belmont, MA 02478 USA. [Mandal, Rajni V.; Mihm, Martin C., Jr.; Zembowicz, Artur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zembowicz, Artur] Lahey Clin Fdn, Dept Pathol, Burlington, MA USA. [Lundquist, Kurt F.; Ragsdale, Bruce D.] Cent Coast Pathol, San Luis Obispo, CA USA. [Murali, Rajmohan; McCarthy, Stanlely W.; Scolyer, Richard A.] Royal Prince Alfred Hosp, Dept Anat Pathol, Camperdown, NSW 2050, Australia. [Murali, Rajmohan; McCarthy, Stanlely W.; Scolyer, Richard A.] Univ Sydney, Discipline Pathol, Melanoma Inst, Australia Sydney Melanoma Unit, Sydney, NSW 2006, Australia. [Heenan, Peter] Cutaneous Pathol, Nedlands, WA, Australia. RP Zembowicz, A (reprint author), Dermatopathol Consultat, 36 Franklin St, Belmont, MA 02478 USA. EM dr.z@DermatopathologyConsultations.com RI MURALI, RAJMOHAN/A-7960-2008; OI MURALI, RAJMOHAN/0000-0001-6988-4295; Scolyer, Richard/0000-0002-8991-0013 NR 23 TC 40 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2009 VL 33 IS 12 BP 1778 EP 1782 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 527XG UT WOS:000272403900005 PM 19773637 ER PT J AU Griesemer, AD Hirakata, A Shimizu, A Moran, S Tena, A Iwaki, H Ishikawa, Y Schule, P Arn, JS Robson, SC Fishman, JA Sykes, M Sachs, DH Yamada, K AF Griesemer, A. D. Hirakata, A. Shimizu, A. Moran, S. Tena, A. Iwaki, H. Ishikawa, Y. Schule, P. Arn, J. S. Robson, S. C. Fishman, J. A. Sykes, M. Sachs, D. H. Yamada, K. TI Results of Gal-Knockout Porcine Thymokidney Xenografts SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Baboon; GalT-KO; life-supporting renal grafts; thymus; xenotransplantation ID PIG THYMUS GRAFTS; MINIATURE SWINE; ALPHA-1,3-GALACTOSYLTRANSFERASE GENE; NONHUMAN-PRIMATES; NUCLEAR TRANSFER; T-CELLS; TRANSPLANTATION; TOLERANCE; XENOTRANSPLANTATION; INDUCTION AB Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous a 1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys (composite thymus and kidneys) prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a preclinical xenotransplant model. Here, we report the results of seven xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole-body irradiation in all but one recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T-cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early primate thymopoiesis, which in turn may induce T-cell tolerance to solid organ xenografts. C1 [Griesemer, A. D.; Hirakata, A.; Shimizu, A.; Moran, S.; Tena, A.; Iwaki, H.; Ishikawa, Y.; Schule, P.; Arn, J. S.; Sykes, M.; Sachs, D. H.; Yamada, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. [Robson, S. C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Transplant Ctr, Boston, MA 02215 USA. [Fishman, J. A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02215 USA. RP Yamada, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. EM kaz.yamada@tbrc.mgh.harvard.edu FU Institutes of Health [PO1 AI045897-07, U01 AI066331]; AST/JDRF Fellowship FX Institutes of Health (PO1 AI045897-07 and U01 AI066331) and Adam Griesemer received support from the AST/JDRF Fellowship. NR 35 TC 49 Z9 51 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 IS 12 BP 2669 EP 2678 DI 10.1111/j.1600-6143.2009.02849.x PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA 524EW UT WOS:000272127600007 PM 19845583 ER PT J AU Kim, JI Lee, MK Moore, DJ Sonawane, SB Duff, PE O'Connor, MR Yeh, H Lian, MM Deng, S Caton, AJ Markmann, JF AF Kim, J. I. Lee, M. K. Moore, D. J. Sonawane, S. B. Duff, P. E. O'Connor, M. R. Yeh, H. Lian, M. M. Deng, S. Caton, A. J. Markmann, J. F. TI Regulatory T-Cell Counter-Regulation by Innate Immunity Is a Barrier to Transplantation Tolerance SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Allograft; inflammation; T-reg; transplant; tolerance ID SELF-PEPTIDE; MEDIATED SUPPRESSION; THYMIC SELECTION; DENDRITIC CELLS; TRANSGENIC MICE; RECEPTOR; ENGAGEMENT; ALLOGRAFTS; REJECTION; RESPONSES AB Innate immune signals foster adaptive immunity through activation of antigen-presenting cells. Recent in vitro evidence suggests that innate signaling may also contribute to immunity by countering the effects of regulatory T cells (T-regs), counter-regulation. We present in vivo evidence using a transgenic skin allograft model that the function of T-regs is lost in the setting of acute skin transplantation but remains intact when grafts were transplanted 1 month prior to allow surgery-induced inflammation to abate. Our findings identify T-reg counter-regulation as a naturally occurring process that accompanies transplantation and an important barrier to T-reg-mediated tolerance. Our finding further highlights the central role of regulatory cell deactivation in the initiation of the immune response. C1 [Kim, J. I.; Duff, P. E.; O'Connor, M. R.; Yeh, H.; Lian, M. M.; Deng, S.; Markmann, J. F.] Massachusetts Gen Hosp, Div Surg, Dept Transplantat, Boston, MA 02114 USA. [Lee, M. K.; Sonawane, S. B.] Hosp Univ Penn, Dept Surg, Harrison Dept Surg Res, Philadelphia, PA 19104 USA. [Moore, D. J.] Vanderbilt Childrens Hosp, Dept Pediat, Div Endocrinol & Diabet, Nashville, TN USA. [Caton, A. J.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, Div Surg, Dept Transplantat, Boston, MA 02114 USA. EM jmarkmann@partners.org RI Moore, Daniel/A-4924-2008 OI Moore, Daniel/0000-0002-6889-9345 FU [NIH R01 AI-048820]; [K01 DK079207-02] FX This work is supported by grants NIH R01 AI-048820 and K01 DK079207-02. NR 24 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 IS 12 BP 2736 EP 2744 DI 10.1111/j.1600-6143.2009.02847.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 524EW UT WOS:000272127600013 PM 19845585 ER PT J AU Fishman, JA AF Fishman, J. A. CA AST Infect Dis Community Practice TI Introduction: Infection in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material DE Donor-derived infection; fungus; immunosuppression; opportunistic infection; prophylaxis; timeline; transplant infectious disease; virus ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSMISSION; DONOR C1 [Fishman, J. A.] Massachusetts Gen Hosp, Transplant Infect Dis Program, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, MGH Transplantat Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Transplant Infect Dis Program, Div Infect Dis, Boston, MA 02114 USA. EM jfishman@partners.org NR 12 TC 35 Z9 36 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S3 EP S6 DI 10.1111/j.1600-6143.2009.02887.x PG 4 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500002 PM 20070692 ER PT J AU Grossi, PA Fishman, JA AF Grossi, P. A. Fishman, J. A. CA AST Infect Dis Community Practice TI Donor-Derived Infections in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Donor safety; donor testing; Infection; high-risk donor; transplantation; window period ID HEPATITIS-C VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSMITTED VIRAL-INFECTIONS; WEST-NILE-VIRUS; LIVER-TRANSPLANTATION; TISSUE DONORS; BLOOD-DONORS; KIDNEY-TRANSPLANTATION; HIV-INFECTION; ANTI-HBC C1 [Grossi, P. A.] Univ Insubria, Infect & Trop Dis Dept, Varese, Italy. [Grossi, P. A.] Natl Ctr Transplantat, Rome, Italy. [Fishman, J. A.] Massachusetts Gen Hosp, Transplant Infect Dis Program, Div Infect Dis, Boston, MA 02114 USA. [Fishman, J. A.] Massachusetts Gen Hosp, MGH Transplantat Ctr, Boston, MA 02114 USA. [Fishman, J. A.] Harvard Univ, Sch Med, Boston, MA USA. RP Grossi, PA (reprint author), Univ Insubria, Infect & Trop Dis Dept, Varese, Italy. EM paolo.grossi@uninsubria.it RI GROSSI, PAOLO/A-6158-2013 FU Italian Ministry of Health [28C5/3] FX This work was partially supported by the Italian Ministry of Health, project number 28C5/3-Controllo delle infezioni nei soggetti immunocompromessi: Infezioni virali. NR 69 TC 37 Z9 39 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S19 EP S26 DI 10.1111/j.1600-6143.2009.02889.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500004 PM 20070680 ER PT J AU Kotton, CN Lattes, R AF Kotton, C. N. Lattes, R. CA AST Infect Dis Community Practice TI Parasitic Infections in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review DE Eosinophilia; malaria; parasite; Strongyloides; transplant ID ORTHOTOPIC LIVER-TRANSPLANTATION; LIPOSOMAL AMPHOTERICIN-B; STRONGYLOIDES HYPERINFECTION SYNDROME; INCURABLE ALVEOLAR ECHINOCOCCOSIS; NONFATAL VISCERAL LEISHMANIASIS; CHAGAS-DISEASE REACTIVATION; OF-THE-LITERATURE; KIDNEY-TRANSPLANT; HEART-TRANSPLANTATION; RENAL-TRANSPLANTATION C1 [Kotton, C. N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Transplant Infect Dis & Compromise, Boston, MA 02115 USA. [Lattes, R.] Inst Nefrol, Dept Transplantat, Buenos Aires, DF, Argentina. RP Kotton, CN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Transplant Infect Dis & Compromise, Boston, MA 02115 USA. EM ckotton@partners.org NR 136 TC 28 Z9 29 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S234 EP S251 DI 10.1111/j.1600-6143.2009.02915.x PG 18 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500030 PM 20070685 ER PT J AU Kotton, CN Hibberd, PL AF Kotton, C. N. Hibberd, P. L. CA AST Infect Dis Community Practice TI Travel Medicine and the Solid Organ Transplant Recipient SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Solid organ transplant; travel medicine; vaccinations; vaccines ID ORTHOTOPIC LIVER-TRANSPLANTATION; HEPATITIS-A VACCINATION; YELLOW-FEVER VACCINE; CURRENT RECOMMENDATIONS; B-VACCINE; IMMUNOGENICITY; IMMUNIZATION; SAFETY; PREVENTION; MORBIDITY C1 [Kotton, C. N.] Massachusetts Gen Hosp, Infect Dis Unit, Transplant Infect Dis & Compromised Host Program, Boston, MA 02114 USA. [Kotton, C. N.] Massachusetts Gen Hosp, Infect Dis Unit, Travelers Advice & Immunizat Ctr, Boston, MA 02114 USA. [Kotton, C. N.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hibberd, P. L.] Tufts Univ, Sch Med, Ctr Global Hlth Res, Boston, MA 02111 USA. [Hibberd, P. L.] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA USA. [Hibberd, P. L.] Dept Med, Boston, MA USA. [Hibberd, P. L.] Dept Pediat, Boston, MA USA. [Hibberd, P. L.] Dept Publ Hlth, Boston, MA USA. [Hibberd, P. L.] Dept Family Med, Boston, MA USA. RP Kotton, CN (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, Transplant Infect Dis & Compromised Host Program, Boston, MA 02114 USA. EM ckotton@partners.org FU NCCIH NIH HHS [K24 AT003683] NR 48 TC 19 Z9 19 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S273 EP S281 DI 10.1111/j.1600-6143.2009.02920.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500035 PM 20070691 ER PT J AU Martin, SI Fishman, JA AF Martin, S. I. Fishman, J. A. CA AST Infect Dis Community Practice TI Pneumocystis Pneumonia in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Pneumocystis; pneumonia; prophylaxis ID HUMAN-IMMUNODEFICIENCY-VIRUS; BONE-MARROW-TRANSPLANTATION; CARINII-PNEUMONIA; HIV-INFECTION; IMMUNOCOMPROMISED PATIENTS; MOLECULAR EVIDENCE; PROPHYLAXIS; PREVENTION; TRANSMISSION; DIAGNOSIS C1 [Martin, S. I.] Ohio State Univ, Med Ctr, Div Infect Dis, Columbus, OH 43210 USA. [Martin, S. I.] Ohio State Univ, Med Ctr, Comprehens Transplant Ctr, Columbus, OH 43210 USA. [Fishman, J. A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Fishman, J. A.] Massachusetts Gen Hosp, Transplantat Ctr, Boston, MA 02114 USA. RP Martin, SI (reprint author), Ohio State Univ, Med Ctr, Div Infect Dis, Columbus, OH 43210 USA. EM stanley.martin@osumc.edu RI Martin, Stanley/E-3600-2011 NR 52 TC 60 Z9 62 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S227 EP S233 DI 10.1111/j.1600-6143.2009.02914.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500029 PM 20070684 ER PT J AU Singh, N Husain, S AF Singh, N. Husain, S. CA AST Infect Dis Community Practice TI Invasive Aspergillosis in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review DE Aspergillosis; prophylaxis; solid organ transplant; treatment ID COLONY-STIMULATING FACTOR; LIPOSOMAL AMPHOTERICIN-B; CHRONIC GRANULOMATOUS-DISEASE; HEMATOPOIETIC STEM-CELL; BRONCHOALVEOLAR LAVAGE FLUID; SYSTEMIC FUNGAL-INFECTIONS; LUNG TRANSPLANTATION; RISK-FACTORS; INTERFERON-GAMMA; ANTIFUNGAL PROPHYLAXIS C1 [Singh, N.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Singh, N.] Univ Pittsburgh, Pittsburgh, PA USA. [Husain, S.] Univ Toronto, Univ Hlth Network, Div Infect Dis & Multiorgan Transplantat, Toronto, ON, Canada. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM nis5+@pitt.edu FU Pfizer; Schering Plough; Merck Frost; Astellas FX Singh N.: Grant Support, Pfizer. Husain S.: Grant Support, Pfizer, Schering Plough, Merck Frost, Astellas. NR 123 TC 67 Z9 68 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S180 EP S191 DI 10.1111/j.1600-6143.2009.02910.x PG 12 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500025 PM 20070679 ER PT J AU Singh, N Forrest, G AF Singh, N. Forrest, G. CA AST Infect Dis Community Practice TI Cryptococcosis in Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Cryptococcus; immune reconstitution syndrome; organ transplantation ID IMMUNE RECONSTITUTION SYNDROME; CALCINEURIN-INHIBITOR AGENTS; INVASIVE FUNGAL-INFECTIONS; PULMONARY CRYPTOCOCCOSIS; NEOFORMANS INFECTION; AMPHOTERICIN-B; IN-VITRO; LIVER-TRANSPLANTATION; INFLAMMATORY SYNDROME; PRACTICE GUIDELINES C1 [Singh, N.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Singh, N.] Univ Pittsburgh, Pittsburgh, PA USA. [Forrest, G.] Portland VA Med Ctr, Portland, OR USA. [Forrest, G.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM nis5+@pitt.edu NR 74 TC 32 Z9 32 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2009 VL 9 BP S192 EP S198 DI 10.1111/j.1600-6143.2009.02911.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 533ZG UT WOS:000272864500026 PM 20070681 ER PT J AU Travi, BL Osorio, EY Saldarriaga, OA Cadena, H Tabares, CJ Peniche, A Lee, S Melby, PC AF Travi, Bruno L. Osorio, Elvia Yaneth Saldarriaga, Omar A. Cadena, Horacio Javier Tabares, Carlos Peniche, Alex Lee, Shuko Melby, Peter C. TI Clinical, Parasitologic, and Immunologic Evolution in Dogs Experimentally Infected with Sand Fly-Derived Leishmania chagasi Promastigotes SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID CANINE VISCERAL LEISHMANIASIS; CELLULAR IMMUNE-RESPONSE; IGG2 ANTIBODY-RESPONSES; INFANTUM PROMASTIGOTES; MEDIATED-IMMUNITY; ASYMPTOMATIC DOGS; BRAZILIAN DOGS; KALA-AZAR; FOLLOW-UP; INFECTIVITY AB Experimental infection of dogs with Leishmania infantum has yielded heterogeneous clinical, parasitologic, and immunologic results. We studied dogs infected with 10(5) or 10(4) sand fly-derived promastigotes delivered by the intradermal (ID) or intravenous (IV) routes. Total mortality over 1 year post-infection reached 23.8%. The mortality and proportion of sustained polysymptomatic dogs was highest in the IV-10(5) group. The early appearance of polysymptoms was associated with ail increased risk of progression to death. Dissemination of the parasite to lymph nodes was faster, and the subsequent infectivity to sand flies higher, in the IV compared with ID-infected dogs. Parasite-specific IgG1 or IgG2 production was similar among the groups, but higher interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) expression was associated with polysymptomatic dogs. On the basis of the data obtained from this study, a sample size analysis using different endpoints for future vaccine trials is described. C1 [Travi, Bruno L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Cadena, Horacio] Univ Antioquia, SIU, Lab 632, Medellin, Colombia. [Javier Tabares, Carlos] Univ Antioquia, Fac Ciencias Agr, Medellin, Colombia. [Lee, Shuko] S Texas Vet Hlth Care Syst, Res Serv 151, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Dept Vet Affairs Med Ctr, Res Serv, San Antonio, TX 78229 USA. Ctr Int Entrenamiento & Invest Med CIDEIM, Cali 5390, Colombia. RP Travi, BL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM travi@uthscsa.edu FU NIH [AI48823]; [2229-04-11723] FX This work was supported by NIH grant AI48823 awarded to P.C. Melby and Colciencias grant 2229-04-11723 awarded to B. L. Travi. NR 50 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2009 VL 81 IS 6 BP 994 EP 1003 DI 10.4269/ajtmh.2009.09-0229 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 531YN UT WOS:000272709600011 PM 19996427 ER PT J AU Citron, DM Babakhani, F Goldstein, EJC Nagaro, K Sambol, S Sears, P Shue, YK Gerding, DN AF Citron, D. M. Babakhani, F. Goldstein, E. J. C. Nagaro, K. Sambol, S. Sears, P. Shue, Y. -K. Gerding, D. N. TI Typing and susceptibility of bacterial isolates from the fidaxomicin (OPT-80) phase II study for C. difficile infection SO ANAEROBE LA English DT Article; Proceedings Paper CT 9th Biennial Congress of the Anaerobe-Society-of-the-Americas CY JUN 24-27, 2008 CL Long Beach, CA SP Anaerobe Soc Amer DE Clostridium; Difficile; OPT-80; Fidaxomicin; PAR-101; CDI ID IN-VITRO ACTIVITIES; CLOSTRIDIUM-DIFFICILE; METRONIDAZOLE; EPIDEMIC; DIARRHEA; DISEASE; AGENTS; STRAIN AB Background: Clostridium difficile infection (CDI) has been increasing in incidence and severity in recent years, coincident with the spread of a "hypervirulent" strain, REA type BI (ribotype 027, PFGE NAP 1). Exacerbating the problem has been the observation that metronidazole may be showing decreased effectiveness, particularly in the more severe cases. Fidaxomicin is an 18-membered macrocycle currently in phase 3 trials for the treatment of C. difficile infection (CDI). An open-label, phase II study in CDI patients has been completed and the clinical results published. C. difficile organisms were isolated from patient stool specimens and typed by restriction endonuclease analysis (REA) in order to determine the frequency and susceptibility of the C. difficile isolates and their response to treatment. Methods: Fecal samples were plated on CCFA agar for isolation of C. difficile. These isolates were tested for susceptibility to fidaxomicin, vancomycin, and metronidazole using CLSI agar dilution methods and were typed by REA. Results: C. difficile was isolated from 38 of 49 subjects and 16 (42%) were the epidemic C. difficile BI group. The BI strain was distributed approximately equally in the three dosing groups. Overall antibiotic susceptibilities were consistent with the previously reported MIC(90) values for the three antibiotics tested, but the MIC(90) of BI strains was two dilutions higher than non-BI strains for metronidazole and vancomycin (for both antibiotics, MIC(90) was 2 mu g/mL vs. 0.5 mu g/ml, P < 0.01 for metronidazole, P = NS for vancomycin). Clinical cure for BI isolates (11/14, 79%) was not significantly different from non-BI isolates (21/22, 95%). Conclusion: These results underscore the high prevalence of the BI epidemic strain and demonstrate that mild to moderate CDI infection as well as severe disease can be caused by these strains. Fidaxomicin cure rates for subjects with BI and with non-BI strains are similar, although the small numbers of subjects preclude a robust statistical comparison. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Babakhani, F.; Sears, P.; Shue, Y. -K.] Optimer Pharmaceut Inc, San Diego, CA 92121 USA. [Citron, D. M.; Goldstein, E. J. C.] RM Alden Res Lab, Culver City, CA USA. [Nagaro, K.; Sambol, S.; Gerding, D. N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Gerding, D. N.] Loyola Univ, Chicago Stritch Sch Med, Maywood, IL 60153 USA. RP Sears, P (reprint author), Optimer Pharmaceut Inc, 10110 Sorrento Valley Rd Ste, San Diego, CA 92121 USA. EM psears@optimerpharma.com FU NIAID NIH HHS [2 R44 AI063692-02A1] NR 21 TC 31 Z9 32 U1 1 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD DEC PY 2009 VL 15 IS 6 SI SI BP 234 EP 236 DI 10.1016/j.anaerobe.2009.09.005 PG 3 WC Microbiology SC Microbiology GA 547XH UT WOS:000273922700004 PM 19755166 ER PT J AU Weiss, A Abramowski, D Bibel, M Bodner, R Chopra, V DiFiglia, M Fox, J Kegel, K Klein, C Grueninger, S Hersch, S Housman, D Regulier, E Rosas, HD Stefani, M Zeitlin, S Bilbe, G Paganetti, P AF Weiss, Andreas Abramowski, Dorothee Bibel, Miriam Bodner, Ruth Chopra, Vanita DiFiglia, Marian Fox, Jonathan Kegel, Kimberly Klein, Corinna Grueninger, Stephan Hersch, Steven Housman, David Regulier, Etienne Rosas, H. Diana Stefani, Muriel Zeitlin, Scott Bilbe, Graeme Paganetti, Paolo TI Single-step detection of mutant huntingtin in animal and human tissues: A bioassay for Huntington's disease SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Time-resolved FRET assay; Intracellular protein quantification; Disease progression; Huntington's disease ID KNOCK-IN MOUSE; INCLUSION-BODY FORMATION; TRANSGENIC MICE; MODEL MOUSE; CAG REPEAT; NEUROPATHOLOGY; REVEALS; NEURONS; GENE; HD AB The genetic mutation causing Huntington's disease is a polyglutamine expansion in the huntingtin protein where more than 37 glutamines cause disease by formation of toxic intracellular fragments, aggregates, and cell death. Despite a clear pathogenic role for mutant huntingtin, understanding huntingtin expression during the presymptomatic phase of the disease or during disease progression has remained obscure. Central to clarifying the role in the pathomechanism of disease is the ability to easily and accurately measure mutant huntingtin in accessible human tissue samples as well as cell and animal models. Here we describe a highly sensitive time-resolved Forster resonance energy transfer (FRET) assay for quantification of soluble mutant huntingtin in brain, plasma, and cerebrospinal fluid. Surprisingly, in mice, soluble huntingtin levels decrease during disease progression, inversely correlating with brain aggregate load. Mutant huntingtin is easily detected in human brain and blood-derived fractions, providing a utility to assess mutant huntingtin expression during disease course as well as a pharmacodynamic marker for disease-modifying therapeutics targeting expression, cleavage, or degradation of mutant huntingtin. The design of the homogeneous one-step method for huntingtin detection is such that it can be easily applied to measure other proteins of interest. (C) 2009 Elsevier Inc. All rights reserved. C1 [Weiss, Andreas; Abramowski, Dorothee; Bibel, Miriam; Klein, Corinna; Grueninger, Stephan; Regulier, Etienne; Stefani, Muriel; Bilbe, Graeme; Paganetti, Paolo] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. [Bodner, Ruth; Housman, David] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Chopra, Vanita; DiFiglia, Marian; Fox, Jonathan; Kegel, Kimberly; Hersch, Steven; Rosas, H. Diana] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Zeitlin, Scott] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. RP Paganetti, P (reprint author), Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. EM paolo.paganetti@novartis.com FU National Institutes of Health (NIH) [P01 NS058793]; Huntington's Disease Society of America (HDSA); Hereditary Disease Foundation (HDF); Novartis Institutes for BioMedical Research FX We thank Alex Bender for collecting and processing the human blood samples. We thank Grazia Ceschi for her support with the statistical analysis. The collection and processing of human brain and blood samples was supported by National Institutes of Health (NIH) grant P01 NS058793 to S. H. Establishment of embryonic stem cells was partly funded by support from the Huntington's Disease Society of America (HDSA) coalition for the cure to M. D., and by a Hereditary Disease Foundation (HDF) grant to K. K. J. F., V. C., K. K., M. D., R. B., D. H., and S. H. were supported by a grant from the Novartis Institutes for BioMedical Research. NR 41 TC 55 Z9 55 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 1 PY 2009 VL 395 IS 1 BP 8 EP 15 DI 10.1016/j.ab.2009.08.001 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 534GK UT WOS:000272884200002 PM 19664996 ER PT J AU Ko, JY Leffert, LR AF Ko, James Y. Leffert, Lisa R. TI Clinical Implications of Neuraxial Anesthesia in the Parturient with Scoliosis SO ANESTHESIA AND ANALGESIA LA English DT Review ID ADOLESCENT IDIOPATHIC SCOLIOSIS; OBSTETRIC EPIDURAL-ANESTHESIA; POSTERIOR SPINAL-FUSION; HARRINGTON RODS; LABOR ANALGESIA; CESAREAN DELIVERY; SURGERY; PATIENT; BLOCK; INSTRUMENTATION AB Scoliosis can pose challenges to the initiation and function of neuraxial anesthetics. We reviewed the available literature exploring neuraxial techniques in parturients with uncorrected or corrected (i.e., surgically instrumented) scoliosis. The 22 articles reported 117 attempted neuraxial procedures (uncorrected n = 24 and corrected n = 93). Of these procedures, 79% of uncorrected patients and 69% of corrected patients were successfully managed with neuraxial anesthesia. Procedures were typically more challenging in corrected patients; 90% of all reported difficulties in this subgroup involved epidural anesthetics. Complications were reported in 3 of 103 patients. We provide suggestions for optimizing efficacy of neuraxial techniques in these patients. (Anesth Analg 2009;109:1930-4) C1 [Ko, James Y.; Leffert, Lisa R.] Massachusetts Gen Hosp, Div Obstet Anesthesia, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Leffert, LR (reprint author), Massachusetts Gen Hosp, Div Obstet Anesthesia, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM lleffert@partners.org FU departmental funds FX Supported by departmental funds. NR 47 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2009 VL 109 IS 6 BP 1930 EP 1934 DI 10.1213/ANE.0b013e3181bc3584 PG 5 WC Anesthesiology SC Anesthesiology GA 522LT UT WOS:000272000100033 PM 19923523 ER PT J AU Mullins, RJ Clark, S Camargo, CA AF Mullins, Raymond James Clark, Sunday Camargo, Carlos A., Jr. TI Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID UNITED-STATES; FOOD ALLERGY; D DEFICIENCY; ULTRAVIOLET-RADIATION; INFECTIOUS-DISEASES; MULTIPLE-SCLEROSIS; SOUTHERN TASMANIA; D INSUFFICIENCY; SKIN-CANCER; EPIDEMIOLOGY AB Background: There is little information on the regional distribution of anaphylaxis in Australia. Objective: To examine the influence of latitude (a marker of sunlight/vitamin D status) as a contributor to anaphylaxis in Australia, with a focus on children from birth to the age of 4 years. Methods: Epinephrine autoinjector (EpiPen) prescriptions (2006-2007) in 59 statistical divisions and anaphylaxis hospital admission rates (2002-2007) in 10 regions were used as surrogate markers of anaphylaxis. Results: EpiPen prescription rates (per 100,000 population per year) were higher in children from birth to the age of 4 years (mean, 951) than in the overall population (mean, 324). In an unadjusted model of children from birth to the age of 4 years, decreasing, absolute latitude was associated with a decrease in EpiPen prescription rates, such that rates were higher in southern compared with northern regions of Australia (beta, -44.4; 95% confidence interval. -57.0 to -31.8, P < .001). Adjusting forage. sex, ethnicity, indexes of affluence, education, or access to medical care (general, specialist allergy, or pediatric) did not attenuate the finding (beta, -51.9; 95% confidence interval. -71.0 to -32.9; P < .001). Although statistical power was limited, anaphylaxis admission rates (most prominent in children aged 0-4 years) showed a similar south-north gradient. such that admission rates were hi-her in Southern compared with northern regions of Australia Conclusions: EptPen prescription rates kind anaphylaxis admissions are more common in southern regions of Australia. These data provide additional support for a possible role of vitamin D in the pathogenesis of anaphylaxis. Ann Allergy Asthma Immunol. 2009:103 488-495 C1 [Mullins, Raymond James] John James Med Ctr, Deakin, ACT 2600, Australia. [Mullins, Raymond James] Australian Natl Univ, Sch Med, Canberra, ACT 0200, Australia. [Mullins, Raymond James] Univ Canberra, Fac Hlth, Canberra, ACT 2601, Australia. [Clark, Sunday] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Div Rheumatol Allergy & Im, Boston, MA USA. RP Mullins, RJ (reprint author), John James Med Ctr, 175 Strickland Crescent,Ste 1, Deakin, ACT 2600, Australia. RI Osborne, Nicholas/N-4915-2015 OI Mullins, Raymond/0000-0002-0267-1591; Osborne, Nicholas/0000-0002-6700-2284 FU Massachusetts General Hospital Center for D-Receptor Activation Research, Boston; CSL Australia (Melbourne); Alphapharm Australia (Sydney); Dey (Napa, USA) FX This study was supported by the Massachusetts General Hospital Center for D-Receptor Activation Research, Boston. Massachusetts (Dr Camargo) Selected data were purchased with funds provided by CSL Australia and Alphapharm Australia Dr Mullins received investigator-initiated funding from CSL Australia (Melbourne) and Alphapharm Australia (Sydney) for data purchase the past and current distributors of EpiPen in Australia. respectively. Dr Clark has received consulting funds from Dey (Napa, USA) Dr Camargo has received investigator-initiated research grants from and consulted for, Dey (Napa, USA). NR 53 TC 63 Z9 63 U1 0 U2 4 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD DEC PY 2009 VL 103 IS 6 BP 488 EP 495 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 534RG UT WOS:000272914400007 PM 20084842 ER PT J AU Bluestein, HM Hoover, TA Banerji, AS Camargo, CA Reshef, A Herscu, P AF Bluestein, Hazel M. Hoover, Todd A. Banerji, Aleena Suryadevara Camargo, Carlos A., Jr. Reshef, Avner Herscu, Paul TI Angiotensin-converting enzyme inhibitor-induced angioedema in a community hospital emergency department SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID CONGESTIVE-HEART-FAILURE; MYOCARDIAL-INFARCTION; ACE-INHIBITORS; ENALAPRIL; MORTALITY; SURVIVAL; MORBIDITY AB Background: Angiotensin-converting enzyme inhibitors (ACE-Is) are associated with angioedema, a potentially life-threatening adverse reaction. Although multiple studies have been conducted in tertiary care emergency departments (EDS), scarce data are available about the presentation and management of ACE-I-induced angioedema (AIIA) in the community hospital ED. Objective: To describe the frequency, presentation, and management of AIIA in patients seen in a community hospital ED. Methods: A 5-year medical record review of all patients seen with angioedema at a community hospital ED. Data abstraction focused on demographic factors, initial clinical characteristics, and ED management and disposition of patients with AIIA. Results: We identified 166 ED visits for angioedema, including a subset of 50 visits for AIIA (30%, 95% confidence interval, 23%-38%). The AIIA was significantly more likely to be associated with an age of 65 years or older (P = .02.). unilateral symptoms (P = .02), and absence of urticaria or itching (P < .001). The ED treatment choices and admission rates were similar between patients with and without AIIA Community hospital admission rates for AIIA (14%) were significantly lower than those from a comparable tertiary care Study (41%) (P = .003) ambulance transport to the ED was nearly 3-fold higher in the tertiary care center study (P = .006). Admission was most strongly related to lack of improvement (P < .001) and history of angioedema in AIIA (P = .009). Conclusions: Angioedema frequency, presentation, and management are similar in community and tertiary care EDs (30%). Urticaria or itching may help differentiate AIIA from allergic reactions, which are otherwise similar in community ED presentation and management. Ann Allergy Asthma Immunol. 2009;103 502-507. C1 [Hoover, Todd A.; Herscu, Paul] Herscu Lab, Div Res, Amherst, MA 01002 USA. [Bluestein, Hazel M.] Montgomery Hosp, Med Ctr, Montgomery Family Practice Residency Program, Norristown, PA USA. [Banerji, Aleena Suryadevara; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Reshef, Avner] Chaim Sheba Med Ctr, Allergy & Immunol Unit, IL-52621 Tel Hashomer, Israel. [Reshef, Avner] Chaim Sheba Med Ctr, Angioedema Ctr, IL-52621 Tel Hashomer, Israel. RP Hoover, TA (reprint author), Herscu Lab, Div Res, 356 Middle St, Amherst, MA 01002 USA. EM hoover@personalizedps.com NR 25 TC 21 Z9 21 U1 1 U2 1 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD DEC PY 2009 VL 103 IS 6 BP 502 EP 507 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 534RG UT WOS:000272914400009 PM 20084844 ER PT J AU Sun, BC Derose, SF Liang, LJ Gabayan, GZ Moore, AA Mower, WR Mangione, CM Hoffman, JR AF Sun, Benjamin C. Derose, Stephen F. Liang, Li-Jung Gabayan, Gelareh Z. Moore, Alison A. Mower, William R. Mangione, Carol M. Hoffman, Jerome R. TI Predictors of 30-Day Serious Events in Older Patients With Syncope SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT; UNEXPLAINED SYNCOPE; RISK STRATIFICATION; SHORT-TERM; PROSPECTIVE VALIDATION; CLINICAL PREDICTORS; DIAGNOSING SYNCOPE; RULE; MANAGEMENT; POPULATION AB Study objective: We identify predictors of 30-day serious events after syncope in older adults. Methods: We reviewed the medical records of older adults (age >= 60 years) who presented with syncope or near syncope to one of 3 emergency departments (EDs) between 2002 and 2005. Our primary outcome was occurrence of a predefined serious event within 30 days after ED evaluation. We used multivariable logistic regression to identify predictors of 30-day serious events. Results: Of 3,727 potentially eligible patients, 2,871 (77%) met all eligibility criteria. We excluded an additional 287 patients who received a diagnosis of a serious clinical condition while in the ED. In the final study cohort (n=2,584), we identified 173 (7%) patients who experienced a 30-day serious event. High-risk predictors included age greater than 90 years, male sex, history of an arrhythmia, triage systolic blood pressure greater than 160 mm Hg, abnormal ECG result, and abnormal troponin I level. A low-risk predictor was a complaint of near syncope rather than syncope. A risk score, generated by summing high-risk predictors and subtracting the low-risk predictor, can stratify patients into low- (event rate 2.5%; 95% confidence interval [CI] 1.4% to 3.6%), intermediate- (event rate 6.3%; 95% CI 5.1% to 7.5%), and high-risk (event rate 20%; 95% CI 15% to 25%) groups. Conclusion: We identified predictors of 30-day serious events after syncope in adults aged 60 years and greater. A simple score was able to stratify these patients into distinct risk groups and, if externally validated, might have the potential to aid ED decisionmaking. [Ann Emerg Med. 2009;54:769-778.] C1 [Sun, Benjamin C.; Liang, Li-Jung; Gabayan, Gelareh Z.; Moore, Alison A.; Mangione, Carol M.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Sun, Benjamin C.; Gabayan, Gelareh Z.] W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. [Derose, Stephen F.] Kaiser Permanente So Calif, Div Res & Evaluat, Pasadena, CA USA. [Mower, William R.; Hoffman, Jerome R.] Univ Calif Los Angeles, Ctr Emergency Med, Los Angeles, CA 90024 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Sun, BC (reprint author), W Los Angeles Vet Affairs Med Ctr, Dept Med, Off 3214A,Mail Stop 111,Bldg 500,Wing 3E,11301 Wi, Los Angeles, CA 90073 USA. EM bsun@mednet.ucla.edu FU UCLA National Institute of Aging K12 [K12AG001004]; American Geriatrics Society Dennis Jahnigen Career Development [20051687]; Resource Centers for Minority Aging Research/Center for Health Improvement of Minority Elderly (RCMAR/CHIME); National Institutes of Health/National Institute on Aging [P30 AG021684]; UCLA/Drew Project EXPORT; National Institutes of Health/National Center for Minority Health and Health Disparities [P20 MD000182]; UCLA Older Americans Independence Center; NIH/NIA [P30-AG028748]; National Institute on Aging or the National Institutes of Health FX Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Dr. Sun is supported by a UCLA National Institute of Aging K12 award (K12AG001004) and an American Geriatrics Society Dennis Jahnigen Career Development Award (20051687). Drs. Mangione and Moore received support from the Resource Centers for Minority Aging Research/Center for Health Improvement of Minority Elderly (RCMAR/CHIME), funded by the National Institutes of Health/National Institute on Aging (P30 AG021684), and from the UCLA/Drew Project EXPORT, funded by the National Institutes of Health/National Center for Minority Health and Health Disparities (P20 MD000182). Dr. Sun received support from the UCLA Older Americans Independence Center, NIH/NIA Grant P30-AG028748, and the content does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. NR 39 TC 30 Z9 32 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2009 VL 54 IS 6 BP 769 EP 778 DI 10.1016/j.annemergmed.2009.07.027 PG 10 WC Emergency Medicine SC Emergency Medicine GA 532FA UT WOS:000272729600004 PM 19766355 ER PT J AU Tucker-Seeley, RD Li, Y Subramanian, SV Sorensen, G AF Tucker-Seeley, Reginald D. Li, Yi Subramanian, S. V. Sorensen, Glorian TI Financial Hardship and Mortality among Older Adults Using the 1996-2004 Health and Retirement Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Mortality; Elderly; Socioeconomic ID SOCIOECONOMIC-STATUS; LIFE-COURSE; ECONOMIC HARDSHIP; SOCIAL SUPPORT; UNITED-STATES; STRESS; ASSOCIATION; INEQUALITY; EVENTS; STRAIN AB PURPOSE: We investigated the effect of financial hardship on mortality risk in a community-dwelling sample of adults 50 years of age and olderin the United States. METHOD: The 1996 Health and Retirement Study cohorts were followed prospectively to 2004 (N = 8,377). Gender-stratified grouped Cox models were used to estimate the difference in the relative risk (RR) of mortality between a specific number of financial hardships (one, two, or three or more) and no hardships; and the predictive utility of each individual financial hardship for mortality during the follow-up period. RESULTS: Gender-stratified models adjusted for demographics, socioeconomic characteristics, and functional limitations in 1996 showed that women reporting one (hazard ratio [HR] = 1.42; 95% confidence interval [CI]: 1.05-1.92) or three or more (HR = 1.60; 95% CI: 1.05-2.46) and men reporting two (HR = 1.80; 95% CI: 1.21-2.69) financial hardships had a substantially higher probability of mortality compared to those reporting no financial hardships. Individual financial hardships that predicted mortality in fully adjusted models for women included receiving Medicaid (HR = 2.23; 95% CI: 1.68-2.98) and for men receiving Medicaid (HR = 2.11; 95% CI: 1.57-2.84) and receiving food stamps (HR = 1.59; 95% CI: 1.09-2.33). CONCLUSIONS: These findings suggest that over and above the influence of traditional measures of socioeconomic status, financial hardship exerts an influence on the risk of mortality among older adults and that the number and type of hardships important in predicting mortality may differ for men and women. Ann Epidemic! 2009;19:850-857. (C) 2009 Elsevier Inc. All rights reserved. C1 [Tucker-Seeley, Reginald D.; Subramanian, S. V.; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Cambridge, MA 02138 USA. [Li, Yi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tucker-Seeley, Reginald D.; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Tucker-Seeley, RD (reprint author), 44 Binney St,LW747, Boston, MA 02115 USA. EM retucker@hsph.harvard.edu FU NHLBI NIH HHS [K25 HL081275-01, K25 HL081275] NR 53 TC 15 Z9 16 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD DEC PY 2009 VL 19 IS 12 BP 850 EP 857 DI 10.1016/j.annepidem.2009.08.003 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 574NR UT WOS:000275997500002 PM 19944348 ER PT J AU Martinelli, G Ryan, G Seymour, JF Nassi, L Steffanoni, S Alietti, A Calabrese, L Pruneri, G Santoro, L Kuper-Hommel, M Tsang, R Zinzani, PL Taghian, A Zucca, E Cavalli, F AF Martinelli, G. Ryan, G. Seymour, J. F. Nassi, L. Steffanoni, S. Alietti, A. Calabrese, L. Pruneri, G. Santoro, L. Kuper-Hommel, M. Tsang, R. Zinzani, P. L. Taghian, A. Zucca, E. Cavalli, F. TI Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group SO ANNALS OF ONCOLOGY LA English DT Article DE breast malignancies; follicular lymphomas; MZLs; primary extranodal lymphomas ID NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; TERM-FOLLOW-UP; STAGE-I; CHEMOTHERAPY; RITUXIMAB; THERAPY; MODEL AB Patients and methods: Patients with histologically proven, previously untreated follicular or marginal-zone PBL (MZL PBL) diagnosed from 1980 to 2003 were included in the study. Major end points were progression-free survival (PFS), overall survival (OS) and potential prognostic factors. Results: We collected data on 60 cases of PBL [36 follicular and 24 marginal-zone lymphoma (MZL)]. Stage was I-E or IIE in 57 patients and IVE in three patients due to bilateral breast involvement. Surgery, chemotherapy and radiotherapy (RT), alone or in combination, were used as first-line treatments in 67%, 42% and 52% of patients, respectively. Overall response rate was 98%, with a 93% complete response rate. Five-year PFS were 56% for MZL and 49% for follicular PBL (P = 0.62). Relapses were mostly in distant sites (18 of 23 cases); no patients relapsed within RT fields. Conclusions: Our data showed an indolent behaviour of MZL PBL, comparable to other primary extranodal MZL. Conversely, patients with follicular PBL had inferior PFS and OS when compared with limited-stage nodal follicular non-Hodgkin's lymphomas, suggesting an adverse prognostic role of primary breast localisation in this histological subgroup. C1 [Martinelli, G.; Nassi, L.; Steffanoni, S.; Alietti, A.; Calabrese, L.] European Inst Oncol, Div Haematol, I-20141 Milan, Italy. [Seymour, J. F.] Peter MacCallum Canc Ctr, Dept Haematol, Melbourne, Vic, Australia. [Pruneri, G.] European Inst Oncol, Div Pathol & Lab Med, Milan, Italy. [Santoro, L.] European Inst Oncol, Div Stat Anal, Milan, Italy. [Kuper-Hommel, M.] Bernhoven Hosp, Dept Internal Med, Oss, Netherlands. [Tsang, R.] Univ Hlth Network, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. [Zinzani, P. L.] Policlin St Orsola, Inst Haematol & Med Oncol, Bologna, Italy. [Taghian, A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Zucca, E.; Cavalli, F.] Oncol Inst So Switzerland, Dept Med Oncol, Bellinzona, Switzerland. RP Martinelli, G (reprint author), European Inst Oncol, Div Haematol, Via Ripamonti 435, I-20141 Milan, Italy. EM giovanni.martinelli@ieo.it RI Zinzani, Pier Luigi/J-9182-2016 OI Zinzani, Pier Luigi/0000-0002-2112-2651 NR 29 TC 26 Z9 31 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2009 VL 20 IS 12 BP 1993 EP 1999 DI 10.1093/annonc/mdp238 PG 7 WC Oncology SC Oncology GA 524XZ UT WOS:000272179000014 PM 19570964 ER PT J AU ElBardissi, AW Regenbogen, SE Greenberg, CC Berry, W Arriaga, A Moorman, D Retik, A Warshaw, AL Zinner, MJ Gawande, AA AF ElBardissi, Andrew W. Regenbogen, Scott E. Greenberg, Caprice C. Berry, William Arriaga, Alex Moorman, Donald Retik, Alan Warshaw, Andrew L. Zinner, Michael J. Gawande, Atul A. TI Communication Practices on 4 Harvard Surgical Services A Surgical Safety Collaborative SO ANNALS OF SURGERY LA English DT Article ID OPERATING-ROOM; PATIENT-CARE; RESIDENTS; SURGEONS; ERRORS AB Background: Communication breakdowns between surgical residents and attending physicians in the pre- and postoperative setting are common contributors to patient injury. These communication transactions might offer an opportunity for safety improvement, but it remains unknown how often resident-attending communi cation fails, what the current level of attending involvement is, and how often attending input changes the plan for patient care. We conducted a prospective study at 4 Harvard teaching It hospitals to address these issues. Methods: Three prospective data collection strategies were employed: (1) we randomly selected surgical services and queried residents for the occurrence of predefined critical patient events and the characteristics of attending communications that ensued, (2) on weekends, randomly selected patients were interviewed and their charts reviewed to identify the frequency of attending visitation and how such visits affected processes of care, and (3) on weekends, senior residents on randomly selected surgical services were queried regarding the occurrence of attending-resident discussion of patients in their care. Results: Of 80 critical patient events identified, 26 (33%) were not communicated to attending surgeons. Residents reported that, when contacted, all attending physicians were receptive to communication, whether they were the primary surgeon or providing cross-coverage. Although residents felt that attending contact was unnecessary for safe patient care in 61 (76%) of these events, discussions with attending physicians changed management in 33% (18/54) of cases in which they occurred. Attending surgeons were found to visit their patients on randomly selected weekend days 42% (n = 37) of the time, while 21% (n = 19) had not visited for 2 or greater days. When attending physicians visited patients, however, resident management was modified 46% (n = 36) of the time. Though residents frequently discussed patient management with attending physicians on randomly selected weekends, they failed to do so 16% (n = 58) of the time, which appeared to be related to service-specific variation (chi(2) = 269, P < 0.0001). Conclusions: In the context of both critical patient events and routine patient care, residents often fail to obtain attending surgeons' input for management decisions. These failures seem to derive more from residents' perception of necessity than from attending physicians' receptiveness or interest in being contacted. Once involved, attending physicians frequently modify resident's management decisions. It seems, therefore, that there is significant potential for communication failure and information loss among our 4 institutions. C1 [ElBardissi, Andrew W.; Greenberg, Caprice C.; Zinner, Michael J.; Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Regenbogen, Scott E.; Warshaw, Andrew L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Berry, William; Arriaga, Alex; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Moorman, Donald] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Retik, Alan] Childrens Hosp, Dept Surg, Boston, MA 02115 USA. RP Gawande, AA (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM agawande@partners.org OI Gawande, Atul/0000-0002-1824-9176 FU Harvard Risk Management Foundation (CRICO/RMF) FX Supported by the Harvard Risk Management Foundation (CRICO/RMF) grant. NR 12 TC 16 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD DEC PY 2009 VL 250 IS 6 BP 861 EP 865 DI 10.1097/SLA.0b013e3181afe0db PG 5 WC Surgery SC Surgery GA 526SM UT WOS:000272313700001 PM 19855264 ER PT J AU Cohen, ME Bilimoria, KY Ko, CY Richards, K Hall, BL AF Cohen, Mark E. Bilimoria, Karl Y. Ko, Clifford Y. Richards, Karen Hall, Bruce L. TI Variability in Length of Stay After Colorectal Surgery Assessment of 182 Hospitals in the National Surgical Quality Improvement Program SO ANNALS OF SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; MEDICAL-CARE; OUTCOMES; SATISFACTION; PERFORMANCE; INFECTION AB Background: Length of postoperative stay (LOS) has gained increasing attention as a potential indicator of surgical efficiency. Our objective was to examine the feasibility of assessing LOS at 182 hospitals to identify institutions with outlying performance. Methods: Patients were identified who underwent colorectal surgery at 182 hospitals participating in the American College of Surgeon's National Surgical Quality Improvement Program (ACS NSQIP) from 2006 to 2007. Regression models for extended LOS (greater than the 75th percentile) were developed to identify hospitals whose ratios of observed to expected events (O/E) were significantly better (low outlier) or worse (high outlier) than expected after adjustment for case mix. To evaluate strategies for evaluating LOS that would be minimally influenced by the occurrence of complications, separate models were developed for patients categorized either by (1) the nonoccurrence or occurrence of any postoperative complication or (2) tercile of preoperative morbidity risk. Results: The 23,098 patients selected for this study were partitioned into groups without complications (0% complications), with complications (100%) or into terciles of preoperative morbidity risk (with 22.4%, 38.7%, and 60.0% of patients having complications, respectively). In general, the greater the complication rate the longer the LOS and the fewer the number of statistical outliers that were identified. Conclusions: ACS NSQIP data can provide individual hospitals with risk-adjusted LOS measures that can be used to identify outlying performance and motivate quality improvement efforts. C1 [Cohen, Mark E.; Bilimoria, Karl Y.; Ko, Clifford Y.; Richards, Karen] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Bilimoria, Karl Y.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Hall, Bruce L.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. RP Cohen, ME (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St, Chicago, IL 60611 USA. EM markcohen@facs.org NR 26 TC 44 Z9 46 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2009 VL 250 IS 6 BP 901 EP 907 DI 10.1097/SLA.0b013e3181b2a948 PG 7 WC Surgery SC Surgery GA 526SM UT WOS:000272313700008 PM 19953710 ER PT J AU Mahmood, F Subramaniam, B Gorman, JH Levine, RM Gorman, RC Maslow, A Panzica, PJ Hagberg, RM Karthik, S Khabbaz, KR AF Mahmood, Feroze Subramaniam, Balachundhar Gorman, Joseph H., III Levine, Robert M. Gorman, Robert C. Maslow, Andrew Panzica, Peter J. Hagberg, Robert M. Karthik, Swaminathan Khabbaz, Kamal R. TI Three-Dimensional Echocardiographic Assessment of Changes in Mitral Valve Geometry After Valve Repair SO ANNALS OF THORACIC SURGERY LA English DT Article ID TRANSESOPHAGEAL ECHOCARDIOGRAPHY; ANNULAR SHAPE; INTRAOPERATIVE MULTIPLANE; LEAFLET CURVATURE; RING SELECTION; SINGLE-PLANE; OVINE MODEL; REGURGITATION; ANNULOPLASTY; RECONSTRUCTION AB Background. Application of annuloplasty rings during mitral valve (MV) repair has been shown to significantly change the mitral annular geometry. Until recently, a comprehensive two-dimensional echocardiographic evaluation of annular geometric changes was difficult owing to its nonplanar orientation. In this study, an analysis of the three-dimensional intraoperative transesophageal echocardiographic evaluation of the MV annulus is presented before and immediately after repair. Methods. We performed three-dimensional geometric analysis on 75 patients undergoing MV repair during coronary artery bypass graft surgery for mitral regurgitation or myxomatous mitral valve disease. Geometric analysis of the MV was performed before and immediately after valve repair with full rings and annuloplasty bands. The acquired three-dimensional volumetric data were analyzed in the operating room. Specific measurements included annular diameter, leaflet lengths, the nonplanarity angle, and the circularity index. Before and after repair data were compared. Results. Complete echocardiographic assessment of the MV was feasible in 69 of 75 patients (92%) within 2 to 3 minutes of acquisition. Placement of full rings resulted in an increase in the nonplanarity angle or a less saddle shape of the native mitral annulus (137 +/- 14 versus 146 +/- 14; p = 0.002. By contrast, the nonplanarity angle did not change significantly after placement of partial rings. Conclusions. Mitral annular nonplanarity can be assessed in the operating room. Application of full annuloplasty rings resulted in the mitral annulus becoming more planar. Partial annuloplasty bands did not significantly change the nonplanarity angle. Neither of the two types of rings restored the native annular planarity. C1 Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care & Pain Management, Cardiovasc Inst, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. Univ Penn, Gorman Cardiovasc Res Grp, Glenoldan Res Lab, Glenoldan, PA USA. RP Mahmood, F (reprint author), Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, CC-470,Deaconess 1 W Campus, Boston, MA 02215 USA. EM fmahmood@bidmc.harvard.edu RI Mahmood, Feroze/B-1383-2008 OI Mahmood, Feroze/0000-0002-7071-0476 FU NHLBI NIH HHS [R01 HL103723, R01 HL073021, R01 HL063954, R01 HL063954-08] NR 34 TC 41 Z9 44 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD DEC PY 2009 VL 88 IS 6 BP 1838 EP 1844 DI 10.1016/j.athoracsur.2009.07.007 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 522VV UT WOS:000272029100017 PM 19932245 ER PT J AU Azadani, AN Jaussaud, N Matthews, PB Ge, L Guy, TS Chuter, TAM Tseng, EE AF Azadani, Ali N. Jaussaud, Nicolas Matthews, Peter B. Ge, Liang Guy, T. Sloane Chuter, Timothy A. M. Tseng, Elaine E. TI Energy Loss Due to Paravalvular Leak With Transcatheter Aortic Valve Implantation SO ANNALS OF THORACIC SURGERY LA English DT Article ID HEART-VALVE; HEMODYNAMIC PERFORMANCE; MITRAL REGURGITATION; STENOSIS; FEASIBILITY; REPLACEMENT; EXPERIENCE; PROSTHESIS AB Background. Mild to moderate paravalvular leaks commonly occur after transcatheter aortic valve (TAV) implantation. Current TAVs match and may exceed hemodynamic performance of surgically implanted bioprostheses based on pressure gradient and effective orifice area. However, these hemodynamic criteria do not account for paravalvular leaks. We recently demonstrated that TAV implantation within 23 mm Perimount bioprostheses (Edwards Lifesciences, Irvine, CA) yields similar hemodynamics to the 23 mm Perimount valve. However, mild paravalvular leakage was seen after TAV implantation. The present study quantifies energy loss during the entire cardiac cycle to assess the impact of TAV paravalvular leaks on the ventricle. Methods. Four TAVs designed to mimic the 23 mm SAPIEN valve (Edwards Lifesciences) were created. Transvalvular energy loss of 19, 21, and 23 mm Carpentier-Edwards bioprostheses were obtained in vitro within a pulse duplicator as a hemodynamic baseline (n = 4). The 23 mm TAVs were subsequently implanted within the 23 mm bioprostheses to assess energy loss due to paravalvular leak. Results. The 23 mm bioprosthesis demonstrated the least energy loss (213.25 +/- 31.35 mJ) compared with the 19 mm (330.00 +/- 36.97 mJ, p = 0.003) and 21 mm bioprostheses (298.00 +/- 37.25 mJ, p = 0.008). The TAV controls had similar energy loss (241.00 +/- 30.55 mJ, p = 0.17) as the 23 mm bioprostheses. However, after TAV implantation, total energy loss increased to 365.33 +/- 8.02 mJ significantly exceeding the energy loss of the 23 mm bioprosthesis (p < 0.001). Due to mild TAV paravalvular leakage, 39% of energy loss occurred during diastole. Conclusions. Substantial energy loss during diastole occurs due to TAV paravalvular leakage. In the presence of mild paravalvular leakage, TAV implantation imposes a significantly higher workload on the left ventricle than an equivalently sized surgically implanted bioprosthesis. C1 [Tseng, Elaine E.] Univ Calif San Francisco, Med Ctr, Div Cardiothorac Surg, Dept Surg, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Tseng, EE (reprint author), Univ Calif San Francisco, Med Ctr, Div Cardiothorac Surg, Dept Surg, 500 Parnassus Ave,Suite 405W,Box 0118, San Francisco, CA 94143 USA. EM elaine.tseng@ucsfmedctr.org FU American Heart Association; Northern California Institute for Research and Education; Federation/Societe Francaise de Cardiologie; Societe Francaise de Chirurugie Thoracique et Cardio-Vasculaire FX This work was supported by the American Heart Association, Northern California Institute for Research and Education, Federation/Societe Francaise de Cardiologie, and Societe Francaise de Chirurugie Thoracique et Cardio-Vasculaire. We thank Christine Frolich for providing us with normal PERIMOUNT bioprostheses and pericardium. NR 31 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD DEC PY 2009 VL 88 IS 6 BP 1857 EP 1863 DI 10.1016/j.athoracsur.2009.08.025 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 522VV UT WOS:000272029100020 PM 19932249 ER PT J AU Azadani, AN Jaussaud, N Matthews, PB Ge, L Guy, TS Chuter, TAM Tseng, EE AF Azadani, Ali N. Jaussaud, Nicolas Matthews, Peter B. Ge, Liang Guy, T. Sloane Chuter, Timothy A. M. Tseng, Elaine E. TI Valve-in-Valve Implantation Using a Novel Supravalvular Transcatheter Aortic Valve: Proof of Concept SO ANNALS OF THORACIC SURGERY LA English DT Article ID EDWARDS PERICARDIAL BIOPROSTHESIS; FAILURE MODES; HEART-VALVE; REPLACEMENT; STENOSIS; POSITION; SURGERY AB Background. Transcatheter valve implantation within degenerated bioprostheses is a potentially promising treatment for high-risk surgical patients. Clinical experience is limited; however, we have shown in vitro that currently available transcatheter aortic valve sizes did not provide acceptable hemodynamics in small bioprostheses. The objective of this study was to develop a new transcatheter valve that would provide good hemodynamics within degenerated bioprostheses. Methods. Supravalvular transcatheter valves were created using a Dacron covered stainless steel stent at the base and trileaflet pericardial leaflets in an open stent above the bioprosthesis. The transcatheter valves were implanted within 19-, 21-, and 23-mm Carpentier-Edwards Perimount bioprostheses with simulated degeneration using BioGlue to achieve a mean pressure gradient of 50 mm Hg. Hemodynamics of valve-in-valve implantation were studied in a pulse duplicator. Results. Supravalvular transcatheter valves successfully relieved bioprosthetic stenosis. Acceptable hemodynamics were achieved with a significant reduction in mean pressure gradient of 54.0 +/- 3.5 to 9.2 +/- 6.3 mm Hg in 23-mm bioprostheses (p < 0.001), from 49.3 +/- 3.1 to 14.4 +/- 4.7 mmHg (p < 0.001) in 21 mm, and from 53.9 +/- 3.8 to 28.3 +/- 9.8 mm Hg (p = 0.013) in 19-mm bioprostheses. Effective orifice area after valve-in-valve implantation increased significantly and was comparable to rereplacement with the same size bioprosthesis. Conclusions. Valve-in-valve implantation was performed using a novel supravalvular transcatheter valve, which successfully relieved bioprosthetic stenosis. The hemodynamics were comparable with standard surgical valve replacement. Further studies are required to assess device safety and efficacy in patients. (Ann Thorac Surg 2009; 88: 1864-70) (C) 2009 by The Society of Thoracic Surgeons C1 [Tseng, Elaine E.] Univ Calif San Francisco, Med Ctr, Div Cardiothorac Surg, Dept Surg, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Tseng, EE (reprint author), Univ Calif San Francisco, Med Ctr, Div Cardiothorac Surg, Dept Surg, 500 Parnassus Ave,Ste 405W,Box 0118, San Francisco, CA 94143 USA. EM elaine.tseng@ucsfmedctr.org FU American Heart Association (AHA); AHA [0565148Y]; Northern California Institute for Research and Education; Federation Francaise de Cardiologie/Societe Francaise de Cardiologie; Societe Francaise de Chirurugie Thoracique et Cardio-Vasculaire FX This work was supported by American Heart Association (AHA) postdoctoral fellowship, AHA Beginning Grant-in-Aid 0565148Y, the Northern California Institute for Research and Education, and Federation Francaise de Cardiologie/Societe Francaise de Cardiologie, Societe Francaise de Chirurugie Thoracique et Cardio-Vasculaire. We thank Christine Frolich for providing us with normal Carpentier-Edwards PERIMOUNT bioprostheses and John Hiebert for providing us with BioGlue. NR 21 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD DEC PY 2009 VL 88 IS 6 BP 1864 EP 1870 DI 10.1016/j.athoracsur.2009.08.004 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 522VV UT WOS:000272029100021 PM 19932250 ER PT J AU Chappell, JH Wang, XD Loeken, MR AF Chappell, James H., Jr. Wang, Xiao Dan Loeken, Mary R. TI Diabetes and apoptosis: neural crest cells and neural tube SO APOPTOSIS LA English DT Review DE Diabetic pregnancy; Congenital defects; Neural tube defect; Cardiac outflow tract defect; Apoptosis; Oxidative stress; Pax3; p53 ID TUMOR ALVEOLAR RHABDOMYOSARCOMA; PERSISTENT TRUNCUS ARTERIOSUS; FOLIC-ACID SUPPLEMENTATION; INDUCED OXIDATIVE STRESS; CARDIAC OUTFLOW TRACT; GLUCOSE IN-VITRO; GENE-EXPRESSION; RAT EMBRYOS; CONGENITAL-MALFORMATIONS; BIRTH-DEFECTS AB Birth defects resulting from diabetic pregnancy are associated with apoptosis of a critical mass of progenitor cells early during the formation of the affected organ(s). Insufficient expression of genes that regulate viability of the progenitor cells is responsible for the apoptosis. In particular, maternal diabetes inhibits expression of a gene, Pax3, that encodes a transcription factor which is expressed in neural crest and neuroepithelial cells. As a result of insufficient Pax3, cardiac neural crest and neuroepithelial cells undergo apoptosis by a process dependent on the p53 tumor suppressor protein. This, then provides a cellular explanation for the cardiac outflow tract and neural tube and defects induced by diabetic pregnancy. C1 [Chappell, James H., Jr.; Wang, Xiao Dan; Loeken, Mary R.] Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02215 USA. RP Loeken, MR (reprint author), Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM james.chappell@joslin.harvard.edu; xiaodan.wang@joslin.harvard.edu; mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU NIH [RO1 DK52865, RO1 DK58300]; American Diabetes Association; Juvenile Diabetes Research Foundation FX This work was supported by grants from the NIH (RO1 DK52865 and RO1 DK58300), the American Diabetes Association, and the Juvenile Diabetes Research Foundation to MRL. NR 177 TC 29 Z9 30 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 EI 1573-675X J9 APOPTOSIS JI Apoptosis PD DEC PY 2009 VL 14 IS 12 BP 1472 EP 1483 DI 10.1007/s10495-009-0338-6 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 514LM UT WOS:000271396200008 PM 19333760 ER PT J AU Galaleldeen, A Strange, RW Whitson, LJ Antonyuk, SV Narayana, N Taylor, AB Schuermann, JP Holloway, SP Hasnain, SS Hart, PJ AF Galaleldeen, Ahmad Strange, Richard W. Whitson, Lisa J. Antonyuk, Svetlana V. Narayana, Narendra Taylor, Alexander B. Schuermann, Jonathan P. Holloway, Stephen P. Hasnain, S. Samar Hart, P. John TI Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE X-ray crystallography; Protein structure; Amyotrophic lateral sclerosis; Leu Gehrig's disease; A4V and G93A ID AMYOTROPHIC-LATERAL-SCLEROSIS; ZINC SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; CRYSTALLOGRAPHIC STRUCTURE DETERMINATION; CU,ZN-SUPEROXIDE DISMUTASE; WILD-TYPE; COPPER CHAPERONE; REDUCED FORM; FAMILIAL ALS; AGGREGATION AB Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper-zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple Studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing Paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here we report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins. Published by Elsevier Inc. C1 [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, San Antonio, TX 78229 USA. [Galaleldeen, Ahmad; Whitson, Lisa J.; Narayana, Narendra; Taylor, Alexander B.; Schuermann, Jonathan P.; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Galaleldeen, Ahmad; Whitson, Lisa J.; Narayana, Narendra; Taylor, Alexander B.; Schuermann, Jonathan P.; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Strange, Richard W.; Antonyuk, Svetlana V.; Hasnain, S. Samar] Univ Liverpool, Sch Biol Sci, Liverpool L69 7ZB, Merseyside, England. RP Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM pjhart@biochem.uthscsa.edu OI Antonyuk, Svetlana/0000-0002-2779-9946 FU NIH-NINDS [R01-NS39112]; Motor Neuron Disease Association, U.K.; NIH [T32AG021890-03]; American Foundation for Aging Research; William and Ella Owens Medical Research Foundation; Judith and jean Pape Adams Charitable Foundation; BBSRC; MRC; EPSRC; NWDA; STFC FX This work was supported by grants NIH-NINDS R01-NS39112 (P.J.H.), the Motor Neuron Disease Association, U.K. (S.S.H., R.W.S), and in part by NIH T32AG021890-03 (J.P.S.), the American Foundation for Aging Research (L.J.W.), the William and Ella Owens Medical Research Foundation and the Judith and jean Pape Adams Charitable Foundation (A.G.). The U.K. group is grateful to BBSRC, MRC, EPSRC, NWDA and STFC for financial support and to STFC Daresbury Laboratory for provision of facilities and also thanks Peter A. Doucette and Joan S. Valentine for the gift of G93A SOD1. Support for the X-ray Crystallography Core Laboratory and the Center for Analytical Ultracentrifugation of Macromolecular Assemblies by the UTHSCSA Executive Research Committee and the San Antonio Cancer Institute is also gratefully acknowledged. NR 67 TC 27 Z9 27 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD DEC PY 2009 VL 492 IS 1-2 BP 40 EP 47 DI 10.1016/j.abb.2009.09.020 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 527XN UT WOS:000272404600005 PM 19800308 ER PT J AU Green, MF Lee, J Cohen, MS Engel, SA Korb, AS Nuechterlein, KH Wynn, JK Glahn, DC AF Green, Michael F. Lee, Junghee Cohen, Mark S. Engel, Steven A. Korb, Alexander S. Nuechterlein, Keith H. Wynn, Jonathan K. Glahn, David C. TI Functional Neuroanatomy of Visual Masking Deficits in Schizophrenia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID EVENT-RELATED FMRI; MULTIPLE TRIAL TYPES; BACKWARD-MASKING; UNAFFECTED SIBLINGS; OBJECT RECOGNITION; OCCIPITAL CORTEX; PERFORMANCE; CHANNELS; REPRESENTATION; VULNERABILITY AB Context: Visual masking procedures assess the earliest stages of visual processing. Patients with schizophrenia reliably show deficits on visual masking, and these procedures have been used to explore vulnerability to schizophrenia, probe underlying neural circuits, and help explain functional outcome. Objective: To identify and compare regional brain activity associated with one form of visual masking (ie, backward masking) in schizophrenic patients and healthy controls. Design: Subjects received functional magnetic resonance imaging scans. While in the scanner, subjects performed a backward masking task and were given 3 functional localizer activation scans to identify early visual processing regions of interest (ROIs). Setting: University of California, Los Angeles, and the Department of Veterans Affairs Greater Los Angeles Healthcare System. Participants: Nineteen patients with schizophrenia and 19 healthy control subjects. Main Outcome Measure: The magnitude of the functional magnetic resonance imaging signal during backward masking. Results: Two ROIs (lateral occipital complex [LO] and the human motion selective cortex [hMT vertical bar]) showed sensitivity to the effects of masking, meaning that signal in these areas increased as the target became more visible. Patients had lower activation than controls in LO across all levels of visibility but did not differ in other visual processing ROIs. Using whole-brain analyses, we also identified areas outside the ROIs that were sensitive to masking effects (including bilateral inferior parietal lobe and thalamus), but groups did not differ in signal magnitude in these areas. Conclusions: The study results support a key role in LO for visual masking, consistent with previous studies in healthy controls. The current results indicate that patients fail to activate LO to the same extent as controls during visual processing regardless of stimulus visibility, suggesting a neural basis for the visual masking deficit, and possibly other visual integration deficits, in schizophrenia. C1 [Green, Michael F.; Lee, Junghee; Cohen, Mark S.; Korb, Alexander S.; Nuechterlein, Keith H.; Wynn, Jonathan K.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Green, Michael F.; Lee, Junghee; Wynn, Jonathan K.] Vet Affairs Greater Los Angeles Healthcare Syst, Minneapolis, MN USA. [Engel, Steven A.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Glahn, David C.] Yale Univ, Sch Med, Olin Neuropsychiat Res Ctr, Inst Living, New Haven, CT USA. [Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Green, MF (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 300 Med Plaza, Los Angeles, CA 90095 USA. EM mgreen@ucla.edu RI Lee, Junghee/C-5226-2014; Wynn, Jonathan/H-3749-2014; Cohen, Mark/C-6610-2011 OI Lee, Junghee/0000-0001-9567-8700; Wynn, Jonathan/0000-0002-1763-8540; Cohen, Mark/0000-0001-6731-4053 FU National Institute of Mental Health [MH43292, MH065707] FX Support for this study came from National Institute of Mental Health grants MH43292 and MH065707 (principal investigator, Dr Green). NR 53 TC 25 Z9 27 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2009 VL 66 IS 12 BP 1295 EP 1303 PG 9 WC Psychiatry SC Psychiatry GA 529CZ UT WOS:000272494700004 PM 19996034 ER PT J AU Woodward, SH Schaer, M Kaloupek, DG Cediel, L Eliez, S AF Woodward, Steven H. Schaer, Marie Kaloupek, Danny G. Cediel, Lucia Eliez, Stephan TI Smaller Global and Regional Cortical Volume in Combat-Related Posttraumatic Stress Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; TOP-DOWN FACILITATION; HUMAN CEREBRAL-CORTEX; HIPPOCAMPAL INACTIVATION DISRUPTS; VISUAL OBJECT RECOGNITION; TEMPORAL GYRUS VOLUMES; SURFACE-BASED ANALYSIS; GRAY-MATTER VOLUME; PARAHIPPOCAMPAL GYRUS; MALTREATED CHILDREN AB Context: Two sets of findings predict smaller cerebral cortical gray matter volume in adult posttraumatic stress disorder (PTSD). Measures of intracranial tissue volume and cerebral tissue volume have been observed to be smaller in adolescents with maltreatment-related PTSD. Second, lower intelligence, a risk factor for PTSD, is associated with smaller cerebral tissue volumes. Nevertheless, to our knowledge, only 1 study has observed globally smaller cerebral tissue volume in adults with PTSD. Objectives: To apply a recently developed method providing improved estimates of cortical volume and to estimate associations between adult PTSD and selected regional cortical volumes not yet investigated. Design: Between-group comparison of global and regional cerebral cortical volumes in adult patients with combat-related PTSD and controls. Setting: Two Department of Veterans Affairs medical centers with large inpatient and outpatient PTSD catchments. Participants: Ninety-seven combat-exposed veterans of the Vietnam and Persian Gulf wars. Main Outcome Measure: Global and regional cortical volumes determined using the FreeSurfer software program and the Desikan et al parcellation (modified). Results: Cerebral cortical volume, thickness, and area were observed to be smaller in association with adult combat-related PTSD. Robust associations were observed between PTSD and smaller cortical volumes in the parahippocampal gyrus, superior temporal cortex, lateral orbital frontal cortex, and pars orbitalis of the inferior frontal gyrus. Conclusions: Cerebral cortical volume, thickness, and area may be smaller in adult chronic severe PTSD; however, the extracted structural variables did not mediate relations between intelligence and PTSD. The 4 regions exhibiting especially smaller cortical volumes in this sample share involvement in mechanisms subserving "topdown" facilitation of the identification of objects and words. Compromise of these regions may result in difficulty in relearning pretrauma schemata for interpreting the civilian physical and social environments. C1 [Woodward, Steven H.] VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, Palo Alto, CA 94304 USA. [Schaer, Marie; Cediel, Lucia; Eliez, Stephan] Univ Geneva, Dept Psychiat, Geneva, Switzerland. [Schaer, Marie] Swiss Fed Inst Technol, Signal Proc Lab, CH-1015 Lausanne, Switzerland. [Kaloupek, Danny G.] VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, Boston, MA USA. [Kaloupek, Danny G.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. RP Woodward, SH (reprint author), VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, Mail Code 334 PTSD,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM steve.woodward@va.gov OI Kaloupek, Danny/0000-0002-0795-593X FU US Army Medical Research and Materiel Command (Department of Defense); Swiss National Research Funds [323500-111165, 3200-063135, 3232063134, PP00B-102864] FX Major funding for this work was provided under a Department of Veterans Affairs/Department of Defense assistance agreement to Drs Woodward and Kaloupek from the US Army Medical Research and Materiel Command (Department of Defense) administered through the Institute for Medical Research (Department of Veterans Affairs). Additional support was provided by Swiss National Research Funds grants 323500-111165 (Dr Schaer) and 3200-063135, 3232063134, and PP00B-102864 (Dr Eliez). NR 96 TC 46 Z9 49 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2009 VL 66 IS 12 BP 1373 EP 1382 PG 10 WC Psychiatry SC Psychiatry GA 529CZ UT WOS:000272494700012 PM 19996042 ER PT J AU Ascherio, A LeWitt, PA Xu, K Eberly, S Watts, A Matson, WR Marras, C Kieburtz, K Rudolph, A Bogdanov, MB Schwid, SR Tennis, M Tanner, CM Beal, MF Lang, AE Oakes, D Fahn, S Shoulson, I Schwarzschild, MA AF Ascherio, Alberto LeWitt, Peter A. Xu, Kui Eberly, Shirley Watts, Arthur Matson, Wayne R. Marras, Connie Kieburtz, Karl Rudolph, Alice Bogdanov, Mikhail B. Schwid, Steven R. Tennis, Marsha Tanner, Caroline M. Beal, M. Flint Lang, Anthony E. Oakes, David Fahn, Stanley Shoulson, Ira Schwarzschild, Michael A. CA Parkinson Study Grp DATATOP TI Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID SERUM URIC-ACID; NUTRITION EXAMINATION SURVEY; MILD COGNITIVE IMPAIRMENT; 3RD NATIONAL-HEALTH; VITAMIN-E; CEREBROSPINAL-FLUID; PLASMA URATE; CONCENTRATION GRADIENTS; ANTIOXIDANT CAPACITY; MULTIPLE-SCLEROSIS AB Background: The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. Objective: To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. Design, Setting, and Participants: Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. Main Outcome Measures: Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. Results: The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile=0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase=0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase=0.75; 95% CI, 0.62-0.89; vs HR for those treated=0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile=0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase=0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. Conclusions: Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression. C1 [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. [Ascherio, Alberto] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. [Xu, Kui; Tennis, Marsha; Schwarzschild, Michael A.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Boston, MA 02129 USA. [Matson, Wayne R.; Bogdanov, Mikhail B.] Bedford Vet Adm Med Ctr, Bedford, England. [LeWitt, Peter A.] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [LeWitt, Peter A.] Wayne State Univ, Sch Med, Detroit, MI 48202 USA. [Eberly, Shirley; Watts, Arthur; Oakes, David] Univ Rochester, Dept Biostat, Rochester, NY 14627 USA. [Kieburtz, Karl; Rudolph, Alice; Schwid, Steven R.; Shoulson, Ira] Univ Rochester, Dept Neurol, Rochester, NY USA. [Beal, M. Flint] Cornell Univ, Dept Neurol & Neurosci, New York, NY 10021 USA. [Fahn, Stanley] Columbia Univ, Dept Neurol, New York, NY USA. [Marras, Connie; Lang, Anthony E.] Univ Toronto, Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Ctr, Toronto, ON M5T 2S8, Canada. [Tanner, Caroline M.] Parkinsons Inst, Dept Clin Res, Sunnyvale, CA USA. RP Schwarzschild, MA (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, 114 16th St, Boston, MA 02129 USA. EM michaels@helix.mgh.harvard.edu FU National Institutes of Health [NS24778, NS27892, NS048517, NS054978, NS060991]; US Department of Defense [W81XWH-04-1-0881]; RJG Foundation; American Federation for Aging Research; Parkinson Disease Foundation; Parkinson Study Group FX This work was Supported by grants NS24778, NS27892, NS048517, NS054978, and NS060991 from the National Institutes of Health, by grant W81XWH-04-1-0881 from the US Department of Defense, and by the RJG Foundation, the Beeson Scholars/Hartford Collaborative Research program of the American Federation for Aging Research, and a data-mining research award from the Parkinson Disease Foundation and the Parkinson Study Group. NR 54 TC 131 Z9 136 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2009 VL 66 IS 12 BP 1460 EP 1468 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 529YB UT WOS:000272554200004 PM 19822770 ER PT J AU Miller, JW AF Miller, Joan W. TI Legacy of the Age-Related Eye Disorder Study SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID HIGH-DOSE SUPPLEMENTATION; MACULAR DEGENERATION; BETA-CAROTENE; VITAMIN-E; RISK-FACTORS; CARDIOVASCULAR-DISEASE; CLINICAL-TRIAL; LUNG-CANCER; VISION LOSS; AREDS C1 Harvard Univ, Sch Med, Dept Ophthalmol, Retina Serv,Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Miller, JW (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Retina Serv,Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM jwmiller@meei.harvard.edu NR 26 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2009 VL 127 IS 12 BP 1680 EP 1685 PG 6 WC Ophthalmology SC Ophthalmology GA 529YC UT WOS:000272554300024 PM 20008728 ER PT J AU Moriarty, AT Clayton, AC Zaleski, S Henry, MR Schwartz, MR Eversole, GM Tench, WD Fatheree, LA Souers, RJ Wilbur, DC AF Moriarty, Ann T. Clayton, Amy C. Zaleski, Sue Henry, Michael R. Schwartz, Mary R. Eversole, Galen M. Tench, William D. Fatheree, Lisa A. Souers, Rhona J. Wilbur, David C. TI Unsatisfactory Reporting Rates 2006 Practices of Participants in the College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytology SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CERVICOVAGINAL CYTOLOGY; SPECIMEN ADEQUACY; TERMINOLOGY AB Context.-Minimum cellular criteria for satisfactory Papanicolaou tests were established with the Bethesda System in 2001, and unsatisfactory rates are used as a quality-reporting measure. Objective.-To evaluate practices and unsatisfactory rates from laboratories responding to the 2007 College of American Pathologists supplemental questionnaire survey. Design.-In 2007, a supplemental questionnaire was mailed to 1621 laboratories enrolled in the 2006 College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytology (PAP Education), requesting data from the 2006 calendar year. Unsatisfactory rates, reasons for unsatisfactory specimens, laboratory size, and specimen preparation type were analyzed. Results.-A total of 42% of the laboratories responded to the survey. Most of those laboratories (637 of 674; 94.5%) used the Bethesda System minimum cellularity criteria. Of those laboratories responding, 79% (527 of 667) used the Bethesda System criteria for atrophic or postirradiation specimens. Unsatisfactory rates have increased since 1996. SurePath preparations were associated with the lowest unsatisfactory rate (50th percentile, 0.30; 95th percentile, 1.3), conventional Papanicolaou tests had the highest 95th percentile rates (50th percentile, 1.0; 95th percentile, 5.90), and ThinPrep specimens had the highest median percentile (50th percentile, 1.1; 95th percentile, 3.4). The most-common reason for unsatisfactory Papanicolaou tests was too few squamous cells. Air-drying artifact was the least-common reason for unsatisfactory reporting for liquid-based preparations. Conclusions.-Use of the Bethesda System criteria for unsatisfactory specimens is widespread. Unsatisfactory rates have increased since 1996; however, the median rates are 1.1% or less for all preparations. Results from the College of American Pathologists PAP Education supplemental questionnaire continue to provide valuable benchmarking data for cytologic quality-improvement programs in laboratories. (Arch Pathol Lab Med. 2009; 133: 1912-1916) C1 [Moriarty, Ann T.] AmeriPath Indiana, Indianapolis, IN 46219 USA. [Clayton, Amy C.; Henry, Michael R.] Mayo Clin, Dept Anat Pathol, Rochester, MN USA. [Zaleski, Sue] Univ Iowa, Dept Pathol, Med Ctr, Iowa City, IA 52242 USA. [Schwartz, Mary R.] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. [Eversole, Galen M.] Quest Diagnost Inc, Las Vegas, NV USA. [Tench, William D.] Palomar Med Ctr, Escondido, CA USA. [Fatheree, Lisa A.] Coll Amer Pathologists, Dept Cytol Surveys, Northfield, IL USA. [Souers, Rhona J.] Coll Amer Pathologists, Dept Biostat, Northfield, IL USA. [Wilbur, David C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Moriarty, AT (reprint author), AmeriPath Indiana, 2560 N Shadeland Ave,Ste A, Indianapolis, IN 46219 USA. EM amoriarty@ameripath.com NR 9 TC 16 Z9 17 U1 0 U2 1 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2009 VL 133 IS 12 BP 1912 EP 1916 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 532DN UT WOS:000272725100005 PM 19961244 ER PT J AU Koreishi, AF Nazarian, RM Saenz, AJ Klepeis, VE McDonald, AG Farris, AB Colvin, RB Duncan, LM Mandal, RV Kay, J AF Koreishi, Aashiyana F. Nazarian, Rosalynn M. Saenz, Adam J. Klepeis, Veronica E. McDonald, Anna G. Farris, Alton Brad Colvin, Robert B. Duncan, Lyn M. Mandal, Rajni V. Kay, Jonathan TI Nephrogenic Systemic Fibrosis A Pathologic Study of Autopsy Cases SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; CONTRAST AGENTS; MULTIORGAN INVOLVEMENT; GADOLINIUM EXPOSURE; DERMOPATHY; GADODIAMIDE; DIALYSIS; SKIN; HEMODIALYSIS; DEPOSITION AB Context.-Nephrogenic systemic fibrosis (NSF) is a rare but serious disorder initially described as a purely dermatologic process. Isolated autopsy reports have described multiorgan involvement by this disease. Objective.-To further illustrate the varied and systemic involvement of NSF by describing the autopsy experience at the Massachusetts General Hospital. Design.-We describe the findings in a series of 4 autopsy cases of patients diagnosed with NSF. This report describes the history of renal dysfunction, exposure to gadolinium-containing contrast agents, specific laboratory parameters, and the extent of systemic involvement identified by postmortem examination. Results.-Causes of death included systemic thromboembolic disease (n = 3) and pneumonia (n = 1). Laboratory parameters and type, dose, or timing of gadolinium-containing contrast-agent exposure did not correlate with clinical findings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcification and fibrosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcification was associated with concurrent hyperparathyroidism or high serum parathyroid hormone levels. Conclusions.-Thromboembolic disease can be a significant clinical complication of NSF. Patients with NSF may also develop characteristic histologic features of fibrosis and calcification in multiple organs, with significant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF. (Arch Pathol Lab Med. 2009; 133: 1943-1948) C1 [Koreishi, Aashiyana F.; Nazarian, Rosalynn M.; Saenz, Adam J.; Klepeis, Veronica E.; McDonald, Anna G.; Farris, Alton Brad; Colvin, Robert B.; Duncan, Lyn M.; Mandal, Rajni V.] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Kay, Jonathan] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mandal, RV (reprint author), NYU, Sch Med, Dept Dermatopathol, 530 1st Ave,Suite 7J, New York, NY 10016 USA. EM rajni.mandal@nyumc.org OI Nazarian, Rosalynn/0000-0003-4003-7193 NR 33 TC 27 Z9 27 U1 0 U2 1 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2009 VL 133 IS 12 BP 1943 EP 1948 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 532DN UT WOS:000272725100010 PM 19961249 ER PT J AU Wilbur, DC Madi, K Colvin, RB Duncan, LM Faquin, WC Ferry, JA Frosch, MP Houser, SL Kradin, RL Lauwers, GY Louis, DN Mark, EJ Mino-Kenudson, M Misdraji, J Nielsen, GP Pitman, MB Rosenberg, AE Smith, RN Sohani, AR Stone, JR Tambouret, RH Wu, CL Young, RH Zembowicz, A Klietmann, W AF Wilbur, David C. Madi, Kalil Colvin, Robert B. Duncan, Lyn M. Faquin, William C. Ferry, Judith A. Frosch, Matthew P. Houser, Stuart L. Kradin, Richard L. Lauwers, Gregory Y. Louis, David N. Mark, Eugene J. Mino-Kenudson, Mari Misdraji, Joseph Nielsen, Gunnlauger P. Pitman, Martha B. Rosenberg, Andrew E. Smith, R. Neal Sohani, Aliyah R. Stone, James R. Tambouret, Rosemary H. Wu, Chin-Lee Young, Robert H. Zembowicz, Artur Klietmann, Wolfgang TI Whole-Slide Imaging Digital Pathology as a Platform for Teleconsultation A Pilot Study Using Paired Subspecialist Correlations SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID VIRTUAL MICROSCOPY; SURGICAL PATHOLOGY; TELEPATHOLOGY; VALIDATION; DESIGN AB Context.-Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. Objective.-To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. Design.-Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. Results.-Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. Conclusions.-Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications. (Arch Pathol Lab Med. 2009; 133: 1949-1953) C1 [Wilbur, David C.; Colvin, Robert B.; Duncan, Lyn M.; Faquin, William C.; Ferry, Judith A.; Frosch, Matthew P.; Houser, Stuart L.; Kradin, Richard L.; Lauwers, Gregory Y.; Louis, David N.; Mark, Eugene J.; Mino-Kenudson, Mari; Misdraji, Joseph; Nielsen, Gunnlauger P.; Pitman, Martha B.; Rosenberg, Andrew E.; Smith, R. Neal; Sohani, Aliyah R.; Stone, James R.; Tambouret, Rosemary H.; Wu, Chin-Lee; Young, Robert H.; Zembowicz, Artur] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Wilbur, David C.; Colvin, Robert B.; Duncan, Lyn M.; Faquin, William C.; Ferry, Judith A.; Frosch, Matthew P.; Houser, Stuart L.; Kradin, Richard L.; Lauwers, Gregory Y.; Louis, David N.; Mark, Eugene J.; Mino-Kenudson, Mari; Misdraji, Joseph; Nielsen, Gunnlauger P.; Pitman, Martha B.; Rosenberg, Andrew E.; Smith, R. Neal; Sohani, Aliyah R.; Stone, James R.; Tambouret, Rosemary H.; Wu, Chin-Lee; Young, Robert H.; Zembowicz, Artur] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Madi, Kalil] Univ Fed Rio de Janeiro, Dept Pathol, Rio De Janeiro, Brazil. [Klietmann, Wolfgang] Corista LLC, Concord, MA USA. RP Wilbur, DC (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM dwilbur@partners.org RI Duncan, Lyn/E-9878-2013 FU NIA NIH HHS [P50 AG005134] NR 14 TC 62 Z9 62 U1 1 U2 4 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2009 VL 133 IS 12 BP 1949 EP 1953 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 532DN UT WOS:000272725100011 PM 19961250 ER PT J AU McClure, LA Boninger, ML Oyster, ML Williams, S Houlihan, B Lieberman, JA Cooper, RA AF McClure, Laura A. Boninger, Michael L. Oyster, Michelle L. Williams, Steve Houlihan, Bethlyn Lieberman, Jesse A. Cooper, Rory A. TI Wheelchair Repairs, Breakdown, and Adverse Consequences for People With Traumatic Spinal Cord Injury SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Equipment failure; Reference standards; Rehabilitation; Spinal cord injuries; Wheelchairs ID ELECTRIC-POWERED WHEELCHAIRS; ANSI/RESNA STANDARDS; MAINTENANCE; DURABILITY; ACCIDENTS; SAFETY; USERS AB McClure LA, Boninger ML, Oyster ML, Williams S, Houlihan B, Lieberman JA, Cooper RA. Wheelchair repairs, breakdown, and adverse consequences for people with traumatic spinal cord injury. Arch Phys Med Rehabil 2009;90:2034-8. Objectives: To investigate the frequency of repairs that occurred in a 6-month period and the consequences of breakdowns on wheelchair users living with spinal cord injuries (SCIs), and to determine whether certain wheelchair and subject characteristics are associated with an increased number of repairs and adverse consequences. Design: Convenience sample survey. Setting: Sixteen Model Spinal Cord Injury Systems Centers that are part of the national database funded through the Department of Education, National Institute on Disability and Rehabilitation Research. Participants: People with SCI who use a wheelchair for more than 40h/wk (N=2213). Intervention: Not applicable. Main Outcome Measures: The frequency of wheelchair repairs and occurrence of adverse consequences caused by a wheelchair breakdown in a 6-month period. Results: Within a 6-month period, 44.8% of full-time wheelchair users completed a repair, and 8.7% had an adverse consequence occur. People who use power wheelchairs required significantly more repairs (P <.001), and adverse consequences occurred more frequently (P<.001) compared with manual wheelchair users. The presence of power seat functions, and a person's occupational status or sex did not influence the number of repairs or adverse consequences. Conclusions: Frequent repairs and breakdown can negatively impact a person's life by decreasing community participation and threatening health and safety. Mandatory compliance with the American National Standards Institute and the Rehabilitation Engineering and Assistive Technology Society of North America standards, changes in insurance reimbursement policy, and patient and clinician education are necessary to reduce the number of repairs and adverse consequences that occur. C1 [McClure, Laura A.; Boninger, Michael L.; Oyster, Michelle L.; Cooper, Rory A.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [McClure, Laura A.; Boninger, Michael L.; Cooper, Rory A.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Boninger, Michael L.; Oyster, Michelle L.; Lieberman, Jesse A.; Cooper, Rory A.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Williams, Steve; Houlihan, Bethlyn] Boston Univ, Dept Phys Med & Rehabil, Boston, MA 02215 USA. RP Boninger, ML (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, 7180 Highland Dr 151R1-H,Bldg 4,2nd Fl, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Boninger, Michael/0000-0001-6966-919X FU National Institute on Disability and Rehabilitation Research, Office of Special Education and Rehabilitation Services, United States Department of Education [H133N000019/H133N060019]; Interdisciplinary Research Training in Assistive Technology [DGE0333420] FX Supported by the National Institute on Disability and Rehabilitation Research, Office of Special Education and Rehabilitation Services, United States Department of Education (grant nos. H133N000019/H133N060019) and Interdisciplinary Research Training in Assistive Technology (grant no. DGE0333420). The material presented here is solely the responsibility of the authors and does not necessarily reflect the opinions of the funding agency or the United States Department of Education. NR 27 TC 24 Z9 24 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2009 VL 90 IS 12 BP 2034 EP 2038 DI 10.1016/j.apmr.2009.07.020 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 592YF UT WOS:000277417200009 PM 19969165 ER PT J AU Cheville, AL Basford, JR Troxel, AB Kornblith, AB AF Cheville, Andrea L. Basford, Jeffrey R. Troxel, Andrea B. Kornblith, Alice B. TI Performance of Common Clinician- and Self-Report Measures in Assessing the Function of Community-Dwelling People With Metastatic Breast Cancer SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Neoplasms; Outcome assessment; Quality of life; Rehabilitation ID TRAUMATIC BRAIN-INJURY; INPATIENT REHABILITATION; PHYSICAL FUNCTION; OUTCOMES ASSESSMENT; ASSESSMENT SCALES; SHORT-FORM; VALIDITY; MOBILITY; CARE; QUESTIONNAIRE AB Cheville AL, Basford JR, Troxel AB, Kornblith AB. Performance of common clinician- and self-report measures in assessing the function of community-dwelling people with metastatic breast cancer. Arch Phys Med Rehabil 2009;90:2116-24. Objective: To characterize the performance of common clinician- and self-report measures of function in assessing community-dwelling people with metastatic breast cancer. Design: Cross-sectional study. Setting: A tertiary medical center outpatient cancer clinic. Participants: A consecutive sample of community-dwelling patients (N=163) with stage IV breast cancer. Interventions: Not applicable. Main Outcome Measures: Medical Outcomes Study 36-Item Short-Form Physical Functioning (PF-10) and Role Physical subscales; the Older Americans Resource Study (OARS) activities of daily living (ADL) and instrumental ADL subscales; Karnofsky Performance Scale (KPS); and the FIM Total and FIM Mobility scores. Results: With the exception of the PF-10 and Role Physical subscales, which demonstrated floor effects, ceiling effects were detected in all the measures and were particularly persistent in the OARS ADL subscale. Instrument and item score distributions varied markedly across KPS-defined subgroups with FIM Mobility, FIM Total, and OARS subscale score distributions deviating least from the normal in the lowest performing (KPS 40-50) participants. Correlations between self-reported (Role Physical subscales, PF-10, OARS ADL subscales) and the clinician-rated (KPS and FIM scales) scales were moderate to high (r=.55-.82); however, clinician-reported scores were more consistently associated with the presence of physical impairments. Conclusions: In this population with stage IV breast cancer, ceiling effects limit the discriminatory capacity of the common functional scales assessed in this study. Instruments and items, particularly when ADL based, tend to perform better at lower levels of function (KPS 40-50) and less well at higher levels. Clinician-rated outcomes may have greater capacity to discriminate the presence of physical impairments. C1 [Cheville, Andrea L.; Basford, Jeffrey R.] Mayo Clin, Dept Phys Med & Rehabil, Rochester, MN 55905 USA. [Troxel, Andrea B.] Univ Penn Hlth Syst, Dept Biostat & Epidemiol, Philadelphia, PA USA. [Kornblith, Alice B.] Dana Farber Canc Inst, Psychooncol Res Program, Med Oncol Serv, Boston, MA 02115 USA. RP Cheville, AL (reprint author), Mayo Clin, Dept Phys Med & Rehabil, 200 1st St SW, Rochester, MN 55905 USA. EM cheville.andrea@mayo.edu OI Troxel, Andrea/0000-0002-1393-3075 FU Department of Defense [DAMD17-03-1-0622] FX Supported by the Department of Defense Congressionally Directed Breast Cancer Research Program Award (no. DAMD17-03-1-0622). NR 42 TC 8 Z9 9 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2009 VL 90 IS 12 BP 2116 EP 2124 DI 10.1016/j.apmr.2009.06.020 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 592YF UT WOS:000277417200022 PM 19969178 ER PT J AU Batista, LM Batista, IM Almeida, JP Carvalho, CH de Castro-Costa, SB de Castro-Costa, CM AF Batista, Leonardo M. Batista, Igor M. Almeida, Joao P. Carvalho, Carlos H. de Castro-Costa, Samuel B. de Castro-Costa, Carlos M. TI PREEMPTIVE ANALGESIC EFFECT OF LIDOCAINE IN A CHRONIC NEUROPATHIC PAIN MODEL SO ARQUIVOS DE NEURO-PSIQUIATRIA LA English DT Article DE pain; postoperative; sciatic neuropathy; analgesia; lidocaine; experimental animal models ID PERIPHERAL MONONEUROPATHY; RATS; RECEPTORS; BEHAVIOR AB Preemptive analgesia inhibits the progression of pain caused by surgical lesions. To analyze the effect of lidocaine on postoperative pain relief, we performed compression of the right sciatic nerve in Wistar rats and observed the differences on behavior between the group that received lidocaine and the group that was not treated with the local anesthetics pre-operatively. Group I was not operated (control); group 2 underwent the sciatic nerve ligature without lidocaine; group 3, underwent surgery with previous local infiltration of lidocaine. Group 2 showed significantly longer scratching times with a peak on day 14 post-operative (p=0.0005) and reduction in the latency to both noxious (p=0.003) and non-noxious (p=0.004) thermal stimulus. Group 3 presented significantly shorter scratching times (p=0.004) and longer latency times when compared to Group 2. Preemptive use of lidocaine 2% can potentially reduce the postoperative neuropathic pain associated with sciatic nerve compression. C1 [Batista, Leonardo M.; Batista, Igor M.; Almeida, Joao P.; Carvalho, Carlos H.; de Castro-Costa, Samuel B.; de Castro-Costa, Carlos M.] Univ Fed Ceara, Sch Med, Dept Physiol & Pharmacol, Lab Neurophysiol & Expt Neurol, Fortaleza, Ceara, Brazil. RP Batista, LM (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 775 Cambridge St,Suite 300, Boston, MA 02114 USA. EM lbatista@nmr.mgh.harvard.edu FU CNPq - National Counsel of Technological and Scientific Development, Brazil FX This study was partially funded by CNPq - National Counsel of Technological and Scientific Development, Brazil. The facilities used in this project were property of the Laboratory of Neurophysiology and Experimental Neurology, Department of Physiology and Pharmacology, School of medicine, Federal University of Ceara, Fortaleza CE, Brazil. NR 18 TC 4 Z9 6 U1 0 U2 0 PU ASSOC ARQUIVOS NEURO- PSIQUIATRIA PI SAO PAULO SP PA PR AMADEU AMARAL 47/33, 01327-010 SAO PAULO SP, BRAZIL SN 0004-282X J9 ARQ NEURO-PSIQUIAT JI Arq. Neuro-Psiquiatr. PD DEC PY 2009 VL 67 IS 4 BP 1088 EP 1092 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 532HG UT WOS:000272736500024 PM 20069225 ER PT J AU Maranhao, P Vincent, MB AF Maranhao-Filho, Pericles Vincent, Maurice B. TI NEUROPAREIDOLIA Diagnostic clues apropos of visual illusions SO ARQUIVOS DE NEURO-PSIQUIATRIA LA English DT Article DE pareidolia; neuroimaging; progressive supranuclear palsy; Wilson's disease; sarcoidosis; glioblastomas; progressive scoliosis and horizontal gaze palsy; Alzheimer's disease; pantothenate kinase-associated neurodegenerative disease ID HORIZONTAL GAZE PALSY; PROGRESSIVE SUPRANUCLEAR PALSY; NERVOUS-SYSTEM; SPINAL-CORD; PANDA SIGN; BRAIN; SCOLIOSIS; DEMENTIA; HALLERVORDEN; DEGENERATION AB Diagnosis in neuroimaging involves the recognition of specific patterns indicative of particular diseases. Pareidolia, the misperception of vague or obscure stimuli being perceived as something clear and distinct, is somewhat beneficial for the physician in the pursuit of diagnostic strategies. Animals may be pareidolically recognized in neuroimages according to the presence of specific diseases. By associating a given radiological aspect with an animal, doctors improve their diagnostic skills and reinforce mnemonic strategies in radiology practice. The most important pareidolical perceptions of animals in neuroimaging are the hummingbird sign in progressive supranuclear palsy, the panda sign in Wilson's disease, the panda sign in sarcoidosis, the butterfly sign in glioblastomas, the butterfly sign in progressive scoliosis and horizontal gaze palsy, the elephant sign in Alzheimer's disease and the eye-of-the-tiger sign in pantothenate kinase-associated neurodegenerative disease. C1 [Maranhao-Filho, Pericles; Vincent, Maurice B.] Univ Fed Rio de Janeiro, Dept Neurol, Rio De Janeiro, Brazil. [Maranhao-Filho, Pericles] Brazilian Natl Canc Inst, Dept Neurosurg, Rio De Janeiro, Brazil. [Vincent, Maurice B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. RP Maranhao, P (reprint author), Av Canal de Marapendi 1680-1802, BR-22631050 Rio De Janeiro, Brazil. EM pmaranhaofilho@gmail.com RI Vincent, Maurice/B-1415-2009 NR 46 TC 3 Z9 4 U1 2 U2 13 PU ASSOC ARQUIVOS NEURO- PSIQUIATRIA PI SAO PAULO SP PA PR AMADEU AMARAL 47/33, 01327-010 SAO PAULO SP, BRAZIL SN 0004-282X J9 ARQ NEURO-PSIQUIAT JI Arq. Neuro-Psiquiatr. PD DEC PY 2009 VL 67 IS 4 BP 1117 EP 1123 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 532HG UT WOS:000272736500033 PM 20069234 ER PT J AU Van de Velde, SK Bingham, JT Hosseini, A Kozanek, M DeFrate, LE Gill, TJ Li, GA AF Van de Velde, Samuel K. Bingham, Jeffrey T. Hosseini, Ali Kozanek, Michal DeFrate, Louis E. Gill, Thomas J. Li, Guoan TI Increased Tibiofemoral Cartilage Contact Deformation in Patients With Anterior Cruciate Ligament Deficiency SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ARTICULAR-CARTILAGE; KNEE OSTEOARTHRITIS; QUANTITATIVE ASSESSMENT; TIBIAL PLATEAU; 3 TESLA; JOINT; KINEMATICS; THICKNESS; BONE; TRANSECTION AB Objective. To investigate the in vivo cartilage contact biomechanics of the tibiofemoral joint following anterior cruciate ligament (ACL) injury. Methods. Eight patients with an isolated ACL injury in 1 knee, with the contralateral side intact, participated in the study. Both knees were imaged using a specific magnetic resonance sequence to create 3-dimensional models of knee bone and cartilage. Next, each patient performed a lunge motion from 0 degrees to 90 degrees of flexion as images were recorded with a dual fluoroscopic system. The three-dimensional knee models and fluoroscopic images were used to reproduce the in vivo knee position at each flexion angle. With this series of knee models, the location of the tibiofemoral cartilage contact, size of the contact area, cartilage thickness at the contact area, and magnitude of the cartilage contact deformation were compared between intact and ACL-deficient knees. Results. Rupture of the ACL changed the cartilage contact biomechanics between 0 degrees and 60 degrees of flexion in the medial compartment of the knee. Compared with the contralateral knee, the location of peak cartilage contact deformation on the tibial plateaus was more posterior and lateral, the contact area was smaller, the average cartilage thickness at the tibial cartilage contact area was thinner, and the resultant magnitude of cartilage contact deformation was increased. Similar changes were observed in the lateral compartment, with increased cartilage contact deformation from 0 degrees to 30 degrees of knee flexion in the presence of ACL deficiency. Conclusion. ACL deficiency alters the in vivo cartilage contact biomechanics by shifting the contact location to smaller regions of thinner cartilage and by increasing the magnitude of the cartilage contact deformation. C1 [Li, Guoan] Harvard Univ, Sch Med, Bioengn Lab, Massachusetts Gen Hosp, Boston, MA 02114 USA. [DeFrate, Louis E.] Duke Univ, Med Ctr, Durham, NC USA. RP Li, GA (reprint author), Harvard Univ, Sch Med, Bioengn Lab, Massachusetts Gen Hosp, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org RI Bingham, Jeffrey/I-6901-2012 OI Bingham, Jeffrey/0000-0002-9590-8526 FU Belgian American Educational Foundation; National Football League Charities Foundation; NIH [R01-AR-052408-02, R21-AR-051078-01] FX Dr. Van de Velde's work was supported by the Belgian American Educational Foundation. Dr. Gill's work was supported by the National Football League Charities Foundation. Dr. Li's work was supported by the NIH (grants R01-AR-052408-02 and R21-AR-051078-01). NR 49 TC 58 Z9 58 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2009 VL 60 IS 12 BP 3693 EP 3702 DI 10.1002/art.24965 PG 10 WC Rheumatology SC Rheumatology GA 531BC UT WOS:000272636700021 PM 19950260 ER PT J AU Siefert, CJ Sinclair, SJ Kehl-Fie, KA Blais, MA AF Siefert, Caleb J. Sinclair, Samuel J. Kehl-Fie, Kendra A. Blais, Mark A. TI An Item-Level Psychometric Analysis of the Personality Assessment Inventory Clinical Scales in a Psychiatric Inpatient Unit SO ASSESSMENT LA English DT Article DE Personality Assessment Inventory (PAI); Multi-item Multi-trait Analysis Program; psychometric properties; personality assessment; psychiatric inpatients; inpatient assessment ID SELF-REPORT; PAI AB Multi-item multiscale self-report measures are increasingly used in inpatient assessments. When considering a measure for this setting, it is important to evaluate the psychometric properties of the clinical scales and items to ensure that they are functioning as intended in a highly distressed clinical population. The present study examines scale properties for a self-report measure frequently employed in inpatient assessments, the Personality Assessment Inventory (PAI). In addition to examining internal consistency statistics, this study extends prior PAI research by considering key issues related to inpatient assessment (e. g., scale distinctiveness, ceiling effects). Coefficient alphas, interitem correlations, and item-scale relationships suggest that the PAI clinical scales and subscales are internally consistent. Items for respective clinical scales generally showed significantly higher item-scale correlations with their intended scale (as compared with their item-scale correlation with scales they were not intended to measure). In addition, scales' coefficient alpha scores were higher than their interscale correlations. Taken as a whole, these results support the hypothesis that PAI scales were measuring relatively distinct constructs in this inpatient sample. Findings are discussed with regard to the implications for scale interpretation in inpatient assessment, functioning of individual scales and subscales, and functioning of specific items. Limitations of the present study and directions for future research are discussed. C1 [Siefert, Caleb J.] Massachusetts Gen Hosp, PEaRL, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Siefert, CJ (reprint author), Massachusetts Gen Hosp, PEaRL, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM csief-ert@partners.org NR 22 TC 10 Z9 10 U1 17 U2 19 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD DEC PY 2009 VL 16 IS 4 BP 373 EP 383 DI 10.1177/1073191109333756 PG 11 WC Psychology, Clinical SC Psychology GA 519QC UT WOS:000271781100006 PM 19419952 ER PT J AU Ruggiero, SL Dodson, TB Assael, LA Landesberg, R Marx, RE Mehrotra, B AF Ruggiero, Salvatore L. Dodson, Thomas B. Assael, Leon A. Landesberg, Regina Marx, Robert E. Mehrotra, Bhoomi TI American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw-2009 Update SO AUSTRALIAN ENDODONTIC JOURNAL LA English DT Article ID MULTIPLE-MYELOMA PATIENTS; PLACEBO-CONTROLLED TRIAL; BONE-MINERAL DENSITY; LONG-TERM EFFICACY; ZOLEDRONIC ACID; RISK-FACTORS; BREAST-CANCER; SKELETAL COMPLICATIONS; JAW OSTEONECROSIS; DOUBLE-BLIND C1 [Ruggiero, Salvatore L.] Stony Brook Sch Dent Med, Div Oral & Maxillofacial Surg, Stony Brook, NY USA. [Mehrotra, Bhoomi] Long Isl Jewish Med Ctr, Div Hematol Med Oncol, New Hyde Pk, NY 11042 USA. [Ruggiero, Salvatore L.] Ctr Orthognath & Maxillofacial Surg, Lake Success, NY USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Assael, Leon A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Landesberg, Regina] Columbia Univ, SDOS Div OMFS, New York, NY USA. [Marx, Robert E.] Univ Miami, Sch Med, Div Oral & Maxillofacial Surg, Miami, FL USA. RP Ruggiero, SL (reprint author), Stony Brook Sch Dent Med, Div Oral & Maxillofacial Surg, Stony Brook, NY USA. NR 71 TC 105 Z9 114 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1329-1947 EI 1747-4477 J9 AUST ENDOD J JI Aust. Endod. J. PD DEC PY 2009 VL 35 IS 3 BP 119 EP 130 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 528GR UT WOS:000272431300001 PM 19961450 ER PT J AU Michalek, K Morshed, SA Latif, R Davies, TF AF Michalek, Krzysztof Morshed, Syed A. Latif, Rauf Davies, Terry F. TI TSH receptor autoantibodies SO AUTOIMMUNITY REVIEWS LA English DT Article DE Thyroid autoimmunity; TSH receptor; Graves' disease; TSHR antibodies; Antibody epitopes; Signal transduction ID THYROID-STIMULATING AUTOANTIBODY; NATIVE THYROTROPIN RECEPTOR; REGULATORY T-CELLS; GRAVES-DISEASE; MONOCLONAL-ANTIBODIES; FOXP3; GENE; AUTOIMMUNITY; ASSOCIATION AB Thyrotropin receptor autoantibodies (TSHR-Abs) of the stimulating variety are the hallmark of Graves' disease. The presence of immune defects leading to synthesis of TSHR-Abs causes hyperthyroidism and is associated with other extrathyroidal manifestations. Further characterization of these antibodies has now been made possible by the generation of monoclonal antibodies with this unique stimulating capacity as well as similar TSHR-Abs not associated with hyperthyroidism. Their present classification divides TSHR-Abs into stimulating, blocking (competing with TSH binding) and neutral (no signaling). Recent studies using monoclonal TSHR-Abs has revealed that stimulating and blocking antibodies bind to the receptor using mostly conformational epitopes, whilst neutral antibodies utilize exclusively linear peptides. Subtle differences in epitopes for stimulating and blocking antibodies account for the diversity of their biological actions. Recently non-classical signaling elicited by neutral antibodies has also been described, raising the need for a new classification of TSHR-Abs. Published by Elsevier B.V. C1 [Michalek, Krzysztof; Morshed, Syed A.; Latif, Rauf; Davies, Terry F.] James J Peters VA Med Ctr, Mt Sinai Sch Med, Thyroid Res Unit, Bronx, NY 10468 USA. RP Davies, TF (reprint author), James J Peters VA Med Ctr, Mt Sinai Sch Med, Thyroid Res Unit, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM terry.davies@mssm.edu FU NIH; NIDDK [DK069713]; VA Merit Award [4535-05-074]; David Owen Segal Endowment FX Supported in part by: NIH grant DK069713 from NIDDK, the VA Merit Award program 4535-05-074 (TFD), and the David Owen Segal Endowment. NR 35 TC 33 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD DEC PY 2009 VL 9 IS 2 BP 113 EP 116 DI 10.1016/j.autrev.2009.03.012 PG 4 WC Immunology SC Immunology GA 526HA UT WOS:000272277100008 PM 19332151 ER PT J AU McMurrich, SL Johnson, SL AF McMurrich, Stephanie L. Johnson, Sheri L. TI The Role of Depression, Shame-Proneness, and Guilt-Proneness in Predicting Criticism of Relatives Towards People With Bipolar Disorder SO BEHAVIOR THERAPY LA English DT Article ID NITHSDALE SCHIZOPHRENIA SURVEYS; WEEKLY SYMPTOMATIC STATUS; EXPRESSED-EMOTION; FAMILY INTERVENTION; MOOD DISORDERS; INDIVIDUAL PSYCHOPATHOLOGY; ONSET SCHIZOPHRENIA; NATURAL-HISTORY; MENTAL-HEALTH; FOLLOW-UP AB Expressed emotion (EE) has been associated with poor patient outcomes in many different psychiatric disorders. Given its robust association with relapse, EE has become a major target of family psychoeducational interventions. Most psychoeducational interventions to date have failed to change EE levels among families of those with bipolar disorder. Better intervention strategies, then, may depend on an increased understanding of the predictors of EE. Although EE has traditionally included many facets, criticism appears to be the most robust predictor of outcome within bipolar disorder. The present study tested three primary predictors of criticism among family members of people with bipolar disorder: shame-proneness, guilt-proneness, and depression. Depressive symptoms were significantly associated with EE. Discussion focuses on limitations and implications of the study and suggestions for future research. C1 [McMurrich, Stephanie L.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [McMurrich, Stephanie L.; Johnson, Sheri L.] Univ Miami, Coral Gables, FL 33124 USA. RP McMurrich, SL (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave,116B, Boston, MA 02130 USA. EM stephanie.mcmurrich@gmail.com RI johnson, sheri/D-8712-2014 OI johnson, sheri/0000-0002-9945-4816 FU NIMH NIH HHS [R01 MH076021, R01 MH076021-01A1] NR 69 TC 11 Z9 11 U1 3 U2 5 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD DEC PY 2009 VL 40 IS 4 BP 315 EP 324 DI 10.1016/j.beth.2008.09.003 PG 10 WC Psychology, Clinical SC Psychology GA 522TX UT WOS:000272022900001 PM 19892077 ER PT J AU Pineles, SL Shipherd, JC Mostoufi, SM Abramovitz, SM Yovel, I AF Pineles, Suzanne L. Shipherd, Jillian C. Mostoufi, Sheeva. M. Abramovitz, Sarah M. Yovel, Iftah TI Attentional biases in PTSD: More evidence for interference SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Attention; Posttraumatic stress disorder; PTSD; Trauma; Information processing; Attentional biases ID POSTTRAUMATIC-STRESS-DISORDER; EMPIRICAL LITERATURE; FACIAL EXPRESSIONS; SOCIAL PHOBIA; THREAT; ANXIETY; INFORMATION; DEPRESSION; CHECKLIST; FEAR AB Attentional biases to trauma-related stimuli have been widely demonstrated in individuals with posttraumatic stress disorder (PTSD). However, the majority of these studies used methods not suited to differentiating difficulty disengaging attention from threatening stimuli (interference) from facilitated detection of threat. In the current study, a visual search task (VST) with a lexical decision component was used to differentiate between attentional interference and facilitation. Forty-six sexual assault survivors with High PTSD or Low PTSD symptoms completed the VST with three types of stimuli (trauma-related, general threat-related, and semantically-related neutral words), to examine the specificity of attentional biases associated with PTSD symptoms. High PTSD participants showed increased interference to trauma-related words relative to Low PTSD participants. Furthermore, the increased attentional interference in High PTSD participants was specific to trauma-related stimuli. No evidence was found for facilitated detection of threatening stimuli in PTSD. These results provide additional support for attentional biases in PTSD relating to attentional interference with trauma-related cues rather than facilitated detection of threat. The implications for this pattern of results are discussed in relation to anxiety disorders that are characterized by rumination and/or intrusions (e.g., PTSD, GAD) rather than those more circumscribed to fight or flight response (e.g., phobias). Published by Elsevier Ltd. C1 [Pineles, Suzanne L.; Shipherd, Jillian C.; Mostoufi, Sheeva. M.; Abramovitz, Sarah M.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA 02130 USA. [Pineles, Suzanne L.; Shipherd, Jillian C.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Yovel, Iftah] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. RP Pineles, SL (reprint author), VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM suzanne.pineles@va.gov; jillian.shipherd@va.gov; sheeva.mostoufi@va.gov; sarah.abramovitz@va.gov; yoveli@mscc.huji.ac.il NR 39 TC 48 Z9 48 U1 5 U2 30 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD DEC PY 2009 VL 47 IS 12 BP 1050 EP 1057 DI 10.1016/j.brat.2009.08.001 PG 8 WC Psychology, Clinical SC Psychology GA 523FO UT WOS:000272057800008 PM 19716122 ER PT J AU Bernardi, RE Lewis, JR Lattal, KM Berger, SP AF Bernardi, Rick E. Lewis, Jason R. Lattal, K. Matthew Berger, S. Paul TI Modafinil reinstates a cocaine conditioned place preference following extinction in rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Modafinil; Cocaine; Conditioned place preference; Reinstatement ID DOPAMINE TRANSPORTERS; NUCLEUS-ACCUMBENS; IN-VIVO; MICE; EXPRESSION; WAKEFULNESS; INHIBITORS; MECHANISM; RELEASE; BINDING AB The current study examined whether modafinil would reinstate an extinguished cocaine conditioned place preference (CPP). Following extinction of a cocaine CPP, rats were administered modafinil (128 mg/kg), cocaine (5 mg/kg) or vehicle and given a 60-min reinstatement test. While the effect of cocaine was transient, modafinil robustly reinstated a cocaine CPP following extinction, suggesting that modafinil may induce relapse or increase the vulnerability of addicts to the reinforcing effects of environmental triggers. (C) 2009 Elsevier B.V. All rights reserved. C1 [Bernardi, Rick E.; Lattal, K. Matthew; Berger, S. Paul] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Berger, S. Paul] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Lewis, Jason R.; Berger, S. Paul] Portland VA Med Ctr, Dept Psychiat, Portland, OR 97239 USA. RP Bernardi, RE (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, Mail Code L470,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM bernardi@ohsu.edu FU Department of Veterans Affairs Merit Review program [07-1003]; National Institute of Mental Health [R01 MH077111]; National Institute on Drug Abuse [R01 DA025922, T32 DA007262, F31 DA022844] FX This research was supported by a grant from the Department of Veterans Affairs Merit Review program (07-1003) to S. Paul Berger, grants from the National Institute of Mental Health (R01 MH077111) and National Institute on Drug Abuse (R01 DA025922) to K. Matthew Lattal, and grants from the National Institute on Drug Abuse (T32 DA007262 and F31 DA022844) to Rick E. Bernardi. NR 27 TC 23 Z9 23 U1 2 U2 3 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 DEC 1 PY 2009 VL 204 IS 1 BP 250 EP 253 DI 10.1016/j.bbr.2009.05.028 PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 489XN UT WOS:000269459700030 PM 19482046 ER PT J AU Tomer, Y Menconi, F AF Tomer, Yaron Menconi, Francesca TI Interferon induced thyroiditis SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE interferon; thyroiditis; autoimmunity ID CHRONIC HEPATITIS-C; HUMAN THYROCYTE CULTURES; CHRONIC VIRAL-HEPATITIS; HIV ENVELOPE PROTEINS; HCV CHRONIC HEPATITIS; GRAVES-DISEASE; ALPHA THERAPY; VIRUS-INFECTION; IFN-ALPHA; AUTOIMMUNE-THYROIDITIS AB Interferon-alpha (IFN alpha) IS used for the treatment of various disorders. most notable chronic hepatitis C Virus (HCV) Infection One of the commonest side effects of IFN alpha therapy is thyroditis, with up to 40% of HCV patients on IFN alpha developing clinical or subclinical disease. In some cases interferon induced thyroiditis (IIT) may result in severe symptomatology necessitating discontinuation of therapy. IIT can manifest as clinical autoimmune thyroiditis, presenting with symptoms of classical Hashimoto's thyroiditis or Graves' disease, or as non-autoimmune thyroiditis Non-autoimmune thyroiditis can manifest as destructive thyroiditis, with early thyrotoxicosis and later hypothyroidism. or as non-autoimmune hypothyroidism While the epidemiology and clinical presentation of IIT have been well characterized the mechanisms causing IIT still poorly understood. It is likely that the hepatitis C Virus (HCV) itself plays a role in the disease, as the association between HCV infection and thyroiditis is well established. It is believed that IFN alpha. induces thyroiditis by both immune stimulatory effects and by direct effects on the thyroid. Early detection and therapy of this condition are Important in order to avoid complications of thyroid disease such as cardiac arrhythmias. (C) 2009 Elsevier Ltd All rights reserved. C1 [Tomer, Yaron] Mt Sinai Sch Med, Div Endocrinol, Dept Med, New York, NY 10029 USA. [Tomer, Yaron] James J Peters VA Med Ctr, New York, NY USA. [Menconi, Francesca] Mt Sinai Med Ctr, Div Endocrinol, New York, NY 10029 USA. RP Tomer, Y (reprint author), Mt Sinai Sch Med, Div Endocrinol, Dept Med, Box 1118,1 Gustave L Levy Pl, New York, NY 10029 USA. FU NIDDK [DK61659]; VA Merit Award FX This work Was Supported in part by: DK61659 from NIDDK and a VA Merit Award (to YT) NR 84 TC 37 Z9 40 U1 1 U2 3 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-690X J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD DEC PY 2009 VL 23 IS 6 BP 703 EP 712 DI 10.1016/j.beem.2009.07.004 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 534WL UT WOS:000272928100003 PM 19942147 ER PT J AU Liwanpo, L Hershman, JM AF Liwanpo, Llanyee Hershman, Jerome M. TI Conditions and drugs interfering with thyroxine absorption SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE thyroxine absorption; interfering drugs; levothyroxine; malabsorption; hypothyroidism ID INTESTINAL-ABSORPTION; CALCIUM-CARBONATE; CELIAC-DISEASE; LEVOTHYROXINE ABSORPTION; HYPOTHYROID PATIENTS; JEJUNOILEAL BYPASS; ALUMINUM HYDROXIDE; THYROID-HORMONE; ORAL THYROXINE; MALABSORPTION AB Food, dietary fibre and espresso coffee interfere with the absorption of levothyroxine. Malabsorptive disorders reported to affect the absorption of levothyroxine Include coeliac: disease, inflammatory bowel disease, lactose intolerance as well as Helicobacter pylon (H. pylori) infection and atrophic gastritis Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine (C) 2009 Elsevier Ltd All rights reserved C1 [Liwanpo, Llanyee; Hershman, Jerome M.] VA Greater Los Angeles Healthcare Syst, Dept Endocrinol, Los Angeles, CA 90073 USA. RP Liwanpo, L (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Endocrinol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 45 TC 76 Z9 78 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-690X EI 1532-1908 J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD DEC PY 2009 VL 23 IS 6 BP 781 EP 792 DI 10.1016/j.beem.2009.06.006 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 534WL UT WOS:000272928100009 PM 19942153 ER PT J AU Biller, BMK Sheppard, M AF Biller, Beverly M. K. Sheppard, Michael TI The Network for the Enhancement of Endocrinology and Oncology Knowledge: A case-based consideration of current practice in Cushing's disease and acromegaly SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE Cushing's disease; acromegaly; adrenocorticotrophic hormone (ACTH) ID CONSENSUS STATEMENT C1 [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit Bulfinch 457B, Boston, MA 02459 USA. [Sheppard, Michael] Univ Birmingham, Birmingham B15 2TT, W Midlands, England. RP Biller, BMK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit Bulfinch 457B, Fruit St, Boston, MA 02459 USA. EM bbiller@partners.org; m.c.sheppard@bham.ac.uk FU NEON; Novartis Pharma FX The authors wish to thank the NEON programme (a CME programme supported by an unrestricted educational grant from Novartis Pharma) for funding the NEON Endocrinology meeting, on which this review is based. The authors would also like to acknowledge CME Scholar Europe for preparation of this manuscript, which was then reviewed and amended by the authors. CME Scholar Europe is a provider of accredited CME programmes whose contribution to this manuscript was also funded by Novartis Pharma. NR 6 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-690X J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD DEC PY 2009 VL 23 SU 1 BP S1 EP S4 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 571ZR UT WOS:000275795900001 PM 20129189 ER PT J AU Stone, RM AF Stone, Richard M. TI Prognostic factors in AML in relation to (ab)normal karyotype SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE acute myeloid leukaemia; AML; cytogenetic; FLT3; gene expression; karyotype; NPM1; prognosis; mutation ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; GENE-EXPRESSION SIGNATURE; KINASE DOMAIN MUTATIONS; STUDY-GROUP ULM; GROUP-B CALGB; NORMAL CYTOGENETICS; FLT3 MUTATIONS; ADULT PATIENTS; PROMYELOCYTIC LEUKEMIA AB Acute myeloid leukaemia (AML) is a complicated, heterogeneous disease and the prognostic factors may be useful in deciding upon appropriate therapy. Cytogenetic testing at diagnosis yields critical prognostic information, but more refinement in prognosis is required. Within cytogenetic subgroups, further important subgroup definitions are possible based on the mutation status and expression analysis of genes such as C-KIT, FLT3, NPM1 and CEBPA, although defining therapies based on such mutations remains controversial. (c) 2009 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Stone, RM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Room M1b-17, Boston, MA 02115 USA. EM rstone@partners.org NR 41 TC 13 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2009 VL 22 IS 4 BP 523 EP 528 DI 10.1016/j.beha.2009.07.003 PG 6 WC Hematology SC Hematology GA 539DP UT WOS:000273234000009 PM 19959103 ER PT J AU Spassieva, SD Mullen, TD Townsend, DM Obeid, LM AF Spassieva, Stefka D. Mullen, Thomas D. Townsend, Danyelle M. Obeid, Lina M. TI Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response SO BIOCHEMICAL JOURNAL LA English DT Article DE autophagy; ceramide; ceramide synthase; endoplasmic reticulum (ER) homoeostasis; growth arrest; unfolded protein response (UPR) ID ENDOPLASMIC-RETICULUM STRESS; LONGEVITY ASSURANCE GENE-1; SQUAMOUS-CELL CARCINOMAS; MEMBRANE-STRUCTURE; MAMMALIAN HOMOLOG; FAMILY-MEMBERS; HUMAN HEAD; DEATH; SPHINGOSINE; ACTIVATION AB Ceramide metabolism has come under recent scrutiny because of its role in cellular stress responses. CerS2 (ceramide synthase 2) is one of the six mammalian isoforms of ceramide synthase and is responsible for the synthesis of VLC (very-long-chain) ceramides, e.g. C(24), C(24:1). To study the role of CerS2 in ceramide metabolism and cellular homoeostasis, we down-regulated CerS2 using siRNA (small interfering RNA) and examined several aspects of sphingolipid metabolism and cell stress responses. CerS2 down-regulation had a broad effect on ceramide homoeostasis, not just on VLC ceramides. Surprisingly, CerS2 down-regulation resulted in significantly increased LC (long-chain) ceramides, e.g. C(14), C(16), and our results suggested that the increase was due to a ceramide synthase-independent mechanism. CerS2-down-regulation-induced LC ceramide accumulation resulted in growth arrest which was not accompanied by apoptotic cell death. Instead, cells remained viable, showing induction of autophagy and activation of PERK [PKR (double-stranded-RNA-dependent protein kinase)-like endoplasmic reticulum kinase] and IRE1 (inositol-requiring 1) pathways [the latter indicating activation of the UPR (unfolded protein response)]. C1 [Spassieva, Stefka D.; Mullen, Thomas D.; Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Townsend, Danyelle M.] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Hosp, Div Gen Internal Med, Charleston, SC 29401 USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [AG016583, ES016975-01] FX This work was supported by the National Institutes of Health [grant numbers AG016583 (to L. M. O.), ES016975-01 (to T D. M.)], and in pan by the Office of Research and Development, Department of Veterans Affairs, Ralph H. Johnson VA Medical Center, Charleston, SC, U.S.A. [MERIT Award (to L. M. O.)]. NR 48 TC 55 Z9 56 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 1 PY 2009 VL 424 BP 273 EP 283 DI 10.1042/BJ20090699 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524HT UT WOS:000272135100012 PM 19728861 ER PT J AU Koreth, J Alyea, EP Murphy, WJ Welniak, LA AF Koreth, John Alyea, Edwin P. Murphy, William J. Welniak, Lisbeth A. TI Proteasome Inhibition and Allogeneic Hematopoietic Stem Cell Transplantation: A Review SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Bortezomib; NFkb; Acute GVHD; Chronic GVHD; Graft-versus tumor ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; APOPTOSIS-INDUCING LIGAND; CONSENSUS DEVELOPMENT PROJECT; CHIMERIC MONOCLONAL-ANTIBODY; MULTIPLE-MYELOMA CELLS; WORKING GROUP-REPORT; REGULATORY T-CELLS AB The proteasome and its associated ubiquitin protein modification system have proved to be an important therapeutic target in the treatment of multiple myeloma and other cancers. In addition to direct antitumor effects, proteasome inhibition also exerts strong effects on nonneoplastic immune cells. This indicates that proteasome inhibition, through the use of agents like bortezomib, could be used therapeutically to modulate immune responses. In this review we explore the emerging data, both preclinical and clinical, highlighting the importance of proteasome targeting of immunologic responses, primarily in the context of allogeneic hematopoietic stem cell transplantation (HSCT), both for the control of transplant-related toxicities like acute and chronic graft-versus-host disease (aGVHD, cGHVHD), and for improved malignant disease control after allogeneic HSCT Biol Blood Marrow Transplant 15: 1502-1512 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Murphy, William J.; Welniak, Lisbeth A.] Univ Calif, Dept Dermatol, Davis Sch Med, Sacramento, CA 95818 USA. [Koreth, John; Alyea, Edwin P.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Murphy, WJ (reprint author), Univ Calif, Dept Dermatol, Davis Sch Med, Res 3,Room 3300,4645 2nd Ave, Sacramento, CA 95818 USA. EM wmjmurphy@ucdavis.edu FU National Institutes of Health [R01 CA102282, P01 CA142106] FX This work was supported in part by National Institutes of Health Grants R01 CA102282 (L.W., W.J.M.) and P01 CA142106 (J.K., E.P.A.) awarded to William J. Murphy and Joseph H. Antin, respectively. We thank Dr. Joseph H.. Antin, Erik Ames, and Matte Alvarez for their critical reading and Nona Simons for her editorial assistance of the manuscript. NR 138 TC 13 Z9 13 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2009 VL 15 IS 12 BP 1502 EP 1512 DI 10.1016/j.bbmt.2009.07.016 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 523UP UT WOS:000272100400002 PM 19896073 ER PT J AU Baker, KS Davies, SM Majhail, NS Hassebroek, A Klein, JP Ballen, KK Bigelow, CL Frangoul, HA Hardy, CL Bredeson, C Dehn, J Friedman, D Hahn, T Hale, G Lazarus, HM LeMaistre, CF Loberiza, F Maharaj, D McCarthy, P Setterholm, M Spellman, S Trigg, M Maziarz, RT Switzer, G Lee, SJ Rizzo, JD AF Baker, K. Scott Davies, Stella M. Majhail, Navneet S. Hassebroek, Anna Klein, John P. Ballen, Karen K. Bigelow, Carolyn L. Frangoul, Haydar A. Hardy, Cheryl L. Bredeson, Christopher Dehn, Jason Friedman, Debra Hahn, Theresa Hale, Gregory Lazarus, Hillard M. LeMaistre, C. F. Loberiza, Fausto Maharaj, Dipnarine McCarthy, Philip Setterholm, Michelle Spellman, Stephen Trigg, Michael Maziarz, Richard T. Switzer, Galen Lee, Stephanie J. Rizzo, J. Douglas TI Race and Socioeconomic Status Influence Outcomes of Unrelated Donor Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic hematopoietic cell transplantation; Unrelated donor; Race; Socioeconomic status; Survival ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; CONGESTIVE-HEART-FAILURE; HLA-IDENTICAL SIBLINGS; QUALITY-OF-CARE; RACIAL-DIFFERENCES; BREAST-CANCER; LIVER-TRANSPLANTATION; GENE POLYMORPHISMS AB Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 14 1), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [Cl] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% Cl 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% Cl 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes. Biol Blood Marrow Transplant 15: 1543-1554 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Baker, K. Scott; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Davies, Stella M.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Majhail, Navneet S.] Univ Minnesota, Minneapolis, MN USA. [Majhail, Navneet S.; Hassebroek, Anna] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Klein, John P.; Rizzo, J. Douglas] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Ballen, Karen K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bigelow, Carolyn L.; Hardy, Cheryl L.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Frangoul, Haydar A.; Friedman, Debra] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Bredeson, Christopher] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Dehn, Jason; Setterholm, Michelle; Spellman, Stephen] Natl Marrow Donor Program, Minneapolis, MN USA. [Hahn, Theresa; McCarthy, Philip] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hale, Gregory] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [LeMaistre, C. F.] Texas Transplant Inst, San Antonio, TX USA. [Loberiza, Fausto] Univ Nebraska, Med Ctr, Omaha, NE USA. [Maharaj, Dipnarine] S Florida Bone Marrow Stem Cell Transplant Inst, Boynton Beach, FL USA. [Trigg, Michael] Merck & Co Inc, Wilmington, DE USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Switzer, Galen] Univ Pittsburgh, Pittsburgh, PA USA. RP Baker, KS (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,Mailstop D5-280, Seattle, WA 98109 USA. EM ksbaker@fhcrc.org FU NCI NIH HHS [U24-CA76518, U24 CA076518-12, U24 CA076518]; NHLBI NIH HHS [U01 HL069294, 5U01HL069294, U01 HL069294-08]; PHS HHS [HHSH234200637015C] NR 52 TC 50 Z9 51 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 DEC PY 2009 VL 15 IS 12 BP 1543 EP 1554 DI 10.1016/j.bbmt.2009.07.023 PG 12 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 523UP UT WOS:000272100400007 PM 19896078 ER PT J AU Bacigalupo, A Ballen, K Rizzo, D Giralt, S Lazarus, H Ho, V Apperley, J Slavin, S Pasquini, M Sandmaier, BM Barrett, J Blaise, D Lowski, R Horowitz, M AF Bacigalupo, Andrea Ballen, Karen Rizzo, Doug Giralt, Sergio Lazarus, Hillard Ho, Vincent Apperley, Jane Slavin, Shimon Pasquini, Marcelo Sandmaier, Brenda M. Barrett, John Blaise, Didier Lowski, Robert Horowitz, Mary TI Defining the Intensity of Conditioning Regimens: Working Definitions SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Conditioning regimens; Reduced intensity; Myeloablative conditioning ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; ACUTE MYELOID-LEUKEMIA; ACUTE MYELOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; VERSUS-HOST-DISEASE; TERM-FOLLOW-UP; REDUCED-INTENSITY; HEMATOLOGIC MALIGNANCIES AB Defining conditioning regimen intensity has become a critical issue for the hemopoietic stem cell transplant (HSCT) community. In the present report we propose to define conditioning regimens in 3 categories: (1) myeloablative (MA) conditioning, (2) reduced-intensity conditioning (RIC), and (3) nonmyeloablative (NMA) conditioning. Assignment to these categories is based on the duration of cytopenia and on the requirement for stem cell (SC) support: MA regimens cause irreversible cytopenia and SC support is mandatory. NMA regimens cause minimal cytopenia, and can be given also without SC support. RIC regimens do not fit criteria for MA or NMA regimens: they cause cytopenia of variable duration, and should be given with stem cell support, although cytopenia may not be irreversible. This report also assigns commonly used regimens to one of these categories, based upon the agents, dose, or combinations. Standardized classification of conditioning regimen intensities will allow comparison across studies and interpretation of study results. Biol Blood Marrow Transplant 15: 1628-1633 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Bacigalupo, Andrea] San Martino Hosp, I-16132 Genoa, Italy. [Ballen, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rizzo, Doug; Pasquini, Marcelo; Horowitz, Mary] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Giralt, Sergio] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lazarus, Hillard] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Ho, Vincent] Dana Farber Canc Inst, Boston, MA 02115 USA. [Apperley, Jane] Hammersmith Hosp, London, England. [Slavin, Shimon] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Sandmaier, Brenda M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Barrett, John] NIH, Bethesda, MD 20892 USA. [Blaise, Didier] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Lowski, Robert] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Bacigalupo, A (reprint author), San Martino Hosp, Lgo R Benzi 10, I-16132 Genoa, Italy. EM andrea.bacigalupo@hsanmartino.it FU NCI NIH HHS [P01 CA018029, P01 CA018029-34, P01 CA078902, P01 CA078902-11]; NHLBI NIH HHS [P01 HL036444, P01 HL036444-29] NR 50 TC 365 Z9 368 U1 2 U2 9 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 DEC PY 2009 VL 15 IS 12 BP 1628 EP 1633 DI 10.1016/j.bbmt.2009.07.004 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 523UP UT WOS:000272100400017 PM 19896087 ER PT J AU Murphy, WJ Artz, AS Champlin, RE Koreth, J Longo, DL AF Murphy, William J. Artz, Andrew S. Champlin, Richard E. Koreth, John Longo, Dan L. TI Blood Stem Cell Transplantation in Older Patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article AB A serious dichotomy currently exists in hematopoietic stem cell transplantation (HSCT) and cancer research. Cancer is a disease that predominantly affects older people, yet there is a paucity of cancer research addressing the very unique needs of this population. Even basic biologic processes that exist in aging (decline in immune competency, increased sensitivities to therapies, etc.) are only beginning to be understood. Proportionally, the vast majority of cancer preclinical research does not involve the use of aged animals due to expense and time. This seriously hampers realistic extrapolation of preclinical findings to the general population affected by cancer. This report recommends research priorities that can help close the gaps in our understanding of aging as it relates to HSCT and cancer. Biol Blood Marrow Transplant 15: 1638-1639 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Murphy, William J.] Univ Calif, Davis Med Ctr, Sacramento, CA 95817 USA. [Artz, Andrew S.] Univ Chicago, Chicago, IL 60637 USA. [Champlin, Richard E.] MD Anderson Canc Ctr, Houston, TX USA. [Koreth, John] Dana Farber Canc Inst, Boston, MA USA. [Longo, Dan L.] NIA, Bethesda, MD 20892 USA. RP Murphy, WJ (reprint author), Univ Calif, Davis Med Ctr, 4645 2nd Ave,Res 3,Room 3300D, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu FU NCI NIH HHS [P30 CA016672] NR 0 TC 2 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2009 VL 15 IS 12 BP 1638 EP 1639 DI 10.1016/j.bbmt.2009.10.014 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 523UP UT WOS:000272100400019 PM 19911448 ER PT J AU Dang, TT Xu, QB Bratlie, KM O'Sullivan, ES Chen, XY Langer, R Anderson, DG AF Dang, Tram T. Xu, Qiaobing Bratlie, Kaitlin M. O'Sullivan, Esther S. Chen, Xiao Y. Langer, Robert Anderson, Daniel G. TI Microfabrication of homogenous, asymmetric cell-laden hydrogel capsules SO BIOMATERIALS LA English DT Article DE Cell encapsulation; Hydrogel microcapsules; Alginate; Diabetes; Polypropylene mesh; Microfabrication ID PANCREATIC-ISLETS; ENCAPSULATION; GENERATION; ENDOSTATIN; RELEASE; TISSUE AB Cell encapsulation has been broadly investigated as a technology to provide immunoprotection for transplanted endocrine cells. Here we develop a new fabrication method that allows for rapid, homogenous microencapsulation of insulin-secreting cells with varying microscale geometries and asymmetrically modified surfaces. Micromolding systems were developed using polypropylene mesh, and the material/surface properties associated with efficient encapsulation were identified. Cells encapsulated using these methods maintain desirable viability and preserve their ability to proliferate and secrete insulin in a glucose-responsive manner. This new cell encapsulation approach enables a practical route to an inexpensive and convenient process for the generation of cell-laden microcapsules without requiring any specialized equipment or microfabrication process. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Langer, Robert; Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Dang, Tram T.; Xu, Qiaobing; Bratlie, Kaitlin M.; Chen, Xiao Y.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Bratlie, Kaitlin M.] Childrens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [O'Sullivan, Esther S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Anderson, DG (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dgander@mit.edu RI Dang, Tram/E-7966-2011 FU Juvenile Diabetes Research Foundation [17-2007-1063]; National Institute of Health [DE016516]; Agency for Science, Technology and Research of Singapore for the A*STAR National Science graduate fellowship; MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNIE) FX This research was supported by the Juvenile Diabetes Research Foundation under grant 17-2007-1063 and the National Institute of Health under grant DE016516. T.D is grateful to the Agency for Science, Technology and Research of Singapore for the A*STAR National Science graduate fellowship. Q X. is grateful to the MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNIE) for the postdoctoral fellowship. NR 24 TC 18 Z9 18 U1 4 U2 24 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD DEC PY 2009 VL 30 IS 36 BP 6896 EP 6902 DI 10.1016/j.biomaterials.2009.09.012 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 523KG UT WOS:000272071400010 PM 19800116 ER PT J AU Zhang, JJ Wang, ML AF Zhang, Jenny J. Wang, Molin TI An Accelerated Failure Time Mixture Cure Model with Masked Event SO BIOMETRICAL JOURNAL LA English DT Article DE Accelerated failure time model; Cure rate; EM algorithm; Masked event; Rank-based estimating equations ID BREAST-CANCER; COMPETING RISKS; CENSORED-DATA; EM ALGORITHM; ESTIMATING EQUATIONS; REGRESSION-MODEL; SURVIVAL-DATA; PREMENOPAUSAL; GOSERELIN; INFERENCE AB We extend the Dahlberg and Wang (Biometrics 2007, 63, 1237-1244) proportional hazards (PH) cure model for the analysis of time-to-event data that is subject to a cure rate with masked event to a setting where the PH assumption does not hold. Assuming an accelerated failure time (AFT) model with unspecified error distribution for the time to the event of interest, we propose rank-based estimating equations for the model parameters and use a generalization of the EM algorithm for parameter estimation. Applying our proposed AFT model to the same motivating breast cancer dataset as Dahlberg and Wang (Biometrics 2007, 63, 1237-1244), our results are more intuitive for the treatment arm in which the PH assumption may be violated. We also conduct a simulation study to evaluate the performance of the proposed method. C1 [Zhang, Jenny J.; Wang, Molin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wang, Molin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Zhang, JJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA. EM jjzhang6@gmail.com FU United States National Cancer Institute [CA-75362]; United States National Institute of Health Cancer FX We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group (IBCSG) Trial VIII. We further acknowledge support from the United States National Cancer Institute (CA-75362) and the United States National Institute of Health Cancer Training Grant (Jing J. Zhang). We express our gratitude to Richard Gelber, Robert Gray, Ann Partridge, and Zhi-Min Yuan for their assistance throughout. We also thank the editor, associate editor, and referee for their insightful comments and suggestions. NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD DEC PY 2009 VL 51 IS 6 BP 932 EP 945 DI 10.1002/bimj.200800244 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 542PR UT WOS:000273507600004 PM 20029894 ER PT J AU DeSantis, SM Houseman, EA Coull, BA Louis, DN Mohapatra, G Betensky, RA AF DeSantis, Stacia M. Houseman, E. Andres Coull, Brent A. Louis, David N. Mohapatra, Gayatry Betensky, Rebecca A. TI A Latent Class Model with Hidden Markov Dependence for Array CGH Data SO BIOMETRICS LA English DT Article DE Array CGH; Hidden Markov Model; Latent class ID COMPARATIVE GENOMIC HYBRIDIZATION; DNA MICROARRAY DATA; BREAST-CANCER; LINEAR-MODELS; PREDICTORS AB P>Array CGH is a high-throughput technique designed to detect genomic alterations linked to the development and progression of cancer. The technique yields fluorescence ratios that characterize DNA copy number change in tumor versus healthy cells. Classification of tumors based on aCGH profiles is of scientific interest but the analysis of these data is complicated by the large number of highly correlated measures. In this article, we develop a supervised Bayesian latent class approach for classification that relies on a hidden Markov model to account for the dependence in the intensity ratios. Supervision means that classification is guided by a clinical endpoint. Posterior inferences are made about class-specific copy number gains and losses. We demonstrate our technique on a study of brain tumors, for which our approach is capable of identifying subsets of tumors with different genomic profiles, and differentiates classes by survival much better than unsupervised methods. C1 [DeSantis, Stacia M.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29403 USA. [Houseman, E. Andres] Brown Univ, Warren Alpert Med Sch, Ctr Environm Hlth & Technol, Providence, RI 02903 USA. [Houseman, E. Andres] Harvard Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02903 USA. [Coull, Brent A.; Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Louis, David N.; Mohapatra, Gayatry] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. [Louis, David N.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP DeSantis, SM (reprint author), Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, 135 Cannon St,Suite 303, Charleston, SC 29403 USA. EM sdesanti@hsph.harvard.edu OI Houseman, Eugene Andres/0000-0003-0703-1830 FU NCI NIH HHS [R01 CA075971, R01 CA057683, R01 CA075971-08, R01 CA057683-08] NR 25 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2009 VL 65 IS 4 BP 1296 EP 1305 DI 10.1111/j.1541-0420.2009.01226.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 524FC UT WOS:000272128200032 PM 19397578 ER PT J AU Perlis, RH Ostacher, MJ Uher, R Nierenberg, AA Casamassima, F Kansky, C Calabrese, JR Thase, M Sachs, GS AF Perlis, Roy H. Ostacher, Michael J. Uher, Rudolf Nierenberg, Andrew A. Casamassima, Francesco Kansky, Christine Calabrese, Joseph R. Thase, Michael Sachs, Gary S. TI Stability of symptoms across major depressive episodes in bipolar disorder SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; factor analysis; major depression; mixed state; psychosis; subtype; suicide; symptom stability ID ATYPICAL DEPRESSION; DSM-IV; UNIPOLAR; FEATURES; SUBTYPES; MELANCHOLIA AB Objective: Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. Methods: We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. Results: A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. Conclusion: While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder. C1 [Perlis, Roy H.; Ostacher, Michael J.; Nierenberg, Andrew A.; Casamassima, Francesco; Kansky, Christine; Sachs, Gary S.] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Perlis, Roy H.; Ostacher, Michael J.; Nierenberg, Andrew A.; Casamassima, Francesco; Kansky, Christine; Sachs, Gary S.] Massachusetts Gen Hosp, Res Program, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Ostacher, Michael J.; Nierenberg, Andrew A.; Casamassima, Francesco; Kansky, Christine; Sachs, Gary S.] Harvard Univ, Sch Med, Boston, MA USA. [Uher, Rudolf] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Calabrese, Joseph R.] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. [Thase, Michael] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Bipolar Clin, 50 Staniford St,5th Floor, Boston, MA 02114 USA. EM rperlis@partners.org RI Uher, Rudolf/A-5477-2008; OI Uher, Rudolf/0000-0002-2998-0546; Ostacher, Michael/0000-0003-0353-7535 FU National Institute of Mental Health (NIMH) [R01 MH086026]; NARSAD; NIMH [N01MH80001] FX We would like to thank the patients and families who have contributed their time to this study and all of the STEP-BD investigators. This analysis was supported by National Institute of Mental Health (NIMH) R01 MH086026 (RHP) and a NARSAD Young Investigator Award (RHP). The STEP-BD project was funded in whole or in part with Federal funds from the NIMH under contract N01MH80001 to Gary S. Sachs (PI), Michael E. Thase (Co-PI), and Mark S. Bauer (Co-PI). Active STEP-BD sites and principal investigators included Baylor College of Medicine (Lauren B. Marangell); Case Western Reserve University (Joseph R. Calabrese); Massachusetts General Hospital and Harvard Medical School (Andrew A. Nierenberg); Portland VA Medical Center (Peter Hauser); Stanford University School of Medicine (Terence A. Ketter); University of Colorado Health Sciences Center (Marshall Thomas); University of Massachusetts Medical Center (Jayendra Patel); University of Oklahoma College of Medicine (Mark D. Fossey); University of Pennsylvania Medical Center (Laszlo Gyulai); University of Pittsburgh, Western Psychiatric Institute and Clinic (Michael E. Thase); University of Texas Health Science Center at San Antonio (Charles L. Bowden). NR 28 TC 9 Z9 9 U1 4 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD DEC PY 2009 VL 11 IS 8 BP 867 EP 875 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 521DI UT WOS:000271899700007 PM 19922555 ER PT J AU Echart, CL Graziadio, B Somaini, S Ferro, LI Richardson, PG Fareed, J Iacobelli, M AF Echart, Cinara L. Graziadio, Barbara Somaini, Simona Ferro, Laura I. Richardson, Paul G. Fareed, Jawed Iacobelli, Massimo TI The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity SO BLOOD COAGULATION & FIBRINOLYSIS LA English DT Article DE defibrotide; fibrinolysis; plasmin; venous occlusive disease ID HEPATIC VENOOCCLUSIVE DISEASE; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; HIGH-RISK POPULATION; SIGNIFICANT TOXICITY; ENDOTHELIAL-CELLS; COMPASSIONATE-USE; ACTIVATOR; BINDING; STIMULATION AB Fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veto-occlusive disease after stem cell transplantation, a microangiopathy characterized by sinusoidal endothelial cell injury. Defibrotide is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties. Numerous clinical studies have shown promising activity of defibrotide in the treatment and prevention of veto-occlusive disease, with minimal toxicity. In corollary laboratory studies, defibrotide has been shown to decrease plasminogen activator inhibitor-1, increase tissue plasminogen activator levels, and increase overall plasma fibrinolytic activity in patients. Plasmin, a potent and nonspecific serine protease, plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. In this study, defibrotide increases the activity of plasmin in hydrolyzing its substrate in a dose-dependent and length-dependent manner. Similar concentration-dependent effects of defibrotide were observed when plasmin was generated by tissue plasminogen activator or urokinase activation of plasminogen. In contrast, defibrotide had no direct effect on the activation of plasminogen to plasmin. Defibrotide was also able to enhance the activity of plasmin in degrading fibrin clot formed from fibrinogen, plasminogen, and thrombin. This effect was also concentration-dependent and directly correlated with the enzymatic activity of plasmin. This study therefore demonstrates that defibrotide is capable of enhancing the activity of plasmin and so contributes to its fibrinolytic activity. Taken together, these results support the effect of defibrotide in restoring the fibrinolytic vascular phenotype, in microangiopathic conditions such as veto-occlusive disease. Blood Coagul Fibrinolysis 20:627-634 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Echart, Cinara L.; Graziadio, Barbara; Somaini, Simona; Ferro, Laura I.; Iacobelli, Massimo] Gentium SpA, Villa Guardia, Como, Italy. [Fareed, Jawed] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Richardson, Paul G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MD USA. RP Echart, CL (reprint author), Gentium SpA, Piazza 1010 Settembre 2, I-22079 Villa Guardia, CO, Italy. NR 46 TC 18 Z9 19 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-5235 J9 BLOOD COAGUL FIBRIN JI Blood Coagul. Fibrinolysis PD DEC PY 2009 VL 20 IS 8 BP 627 EP 634 DI 10.1097/MBC.0b013e32832da1e3 PG 8 WC Hematology SC Hematology GA 516OE UT WOS:000271551000003 PM 19809307 ER PT J AU Pereira, RC Juppner, H Azucena-Serrano, CE Yadin, O Salusky, IB Wesseling-Perry, K AF Pereira, Renata C. Juppner, Harald Azucena-Serrano, Carlos E. Yadin, Ora Salusky, Isidro B. Wesseling-Perry, Katherine TI Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease SO BONE LA English DT Article DE Osteocyte; Renal osteodystrophy; MEPE; DMP1; FGF-23 ID DENTIN MATRIX PROTEIN-1; HYPOPHOSPHATEMIC RICKETS; BREAST-CARCINOMA; IN-VIVO; BONE; PHOSPHATE; FGF23; ALPHA; OSTEOMALACIA; PHOSPHORUS AB Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus. expression of these three proteins was characterized by immunohistochemistry in 32 pediatric and young adult patients with CKD stages 2-5. When compared to normal controls, bone FGF-23 and DMP1 expression were increased in all stages of CKD; significant differences in bone FGF-23 and DMP1 expression were not detected between pre-dialysis CKD and dialysis patients. Bone MEPE expression in CKD did not differ from controls. FGF-23 was expressed in osteocyte cell bodies located at the trabecular periphery. DMP1 was widely expressed in osteocyte cell bodies and dendrites throughout bone. MEPE was also expressed throughout bone, but only in osteocyte cell bodies. Bone FGF-23 expression correlated directly with plasma levels of the protein (r=0.43, p<0.01) and with bone DMP1 expression (r=0.54, p<0.01) and expression of both proteins were inversely related to osteoid accumulation. Bone MEPE expression was inversely related to bone volume. In conclusion, skeletal FGF-23 and DMP1 expression are increased in CKD and are related to skeletal mineralization. The patterns of expression of FGF-23, MEPE, and DMP1 differ markedly in trabecular bone, suggesting that individual osteocytes may have specialized functions. Increases in bone FGF-23 and DMP1 expression suggest that osteocyte function is altered early in the course of CKD. (C) 2009 Elsevier Inc. All rights reserved. C1 [Pereira, Renata C.; Azucena-Serrano, Carlos E.; Yadin, Ora; Salusky, Isidro B.; Wesseling-Perry, Katherine] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Juppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Juppner, Harald] Harvard Univ, Sch Med, Boston, MA USA. RP Wesseling-Perry, K (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, A2-383 MDCC,650 Charles Young Dr E, Los Angeles, CA 90095 USA. EM kwesseling@mednet.ucla.edu FU USPHS [DK-35423, DK-67563, MO1-RR00865]; Casey Lee Ball Foundation FX This study was supported by USPHS grants DK-35423, DK-67563 and MO1-RR00865 and by funds from the Casey Lee Ball Foundation. NR 34 TC 118 Z9 123 U1 2 U2 14 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 DEC PY 2009 VL 45 IS 6 BP 1161 EP 1168 DI 10.1016/j.bone.2009.08.008 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 521JJ UT WOS:000271916900017 PM 19679205 ER PT J AU Butterly, A Bittner, E Sandberg, W Eikermann, M Schmidt, U AF Butterly, A. Bittner, E. Sandberg, W. Eikermann, M. Schmidt, U. TI Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Meeting Abstract CT 9th International Neuromuscular Meeting CY JUL 01-07, 2009 CL Munich, GERMANY DE complications; muscle relaxants; recovery ID POSTANESTHESIA CARE-UNIT; BLOCKADE; EVENTS C1 [Butterly, A.; Bittner, E.; Sandberg, W.; Eikermann, M.; Schmidt, U.] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD DEC PY 2009 VL 103 IS 6 BP 911 EP 912 PG 2 WC Anesthesiology SC Anesthesiology GA 523OQ UT WOS:000272084000036 ER PT J AU Frick, CG Helming, M Martyn, JAJ Blobner, M Fink, H AF Frick, C. G. Helming, M. Martyn, J. A. J. Blobner, M. Fink, H. TI Continuous administration of pyridostigmine improves immobilization-induced neuromuscular weakness SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Meeting Abstract CT 9th International Neuromuscular Meeting CY JUL 01-07, 2009 CL Munich, GERMANY DE muscle relaxants; muscle weakness; reversal C1 [Frick, C. G.; Helming, M.; Blobner, M.; Fink, H.] Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, D-8000 Munich, Germany. [Frick, C. G.; Martyn, J. A. J.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Frick, C. G.; Martyn, J. A. J.] Harvard Univ, Sch Med, Shriners Hosp Children, Boston, MA USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD DEC PY 2009 VL 103 IS 6 BP 911 EP 911 PG 1 WC Anesthesiology SC Anesthesiology GA 523OQ UT WOS:000272084000035 ER PT J AU Negri, JM McMillin, DW Delmore, J Mitsiades, N Hayden, P Klippel, S Hideshima, T Chauhan, D Munshi, NC Buser, CA Pollard, J Richardson, PG Anderson, KC Mitsiades, CS AF Negri, Joseph M. McMillin, Douglas W. Delmore, Jake Mitsiades, Nicholas Hayden, Patrick Klippel, Steffen Hideshima, Teru Chauhan, Dharminder Munshi, Nikhil C. Buser, Carolyn A. Pollard, John Richardson, Paul G. Anderson, Kenneth C. Mitsiades, Constantine S. TI In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myeloma; kinase inhibition; microenvironment ID REFRACTORY MULTIPLE-MYELOMA; CANCER; THERAPY; OVEREXPRESSION; DEXAMETHASONE AB P>This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), doxorubicin (Doxo) and bortezomib showed no antagonism. Our study highlights the potential role of the tumour microenvironment in modulating the activity of this drug class. C1 [Negri, Joseph M.; McMillin, Douglas W.; Delmore, Jake; Mitsiades, Nicholas; Hayden, Patrick; Klippel, Steffen; Hideshima, Teru; Chauhan, Dharminder; Munshi, Nikhil C.; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. [Negri, Joseph M.; McMillin, Douglas W.; Delmore, Jake; Mitsiades, Nicholas; Hayden, Patrick; Klippel, Steffen; Hideshima, Teru; Chauhan, Dharminder; Munshi, Nikhil C.; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Buser, Carolyn A.] Merck & Co Inc, Res Labs, Whitehouse Stn, NJ USA. [Pollard, John] Vertex Pharmaceut Ltd, Oxford, England. RP Mitsiades, CS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Constantine_Mitsiades@dfci.harvard.edu FU Dunkin Donuts Rising Stars; Chambers Medical Foundation; Richard J. Corman Fund; Cobb Family Fellowship; National Institutes of Health [R01CA050947, PO-1-78378] FX Supported in part by the 'Dunkin Donuts Rising Stars' Programme at the Dana-Farber Cancer Institute (to C.S.M), the Chambers Medical Foundation (P.G.R and C.S.M.), the Richard J. Corman Fund (P.G.R and C.S.M.), the Cobb Family Fellowship (to D.W.M), and National Institutes of Health grants R01CA050947 (KCA and CSM) and PO-1-78378 (KCA). NR 14 TC 20 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2009 VL 147 IS 5 BP 672 EP 676 DI 10.1111/j.1365-2141.2009.07891.x PG 5 WC Hematology SC Hematology GA 517OW UT WOS:000271626500007 PM 19751238 ER PT J AU Gertz, MA Abonour, R Heffner, LT Greipp, PR Uno, H Rajkumar, SV AF Gertz, Morie A. Abonour, Rafat Heffner, Leonard T. Greipp, Philip R. Uno, Hajime Rajkumar, S. V. TI Clinical value of minor responses after 4 doses of rituximab in Waldenstrom macroglobulinaemia: a follow-up of the Eastern Cooperative Oncology Group E3A98 trial SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE lymphoplasmacytic lymphoma; monoclonal IgM protein; rituximab; Waldenstrom macroglobulinaemia ID CONSENSUS PANEL RECOMMENDATIONS; 3RD INTERNATIONAL WORKSHOP; PROGNOSTIC-FACTORS; UPDATE; THERAPY AB P>Waldenstrom macroglobulinaemia is a low-grade, lymphoplasmacytic lymphoma that is responsive to rituximab. We report the role of a minor response in predicting overall outcomes. We extended follow-up of a previously described cohort (n = 69) treated with 4 weekly doses of rituximab and observed durable responses (median time to progression, 30 months; 5-year survival rate, 66%). Patients achieving a minor response [25-50% immunoglobulin M (IgM) reduction] appeared to do as well as those achieving an objective response (> 50% IgM reduction), which suggests that more aggressive or intensive therapy for minor responders is not required. Future studies of Waldenstrom macroglobulinaemia should report minor responses because they are associated with clinically meaningful benefits. This trial was registered at http://www.clinicaltrials.gov as #NCT00005609. C1 [Gertz, Morie A.; Greipp, Philip R.; Rajkumar, S. V.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Abonour, Rafat] Indiana Univ, Simon Canc Ctr, Div Hematol, Indianapolis, IN 46204 USA. [Heffner, Leonard T.] Winship Canc Ctr, Emory Clin, Atlanta, GA USA. [Uno, Hajime] Dana Farber Canc Inst, Div Biostat, Boston, MA 02115 USA. RP Gertz, MA (reprint author), Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM gertz.morie@mayo.edu OI Rajkumar, S. Vincent/0000-0002-5862-1833 FU NCI NIH HHS [P30 CA082709, R01 CA111345, U10 CA013650, U10 CA021115, U10 CA023318, U10 CA049883, U10 CA066636] NR 12 TC 27 Z9 28 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2009 VL 147 IS 5 BP 677 EP 680 DI 10.1111/j.1365-2141.2009.07892.x PG 4 WC Hematology SC Hematology GA 517OW UT WOS:000271626500008 PM 19751237 ER PT J AU Janckila, AJ Yam, LT AF Janckila, Anthony J. Yam, Lung T. TI Biology and Clinical Significance of Tartrate-Resistant Acid Phosphatases: New Perspectives on an Old Enzyme SO CALCIFIED TISSUE INTERNATIONAL LA English DT Review DE Tartrate-resistant acid phosphatase; Osteoclast; Bone resorption; Macrophage; Inflammation ID MICROPHTHALMIA TRANSCRIPTION FACTOR; BONE-RESORPTION MARKER; BREAST-CANCER-PATIENTS; CHRONIC KIDNEY-DISEASE; MONITORING ALENDRONATE TREATMENT; RANKL-INDUCED TRANSCRIPTION; HUMAN OSTEOCLAST CULTURES; ROS-GENERATING ACTIVITY; HAIRY-CELL LEUKEMIA; STAGE RENAL-DISEASE AB Type 5 tartrate-resistant acid phosphatase (TRAP) has been a clinically relevant biomarker for about 50 years. It has always been a reliable and specific cytochemical marker for hairy cell leukemia and for differentiated cells of monocytic lineage. Only recently has the test for serum TRAP activity been accepted as sensitive and specific enough for clinical use as a marker of osteoclasts and bone resorption. This has come about through steady advances in knowledge about TRAP enzymology, structure, function, and molecular regulation and a consequent appreciation that TRAP isoforms 5a and 5b have very different clinical significance. As a measure of osteoclast number and bone resorption, TRAP 5b has diagnostic and prognostic applications in osteoporosis, cancers with bone metastasis, chronic renal failure, and perhaps other metabolic and pathologic bone diseases. Serum TRAP 5a, on the other hand, has no relationship to bone metabolism but seems instead to be a measure of activated macrophages and chronic inflammation. Exploration of the real clinical usefulness of serum TRAP 5a for diagnosis and disease management in a wide variety of chronic inflammatory diseases is only now beginning. This perspective traces the important basic scientific developments that have led up to the refinement of serum TRAP isoform immunoassays and their validation as biomarkers of disease. Many unanswered questions remain, providing a wealth of opportunity for continued research of this multifaceted enzyme. C1 [Janckila, Anthony J.; Yam, Lung T.] US Dept Vet Affairs, Special Hematol Lab, Med Ctr, Louisville, KY 40206 USA. [Janckila, Anthony J.] Univ Louisville, Dept Microbiol & Immunol, Louisville, KY 40292 USA. [Yam, Lung T.] Univ Louisville, Dept Med, Louisville, KY 40292 USA. RP Janckila, AJ (reprint author), US Dept Vet Affairs, Special Hematol Lab, Med Ctr, 800 Zorn Ave, Louisville, KY 40206 USA. EM anthony.janckila@va.gov; lung.yam@va.gov FU U.S. Department of Veterans Affairs; Clinical Research Foundation FX The authors fondly acknowledge the long friendship and collaborations of Dr. Chin-Yang Li and Dr. Kwok-Wai `` Bill'' Lam since the initiation of our studies on TRAP. Early success was possible only through their hard work and dedication. The dedication and support of our wives, Barbara and Julia, have been equally important during long hours in the lab. The valuable contributions made in the lab and clinic over the years by colleagues, fellows, residents, students, and associates at the University of Louisville, School of Medicine, are also heartily acknowledged. We also thank Dr. Jussi Halleen and his colleagues and students from the Anatomy Department, University of Turku, who so generously shared their talents, ideas, and data about TRAP and bone metabolism. Dr. Tsu-Yi Chao and members of his Hematology/Oncology Division at the TriService General Hospital in Taipei deserve our many thanks for their tireless efforts to promote clinical research on the application of TRAP in cancer and other diseases. The authors are supported by grants from the Research Service of the U.S. Department of Veterans Affairs and by funds from the Clinical Research Foundation. NR 211 TC 34 Z9 35 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD DEC PY 2009 VL 85 IS 6 BP 465 EP 483 DI 10.1007/s00223-009-9309-8 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527NI UT WOS:000272373400001 PM 19915788 ER PT J AU Brandt, WD Matsui, W Rosenberg, JE He, XB Ling, SZ Schaeffer, EM Berman, DM AF Brandt, William D. Matsui, William Rosenberg, Jonathan E. He, Xiaobing Ling, Shizhang Schaeffer, Edward M. Berman, David M. TI Urothelial carcinoma: Stem cells on the edge SO CANCER AND METASTASIS REVIEWS LA English DT Review DE Differentiation; Cancer stem cell; Stroma; Bladder; Wnt; Carcinoma in situ ID ACUTE MYELOID-LEUKEMIA; BREAST-TUMOR HETEROGENEITY; GENE-EXPRESSION SIGNATURE; FREQUENT FGFR3 MUTATIONS; ADVANCED BLADDER-CANCER; HA-RAS ONCOGENE; SIDE-POPULATION; URINARY-BLADDER; OVARIAN-CANCER; IN-SITU AB Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose-across the entire spectrum of cancers-investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about "stemness" in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated. C1 [Brandt, William D.; He, Xiaobing; Ling, Shizhang; Berman, David M.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Matsui, William; Berman, David M.] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21231 USA. [Schaeffer, Edward M.; Berman, David M.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21231 USA. [Rosenberg, Jonathan E.] Dana Farber Canc Inst, Lank Ctr Genitourinary Canc, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Berman, DM (reprint author), Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. EM dberman@jhmi.edu RI Ling, Shizhang/J-6114-2014; OI Matsui, William/0000-0002-3088-0964 FU NIH [R01DK072000, P01CA077664]; Bladder Cancer Research Center at Johns Hopkins University; Stemline Therapeutics FX Our work is supported by NIH Grant Numbers R01DK072000, P01CA077664; The Bladder Cancer Research Center at Johns Hopkins University, and Stemline Therapeutics. NR 122 TC 34 Z9 36 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD DEC PY 2009 VL 28 IS 3-4 BP 291 EP 304 DI 10.1007/s10555-009-9187-6 PG 14 WC Oncology SC Oncology GA 536FW UT WOS:000273031300004 PM 20012172 ER PT J AU Echchgadda, I Kota, S DeLa Cruz, I Sabbah, A Chang, T Harnack, R Mgbemena, V Chatterjee, B Bose, S AF Echchgadda, I. Kota, S. DeLa Cruz, I. Sabbah, A. Chang, T. Harnack, R. Mgbemena, V. Chatterjee, B. Bose, S. TI Anticancer oncolytic activity of respiratory syncytial virus SO CANCER GENE THERAPY LA English DT Article DE oncolytic; respiratory syncytial virus; anticancer; prostate cancer; apoptosis ID HUMAN PROSTATE-CANCER; INNATE ANTIVIRAL RESPONSE; NEWCASTLE-DISEASE VIRUS; LUNG EPITHELIAL-CELLS; KAPPA-B ACTIVATION; MEDIATED APOPTOSIS; CASPASE ACTIVATION; TYPE-3 INFECTION; EXPRESSION; REPLICATION AB Oncolytic virotherapy is an emerging biotherapeutic platform for cancer treatment, which is based on selective infection/killing of cancer cells by viruses. Herein we identify the human respiratory syncytial virus (RSV) as an oncolytic virus. Using prostate cancer models, we show dramatic enhancement of RSV infectivity in vitro in the androgen-independent, highly metastatic PC-3 human prostate cancer cells compared to the non-tumorigenic RWPE-1 human prostate cells. The oncolytic efficiency of RSV was established in vivo using human prostate tumor xenografts in nude mice. Intratumoral and intraperitoneal injections of RSV led to a significant regression of prostate tumors. Furthermore, enhanced viral burden in PC-3 cells led to selective destruction of PC-3 cancer cells in vitro and in xenograft tumors in vivo due to apoptosis triggered by the downregulation of nuclear factor-kappa B (NF-kappa B) activity (and the resulting loss of anti-apoptotic function of NF-kappa B) in RSV-infected PC-3 cells. The intrinsic (mitochondrial) pathway constitutes the major apoptotic pathway; however, the death-receptor-dependent extrinsic pathway, mediated by the paracrine/autocrine action of tumor necrosis factor-alpha produced from infected cells, also partly contributed to apoptosis. Thus, the oncolytic property of RSV can potentially be exploited to develop targeted therapeutics for the clinical management of prostate tumors. Cancer Gene Therapy (2009) 16, 923-935; doi: 10.1038/cgt.2009.34; published online 15 May 2009 C1 [Echchgadda, I.; Kota, S.; Sabbah, A.; Chang, T.; Harnack, R.; Mgbemena, V.; Bose, S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Echchgadda, I.; DeLa Cruz, I.; Chatterjee, B.] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78229 USA. [Chatterjee, B.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Bose, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, 7703 Floyd Curl Dr,MC-7758, San Antonio, TX 78229 USA. EM chatterjee@uthscsa.edu; bose@uthscsa.edu FU American Lung Association National Biomedical Research [RG-49629-N]; NIH [AI069062, CA129246, T32-DE14318, P30 CA54174]; University of Texas Health Science Centre-San Antonio Cancer Institute (SACI) [AG10486, AG19660]; VA Merit Review; Institutional SALSI FX This work was supported by American Lung Association National Biomedical Research Grant (RG-49629-N) (S Bose), NIH grants AI069062 (S Bose), CA129246 (S Bose and B Chatterjee), T32-DE14318 (S Bose and A Sabbah), grant from University of Texas Health Science Centre-San Antonio Cancer Institute (SACI) ( S Bose and B Chatterjee), AG10486 (B Chatterjee), AG19660 (B Chatterjee), VA Merit Review Grant (B Chatterjee) and Institutional SALSI Grant (B Chatterjee). BC is a VA Senior Research Career Scientist. FACS analysis at the Core Facility was supported by the San Antonio Cancer Institute grant from NIH-P30 CA54174. We thank Dr Mark E Peeples (Columbus Children's Hospital and Ohio State University) and Dr Peter L Collins (NIAID, NIH) for providing the GFP-expressing RSV. NR 46 TC 11 Z9 13 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD DEC PY 2009 VL 16 IS 12 BP 923 EP 935 DI 10.1038/cgt.2009.34 PG 13 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 518KZ UT WOS:000271691900006 PM 19444304 ER PT J AU Yang, G Thieu, K Tsai, KY Piris, A Udayakumar, D Njauw, CNJ Ramoni, MF Tsao, H AF Yang, Guang Thieu, Khanh Tsai, Kenneth Y. Piris, Adriano Udayakumar, Durga Njauw, Ching-Ni Jenny Ramoni, Marco F. Tsao, Hensin TI Dynamic Gene Expression Analysis Links Melanocyte Growth Arrest with Nevogenesis SO CANCER RESEARCH LA English DT Article ID FACTOR-BETA; MALIGNANT-MELANOMA; NEURAL CREST; NEVUS CELLS; LESIONS; AUTOCRINE; ISOFORMS; SKIN AB Like all primary cells in vitro, normal human melanocytes exhibit a physiologic decay in proliferative potential as it transitions to a growth-arrested state. The underlying transcriptional program(s) that regulate this phenotypic change is largely unknown. To identify molecular determinants of this process, we performed a Bayesian-based dynamic gene expression analysis on primary melanocytes undergoing proliferative arrest. This analysis revealed several related clusters whose expression behavior correlated with the melanocyte growth kinetics; we designated these clusters the melanocyte growth arrest program (MGAP). These MGAP genes were preferentially represented in benign melanocytic nevi over melanomas and selectively mapped to the hepatocyte fibrosis pathway. This transcriptional relationship between melanocyte growth stasis, nevus biology, and fibrogenic signaling was further validated in vivo by the demonstration of strong pericellular collagen deposition within benign nevi but not melanomas. Taken together, our study provides a novel view of fibroplasia in both melanocyte biology and nevogenesis. [Cancer Res 2009;69(23):9029-37] C1 [Yang, Guang; Thieu, Khanh; Udayakumar, Durga; Njauw, Ching-Ni Jenny; Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Piris, Adriano] Massachusetts Gen Hosp, Div Dermatopathol, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Melanoma & Pigmented Les Ctr, Boston, MA 02114 USA. [Ramoni, Marco F.] Brigham & Womens Hosp, Harvard Partners Ctr Genet & Genom, Boston, MA 02115 USA. [Tsai, Kenneth Y.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77030 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Edwards 211,55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org RI Njauw, Ching-Ni/H-8046-2012 FU MGH FX Financial help from the generous philanthropic donors at MGH. NR 20 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2009 VL 69 IS 23 BP 9029 EP 9037 DI 10.1158/0008-5472.CAN-09-0783 PG 9 WC Oncology SC Oncology GA 527JH UT WOS:000272362800025 PM 19903842 ER PT J AU Schmidt, EJ Mallozzi, RP Thiagalingam, A Holmvang, G d'Avila, A Guhde, R Darrow, R Slavin, GS Fung, MM Dando, J Foley, L Dumoulin, CL Reddy, VY AF Schmidt, Ehud J. Mallozzi, Richard P. Thiagalingam, Aravinda Holmvang, Godtfred d'Avila, Andre Guhde, Renee Darrow, Robert Slavin, Glenn S. Fung, Maggie M. Dando, Jeremy Foley, Lori Dumoulin, Charles L. Reddy, Vivek Y. TI Electroanatomic Mapping and Radiofrequency Ablation of Porcine Left Atria and Atrioventricular Nodes Using Magnetic Resonance Catheter Tracking SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE catheter ablation; MRI; electrophysiology mapping ID FIBRILLATION ABLATION; INITIAL-EXPERIENCE; IMAGE INTEGRATION; SCAR; ARRHYTHMIA; GUIDANCE; THROMBI; LESIONS; SWINE; MODEL AB Background-The MRI-compatible electrophysiology system previously used for MR-guided left ventricular electroanatomic mapping was enhanced with improved MR tracking, an MR-compatible radiofrequency ablation system and higher-resolution imaging sequences to enable mapping, ablation, and ablation monitoring in smaller cardiac structures. MR-tracked navigation was performed to the left atrium (LA) and atrioventricular (AV) node, followed by LA electroanatomic mapping and radiofrequency ablation of the pulmonary veins (PVs) and AV node. Methods and Results-One ventricular ablation, 7 PV ablations, 3 LA mappings, and 3 AV node ablations were conducted. Three MRI-compatible devices (ablation/mapping catheter, torqueable sheath, stimulation/pacing catheter) were used, each with 4 to 5 tracking microcoils. Transseptal puncture was performed under x-ray, with all other procedural steps performed in the MRI. Preacquired MRI roadmaps served for real-time catheter navigation. Simultaneous tracking of 3 devices was performed at 13 frames per second. LA mapping and PV radiofrequency ablation were performed using tracked ablation catheters and sheaths. Ablation points were registered and verified after ablation using 3D myocardial delayed enhancement and postmortem gross tissue examination. Complete LA electroanatomic mapping was achieved in 3 of 3 pigs, Right inferior PV circumferential ablation was achieved in 3 of 7 pigs, with incomplete isolation caused by limited catheter deflection. During AV node ablation, ventricular pacing was performed, 3 devices were simultaneously tracked, and intracardiac ECGs were displayed. 3D myocardial delayed enhancement visualized node injury 2 minutes after ablation. AV node block succeeded in 2 of 3 pigs, with 1 temporary block. Conclusions-LA mapping, PV radiofrequency ablation, and AV node ablation were demonstrated under MRI guidance. Intraprocedural 3D myocardial delayed enhancement assessed lesion positional accuracy and dimensions. (Circ Arrhythm Electrophysiol. 2009; 2: 695-704.) C1 [Schmidt, Ehud J.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Schmidt, Ehud J.; Thiagalingam, Aravinda; Holmvang, Godtfred; Foley, Lori] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Mallozzi, Richard P.; Guhde, Renee; Darrow, Robert] ONI Med Syst Inc, Wilmington, MA USA. [d'Avila, Andre; Reddy, Vivek Y.] Univ Miami, Dept Cardiol, Miami, FL USA. [Mallozzi, Richard P.; Guhde, Renee; Darrow, Robert] GE Global Res, Niskayuna, NY USA. [Slavin, Glenn S.; Fung, Maggie M.] GE Healthcare Appl Sci Lab, Bethesda, MD USA. [Dando, Jeremy] St Jude Med, Minnetonka, MN USA. [Dumoulin, Charles L.] Cincinnati Childrens Hosp, Dept Radiol, Med Ctr, Cincinnati, OH USA. RP Schmidt, EJ (reprint author), Brigham & Womens Hosp, Dept Radiol, Room LM 010C,221 Longwood Ave, Boston, MA 02115 USA. EM eschmidt3@partners.org RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; FU GE Healthcare; St Jude Medical; National Institutes of Health [HL68064] FX This work was supported by GE Healthcare, St Jude Medical, and National Institutes of Health grant HL68064 (to Dr Reddy). NR 25 TC 27 Z9 27 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD DEC PY 2009 VL 2 IS 6 BP 695 EP + DI 10.1161/CIRCEP.109.882472 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 533AM UT WOS:000272794300013 PM 19841033 ER PT J AU Wiederhold, NP Thornton, CR Najvar, LK Kirkpatrick, WR Bocanegra, R Patterson, TF AF Wiederhold, Nathan P. Thornton, Christopher R. Najvar, Laura K. Kirkpatrick, William R. Bocanegra, Rosie Patterson, Thomas F. TI Comparison of Lateral Flow Technology and Galactomannan and (1 -> 3)-beta-D-Glucan Assays for Detection of Invasive Pulmonary Aspergillosis SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID NEUTROPENIC PATIENTS; ENZYME-IMMUNOASSAY; ANTIFUNGAL THERAPY; FUNGAL-INFECTIONS; DIAGNOSIS; LEUKEMIA AB We compared a lateral flow device to galactomannan and (1 -> 3)-beta-D-glucan assays to detect invasive aspergillosis in an established guinea pig model of pulmonary disease. The lateral flow device became positive earlier ( =day 3) than the (1 -> 3)-beta-D-glucan and galactomannan assays ( day 5), with all samples positive by each assay on day 7. C1 [Wiederhold, Nathan P.; Najvar, Laura K.; Kirkpatrick, William R.; Bocanegra, Rosie; Patterson, Thomas F.] UTHSCSA, San Antonio, TX 78229 USA. [Wiederhold, Nathan P.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Thornton, Christopher R.] Univ Exeter, Exeter, Devon, England. [Najvar, Laura K.; Kirkpatrick, William R.; Bocanegra, Rosie; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Wiederhold, NP (reprint author), UTHSCSA, PERC MC 6220,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM wiederholdn@uthscsa.edu OI Wiederhold, Nathan/0000-0002-2225-5122 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [N01-AI-30041]; CyDex Pharmaceuticals; Pfizer; Schering-Plough; Basilea; Merck; Toyoma FX N. P. W. has received research support from CyDex Pharmaceuticals, Pfizer, and Schering-Plough. T. F. P. has received research support from Basilea, Merck, Pfizer, and Schering-Plough, has received speaker fees from Merck and Pfizer, and has been a consultant for Basilea, Merck, Pfizer, and Toyoma. L. K. N., W. R. K., and R. B. have no such disclosures to report. NR 9 TC 27 Z9 29 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD DEC PY 2009 VL 16 IS 12 BP 1844 EP 1846 DI 10.1128/CVI.00268-09 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 524QG UT WOS:000272157200020 PM 19793899 ER PT J AU Fulciniti, M Hideshima, T Vermot-Desroches, C Pozzi, S Nanjappa, P Shen, ZX Patel, N Smith, ES Wang, W Prabhala, R Tai, YT Tassone, P Anderson, KC Munshi, NC AF Fulciniti, Mariateresa Hideshima, Teru Vermot-Desroches, Claudine Pozzi, Samantha Nanjappa, Puru Shen, Zhenxin Patel, Nipun Smith, Ernest S. Wang, Wei Prabhala, Rao Tai, Yu-tzu Tassone, Pierfrancesco Anderson, Kenneth C. Munshi, Nikhil C. TI A High-Affinity Fully Human Anti-IL-6 mAb, 1339, for the Treatment of Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; INDUCED APOPTOSIS; PRECLINICAL MODELS; INTERLEUKIN-6; BONE; DEXAMETHASONE; GROWTH; CELLS; DIFFERENTIATION; INHIBITION AB Purpose: We investigated the in vitro and in vivo anti-multiple myeloma activity of monoclonal antibody (mAb) 1339, a high-affinity fully humanized anti-interleukin 6 mAb (immunoglobulin G1), alone and in combination with conventional and novel anti-multiple myeloma agents, as well as its effect on bone turnover. Experimental Design: We examined the growth inhibitory effect of 1339 against multiple myeloma cell lines in the absence and in the presence of bone marrow stromal cells, alone or in combination with dexamethasone, bortezomib, perifosine, and Revlimid. Using the severe combined immunodeficient (SCID)-hu murine model of multiple myeloma, we also examined the effect of 1339 on multiple myeloma cell growth and multiple myeloma bone disease. Results: mAb 1339 significantly inhibited growth of multiple myeloma cell in the presence of bone marrow stromal cell in vitro, associated with inhibition of phosphorylation of signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, and Akt. In addition, mAb 1339 enhanced cytotoxicity induced by dexamethasone, as well as bortezomib, lenalidomide, and perifosine, in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory effects of dexamethasone in vivo in SCID-hu mouse model of multiple myeloma. mAb 1339 treatment also resulted in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model. Conclusions: Our data confirm in vitro and in vivo anti-multiple myeloma activity of, as well as inhibition of bone turnover by, fully humanized mAb 1339, as a single agent and in combination with conventional and novel agents, providing a rationale for its clinical evaluation in multiple myeloma. (Clin Cancer Res 2009;15(23):7144-52) C1 [Fulciniti, Mariateresa; Hideshima, Teru; Pozzi, Samantha; Nanjappa, Puru; Tai, Yu-tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Fulciniti, Mariateresa; Prabhala, Rao; Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. [Shen, Zhenxin; Patel, Nipun] Ctr Adv Orthoped Studies, Boston, MA USA. [Fulciniti, Mariateresa; Tassone, Pierfrancesco] Magna Graecia Univ Catanzaro, Catanzaro, Italy. [Vermot-Desroches, Claudine] IDD Biotech, Dardilly, France. [Smith, Ernest S.; Wang, Wei] Vaccinex, Rochester, NY USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St,D1B06, Boston, MA 02115 USA. EM Nikhil_Munshi@dfci.harvard.edu RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU AIRC (Associazione Italiana per la Ricerca sul Cancro); NIH [R01-124929, P50-100007, P01-78378]; IDD Biotech FX AIRC (Associazione Italiana per la Ricerca sul Cancro) (P. Tassone) Department of Veterans Affairs Merit Review Awards, NIH grants R01-124929 (N.C. Munshi) and P50-100007 and P01-78378 (N.C. Munshi and K.C. Anderson), and a commercial research grant from IDD Biotech (N.C. Munshi). NR 30 TC 63 Z9 67 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2009 VL 15 IS 23 BP 7144 EP 7152 DI 10.1158/1078-0432.CCR-09-1483 PG 9 WC Oncology SC Oncology GA 527JQ UT WOS:000272363700008 PM 19934301 ER PT J AU Ooi, MG Hayden, PJ Kotoula, V McMillin, DW Charalambous, E Daskalaki, E Raje, NS Munshi, NC Chauhan, D Hideshima, T Buon, L Clynes, M O'Gorman, P Richardson, PG Mitsiades, CS Anderson, KC Mitsiades, N AF Ooi, Melissa G. Hayden, Patrick J. Kotoula, Vassiliki McMillin, Douglas W. Charalambous, Elpida Daskalaki, Emily Raje, Noopur S. Munshi, Nikhil C. Chauhan, Dharminder Hideshima, Teru Buon, Leutz Clynes, Martin O'Gorman, Peter Richardson, Paul G. Mitsiades, Constantine S. Anderson, Kenneth C. Mitsiades, Nicholas TI Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib SO CLINICAL CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA CELLS; INHIBITOR PS-341; ANTIMYELOMA ACTIVITY; P53 PATHWAY; CANCER; APOPTOSIS; GENE; MDM2; SENSITIVITY; ANTAGONISTS AB Purpose: p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM). Experimental Design: We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3. Results: The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells. Conclusions: This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy. (Clin Cancer Res 2009;15(23):7153-60) C1 [Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Raje, Noopur S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. [Kotoula, Vassiliki; Charalambous, Elpida; Daskalaki, Emily] Aristotle Univ Thessaloniki, Sch Med, Dept Pathol, GR-54006 Thessaloniki, Greece. [Clynes, Martin] Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland. [O'Gorman, Peter] Mater Misericordiae Univ Hosp, Dept Haematol, Dublin, Ireland. RP Mitsiades, CS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Mayer Bldg,Room M555,44 Binney St, Boston, MA 02115 USA. EM Constantine_Mitsiades@dfci.harvard.edu FU NCI NIH HHS [R01 CA050947-17A1, R01 CA050947] NR 28 TC 41 Z9 46 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2009 VL 15 IS 23 BP 7153 EP 7160 DI 10.1158/1078-0432.CCR-09-1071 PG 8 WC Oncology SC Oncology GA 527JQ UT WOS:000272363700009 PM 19934289 ER PT J AU Kim, K Pollard, JM Norris, AJ McDonald, JT Sun, YL Micewicz, E Pettijohn, K Damoiseaux, R Iwamoto, KS Sayre, JW Price, BD Gatti, RA McBride, WH AF Kim, Kwanghee Pollard, Julianne M. Norris, Andrew J. McDonald, J. Tyson Sun, Yingli Micewicz, Ewa Pettijohn, Kelly Damoiseaux, Robert Iwamoto, Keisuke S. Sayre, James W. Price, Brendan D. Gatti, Richard A. McBride, William H. TI High-Throughput Screening Identifies Two Classes of Antibiotics as Radioprotectors: Tetracyclines and Fluoroquinolones SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE ACETYLTRANSFERASE; EXTRACELLULAR ADENOSINE; IONIZING-RADIATION; TUMOR-CELLS; MICE; ACETYLATION; DAMAGE; CHROMATIN; REPAIR; TIP60 AB Purpose: Discovery of agents that protect or mitigate normal tissue from radiation injury during radiotherapy, accidents, or terrorist attacks is of importance. Specifically, bone marrow insufficiency, with possible infection due to immunosuppression, can occur after total body irradiation (TBI) or regional irradiation and is a major component of the acute radiation syndrome. The purpose of this study was to identify novel radioprotectors and mitigators of the hematopoietic system. Experimental Design: High-throughput screening of small-molecule libraries was done using viability of a murine lymphocyte line as a readout with further validation in human lymphoblastoid cells. The selected compounds were then tested for their ability to counter TBI lethality in mice. Results: All of two major classes of antibiotics, tetracyclines and fluoroquinolones, which share a common planar ring moiety, were radioprotective. Furthermore, tetracycline protected murine hematopoietic stem/progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacine also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure. Conclusions: Tetracyclines and fluoroquinolones can be robust radioprotectors and mitigators of the hematopoietic system with potential utility in anticancer radiotherapy and radiation emergencies. (Clin Cancer Res 2009;15(23):7238-45) C1 [McBride, William H.] Univ Calif Los Angeles, David Geffen Sch Med, Roy E Coats Res Labs, Dept Radiat Oncol, Los Angeles, CA 90095 USA. [Pollard, Julianne M.; Pettijohn, Kelly; Gatti, Richard A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Sayre, James W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Publ Hlth Biostat Radiol, Los Angeles, CA 90095 USA. [Norris, Andrew J.] Univ Calif Los Angeles, David Geffen Sch Med, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA. [Sun, Yingli; Price, Brendan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Damoiseaux, Robert] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol Screening Shared Resource, Los Angeles, CA 90095 USA. RP McBride, WH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Roy E Coats Res Labs, Dept Radiat Oncol, Room B3-109,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM wmcbride@mednet.ucla.edu RI Damoiseaux, Robert/F-1086-2011; OI Damoiseaux, Robert/0000-0002-7611-7534; McDonald, J. Tyson/0000-0003-1955-6052; McDonald, John/0000-0003-4300-6827 FU University of California at Los Angeles Center for Biological Radioprotectors [U19 A1067769]; NIAID; Dana-Farber/Harvard Center for Medical Counter Measures Against Radiation [U19 A1067751] FX Grant support: University of California at Los Angeles Center for Biological Radioprotectors grant U19 A1067769/NIAID and Dana-Farber/Harvard Center for Medical Counter Measures Against Radiation grant U19 A1067751. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). NR 41 TC 29 Z9 30 U1 1 U2 3 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 DEC 1 PY 2009 VL 15 IS 23 BP 7238 EP 7245 DI 10.1158/1078-0432.CCR-09-1964 PG 8 WC Oncology SC Oncology GA 527JQ UT WOS:000272363700018 PM 19920105 ER PT J AU Ogino, S Meyerhardt, JA Irahara, N Niedzwiecki, D Hollis, D Saltz, LB Mayer, RJ Schaefer, P Whittom, R Hantel, A Benson, A Goldberg, RM Bertagnolli, MM Fuchs, CS AF Ogino, Shuji Meyerhardt, Jeffrey A. Irahara, Natsumi Niedzwiecki, Donna Hollis, Donna Saltz, Leonard B. Mayer, Robert J. Schaefer, Paul Whittom, Renaud Hantel, Alexander Benson, Al B., III Goldberg, Richard M. Bertagnolli, Monica M. Fuchs, Charles S. CA Canadian Canc Soc Res Inst TI KRAS Mutation in Stage III Colon Cancer and Clinical Outcome Following Intergroup Trial CALGB 89803 SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC COLORECTAL-CANCER; ISLAND METHYLATOR PHENOTYPE; K-RAS MUTATION; MICROSATELLITE INSTABILITY; PIK3CA MUTATION; CETUXIMAB; CHEMOTHERAPY; PROGNOSIS; THERAPY; FLUOROURACIL AB Purpose: Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy. Methods: We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status. Results: Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions: In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. (Clin Cancer Res 2009;15(23):7322-9) C1 [Ogino, Shuji] Harvard Univ, Dana Farber Canc Inst, Brigham & Womens Hosp, Sch Med,Ctr Mol Oncol Pathol,Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Meyerhardt, Jeffrey A.; Irahara, Natsumi; Mayer, Robert J.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Niedzwiecki, Donna; Hollis, Donna] Duke Univ, Med Ctr, CALGB Stat Ctr, Durham, NC USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schaefer, Paul] Toledo Community Hosp, Oncol Program, Toledo, OH USA. [Whittom, Renaud] Hop Sacre Coeur, Montreal, PQ H4J 1C5, Canada. [Hantel, Alexander] Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. [Benson, Al B., III] Northwestern Univ, Chicago, IL 60611 USA. [Goldberg, Richard M.] Univ N Carolina, Chapel Hill, NC USA. RP Ogino, S (reprint author), Harvard Univ, Dana Farber Canc Inst, Brigham & Womens Hosp, Sch Med,Ctr Mol Oncol Pathol,Dept Pathol, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu RI Goldberg , Richard/M-1311-2013; OI Saltz, Leonard/0000-0001-8353-4670 FU Baptist Cancer Institute CCOP, Memphis, TN - Lee S. Schwartzberg, M.D. [CA71323]; Christiana Care Health Services, Inc. CCOP, Wilmington, DE - Stephen Grubbs, M.D. [CA45418]; Dana-Farber Cancer Institute, Boston, MA - Eric P. Winer, M.D. [CA32291]; Dartmouth Medical School - Norris Cotton Cancer Center, Lebanon, NH - Marc S. Ernstoff, M.D. [CA04326]; Duke University Medical Center, Durham, NC - Jeffrey Crawford, M.D. [CA47577]; Georgetown University Medical Center, Washington, DC Minetta C. Liu, M.D. [CA77597]; Cancer Centers of the Carolinas, Greenville, SC - Jeffrey K. Giguere, M.D. [CA29165]; Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY - Jeffrey Kirshner, M.D. [CA45389]; Long Island Jewish Medical Center, Lake Success, NY - Kanti R. Rai, M.D. [CA11028]; Massachusetts General Hospital, Boston, MA - Jeffrey W. Clark, M.D. [CA12449]; Memorial Sloan-Kettering Cancer Center, New York, NY Clifford A. Hudis, M.D. [CA77651]; Missouri Baptist Medical Center, St. Louis, MO - Alan P. Lyss, M.D. [CA114558-02]; Mount Sinai Medical Center, Miami, FL - Rogerio C. Lilenbaurn, M.D. [CA45564]; Mount Sinai School of Medicine, New York, NY - Lewis R. Silverman, M.D. [CA04457]; Nevada Cancer Research Foundation CCOP, Las Vegas, NV John A. Ellerton, M.D. [CA35421]; North Shore-Long Island Jewish Health System, New Hyde Park, NY - Daniel Budman, M.D. [CA35279]; Rhode Island Hospital, Providence, RI - William Sikov, M.D. [CA08025]; Roswell Park Cancer Institute, Buffalo, NY - Ellis Levine, M.D. [CA02599]; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro [CA45808]; State University of New York Upstate Medical University, Syracuse [CA21060]; Ohio State University Medical Center, Columbus, OH [CA77658]; University of California at San Diego, San Diego, CA [CA11789]; University of California at San Francisco, San Francisco [CA60138]; University of Chicago, Chicago, IL [CA41287]; University of Illinois MBCCOP, Chicago, IL [CA74811]; University of Iowa, Iowa City, IA [CA47642]; University of Maryland Greenebaurn Cancer Center, Baltimore, MD [CA31983]; University of Massachusetts Medical School, Worcester [CA37135]; University of Minnesota, Minneapolis, MN [CA16450]; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO [CA12046]; University of Nebraska Medical Center, Omaha, NE [CA77298]; University of North Carolina [CA47559]; University of Tennessee Memphis, Memphis, TN [CA47555]; University of Vermont, Burlington, VT [CA77406]; Wake Forest University School of Medicine, Winston-Salem, NC [CA03927]; Walter Reed Army Medical Center, Washington, DC [CA26806]; Washington University School of Medicine, St. Louis, MO [CA77440]; Weill Medical College of Cornell University, New York [CA07968] FX Weill Medical College of Cornell University, New York, NY John Leonard, M.D., supported by CA07968 NR 46 TC 105 Z9 111 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 DEC 1 PY 2009 VL 15 IS 23 BP 7322 EP 7329 DI 10.1158/1078-0432.CCR-09-1570 PG 8 WC Oncology SC Oncology GA 527JQ UT WOS:000272363700027 PM 19934290 ER PT J AU Wolchok, JD Hoos, A O'Day, S Weber, JS Hamid, O Lebbe, C Maio, M Binder, M Bohnsack, O Nichol, G Humphrey, R Hodi, FS AF Wolchok, Jedd D. Hoos, Axel O'Day, Steven Weber, Jeffrey S. Hamid, Omid Lebbe, Celeste Maio, Michele Binder, Michael Bohnsack, Oliver Nichol, Geoffrey Humphrey, Rachel Hodi, F. Stephen TI Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria SO CLINICAL CANCER RESEARCH LA English DT Article ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; METASTATIC MELANOMA; PHASE-I/II; 2 CYCLES; CANCER; IPILIMUMAB; BLOCKADE; AUTOIMMUNITY; CHEMOTHERAPY; REGRESSION AB Purpose: Immunotherapeutic agents produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes. Resulting clinical response patterns extend beyond those of cytotoxic agents and can manifest after an initial increase in tumor burden or the appearance of new lesions (progressive disease). Response Evaluation Criteria in Solid Tumors or WHO criteria, designed to detect early effects of cytotoxic agents, may not provide a complete assessment of immunotherapeutic agents. Novel criteria for the evaluation of antitumor responses with immunotherapeutic agents are required. Experimental Design: The phase II clinical trial program with ipilimumab, an antibody that blocks CTL antigen-4, represents the most comprehensive data set available to date for an immunotherapeutic agent. Novel immune therapy response criteria proposed, based on the shared experience from community workshops and several investigators, were evaluated using data from ipilimumab phase II clinical trials in patients with advanced melanoma. Results: Ipilimumab monotherapy resulted in four distinct response patterns: (a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions. All patterns were associated with favorable survival. Conclusion: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria. Further prospective evaluations of the immune-related response criteria, particularly their association with overall survival, are warranted. (Clin Cancer Res 2009;15(23):7412-20) C1 [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, New York, NY 10021 USA. [Hoos, Axel; Humphrey, Rachel] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [O'Day, Steven; Hamid, Omid] Angeles Clin & Res Inst, Santa Monica, CA USA. [Weber, Jeffrey S.] Univ S Florida, Dept Oncol Sci, Tampa, FL USA. [Lebbe, Celeste] St Louis Hosp, Dept Dermatol, Paris, France. [Maio, Michele] Univ Hosp Siena, Ist Toscano Tumori, Div Med Oncol & Immunotherapy, Siena, Italy. [Binder, Michael] Med Univ Vienna, Dept Dermatol, Vienna, Austria. [Bohnsack, Oliver] Percept Informat, Berlin, Germany. [Nichol, Geoffrey] Medarex Inc, Princeton, NJ USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wolchok, JD (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave,Room Z-1462, New York, NY 10021 USA. EM wolchokj@mskcc.org OI coral, sandra/0000-0002-1308-3082 FU Bristol-Myers Squibb Company FX Grant support: Bristol-Myers Squibb Company. NR 29 TC 973 Z9 1008 U1 7 U2 28 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 DEC 1 PY 2009 VL 15 IS 23 BP 7412 EP 7420 DI 10.1158/1078-0432.CCR-09-1624 PG 9 WC Oncology SC Oncology GA 527JQ UT WOS:000272363700039 PM 19934295 ER PT J AU Kelley, WE Januzzi, JL Christenson, RH AF Kelley, Walter E. Januzzi, James L. Christenson, Robert H. TI Increases of Cardiac Troponin in Conditions other than Acute Coronary Syndrome and Heart Failure SO CLINICAL CHEMISTRY LA English DT Review ID ACUTE AORTIC DISSECTION; CRITICALLY-ILL PATIENTS; RADIOFREQUENCY CATHETER ABLATION; ACUTE MYOCARDIAL-INFARCTION; ACUTE ISCHEMIC-STROKE; ASSOCIATION STATISTICS-COMMITTEE; RESPIRATORY-DISTRESS-SYNDROME; ACUTE ALLOGRAFT-REJECTION; ACUTE PULMONARY-EMBOLISM; INTENSIVE-CARE-UNIT AB BACKGROUND: Although cardiac troponin (cTn) is a cornerstone marker in the assessment and management of patients with acute coronary syndrome (ACS) and heart failure (HF), cTn is not diagnostically specific for any single myocardial disease process. This narrative review discusses increases in cTn that result from acute and chronic diseases, iatrogenic causes, and myocardial injury other than ACS and HF. CONTENT: Increased cTn concentrations have been reported in cardiac, vascular, and respiratory disease and in association with infectious processes. In cases involving acute aortic dissection, cerebrovascular accident, treatment in an intensive care unit, and upper gastrointestinal bleeding, increased cTn predicts a longer time to diagnosis and treatment, increased length of hospital stay, and increased mortality. cTn increases are diagnostically and prognostically useful in patients with cardiac inflammatory diseases and in patients with respiratory disease; in respiratory disease cTn can help identify patients who would benefit from aggressive management. In chronic renal failure patients the diagnostic sensitivity of cTn for ACS is decreased, but cTn is prognostic for the development of cardiovascular disease. cTn also provides useful information when increases are attributable to various iatrogenic causes and blunt chest trauma. SUMMARY: Information on the diagnostic and prognostic uses of cTn in conditions other than ACS and heart failure is accumulating. Although increased cTn in settings other than ACS or heart failure is frequently considered a clinical confounder, the astute physician must be able to interpret cTn as a dynamic marker of myocardial damage, using clinical acumen to determine the source and significance of any reported cTn increase. (C) 2009 American Association for Clinical Chemistry C1 [Kelley, Walter E.] Univ Maryland, Med Ctr, Dept Pathol, Sch Med, Baltimore, MD 21201 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Dept Med, Cardiac Unit, Boston, MA 02114 USA. RP Kelley, WE (reprint author), Univ Maryland, Med Ctr, Dept Pathol, Sch Med, NBW-64,22 S Greene St, Baltimore, MD 21201 USA. EM walterkelleydo@gmail.com NR 145 TC 97 Z9 103 U1 1 U2 5 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD DEC PY 2009 VL 55 IS 12 BP 2098 EP 2112 DI 10.1373/clinchem.2009.130799 PG 15 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 529LP UT WOS:000272518500011 PM 19815610 ER PT J AU Milbury, CA Li, J Makrigiorgos, GM AF Milbury, Coren A. Li, Jin Makrigiorgos, G. Mike TI COLD-PCR-Enhanced High-Resolution Melting Enables Rapid and Selective Identification of Low-Level Unknown Mutations SO CLINICAL CHEMISTRY LA English DT Article ID CELL LUNG-CANCER; REAL-TIME PCR; SENSITIVE DETECTION; DYE CONCENTRATION; CURVE ANALYSIS; KINASE DOMAIN; P53 MUTATIONS; DIGITAL PCR; EGFR; AMPLIFICATION AB BACKGROUND: Analysis of clinical samples often necessitates identification of low-level somatic mutations within wild-type DNA; however, the selectivity and sensitivity of the methods are often limiting. COLD-PCR (coamplification at lower denaturation temperature-PCR) is a new form of PCR that enriches mutation-containing amplicons to concentrations sufficient for direct sequencing; nevertheless, sequencing itself remains an expensive mutation-screening approach. Conversely, high-resolution melting (HRM) is a rapid, inexpensive scanning method, but it cannot specifically identify the detected mutation. To enable enrichment, quick scanning, and identification Of low-level unknown mutations, we combined COLD-PCR with HRM mutation scanning, followed by sequencing of positive samples. METHODS: Mutation-containing cell-line DNA serially diluted into wild-type DNA and DNA samples from human lung adenocarcinomas containing low-level mutations were amplified via COLD-PCR and via conventional PCR for TP53 (tumor protein p53) exons 6-8, and the 2 approaches were compared. HRM analysis was used to screen amplicons for mutations; mutation-positive amplicons were sequenced. RESULTS: Dilution experiments indicated an approximate 6- to 20-fold improvement in selectivity with COLD-PCR/HRM. Conventional PCR/HRM exhibited mutation-detection limits of approximately 2% to 10%, whereas COLD-PCR/HRM exhibited limits from approximately 0.1% to 1% mutant-to-wild-type ratio. After HRM analysis of lung adenocarcinoma samples, we detected 7 mutations by both PCR methods in exon 7; however, in exon 8 we detected 9 mutations in COLD-PCR amplicons, compared with only 6 mutations in conventional-PCR amplicons. Furthermore, 94% of the HRM-detected mutations were successfully sequenced with COLD-PCR amplicons, compared with 50% with conventional-PCR amplicons. CONCLUSIONS: COLD-PCR/HRM improves the mutation-scanning capabilities of HRM and combines high selectivity, convenience, and low cost with the ability to sequence unknown low-level mutations in clinical samples. (C) 2009 American Association for Clinical Chemistry C1 [Milbury, Coren A.; Li, Jin; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol,Div Med Phys & Biophys, Boston, MA USA. [Milbury, Coren A.; Li, Jin; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Div Genome Stabil & DNA Repair, Boston, MA 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 FU National Cancer Institute [T32-CA009078]; JCRT Foundation; NIH [CA-138280, CA-111994] FX This project was supported by T32-CA009078 from the National Cancer Institute (C.A. Milbury), the JCRT Foundation (J. Li), and NIH grants CA-138280 and CA-111994. Expert Testimony: None declared. NR 33 TC 45 Z9 49 U1 1 U2 7 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD DEC PY 2009 VL 55 IS 12 BP 2130 EP 2143 DI 10.1373/clinchem.2009.131029 PG 14 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 529LP UT WOS:000272518500014 PM 19815609 ER PT J AU Lo, J You, SM Wei, J Canavan, B Grinspoon, S AF Lo, Janet You, Sung M. Wei, Jeffrey Canavan, Bridget Grinspoon, Steven TI Relationship of peak growth hormone to cardiovascular parameters, waist circumference, lipids and glucose in HIV-infected patients and healthy adults SO CLINICAL ENDOCRINOLOGY LA English DT Article ID BODY-COMPOSITION; FAT ACCUMULATION; ADIPOSE-TISSUE; BLOOD-PRESSURE; RISK MARKERS; DEFICIENCY; LIPODYSTROPHY; SECRETION; MEN; HYPOPITUITARISM AB P>Objective Relative growth hormone (GH) deficiency is highly prevalent in patients with HIV. The purpose of this study was to investigate relationships of GH to metabolic and anthropometric parameters in HIV patients and non-HIV controls. Design Peak GH and metabolic parameters were assessed in a cross-sectional study of 191 HIV patients and 62 age and BMI-matched healthy controls. Methods Peak GH was assessed by GHRH/arginine stimulation testing. Results HIV patients demonstrated similar BMI, but increased waist circumference (WC) and reduced peak GH to GHRH/arginine compared with control subjects [median = 12 center dot 4 (interquartile range: 6 center dot 3-24 center dot 8) vs. 21 center dot 3 (8 center dot 8, 34 center dot 5) mu g/l, P = 0 center dot 006, HIV vs. control]. Among HIV and non-HIV groups, peak GH was inversely associated with WC (rho = -0 center dot 44, P < 0 center dot 0001; rho = -0 center dot 63, P < 0 center dot 0001; HIV patients and controls, respectively), blood pressure (rho = -0 center dot 17, P = 0 center dot 02; rho = -0 center dot 36, P = 0 center dot 004), triglycerides (rho = -0 center dot 37, P < 0 center dot 0001; rho = -0 center dot 43, P = 0 center dot 001), glucose (rho = -0 center dot 34, P < 0 center dot 0001; rho = -0 center dot 30, P = 0 center dot 02), insulin (rho = -0 center dot 43, P < 0 center dot 0001; rho = -0 center dot 60, P < 0 center dot 0001) and CRP (rho = -0 center dot 29, P < 0 center dot 0001; rho = -0 center dot 59, P < 0 center dot 0001). Among HIV patients, the inverse association between peak GH and fasting glucose remained significant (beta = -0 center dot 006 mmol/l change in glucose per mu g/l change in GH, P = 0 center dot 004) controlling for age, gender, race, BMI, WC, protease inhibitor (PI) and nucleoside reverse transcriptase inhibitors. Similarly, the inverse association between peak GH and triglycerides remained significant (beta = -0 center dot 01 mmol/l change in triglycerides per mu g/l change in GH, P = 0 center dot 02) controlling for age, gender, race, BMI, WC, PI and lipid-lowering medications. HIV men with peak GH < 7 center dot 5 mu g/l demonstrated higher BMI, WC, SBP, triglycerides, glucose and CRP. Conclusions Reduced GH secretion is independently associated with dyslipidaemia and higher glucose, among HIV patients with abdominal fat accumulation. C1 [Lo, Janet] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM jlo@partners.org FU NIH [RO1 DK063639, M01 RR01066-25S1, K23 HL092792, K24 DK0645450] FX The authors wish to thank the nursing and bionutrition staff of the Clinical Research Centers of MGH and MIT, Jeff Breu, and all of the participants in this study. This study was supported in part by NIH RO1 DK063639, NIH M01 RR01066-25S1, NIH K23 HL092792 and NIH K24 DK0645450. NR 28 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2009 VL 71 IS 6 BP 815 EP 822 DI 10.1111/j.1365-2265.2009.03603.x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 517PK UT WOS:000271628100010 PM 19508594 ER PT J AU McCormack, S Mitchell, DM Woo, M Levitsky, LL Ross, DS Misra, M AF McCormack, Shana Mitchell, Deborah M. Woo, Melissa Levitsky, Lynne L. Ross, Douglas S. Misra, Madhusmita TI Radioactive iodine for hyperthyroidism in children and adolescents: referral rate and response to treatment SO CLINICAL ENDOCRINOLOGY LA English DT Article ID CHILDHOOD GRAVES-DISEASE; LONG-TERM TREATMENT; RADIOIODINE TREATMENT; PREPUBERTAL CHILDREN; MEDICAL THERAPY; THYROID VOLUME; I-131; REMISSION; PROPYLTHIOURACIL; THYROTOXICOSIS AB P>Objectives Radioactive iodine (131I) therapy is increasingly viewed as a safe and effective treatment for paediatric and adolescent hyperthyroidism. Our objective was to estimate treatment response and its predictors and describe current referral practices for 131I therapy. Design Retrospective study. Patients One hundred and thirty-one children 30 days-21 years old with laboratory evidence of hyperthyroidism, seen in an academic paediatric and adolescent endocrinology practice. Measurements Rate of referral, indications for 131I, predictors of poor treatment response. Results Thirty-eight of 102 patients with persistent hyperthyroidism (37%) received 131I (160 mu Ci/g thyroid tissue/131I uptake), as did an additional 10 patients initially evaluated by adult thyroidologists. Primary indications were intolerance to (29%) or poor control on (19%) antithyroid drugs, patient preference (50%) and unknown (2%). Of 48 patients treated with 131I, 89% and 11% became hypothyroid after one and two 131I doses, respectively. The goal of 131I therapy was attainment of hypothyroidism. 'Poor treatment response' (seen in 27%) was defined as requirement for a second 131I dose or failure to achieve hypothyroidism after 6 months. Predictors of poor treatment response included: previous use of antithyroid drugs (37%vs. 0%, P = 0 center dot 02), ophthalmopathy (58%vs. 8%, P = 0 center dot 002), and an interval of >= 12 months from diagnosis to 131I (50%vs. 10%, P = 0 center dot 003). A very elevated free T4 tended to be more prevalent in those with poor response. Conclusions In children and adolescents with hyperthyroidism, high rates of success after 131I are achievable. Use of antithyroid drugs, pre-existing eye disease and prolonged time to 131I may confer relative resistance to 131I. C1 [McCormack, Shana; Mitchell, Deborah M.; Woo, Melissa; Levitsky, Lynne L.; Misra, Madhusmita] MassGeneral Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Ross, Douglas S.] MassGeneral Hosp Children, Thyroid Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Misra, M (reprint author), MassGeneral Hosp Children, Pediat Endocrine Unit, 55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org OI Mitchell, Deborah/0000-0003-0364-9107 NR 28 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2009 VL 71 IS 6 BP 884 EP 891 DI 10.1111/j.1365-2265.2009.03565.x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 517PK UT WOS:000271628100021 PM 19250263 ER PT J AU Borzutzky, A Crompton, B Bergmann, AK Giliani, S Baxi, S Martin, M Neufeld, EJ Notarangelo, LD AF Borzutzky, Arturo Crompton, Brian Bergmann, Anke K. Giliani, Silvia Baxi, Sachin Martin, Madelena Neufeld, Ellis J. Notarangelo, Luigi D. TI Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter SO CLINICAL IMMUNOLOGY LA English DT Article DE Hereditary folate malabsorption; PCFT; Folic acid; Severe combined immunodeficiency; Recent thymic emigrants ID LYMPHOCYTES IN-VITRO; CONGENITAL MALABSORPTION; FOLIC-ACID; PROLIFERATION; FAMILY; DEFECT; GENE AB Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and tack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naive T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral. folinic acid repletion. (C) 2009 Elsevier Inc. All rights reserved. C1 [Borzutzky, Arturo; Giliani, Silvia; Baxi, Sachin; Notarangelo, Luigi D.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Crompton, Brian; Bergmann, Anke K.; Neufeld, Ellis J.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Crompton, Brian; Neufeld, Ellis J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Martin, Madelena] UMass Mem Med Ctr, Pediat Genet Div, Worcester, MA USA. RP Borzutzky, A (reprint author), 300 Longwood Ave, Boston, MA 02115 USA. EM arturo.borzutzky@childrens.harvard.edu RI Neufeld, Ellis/F-9331-2011; Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Borzutzky, Arturo/0000-0002-7904-262X FU NHLBI [HL004184] FX This research was partly funded by NHLBI K24 grant HL004184. NR 23 TC 27 Z9 28 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD DEC PY 2009 VL 133 IS 3 BP 287 EP 294 DI 10.1016/j.clim.2009.08.006 PG 8 WC Immunology SC Immunology GA 519PP UT WOS:000271779600001 PM 19740703 ER PT J AU Koo, S Bryar, JM Page, JH Baden, LR Marty, FM AF Koo, Sophia Bryar, Julie M. Page, John H. Baden, Lindsey R. Marty, Francisco M. TI Diagnostic Performance of the (1 -> 3)-beta-D-Glucan Assay for Invasive Fungal Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BETA-D-GLUCAN; GALACTOMANNAN ENZYME-IMMUNOASSAY; CIRCULATING GALACTOMANNAN; TRANSPLANT RECIPIENTS; CELL TRANSPLANTATION; NEUTROPENIC PATIENTS; REACTIVE MATERIAL; MEMBRANE FILTERS; LIMULUS TEST; INFECTIONS AB Background. Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1 -> 3)-beta-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. Methods. We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. Results. A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level >= 80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59-8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level >= 80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. Conclusions. BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD. C1 [Koo, Sophia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Koo, Sophia; Baden, Lindsey R.; Marty, Francisco M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Koo, Sophia; Baden, Lindsey R.; Marty, Francisco M.] Harvard Univ, Sch Med, Boston, MA USA. [Bryar, Julie M.; Page, John H.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Koo, S (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St,PBB-A4, Boston, MA 02115 USA. EM skoo@partners.org OI Koo, Sophia/0000-0002-4973-7439 NR 41 TC 113 Z9 124 U1 0 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2009 VL 49 IS 11 BP 1650 EP 1659 DI 10.1086/647942 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 515XC UT WOS:000271505200005 PM 19863452 ER PT J AU Sun, HY Alexander, BD Lortholary, O Dromer, F Forrest, GN Lyon, GM Somani, J Gupta, KL del Busto, R Pruett, TL Sifri, CD Limaye, AP John, GT Klintmalm, GB Pursell, K Stosor, V Morris, MI Dowdy, LA Munoz, P Kalil, AC Garcia-Diaz, J Orloff, S House, AA Houston, S Wray, D Huprikar, S Johnson, LB Humar, A Razonable, RR Husain, S Singh, N AF Sun, Hsin-Yun Alexander, Barbara D. Lortholary, Olivier Dromer, Francoise Forrest, Graeme N. Lyon, G. Marshall Somani, Jyoti Gupta, Krishan L. del Busto, Ramon Pruett, Timothy L. Sifri, Costi D. Limaye, Ajit P. John, George T. Klintmalm, Goran B. Pursell, Kenneth Stosor, Valentina Morris, Michelle I. Dowdy, Lorraine A. Munoz, Patricia Kalil, Andre C. Garcia-Diaz, Julia Orloff, Susan House, Andrew A. Houston, Sally Wray, Dannah Huprikar, Shirish Johnson, Leonard B. Humar, Atul Razonable, Raymund R. Husain, Shahid Singh, Nina TI Lipid Formulations of Amphotericin B Significantly Improve Outcome in Solid Organ Transplant Recipients with Central Nervous System Cryptococcosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; HEMATOPOIETIC STEM-CELL; NEOFORMANS INFECTION; MENINGITIS; COMBINATION; AIDS; PROPHYLAXIS; MANAGEMENT; TOXICITY; AMBISOME AB Background. Whether outcome of central nervous system (CNS) cryptococcosis in solid organ transplant recipients treated with lipid formulations of amphotericin B is different from the outcome of the condition treated with amphotericin B deoxycholate (AmBd) is not known. Methods. We performed a multicenter study involving a cohort comprising consecutive solid organ transplant recipients with CNS cryptococcosis. Results. Of 75 patients treated with polyenes as induction regimens, 55 (73.3%) received lipid formulations of amphotericin B and 20 (26.7%) received AmBd. Similar proportions of patients in both groups had renal failure at baseline (P = .94). Overall, mortality at 90 days was 10.9% in the group that received lipid formulations of amphotericin B and 40.0% in the group that received AmBd. In univariate analysis, nonreceipt of calcineurin inhibitors (P = .034), renal failure at baseline (P = .016), and fungemia (P = .003) were significantly associated with mortality. Compared with AmBd, lipid formulations of amphotericin B were associated with a lower mortality (P = .007). Mortality did not differ between patients receiving lipid formulations of amphotericin B with or without flucytosine (P = .349). In stepwise logistic regression analysis, renal failure at baseline (odds ratio [OR], 4.61; 95% confidence interval [CI], 1.02-20.80; P = .047) and fungemia (OR, 10.66; 95% CI, 2.08-54.55; P = .004) were associated with an increased mortality, whereas lipid formulations of amphotericin B were associated with a lower mortality (OR, 0.11; 95% CI, 0.02-0.57; P = .008). Conclusions. Lipid formulations of amphotericin B were independently associated with better outcome and may be considered as the first-line treatment for CNS cryptococcosis in these patients. C1 [Husain, Shahid; Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. [Sun, Hsin-Yun; Singh, Nina] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Alexander, Barbara D.] Duke Univ, Med Ctr, Durham, NC USA. [Forrest, Graeme N.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Lyon, G. Marshall; Somani, Jyoti] Emory Univ, Atlanta, GA 30322 USA. [del Busto, Ramon] Henry Ford Hosp, Detroit, MI 48202 USA. [Johnson, Leonard B.] St Johns Hosp, Detroit, MI USA. [Pruett, Timothy L.; Sifri, Costi D.] Univ Virginia, Charlottesville, VA USA. [Limaye, Ajit P.] Univ Washington, Seattle, WA 98195 USA. [Klintmalm, Goran B.] Baylor Univ, Med Ctr, Dallas, TX USA. [Pursell, Kenneth] Univ Chicago, Chicago, IL 60637 USA. [Stosor, Valentina] Northwestern Univ, Chicago, IL 60611 USA. [Morris, Michelle I.; Dowdy, Lorraine A.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Houston, Sally] Tampa Gen Hosp, Tampa, FL 33606 USA. [Kalil, Andre C.] Univ Nebraska, Omaha, NE 68182 USA. [Garcia-Diaz, Julia] Alton Ochsner Med Fdn & Ochsner Clin, New Orleans, LA 70121 USA. [Orloff, Susan] Oregon Hlth & Sci Univ, Portland, OR USA. [Wray, Dannah] Med Univ S Carolina, Charleston, SC 29425 USA. [Huprikar, Shirish] Mt Sinai Med Ctr, New York, NY 10029 USA. [Razonable, Raymund R.] Mayo Clin, Rochester, MN USA. [Sun, Hsin-Yun] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Sun, Hsin-Yun] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Dromer, Francoise] Inst Pasteur, Paris, France. [Lortholary, Olivier] Hop Necker Enfants Malad, Fac Med Paris Descartes, Paris, France. [Lortholary, Olivier] Hop Necker Enfants Malad, Inst Pasteur, Paris, France. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [John, George T.] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Munoz, Patricia] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. [Munoz, Patricia] CIBER Enfermedades Resp, Madrid, Spain. [House, Andrew A.] Univ Western Ontario, London, ON, Canada. [Humar, Atul] Toronto Gen Hosp, Univ Hlth Network, Toronto, ON, Canada. RP Singh, N (reprint author), VA Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu RI Garcia-Diaz, Julia/D-3555-2011; OI Munoz Garcia, Patricia Carmen/0000-0001-5706-5583; SUN, HSIN-YUN/0000-0003-0074-7721 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01 AI 054719-01] FX National Institutes of Health, National Institute of Allergy and Infectious Diseases (R01 AI 054719-01 to N.S.) NR 36 TC 28 Z9 28 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2009 VL 49 IS 11 BP 1721 EP 1728 DI 10.1086/647948 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 515XC UT WOS:000271505200015 PM 19886800 ER PT J AU Jorgensen, JH Ferraro, MJ AF Jorgensen, James H. Ferraro, Mary Jane TI Antimicrobial Susceptibility Testing: A Review of General Principles and Contemporary Practices SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BACTERIAL IDENTIFICATION; SELECTION; RESISTANT; AGENTS; SYSTEM AB An important task of the clinical microbiology laboratory is the performance of antimicrobial susceptibility testing of significant bacterial isolates. The goals of testing are to detect possible drug resistance in common pathogens and to assure susceptibility to drugs of choice for particular infections. The most widely used testing methods include broth microdilution or rapid automated instrument methods that use commercially marketed materials and devices. Manual methods that provide flexibility and possible cost savings include the disk diffusion and gradient diffusion methods. Each method has strengths and weaknesses, including organisms that may be accurately tested by the method. Some methods provide quantitative results (eg, minimum inhibitory concentration), and all provide qualitative assessments using the categories susceptible, intermediate, or resistant. In general, current testing methods provide accurate detection of common antimicrobial resistance mechanisms. However, newer or emerging mechanisms of resistance require constant vigilance regarding the ability of each test method to accurately detect resistance. C1 [Jorgensen, James H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Jorgensen, JH (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM jorgensen@uthscsa.edu FU BD Diagnostics; bioMerieux; Merck; Pfizer; Siemens Healthcare FX J.H.J. and M.J.F. disclose their membership on microbiology advisory committees for BD Diagnostics and bioMerieux. J.H.J. has advised Accelr8 Technology and has received research support from BD Diagnostics, bioMerieux, Merck, Pfizer, and Siemens Healthcare. NR 25 TC 162 Z9 171 U1 13 U2 74 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2009 VL 49 IS 11 BP 1749 EP 1755 DI 10.1086/647952 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 515XC UT WOS:000271505200022 PM 19857164 ER PT J AU Bhan, I Thadhani, R AF Bhan, Ishir Thadhani, Ravi TI Vascular Calcification and ESRD: A Hard Target SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT Conference of the ESRD - State of the Art and Charting the Challenges for the Future CY APR 23-26, 2009 CL Boston, MA SP Amer Soc Nephrol, Int Soc Nephrol, Natl Kidney Fdn, Renal Phys Assoc, European Dialy, Transplant Assoc, European Renal Assoc ID CORONARY-ARTERY CALCIFICATION; STAGE RENAL-DISEASE; D-RECEPTOR ACTIVATORS; PULSE-WAVE VELOCITY; VITAMIN-D LEVELS; HEMODIALYSIS-PATIENTS; AORTIC CALCIFICATION; CALCIUM ACETATE; UREMIC RATS; ALL-CAUSE AB End-stage renal disease (ESRD) is associated with both accelerated cardiovascular disease and alterations in vitamin D and mineral metabolism. Calcification of both coronary and extra-cardiac vessels is common in ESRD. Several studies suggest that vascular calcification is associated with coronary atherosclerosis, vascular wall stiffness, left ventricular hypertrophy, and subsequent increased mortality, but it is not yet clear if vascular calcification is a direct cause of these changes or merely a marker of disease. Reviewed here is the current state of research on the biology and the significance of vascular calcification in ESRD, the role of vitamin D therapy in its development, and options for management. Clin J Am Soc Nephrol 4: S102-S105, 2009. doi: 10.2215/CJN.04800709 C1 [Bhan, Ishir; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, Bullfinch 127, Boston, MA 02114 USA. EM thadhani.r@mgh.harvard